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Volume 7 Issue 4

Peer Reviewed International Pharmaceutical Industry

Supporting the industry through communication

Physicians’ Preferences on Contact Methods And Survey Administration in Asia Pacific Redefining Value in the Pharmaceutical Industry And the Role of Packaging Effecting Change in the R&D Supply Chain To Deliver value in the Industry A Quality-by-Design Approach To Upstream Bioprocess Interrogation and Intensification

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Contents 06 Editor’s Letter REGULATORY & MARKETPLACE

International Pharmaceutical Industry

Supporting the industry through communication

DIRECTORS: Martin Wright Mark A. Barker EDITOR: Orsolya Balogh orsolya@pharmapubs.com EDITORIAL ASSISTANT Frances Lee BOOK MANAGER: Anthony Stewart anthony@ipimedia.com BUSINESS DEVELOPMENT: John Sympson john@ipimedia.com DESIGN DIRECTOR: Fiona Cleland CIRCULATION MANAGER: Dorothy Brooks dorothy@pharmapubs.com FINANCE DEPARTMENT: Martin Wright martin@ipimedia.com RESEARCH & CIRCULATION: Heather Bayran Heather@pharmapubs.com COVER IMAGE: iStockphoto © PUBLISHED BY: Pharma Publications Unit J413, The Biscuit Factory Tower Bridge Business Complex 100 Clements Road, London SE16 4DG Tel: +44 (0)20 7237 2036 Fax: +44 (0)01 480 247 5316 Email: info@ipimedia.com www.ipimedia.com All rights reserved. No part of this publication may be reproduced, duplicated, stored in any retrieval system or transmitted in any form by any means without prior written permission of the Publishers. The next issue of IPI will be published in Spring 2016. ISSN No. International Pharmaceutical Industry ISSN 1755-4578. The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright. 2015 PHARMA PUBLICATIONS Volume 7 issue 4 - Winter- 2015

08 Physicians’ Preferences on Contact Methods and Survey Administration in Asia Pacific Email is the most commonly-used method to contact physicians for feasibility studies. Feasibility studies often have a short turnaround time, requiring physicians to complete the survey expeditiously. The objective of this article is to find out the preferred method of contact by the physicians as well as their acceptance of the various methods of survey administration, hence facilitating the process for short response time. Audrey Ho at Quintiles guides us into the Asia Pacific, explaining physicians’ preferences on contact methods and survey administration. 16 Handling Increasing Case Volumes in Pharmacovigilance while Controlling Costs Over the last several years, experts and regulators have envisioned potential new paradigms in drug safety processing that focus on continual automated assessment of large pools of healthcare data to develop product safety profiles, and a corresponding reduction in reliance on individual case safety reports. However, at the tactical level, safety departments have seen little progress in this direction, and continue to struggle with controlling costs while having to deal with increasing volumes of individual case safety reports to be processed. This white paper is about handling increasing case volumes in pharmacovigilance by the Vice President of ARIS Global, Ambrish Mathur. 22 It’s Time to Address the Claims Management Disconnect One of the fundamental pillars of the life sciences industry is the accuracy of the claims that it makes for its products. Over decades, the industry has strived to become second to none in terms of testing and transparency, because what it says about its products has the potential to impact ultimately upon hundreds of millions of patients and consumers. And arguably, no other industry is subject to the same level of regulatory scrutiny. James Brown, VP & GM Commercial Content at Veeva/Zinc reflects on the claims management disconnect. 26 Tamper-evidence – A Vital Matter of Safety This article, written by Alessio Bressan at I.G.B. S.r.l. and starting from the concept of falsified medicine as postulated in the European directive, focuses on the options actually on the market concerning tamper-evident systems. It closes by demonstrating how a system integrated in the outer packaging and completely mechanical is able to improve the safety of the outer packaging and protect it against counterfeit attempts in an effective way. DRUG DISCOVERY, DEVELOPMENT & DELIVERY 30 High Quality, Fast Antibody Conjugates in Complete ELISA Kits Every immunoassay exploits the ability of an antibody (referred to as a primary antibody) to bind selectively to a particular target antigen, which is usually presented in a complex fluid such as serum, blood or urine, or in a solid matrix such as a slice of tissue, a cell monolayer, a nitrocellulose blot or a plastic microplate. The antibody, in conjunction with a label that provides measurability, allows the quantity and/or distribution of the antigen to be determined. Amy Adams, Technical Support and Customer Service Supervisor at Innova Biosciences, with Professor Paul J. Davis, Founder/CSO and Julie Thompson, Research scientist at Mologic focus on fast antibody conjugates. 34 The Use of Preclinical Models to Drive Immunotherapy Cancer Research and Combination Strategies The ideal treatment for any disease is one that can cure it or prevent spreading with minimal impact on the patient’s quality of life. In the case of cancer, therapeutic agents were initially designed to kill rapidly dividing cells. Dr Jean Pierre Wery, President of

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Contents Crown Bioscience, reflects on the use of preclinical models to drive immunotherapy cancer research and combination strategies highlighting syngenic mouse models for immunotherapy and radiotherapy, combination therapies and strategies. CLINICAL RESEARCH 40 Rare Diseases: Ethical Considerations in the Clinical Development The drugs used to treat rare diseases are called “orphan drugs”. There are limited numbers of patients available for enrolment in clinical trials, so it is difficult to ascertain the safety and effectiveness of the product being tested for use. It is important that the risk/ benefit ratio is carefully weighed, and that trials be designed to systematically observe patients and attempt to collect adequate data to demonstrate effectiveness, as well as to determine the optimal dosage. Balamuralidhara V. and his colleagues at JSS College of Pharmacy focus on rare diseases and their ethical considerations in clinical development.

64 How do Kelvin Hours Help with Assessing the “Thermal Challenge” to Create a Standard Version of Performance in Temperaturecontrolled Packaging? With the ever-evolving developments in the biopharmaceutical industry, there has never been a greater need for assured reliability when it comes to the transportation of pharmaceutical payloads, and the guaranteed robustness of temperature-controlled packaging is proving ever more vital. The main angle of the following white paper is temperature-controlled packaging by Richard Wood, Design Manager at Peli BioThermal. 70 An Interview with va-Q-tec AG, a Leader in Thermal Packaging Product Orsolya Balogh, Managing Editor at Pharma Publications, speaks with Dominic Hyde, Managing Director of va-Q-tec Ltd, about how the temperature-controlled logistics industry is moving forward the key changes and challenges in the industry.

46 Technology Advances in Feasibility, Recruitment and Retention Biopharmaceuticals are intensely focused on efficiency and time to market; however, the nature of clinical trials continues to present obstacles to attaining these goals. Today’s trials are still far too costly, and study cycle times remain too long to achieve a recoverable time to market. In response, many biopharmaceuticals are focused on reducing study cycle time by pinpointing the right countries, sites and patients. Paul Evans and Xavier Flinois at Parexel share their thoughts with the public on technology advances in feasibility, recruitment and retention. TECHNOLOGY 50 Healthware – Beyond Bracelets and Watches Norman J. Holter, regarded as the “Father of mobile ECG monitoring”, developed the world’s first ambulatory cardiology monitor, and arguably, the world’s first wearable device, in 1954. The device weighed 85 pounds and had to be strapped to the patient like a bulky backpack. For the very first time, the patient’s cardiac wellbeing could be tested in his natural state, at any point during the day. No longer did the physician wait by the patient’s bedside to detect an arrhythmia, nor did the testing have to happen in a controlled clinical environment. Bhargav Rajan, senior research analyst at TechVision, concentrates on ECG monitoring. 54 Leveraging Cloud-based EDC for Data Acquisition and Sharing A primary challenge faced by clinical trial professionals around the world is the means by which data is collected and logged for their studies. There are three principle ways of recording this data: pen and paper, traditional computerised data capturing applications, and more recently, cloud-based electronic data capture (EDC). Glenn Keet, CEO of Clinovo, submits a technical article on cloudbased EDC. LOGISTICS AND SUPPLY CHAIN 58 Effecting Change in the R&D Supply Chain to Deliver Value in the Industry As we enter a new phase of growth by 2020, some key decisions need to be taken to ensure that the pharmaceutical industry remains stable and continues to take advantage of growth and profit opportunities offered to it in the coming years. Whilst pharma development in the bid to advance human health is seen as one of the most research-intensive activities cross-industries, the pace of change is slow and the timely adoption of new technologies and ideas is potentially one of its biggest opportunities to counteract some of the challenges it faces. Cathy O’Brien, Industry Marketing Director at TNT, deals with the R&D supply chain in the pharmaceutical industry.

2 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Winter 2015 Volume 7 Issue 4


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Contents MANUFACTURING 74 Reducing Particulate from Metal Products in Medical Devices As the medical device market evolves to become highly sophisticated and advanced, metal part manufacturers face constant pressures in being able to reduce particulate in the production and assembly of components. For medical device component manufacturers, developing new methods to reduce particulate is becoming increasingly important. Graham Perkins, Medical Sales Manager at Advanex, discusses the reduction of particulate from metal products in medical devices. 78 A Quality-by-design Approach to Upstream Bioprocess Interrogation and Intensification Efficient biopharmaceutical process development relies on the quality-by-design (QbD) paradigm. QbD is a scientific, risk-based proactive approach to drug development that aims to have a full understanding of how the process and product are related. This knowledge is gained by process analytical technology (PAT). Stephen Craven and Ulrike Becken at Eppendorf deal with upstream bioprocess interrogation and intensification. PACKAGING 82 Redefining Value in the Pharmaceutical Industry and the Role of Packaging Providing safe and efficacious treatment of disease is no longer sufficient for new drug products. Today’s medicines must address an unmet need or be a much better solution than existing products. They need to increase patient adherence, be easy to use, prevent counterfeiting and tampering, be traceable and of course be costeffective. Guy Tiene MA, Director of Strategic Content at That’s Nice LLC - Nice Insight, provides an overview of the pharmaceutical industry and the role of packaging. 88 Relating Tamper-evident Technology to Market and Product Fraud Risk To make a pharmaceutical folding box tamper-evident may be as simple as taping the flaps. This method will reduce some less severe types of fraud, such as taking a blister out of the box, at a shop or warehouse, without notice. However in high-risk environments, fraudsters may elaborate fancy methods to harvest even securitysealing labels on original packaging for reuse. Dr Marietta Ulrich-Horn at Securikett, together with devoted clients, works on a systematic approach to close the loopholes in tamper-evident technology. 92 Serialisation – Commercial Versus Clinical Perspectives There is a significant amount of activity in the pharmaceutical industry in mobilising to meet the requirements of recent Drug Quality and Safety Act (DQSA) legislation, passed by the United States Congress with the intention of limiting the spread of counterfeit or otherwise falsified medicines to patients for prescription drug products. Justin Schroeder, Executive Director, Marketing, Business Development & Design at PCI Pharma Services (PCI), reviews serialisation from the perspective of commercial versus clinical.

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Winter 2015 Volume 7 Issue 4


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Editor's Letter 2015 was a strong year for the pharmaceutical i n d u s t r y . Te c h n o l o g i c a l innovations and new healthcare standards have been driving industry changes. Looking at the pharmaceutical industry trends, 2015 has also made a push towards increased development of personalised medicine. The industry has already contributed to significant improvements in patient wellbeing. CPHI 2015 brought many new clients on board. One of the biggest events of this era created the opportunity to meet with new professionals within the pharmaceutical outsourcing industry. Providing safe and efficacious treatment of disease is no longer sufficient for new drug products. Today’s medicines must address an unmet need or be a much better solution than existing products. They need to increase patient adherence, be easy to use, prevent counterfeiting and tampering, be traceable and of course be cost-effective. Guy Tiene, Director of Strategic Content at That’s Nice LLC - Nice Insight, provides an overview of the pharmaceutical industry and the role of packaging. As we enter a new phase of growth, some key decisions need to be taken to ensure that the pharmaceutical industry remains stable

and continues to take advantage of growth and profit opportunities offered to it in the coming years. Whilst pharma development in the bid to advance human health is seen as one of the most research-intensive activities crossindustries, the pace of change is slow and the timely adoption of new technologies and ideas is potentially one of its biggest opportunities to counteract some of the challenges it faces. Cathy O’Brien, Industry Marketing Director at TNT, deals with the R&D supply chain in the pharmaceutical industry. More companies in the pharmaceutical industry today are adopting the principles of quality by design (QbD) for pharmaceutical development and manufacturing. Described in ICH Q8, Q9 and Q10 guidance documents, QbD enables enhanced process understanding, and a more systematic and scientific approach to development, so that better controls may be implemented. The end goal is more robust manufacturing processes than those that typically result from traditional approaches to drug development.

interrogation and intensification. Email is the most commonly used method to contact physicians for feasibility studies. Feasibility studies often have short turnaround time, requiring physicians to complete the survey expeditiously. The objective of this article is to find out the preferred method of contact by the physicians, as well as their acceptance of the various methods of survey administration, hence facilitating the process for short response time. Audrey Ho at Quintiles guides us into the Asia Pacific region, explaining physicians’ preferences on contact methods and survey administration. International Pharmaceutical Industry has closed another successful year, and the Pharma Publications team are happy to develop their connections between the industry’s professionals. We wish you all a Very Merry Christmas and a Happy and Prosperous New Year. I look forward to seeing you all in 2016.

Efficient biopharmaceutical process development relies on the quality by design (QbD) paradigm. QbD is a scientific, risk-based proactive approach to drug development that aims to have a full understanding of how the process and product are related. This knowledge is gained by process analytical technology (PAT). Stephen Craven and Ulrike Becken at Eppendorf deal with upstream bioprocess

Editorial Advisory Board Bakhyt Sarymsakova, Head of Department of International Cooperation, National Research Center of MCH, Astana, Kazakhstan

Jagdish Unni Vice President- Beroe Risk and Industry Delivery Lead- Healthcare, Beroe Inc.

Catherine Lund, Vice Chairman, OnQ Consulting

Jeffrey Litwin, M.D., F.A.C.C. Executive Vice President and Chief Medical Officer of ERT

Deborah A. Komlos, Senior Medical & Regulatory Writer, Thomson Reuters Diana L. Anderson, Ph.D president and CEO of D. Anderson & Company Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group Francis Crawley. Executive Director of the Good Clinical Practice Alliance – Europe (GCPA) and a World Health Organization (WHO) Expert in ethics Georg Mathis Founder and Managing Director, Appletree AG Heinrich Klech, Professor of Medicine, CEO and Executive Vice President, Vienna School of Clinical Research 6 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Jeffrey W. Sherman, Chief Medical Officer and Senior Vice President, IDM Pharma Jim James DeSantihas, Chief Executive Officer, PharmaVigilant Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation Maha Al-Farhan, Vice President, ClinArt International, Chair of the GCC Chapter of the ACRP Nermeen Varawalla, President & CEO, ECCRO – The Pan Emerging Country Contract Research Organisation

Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmac Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai) Stefan Astrom, Founder and CEO of Astrom Research International HB Steve Heath, Head of EMEA Medidata Solutions, Inc T S Jaishankar, Managing Director, QUEST Life Sciences

Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

Winter 2015 Volume 7 Issue 4


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Regulatory & Marketplace

Physicians’ Preferences on Contact Methods and Survey Administration in Asia Pacific Email is the most commonly used method to contact physicians for feasibility studies. Feasibility studies often have short turnaround time, requiring physicians to complete the survey expeditiously. The objective of this article is to find out the preferred method of contact by the physicians, as well as their acceptance of the various methods of survey administration, hence facilitating the process for short response time. Between March and April 2014, 232 physicians from 11 Asian countries were randomly selected and contacted to complete a survey pertaining to their preferences. 96 completed surveys were received. 72.9% of physicians indicated their preference for contact via email; 51.6% were agreeable to using weblinks for feasibility surveys, and 44.2% have done so in the past; 49.4% were agreeable to using smartphone to answer feasibility surveys, and 7.8% have done so in the past; 71.9% were able to accept interviews conducted remotely; and 92.7% were able to accept contact by back-end office. We conclude that the authors’ company’s network of physicians in Asia Pacific have a preference for a less intrusive mode of contact, and where technology allows, are willing to use alternative methods for survey administration. Feasibility Assessments: First Steps The first step to determine the feasibility of conducting a clinical trial at a site usually involves a survey to be completed by physicians who are potential principal investigators. These surveys contain protocol information and comprise questions on the investigator’s interest in the protocol, standard of care, availability of patient populations and resources required for the trial. Advances in technology and the internet space have provided multiple modes to contact physicians for surveys, and a variety of choices for survey administration1. This article explores the method of contact preferred by our network of physicians in Asia Pacific and their acceptance of the choices available for 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

survey administration. It is recognised that multiple factors contribute to physicians’ response time for feasibility studies. These factors include the capacity of physicians to take on trials, their interest in protocol design and study compound, length/complexity of surveys, how the physicians are being contacted and how the surveys are administered. This article will discuss the physicians’ preferred mode of contact and method of survey administration. The contact methods employed by our company’s Asia feasibility team for feasibility studies vary across the individual Asia Pacific countries. An initial internal assessment revealed that emails and telephone calls made directly to the physicians are the main methods used. Other methods include the use of fax and indirect communication with physicians through the physicians’ administrative assistants or study coordinators (SCs). For survey administration, choices available to this feasibility team include Word document surveys sent through email; web-based surveys optimised for both desktops and smartphones; interviews conducted either face-to-face or remotely (telephone and video); and back-end office support. Understanding the preferred and acceptable modes of contact and survey administration is crucial as it affects the likelihood of receiving feedback within a stipulated time2; it is a necessary foundation for the maintenance of relationships with the physicians. Materials and Methods A survey was designed to investigate the methods preferred by our physicians in our outreach to them for feasibility studies. The survey consisted of seven closed-ended questions and one openended question, covering the following categories: • • •

Preferred mode of contact Acceptance of surveys hosted on electronic platforms Acceptance of interviews conducted

• •

via tele- or video-conferencing Usage of smartphones to answer surveys Acceptance of contact from backend office (i.e. call centre that is not located in the country of survey)

The survey was launched between March and April 2014 in 11 Asian countries – China (CN), Hong Kong (HK), India (IN), Indonesia (ID), Malaysia (MY), the Philippines (PH), Singapore (SG), South Korea (KR), Taiwan (TW), Thailand (TH), and Vietnam (VN). Sample size calculations were performed using n-Query, a two-group continuity corrected Chi-square test with a 0.050 two-sided significance level and 87% power to detect the difference between a Group 1 (email group) proportion of 0.200 and a Group 2 (phone group) proportion of 0.400. The planned sample size of physicians to contact for each group is approximately 110. If no response was received from a physician, the physician would be classified as a non-responder. The proportion of responders (based on the initial response from five days) from each group were compared. A sequential mixed-mode contact method was used to contact the physicians (Figure 1). This method, which involved a combination of email and phone contact, was chosen to allow us to capture physicians who may have a preference for contact via either method, and hence yield the highest possible response rate3, 4. The database of physicians located in the Asia Pacific region was extracted from CTMS in the form of an Excel spreadsheet, then further categorised by countries. The database consists of contact information of physicians from all specialities, and includes both physicians who have experience in clinical trials managed by us and those without, but are potential investigators for future Winter 2015 Volume 7 Issue 4


DIAMOND BIOPHARM LIMITED

Chapter Title

HITS THE BIG 10! This October, Diamond BioPharm Ltd celebrates 10 years of supporting the pharmaceutical and biotech industry

October of 2005 - the doors to Diamond BioPharm Limited, a Regulatory Affairs consulting organisation, opened. “To make the decision to move away from the security of working for a pharmaceutical company, and starting a business is scary, to say the least – but it had to be done!” explains company founder, Dr. Maureen Graham. Dr. Graham gleaned extensive regulatory and development experience across many product types, from major multi-nationals such as Amgen, Merck Sharp and Dohme, Ivax (now Teva) and Glaxo before stepping out alone. “I knew I wanted to continue to work with people around me rather than on my own, so I started out in a serviced office with an administration person. Over the 10 years, the organisation has grown and currently has around 20 people across the UK and US. I cannot mention them all here, but they are a fabulous strong team”. Reflecting over the 10 years Maureen said: “Over the last 10 years, a number of challenges have presented themselves to the pharmaceutical and biotech industry. Diamond BioPharm Limited has sought to overcome these for our clients in order to ensure regulatory challenges and changes are met with innovation and compliance. Our team are able to draw on a wealth of experience and we continue to look to provide services that offer maximum value to our clients in the most efficient and cost effective manner.” And what was the hardest thing in starting a business? “Choosing the name – but, for my ex-Amgen colleagues, it had to feature Diamonds!”

Diamond Pharma Services, Inc, opened for business in February 2015 with US consultant Nancy Markovitz, Diamond Pharma Inc’s Director of Regulatory Affairs (pictured left) following an increase in the number of pharmaceutical and biotech clients seeking to undertake parallel development for Europe and the US. As a result of this upturn in requests for a joint solution, Diamond took the bold move to establish itself personally in this highly competitive space. “Outsourcing regulatory support for the opposite region between unrelated European and US organisations is fairly common practise.” explained Sean Russell, Managing Director, Diamond Pharma Services, Inc. “We believe that our clients can only truly receive the best solutions to this joint development approach when seamlessly integrating the requirements of both regions and as such, an organic expansion with our own employees was the only solution for us”. Diamond Pharma Services, Inc. are focussing predominantly on the support of biotech companies developing advanced therapy medicinal products (ATMPs), in particular cell and gene therapy products, but also providing a soft landing for companies already working with Diamond BioPharm Ltd (the European regulatory company) and looking to explore the benefits of communicating with the FDA through known and trusted professionals.”

Dr David Crome, Managing Director of Diamond Compliance & Quality Limited, is developing and growing the compliance and quality service portfolio offered to existing and potential new clients of Diamond Pharma Services. David brings over 35 years of international product life cycle experience with both innovative and generic manufacturers, and has experience of over 50 regulatory inspections undertaken by various agencies including the MHRA, IMB, EMA, SUKL, USFDA, MCC and Anvisa in Europe, South America and India. As a registered Qualified Person for both commercial and IMP’s batch release, and having undertaken over 150 audits covering the whole product life cycle including R&D, analytical laboratories, excipients, API’s, primary and secondary packaging, sterilisers, supply chains, distribution hubs, warehouses and Finished Dosage Form manufacturers throughout the world, he can offer clients advice and support to ensure that they are always compliant and regulatory inspection ready.

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Regulatory & Marketplace purpose of the survey was provided. If the physicians were agreeable, an email containing the Word document survey and web-based link was sent to them. Results 232 physicians were contacted. Overall, 96 (41.4%) responses from over 11 countries were Figure 1. Sequential mixed-mode method used to contact physicians received after the full survey cycle of 5-3-3 days, with the clinical trials. All physicians in the list largest number of respondents in China: were assigned a randomly generated detailed information is presented in Table number using Excel’s randomisation function, and subsequently sorted in order 1. of their assigned number from smallest to largest. The first 60 physicians per country were selected and randomised to either the phone or email contact group using a stratified block randomisation list of physician identification numbers. A stratified block randomisation list was generated for each stratum (country considered as stratum), with each list consisting of 15 blocks of four. Each block either contained a phone or an email contact group.

Physicians who were contacted via email received a phone call reminder if a completed survey or a notification that they declined to participate was not received from them after five days. Three days post first reminder, an email would be sent as a second reminder. The survey was closed three days after the second email reminder was sent, regardless of the response status.

Response after Initial Contact Out of 232 physicians, 123 and 109 were contacted by email and phone respectively. Thirteen (10.6%) and 29 (26.6%) physicians responded in the email and the phone group, respectively. The difference in response rate was statistically significant between the two groups after initial contact (Table 2). The response rate for the phone group was greater than for the email group. Response from Non–responders Group after First Reminder The difference in response rate was

not statistically significant after the first reminder (p=0.8313). After the initial contact, the mode of contact was switched (email group to phone group; phone group to email group) for the nonresponders. Response from Non–responders Group after Second Reminder The difference in response rate was not statistically significant after the second reminder (p =0.2944). After the first reminder, the mode of contact was switched back to the original mode (email group to phone group back to email group; phone group to email group back to phone group) for the non-responders. Preferred Mode of Contact for Feasibility Surveys and Reminders Physicians were asked to indicate their preferred mode of contact for feasibility surveys (Table 3). Overall, 72.9% of physicians (n=70) preferred emails. The next preferred mode of contact was a phone call that provided brief study information, followed by an email if the physicians were interested to explore potential participation further (n=19; 19.8%). These numbers include counts of physicians who selected more than one option. Physicians also had a preference for direct communication over indirect communication for feasibility surveys. Only 3.1% of the physicians (n= 3) opted

Physicians allocated to contact by phone call were followed up with an email reminder at day five and a phone reminder at day eight. For physicians contacted by emails, the purpose of the survey was outlined and a Word document survey was attached to the email. In addition, a web-based link for online completion was also provided. Physicians were allowed to reply either by returning the Word document via email or fax, or by completing the survey online. For physicians randomised to contact by phone, a brief introduction of the 10 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Table 1. Response rates per country.

Table 2. Response rates over survey cycle of 5-3-3 days. Winter 2015 Volume 7 Issue 4


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Regulatory & Marketplace for contact only through their secretaries or study coordinators. The remainder chose a combination of direct contact and through their secretaries or study coordinators; and direct contact only. While there was an overall preference for email observed across the 11 countries, no clear preference was observed in China where there were four distinct selections (Figure 2). Emails were the top choice for reminders (81.0%) (n=77), followed by a phone call directly to physicians (n=12; 12.6%). Feedback from physicians in China and the Philippines showed that SMS (short message services) reminders would be welcomed.

Table 3. Physicians’ preferred mode of contact, by countries.

Table 4 presents the physicians’ acceptance of various methods of survey administration. Table 5 provides a summary of the comments provided by physicians regarding their acceptance of surveys delivered through different methods. Discussion There is diversity in the cultural and technological landscape amongst Asia Pacific countries. Due to the limited sample size, this paper was only able to analyse the overall preferred mode of contact and survey administration of our network of physicians within Asia Pacific. Physicians contacted to work with us or for any other CRO have a high level of responsibility for the safe execution of a sponsor’s clinical studies and for evaluating the safety and efficacy of new potential treatments in patients. These physicians sampled from our network are representative of trained and experienced investigators capable of running clinical trials as per required regulatory guidelines in a country. This article also recognised that physicians’ preferences are influenced by the level of their access to technology. Telephone services, and email and internet technology, are available to most qualified physicians, and have been used in practice by physicians in the selected countries. It is therefore a subject of interest to investigate the most preferred method of contact by the physicians. The observed trend indicated that physicians have a preference for a less intrusive mode of contact, i.e., email. Email offers physicians the flexibility to respond as and when allowed by their schedules. For reminders, it was 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Table 4. Results demonstrating acceptance of various methods of survey administration.

Table 5. Summary of comments.

Figure 2. Physicians’ preferred mode of contact for feasibility surveys. (N) indicates number of respondents for the country. Winter 2015 Volume 7 Issue 4


Corporate Profile

How does it work?

goMed2Med aims to stimulate communication and collaboration between companies in the medical world in an easy and efficient way! Therefore www.gomed2med.com the unique b2b online matchmaking platform for business development, based on mutual demands was designed. The site is for manufacturers, distributors, licensing companies, contract services and universities in the medical, pharmaceutical and basic ingrediedients industry, both human and veterinarian, to be matched with each other based on mutual demands to expand their markets and product ranges in a particular region or even worldwide. The matchmaking process is developed for the matching of company’s needs by using an advanced algorithm based on several criteria including geographic location, industry sector and specific product categories and sub categories Matching notifications are sent automatically through the company e-mail and are solely based on corresponding mutual demands (patent pending). The back office staff is located in the main office in the Netherlands from where new member applications are actively monitored to ensure sufficient information is provided, guaranteeing the quality of the information and ensuring that relevant results are found. The business model is based on a Membership Fee. With Full Membership companies can; be found and automatically matched connect with business partners search for business partners in a certain region with common business interests start business development in an easy and efficient way search through the system for a reliable contact introduce their company introduce their products visit their My Matches page to see which companies matched including the matching specifications visit their My Alerts page to see which companies “found” their company incl. the alert specification directly follow up with the potential business partner through the my matches or my alerts page

The Vision of Dr.Heinrich Handel-Mazzetti and Esther van der Graaf We have decades-long experience in the healthcare industry. In our daily business we often deal with the challenge of finding suitable business partners for various corporations who want to expand their markets or product ranges in a particular region, or even worldwide. It was through this continued challenge that a determination arose to solve this problem, and make finding the right business partners a lot more efficient and convenient. A leading design philosophy was to stay true to the primary goal of bringing together business partners based on mutual demands. Therefore we committed ourselves to provide an independent, accessible, easy to use site with a low priced membership so every interested company can afford to become a member. As such, we believe we have created the greatest independent international platform for reliable business partners, truly bringing the medical world together in an easy and efficient way! After two years in development gomed2med.com was launched in April 2015. Users; presently we have about 800 members using our site and have 20 new users joining each week. Site visits; 100 to 400 visitors daily, where depending upon the activity required we perform from our office performs functions such as direct mailing, search engine activities ( google ads) and activities on social media like LinkedIn. Each visitor visits 3 pages and the average visit duration is about 3 minutes/visit.

In addition full members can directly search the site, filter information to customize a search and save the search for future reference.

We have exhibited at CPHI/Madrid and Medica Düsseldorf, and got very positive reactions from our members getting matched 365 days/7 days a week!

If a member chooses to contact a potential business partner then this happens outside of the site through the regular e-mail, phone or other means which guarantees that communications are private and between members only.

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 13


Regulatory & Marketplace interesting to note preferred emails.

that

physicians

It was observed that physicians generally prefer to be contacted by the same mode for both reminders and initial contact. In practice, in the event of nonresponse, a switch-mode or multi-mode contact method is employed to maximise our chances of success in contacting physicians4. The responses obtained after the initial contact, however, showed that physicians contacted via phone were more likely to reply than physicians contacted via email (p=0.015; Table 2). Responses obtained after the first reminder was made (physicians have received contact via both email and phone) indicated that the order of contact does not affect response rate (p=0.686). This is an interesting observation, showing that contacting physicians via their preferred mode of contact need not necessarily yield their response5. To maintain a balance between physicians’ preference, maintenance of good working relationship, and requirements of feasibility exercises, this observation suggests that more intrusive contact (phone or even face-to-face visits) be reserved for more time-constrained exercises. Selection for contact only via administrative assistants or study coordinators is low at 3.1%, and limited to Korea, the Philippines and Taiwan (Figure 2). Although this demonstrated that the physicians preferred direct contact, indirect contact via administrative assistants (admins) or study coordinators is employed in real-world practice. This method also provides the added value of allowing the admins’ or SCs’ non-clinical inputs (i.e., site profile information) to be included in responses to feasibility surveys. Use of Web-links The ever-changing landscape in technology has provided the means to contact and provide information to our physicians on the move, allowing for shorter turnaround time6. Surveys that used to be administered only via pen-andpaper methodology have now evolved to another level, whereby information can be provided and captured via a webbased repository7. These web-based repositories provide an added solution whereby information may be prepopulated for repeat survey responders, 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

further increasing efficiencies. The direct use of web-links by physicians also reduces transcriptional errors and errors that may arise from deciphering handwriting in the transfer of responses from pen-and-paper surveys7. Use of Smartphones Employment of web-based surveys optimised for smartphones is now a common trend8. The growth in smartphone penetration rates in Asia Pacific countries9 has opened up another level of accessibility to our physicians for survey administration. It is interesting to note that smartphone ownership does not directly correlate to physicians using them to answer surveys (Table 4). Smartphones pose certain challenges for administration of survey, in particular their small screen size (Table 5)10. Other comments provided include comparative ease of use with a desktop and connection instability with a smartphone. However, this should not discourage the use of smartphones for future surveys. Conciseness remains the key to increasing responses and reducing turnaround time11: by providing only concise information and asking only key questions, usage of smartphones to answer surveys remains a viable option. Conduct of Interviews via Tele/Videoconference Interviews are traditionally conducted face-to-face by feasibility specialists for in-depth discussions with key physicians on protocol designs. Where requested by sponsors, interviews are conducted by CRO-based medical advisors via teleconference for cost-efficiencies. Faceto-face interviews are valued for their superiority of quality of information collected compared with verbal or written responses12, and for their value in relationship-building. Asian cultures are generally considered high context and the concept of ‘face-giving’ is of utmost importance13: the value of face-to-face interviews in Asia may therefore far exceed that which is measureable14. Conduct of interviews via tele- or video-conference is explored not only for cost and time efficiencies, but also for the possibility of remote contributions from colleagues based in other countries. Physicians in China and Vietnam who did not opt for tele- or videoconference highlighted technological limitations at their institutions (Table 5).

The lack of infrastructure required for videoconferences along with connection instability may limit their conduct for certain institutions in these two countries. It should be noted that the same technological limitations apply to other parts of Asia, including India, Indonesia, the Philippines, and Thailand15. The strategy of face-to-face interviews coupled with the option of teleconference allows for quality interviews to be conducted in an economical way in these countries. Acceptance of Contact by Back-end Office We have local feasibility representatives in each of the Asia Pacific countries. To further increase operational efficiencies, acceptance of back-end offices liaising with physicians is explored. The scope of work explored for back-end offices is limited to follow-ups and provision of protocol clarifications in place of local representatives. Preference for contact by local representatives was raised by physicians from China and the Philippines, and is due to desired communication in local languages, and ease of comprehension of accent where English is spoken. Despite English being the global language of business, local languages are still widely used in many Asian countries for business16; the requirement for contact by local representative hence remains strong. The engagement of back-end offices for contact of physicians in Asia Pacific remains a viable option with modifications to the scope of contact. For countries where usage of local language is strongly preferred, back-end office contact to provide physicians with reminder and provision of protocol clarifications may need to be limited to administrative work, i.e., pre-population of information in surveys, or written communication for follow-ups or clarifications. Where indepth discussion is required, engagement of local representatives may be more appropriate and effective. Concluding Comments Multiple factors affect physicians' response rates and turnaround time for feasibility surveys. We conclude that our network of physicians in Asia Pacific has a preference for a less intrusive mode of contact, and where technology allows, is willing to use alternative Winter 2015 Volume 7 Issue 4


Regulatory & Marketplace methods for survey administration. In Asia Pacific, where diversity in cultures and technological advances is observed both between and within countries, efforts to track individual or at least key physicians’ preferences, though tedious, may provide greater returns and build better relationships. In Asia Pacific, where value of ‘face’ is of great importance, relationship-building should never be undermined. Acknowledgements The authors would like to thank Jessica Lee, Lixia Zhang and Qing Zhang for reaching out to the physicians to complete the survey; our team members across the region who have participated in the internal assessment of the contact methods used for outreach to investigators for feasibility, and helped verify investigators’ contact information, particularly Evangeline Costelo, Henu Tonang, Liling Chen, Manish Thadhani, Miae Leem, Pi-Lien Hung, Piyanuch Tiativiriyakul, Qian Ru, Tho Huynh, Wayland Hui, Yi Chin Ong; Rick Turner and Judith Beach for manuscript review; and Desmond Lim for administrative support.

References 1. Thomas M, Rogers R, Maclean R (2002) Collecting Data from Physicians Via Web-Based Surveys: Recommendations for Improving Response Rates. The Internet Journal of Medical Informatics 1. 2. Benfield JA, Szlemko WJ (2006) Internet-Based Data Collection: Promises and Realities. Journal of Research Practice 2. 3. Millar MM, Dillman DA (2011) Improving Response to Web and Mixed-Mode Surveys. Public Opinion Research. 4. de Leeuw ED (2005) To Mix or Not to Mix Data Collection Modes in Surveys. Journal of Official Statistics 21: 233 - 255. 5. Olson K, Smyth JD, Wood HM (2012) Does giving people their preferred survey mode actually increase survey participation rates? An Experimental Examination. Public Opinion Research. 6. Gi WY, Trumbo CW (2006) Comparative Response to a Survey Executed by Post, E-mail, & Web Form. Journal of Computer-Mediated Communication 7. Wyatt JC (2000) When to Use Web-based Surveys. Journal of the American Medical Informatics Association 7: 426 - 429. 8. Buskirk TD, Andrus C (2012) Smart Surveys for Smart Phones: Exploring Various Approaches for Conducting Online Mobile Surveys via Smartphones. Survey Practice 5. 9. Nielsen (2014) The Asian Mobile Consumer Decoded. 10. Stapleton CE (2013) The Smartphone Way to Collect Survey Data. Survey Practice 6. 11. ORACLE (2012) Best Practices for Improving Survey Participation. 12. Crawford IM (1997) Marketing Research and Information Systems. (Marketing and Agribusiness Texts - 4). In: FAO, editor. Chapter 5: Personal Interviews. 13. Okoro E (2013) International Organizations and Operations: An Analysis of Cross-Cultural Communication Effectiveness and Management Orientation. Journal of Business & Management. 14. Arvey RD Why Face-to-Face Business Meetings Matter. 15. Nair C (2012) The Myth of Technological Progress. South Asia Journal. 16. GlobalawLimited Doing Business in Asia Pacific

Audrey Ho, Therapeutic Science and Strategy Unit, Quintiles East Asia Pte Ltd, Singapore is a Patient and Site Services Lead with Quintiles based in Singapore, responsible for delivering accurate and robust feasibility studies for clinical trials involving countries in Asia. Through her close interaction with physicians, Audrey ensures that efficiency and quality are priorities in the initial stages of planning a clinical trial. Email: audrey.hqh@gmail.com Elvira Zenaida Lansang, Therapeutic Science and Strategy Unit, Quintiles East Asia Pte Ltd, Singapore Varun Talwar, Biostatistics, Quintiles Technologies India Pvt Ltd, Bengaluru, Karnataka, India Neetu Badhoniya, Biostatistics, Quintiles Technologies India Pvt Ltd, Bengaluru, Karnataka, India Stephanie Tan, Site and Patient Networks, Quintiles East Asia Pte Ltd, Singapore HyunSuk Hong, Therapeutic Science and Strategy Unit, Quintiles East Asia Pte Ltd, Singapore Dr Karen Wai, Real World Late Phase Research, Quintiles East Asia Pte Ltd, Singapore is an experienced medical and operational drug-development expert; she has served as Medical and Scientific Advisor for more than 60 clinical trial protocols and led multiple business units. She currently leads Quintiles’ Real World & Late Phase Research unit in Asia-Pacific, developing best practices in the real world evidence setting. Email: karen.wai@quintiles.com

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Regulatory & Marketplace

Handling Increasing Case Volumes in Pharmacovigilance while Controlling Costs Over the last several years, experts and regulators have envisioned potential new paradigms in drug safety processing that focus on continual automated assessment of large pools of healthcare data to develop product safety profiles, and a corresponding reduction in reliance on individual case safety reports. However, at the tactical level, safety departments have seen little progress in this direction, and continue to struggle with controlling costs while having to deal with increasing volumes of individual case safety reports to be processed. There are multiple reasons for companies facing an increasing volume of reported adverse events. Safety issues with several high-profile products over the last few years have resulted in heightened consumer awareness and regulatory oversight. Recent legislation in Europe requires regulators to increase their outreach to consumers on safety issues, including added support for direct-from-patient safety reporting. Manufacturer outreach to patients has also increased significantly through patient support programmes, market research programmes, or through enhanced social media presence. In some cases, an increase in the number of clinical studies or in product litigations have also led to additional safety case processing volumes. Being Prepared How do safety officers ensure that their business is prepared to scale up to handle these increasing case volumes, while controlling costs? There are three broad areas safety managers need to invest in to ensure they are prepared for the long term to handle increasing case volumes while keeping costs under control: • • •

Set up outsourcing relationships Implement scalable global operational processes – spread the load Maximise automation in case processing

16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Outsourcing Relationships We are witnessing a major transformation in resourcing strategies across the industry in the new global economy. Historically, companies have utilised service providers primarily in clinical development stages. However, setting up outsourcing relationships for postmarketing and traditionally in-house activities, such as safety processing, has quickly become an essential component of strategies to keep cost of operations low. When looking for potential outsourcing relationships, companies should look for both technology and business process outsourcing (BPO) partners. A technology partner can help move systems operations to the cloud, while a BPO partner can provide the elasticity to support growth in business more economically. It is important to do an assessment, both internal and of potential partners, to ensure the right levels of relationships are developed and accepted within the company. A proper assessment may include answering questions such as: • • • • • • •

• •

What aspects of processing are you comfortable outsourcing? Are vendor capabilities and security infrastructure able to meet your requirements? Does the vendor have experience with systems that you use? Does the (technology) vendor have experience with supporting a regulated cloud? Is the vendor able to demonstrate a capability to scale up the system or operations? Does the vendor offer a flexible cost structure, including transactionsbased pricing? Is there geographical presence to support business continuity, disaster recovery, and data privacy/safe harbour requirements? What other services can they provide? Are they flexible enough to initiate relationships with selective processing – specific support programme/specific study/etc?

Setting up appropriate technology and BPO outsourcing partners ensures scalability as workload increases, while allowing the company to benefit from cost structures that these partners can provide, due to economies of scale. Scalable Global Operational Processes Inbound Large pharma, typically marketing across the world, have many local safety offices or affiliates distributed across different regions and countries. All these offices are receiving centres for local safety reports. Other sources of potential safety reports may include licensing partners, clinical study sites, service providers for patient support or market research programmes, call centres for products, quality or medical information departments, etc. These different providers of potential safety cases may utilise different formats and media (email, fax, postal, electronic file transfer) to forward items. To be ready to handle growing volumes of cases, it is extremely important for companies to automate the receipt and handling of these inbound items. This would eliminate manual handling of items, resulting in efficiencies. Such an automation shall also enable harmonisation of inbound processes across local company offices, resulting in better tracking, compliance monitoring, and inspection-readiness. Outbound Mirroring the receipt process on the outbound side, mature companies selling in multiple markets typically have a large number of health authorities and licensing partners who need to receive processed safety reports. As processing volumes grow, companies need to implement operational efficiencies to ensure the ability to scale up. This must be addressed by delegating submissions management to the local safety offices, while also deploying common harmonised processes and systems to support this. Management of local submissions in country offices ensures that as case processing, and thus, submissions, Winter 2015 Volume 7 Issue 4


Chapter Title


Regulatory & Marketplace volumes grow, the additional workload is distributed across company units, rather than over-burdening the central (or regional) processing centres. This allows for more scalable operations. Local Tracking Systems Distributed inbound and outbound processes need to be supported by common systems that allow automation and local tracking of processed items. Such systems enable: • • • • •

Automation of receipt and submission (email, gateway, fax, online) Spreading the case intake/ submission processing load across company units Automation of receipts from call centres, EDC, and other systems Electronic workflow with distribution of work Distributed due diligence communications tracking

Such tracking systems, in conjunction with distributed common processes across company units, ensure that the safety department is better equipped to handle increasing case processing volumes. Automation in Case Processing The third area to invest in to achieve long-term operational efficiencies and readiness for handling increasing case volumes is the implementation of automation in individual steps of the case processing workflow. While individual case safety processing is generally considered a mature function supported by standardised software systems, it continues to absorb a significant portion of the safety budget and human resources for ongoing operations. This is also the area most directly impacted by the increase in workload due to growing case processing volumes. Therefore, it is very important that the fullest level of automation is implemented in individual steps spanning the overall case processing cycle. Initial Receipt and Triage In many companies, the inbound process, involving the receipt and review of potential safety cases, is still not fully automated. This leads to a significant amount of manual handling, leading to inefficiencies and an inability to scale up 18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

as processing volumes grow. Companies can benefit immensely by ensuring that the inbound process is supported by an automation system that allows incoming emails, faxes, webbased adverse event (AE) forms, E2B messages, forwarded items from call centres or other company departments, etc., to be contextually routed for review to inboxes of the appropriate (distributed) processing groups. Such a system would then allow initial review and triage of the received item as a new case, follow-up case, duplicate, etc., and also support promotion of the item (documents and data) to the core case processing system (Fig. 1).

the AE forms can be deployed via a portal that then feeds into the company’s initial receipt and triage system. Alternatively, where possible, providers can email structured forms (Word, PDF) from which data can be auto-extracted, thus avoiding rekeying. Extract data using optical character recognition (OCR) technology from emailed/faxed/scanned paper forms. Assuming a good resolution of the original documents, this should be feasible for fixed format forms. Of course, this step may be followed by a manual review by a processing service handling the inbound process.

Fig. 1. Automated receipt and triage Case Data Intake Avoiding double data entry has always been a goal of data collection systems. This eliminates inefficiencies by ensuring data entered at source can be utilised downstream without having to be re-entered from source documents. However, companies continue to receive “paper” forms (faxes, PDFs, hard copy) from which data is entered again in the safety data collection system. While the cost of this re-entry can be lowered through offshore outsourcing, companies should work on strategies to go paperless. This needs to be addressed using a multi-pronged approach that minimises “paper” handling: •

Collect structured data at source: This can be achieved by deploying standard online AE forms for data collection to company local offices. This can be a capability provided by the initial receipt and triage system discussed earlier. For external providers, such as patient support or market research programmes,

There are advances in natural language processing (NLP) that can be explored for processing free-form (unstructured) documents to auto-extract data pertaining to patient, product, event description, etc. This can be followed by a manual review. Case Quality Check Upon initial data entry completion, a case data quality check is generally done. Much of this check can be automated as the criteria are typically preset. Most safety systems support some level of edit checks. These need to be configured appropriately so that minimal manual review is needed. If your system supports it, it is also good to score the quality and, if deficient, reroute the case to data entry for corrections or additions. This level of automation in quality assessment eliminates manual review and allows cases to move to further processing steps with the assurance of an appropriate level of data quality. Coding Coding events, symptoms, diseases, drugs, etc., against MedDRA, WHO Drug Winter 2015 Volume 7 Issue 4


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Regulatory & Marketplace Dictionary, or the company’s product dictionary, can be a tedious manual activity, often (in larger companies) requiring attention from a central coding group. With increasing case volumes, this can significantly slow down case processing times unless a high level of automation has been implemented. Over time, the goal should be to completely eliminate manual coding efforts by ensuring matches are found for verbatim reported terms in a synonyms list that maps reported terms to corresponding dictionary terms. Of course, such a list can only grow over time, eventually greatly minimising manual coding (at least for cases involving mature products). Where manual coding becomes necessary, as no matching term is found in the synonyms list, automation should be implemented to utilise smart algorithms to present potential matches to the coder, thus minimising the coding effort. Once coded, the match should be added to the mapping list for future use. Seriousness Assignment Seriousness assignment or upgrade/ downgrade can in most cases be autocalculated, based on certain case/ event characteristics. Companies should implement these auto-assignments both for initial cases as well as follow-ups with new information that may require upgrade/downgrade of seriousness. Medical Review and Causality Assessment This step generally utilises expensive medical reviewer resources to assess causality and write/edit the case narrative. Assessing drug-event causality is a difficult task, sometimes constrained by the data available with the case. There have been attempts to develop algorithms to calculate causality (Naranjo, French Imputability, Roussel-Uclaf, WHO, etc.). However, the assessment continues to depend to a great extent on the clinical judgment (global introspection) of a physician. At the same time, efficiencies may be implemented in this step by showing chosen algorithmic score(s) to the reviewer, presenting all medically relevant case information in a special assessment form built for purpose, and providing other tools to quickly look at analysis of similar events, past medical history, etc. 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Narrative Generation The case narrative is built using data in the case, including event description, past medical history, causality assessment, etc. Auto-narrative generators can be developed that utilise templates built using standard statements with data fields populated from the case. An appropriate level of granularity of statements, together with flexibility in combining statements, can greatly reduce manual effort in the creation of the narrative. Recent advances in natural language generation (NLG) technology also holds promise for greatly automating this step. Distribution and Submission Once the case has been processed, it needs to be submitted to qualifying regulatory authorities and co-licensing/ marketing partners. Even a small number of products marketed across the world may lead to a large number of rules applicable for distribution of safety reports to various recipients. Having a capability to flexibly maintain and execute these rules helps eliminate the need to manually assess for reporting. Much of this reporting globally could be through local offices. Implementing a system that auto-qualifies and distributes relevant case reports to country offices for submission to local partners and authorities helps achieve efficiencies while also providing a global tracking system for submissions. Such a system also enables companies to implement common submission processes globally and better monitor compliance. Compliance and CAPA Management In a global environment, monitoring submission compliance and initiating appropriate corrective and preventive actions can be a challenging task if done with retroactive data collection. A better approach, which also scales up well as processing volumes grow, is to collect lateness data during case processing and submission. Thus, with each completed task in the case processing workflow, an automated system would assess the case for lateness and prompt the user for the reason. This way, for most cases, the lateness data is available as part of the case processing life cycle. The compliance team is then required to assess overall lateness reason only for a small percentage of the cases, where the assessment could not be automatically made.

Such a system brings significant efficiencies to compliance monitoring, and better prepares the compliance team for handling growth in case volumes. In Summary Drug safety strategies call for moving to “proactive pharmacovigilance,� with increasing emphasis on signalling and benefit-risk management as against mere reporting compliance. However, most safety departments are having to deal with a consistent growth in yearto-year case processing volumes, with the high allocation of resources to ICSR processing not going down any time soon. There are multiple factors driving this increase in volumes, including sales growth, new product launches, increasing patient support programmes, new clinical studies, etc. However, budgets for safety processing do not generally reflect a similar upward trend, as companies continue to cut costs and expect departments to do more with less. To continue to ensure regulatory reporting compliance, companies have to consider all options to handle this growth in case volumes cost-efficiently. These options may span across resourcing strategies, business process re-engineering, and enhancements to systems and technology to gain efficiencies in operations. In this article, we looked at some of the options over the long term that safety departments and technology providers need to consider to ensure ongoing capability to manage the increasing case processing workload while controlling costs.

Ambrish Mathur is Vice President, Strategic Development, at ArisGlobal and has worked in the life sciences industry for over 20 years. He has had leadership roles in product development, product management and strategy, technology, and sales support. At ArisGlobal, he has led the development of systems for pharmacovigilance and drug safety, clinical trials management, registrations tracking, and medical communications. His current job focus is in the area of safety reporting and analytics. He has been a presenter at several Annual DIA conferences, and has also been published in Applied Clinical Trials, Drug Safety Directions, and Life Science Leader magazines. Winter 2015 Volume 7 Issue 4


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Regulatory & Marketplace

It’s Time to Address the Claims Management Disconnect One of the fundamental pillars of the life sciences industry is the accuracy of the claims that it makes for its products. Over decades, the industry has strived to become second to none in terms of testing and transparency, because what it says about its products has the potential to impact ultimately upon hundreds of millions of patients and consumers. And arguably, no other industry is subject to the same level of regulatory scrutiny. This is why it’s all the more astonishing, and frankly worrying, that so many life sciences companies still lack the ability to track and, most importantly, effectively withdraw promotional material from the multiple channels it is distributed across in our hyper-connected, digital world. In terms of asset management, many companies continue to operate as though they still exist in a pre-online market rather than the fluid and demanding global economy we now do business in. This has led to a serious disconnect between the promotional material that companies continue to distribute and their ability to control the claims in that material when they become outdated. And if companies can’t demonstrate that they have effective means in place to withdraw this material, the regulatory, reputational, and business consequences can be severe. The competition is fierce in life sciences and new markets are opening up all the time, which has led to an explosion in the volume of promotional content – companies spent US$4.5 billion on marketing prescription drugs in 2014, up from $3.5 billion in 20121. Critically, the nature and breadth of this content has also changed over the past few years – companies are no longer just producing paper-based brochures and leaflets, but also websites, mobile apps, and online videos. Not only do all of the claims in these materials have to be rigorously approved in the first place, but they also need to be regularly monitored and their usage tracked to ensure that they remain accurate. And then they need to be withdrawn in a timely fashion once they stop being current. There

are

further

complications

22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to working in a global market. The speed of messaging has accelerated dramatically and the process of creating, sharing, and approving vast quantities of marketing materials involves many stakeholders and departments, often spread around the world. Additionally, the preference for international brand alignment and the need to achieve cost efficiencies via reuse of materials has led to marketing campaigns in which assets are shared, distributed and repurposed in multiple countries – however, each of these territories has its own regulatory requirements. It’s not surprising then that managing compliance in this new world is both complex and time-consuming. On this basis, it would seem vital that companies should have effective digital asset management (DAM) systems in place, which are capable of dealing with these end-to-end challenges. However, the reality is that the great majority of companies are still struggling with the intricacies of managing and controlling the claims they make for their products. Preliminary findings from the Veeva 2015 Life Sciences Promotional Content Management Survey, which looked at the impact of changing from paperbased to digital asset management processes, revealed startling levels of inefficiency from creation and review of materials to expiration and withdrawal: 81% of respondents can’t report on where claims and content are in use, and 77% are unable to withdraw expired or outdated content from multiple channels. And almost half (49%) of respondents do not have primary systems that provide end-to-end audit trails to manage promotional content throughout its lifecycle, despite this being an essential element of compliance. Although the materials themselves are no longer just paper-based, many companies are still struggling to manage massive amounts of promotional assets via cumbersome manual, paper-based processes, where opportunities for human error and inefficiency are rife. For example, discrepancies can arise when brand teams in many departments on several continents have different versions of a promotional piece. And

with paper, there is no inventory that lists every appearance of every claim across promotional materials, and therefore no easy way to identify all locations of a specific claim to ensure that each mention is withdrawn quickly. Even when technology has been deployed to manage and keep track of materials, the process often remains disjointed and is not end-to-end. Most of the companies surveyed (88%) said their content management function is scattered among many systems and methods, which suggests serious break points in the process. In fact, respondents said that, on average, they use four different systems for promotional materials management. And for 31% of companies, the picture is even more challenging, with between five and 20 systems in place. It is impossible to be entirely efficient when multiple systems are in use, because the likelihood of them talking to each other in a joined-up fashion is practically zero. The risk of data duplication is high, not to mention the time and cost overhead of maintaining and updating the different systems. But in compliance terms, this is a disaster waiting to happen. For instance, if the US FDA instructs a company to remove all claims from promotional materials for a given product, the company’s regulatory department faces the daunting task of quickly finding an improper claim amid a vast assortment of promotional materials spread across multiple channels. The company must remove the claim and then prove to the regulatory authorities that it has been deleted from the public domain. To locate and remove a single claim in that situation, the company might have no choice but to pull an entire campaign, which leads to lost promotion time as many multichannel assets are stripped of usable, approved content. Non-compliance, or rather, the inability to comply with such a regulatory request, can be very costly indeed. Not only can companies face significant fines, but there are also costs relating to lost productivity, legal disputes, and reputational damage. In the UK, there are approximately 70 code breaches Winter 2015 Volume 7 Issue 4


Regulatory & Marketplace every year, and the average penalty for offending companies is half a million pounds. Most companies do recognise the value of using technology to automate their promotional materials management; over half (52%) of the respondents to the Veeva 2015 Life Sciences Promotional Content Management Survey have already automated the content review and approval end of the process. But it’s at the potentially more painful end of the process, when obsolete and incorrect claims need to be withdrawn from all channels, that companies are still failing to use technology to help them. Overwhelmingly, the evidence points to companies with end-to-end DAM systems that encompass the entire digital supply chain – capable of providing a reliable audit trail for keeping track of assets from creation through approval to distribution and withdrawal – being in the best position as regards claims management: 100% of respondents using end-to-end systems report satisfaction

with their ability to adhere to compliance requirements across channels, while 88% are satisfied with their ability to electronically withdraw outdated content. In contrast, only 54% of respondents not using end-to-end systems are satisfied with their processes.

promotional materials to market faster. In addition, a complete DAM solution allows assets to be securely shared along the digital supply chain with affiliates in multiple territories and across multiple channels. Content reuse brings dramatic savings of time and money, plus helps ensure consistent messaging, whether a communication is sent via email from a sales rep, through a digital detail online, or in an advertisement produced by the brand team. Likewise, outdated materials or claims can be removed, revised, and redistributed quickly – significantly reducing the risk of non-compliance and saving both marketing and regulatory teams the chore of manually searching for every instance of a claim or asset. Overhead costs for the review, rework, and distribution of materials plummet. Indeed, even marginal cost savings across the many stages of the digital supply chain can result in significant return on investment for a life sciences company. Also, an end-to-end DAM system frees up regulatory department resources by streamlining approval,

What does an end-to-end DAM system look like? Essentially, it is a single solution with life sciences-specific functionality, including claims creation and approval, claims search, review and approval workflow, audit trail, distribution, claims obsolescence, a digital asset library, and a claims library. With such a system, companies can quickly search for a claim across all global assets anywhere in the digital supply chain, which means that offices around the world can run local promotional programmes while complying with in-country regulatory standards. It also allows real-time collaboration for quicker content development and fewer iterations of an asset as it circulates through review and approval cycles. This mitigates the potential for errors and ultimately brings

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Regulatory & Marketplace

reuse, and distribution of materials to global company sites. Perhaps most importantly, an end-toend DAM system with digitised claims can help solve a persistent, costly problem for regulatory departments − replacing claims that become outdated as new scientific data or regulatory requirements emerge. With more research being conducted and new findings happening every day, this is an issue that will only get trickier for those without end-to-end automation. A disconnected or paper-based system doesn’t have an accurate or easy way to amend or remove outdated claims, whereas digital asset management enables claims to be updated in real time across multiple promotional materials. In the life sciences industry, there is a lot riding on this issue. Old approaches to managing promotional claims are inefficient at best, and risky at worst. The cost of failing to manage claims properly is high, whether due to heavy fines or because of extended time to market leading to lost revenue. Additionally, life sciences companies are currently racing against the clock to meet FDA requirements to submit promotional materials via the electronic submissions 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

gateway from May 2017. Companies using paper-based claims inventories face the immense task of transferring their records to the digital, standardised submission forms required by the FDA. A next-generation technology with claims management across the digital supply chain would make preparing FDA submissions easier and faster. We operate in a market where it’s no longer possible to ignore the disconnect between the amount of promotional materials produced and the claims made therein, and companies’ inability to manage these materials effectively once they’ve been released into the world. Being unable to withdraw inaccurate and outdated content in a timely fashion eats away at the very foundations of the life sciences industry, as well as increasingly attracting the wrath of regulatory authorities. It may seem like a major wrench to throw out old systems and processes once and for all, but the benefits of automated end-to-end materials management are clear. Not only does a fully digital supply chain make compliance a lot easier, it also enables companies to compete on an equal footing in the 21st century life sciences economy.

Reference 1. “DTC Ad Spend Is Back Stronger Than Ever, Baby!” Pharma Marketing Blog, March 2015: http://pharmamkting.blogspot. com/2015/03/dtc-ad-spend-isback-stronger-than-ever.html

James Brown, VP and GM, Commercial Content Veeva Systems. Having graduated with a degree in biochemistry from the University of Nottingham, James spent nine years at Merck & Co in sales and marketing roles before leaving in 2001 to start Zinc Ahead. Over the last 14 years, James has firmly established Zinc as the gold-standard compliance solution for life science companies. Zinc was awarded a Queen’s Award for Enterprise (International Trade) in 2013 and 2015. Winter 2015 Volume 7 Issue 4


Chapter Title

WE’RE SOARING TO NEW HEIGHTS End to End Services for Patient Recruitment and Retention

THE PATIENT RECRUITMENT-RETENTION REVOLUTION “Over MediciGroup’s 24 year history, the last 4 years has witnessed more change than the previous 20 years. The speed of change is unprecedented as more than 85% of patients and families obtain health and clinical trial information online. Medici is proud to be at the forefront of this digital revolution, spearheading more than 30 global online patient communities, and leading in the delivery of successful patient recruitment through digital and social media on a global scale.” Liz Moench, President & CEO MediciGroup® Inc.

BioClinica Patient Recruitment / Retention Services

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 25


Regulatory & Marketplace Tamper-evidence – A Vital Matter of Safety

Abstract This article, starting from the concept of falsified medicine as postulated in the European directive, focuses on the options actually on the market concerning tamper-evidence systems. It closes by demonstrating how a system integrated in the outer packaging and completely mechanical is able to improve the safety of the outer packaging and protect it against attempts to counterfeit in an effective way. Foreword – Some Data According to the WHO1 (World Health Organization) the incidence of falsified medicines in industrialised countries in possession of legislative systems capable of effectively regulating the drug market is below 1%. However, the percentage changes in several areas of Africa, Asia and South America. The differences aren’t only between geographic regions, but also within countries between urban and rural areas and different cities. Counterfeit drugs are of different kinds, from plain painkillers to anticancer drugs, and in 50% of cases people buy them online through illegal websites. The counterfeit drugs represent a risk for public health, as their composition may miss an important active principle or could be dangerous. Consequently, the treatment could be useless, or in the worst case could cause the death of the patient, as happened in the case of antidiabetes medicines in China in 2009, which caused the deaths of two people. The European Directive A great challenge of these last years is to guarantee the safety of the drugs placed on the market in order to counteract the rising wave of counterfeits. The European Union, with the Falsified Medicine Directive (Dir. 62/2011/EU) has helped by giving a legislative frame to the problem: it has extended, indeed, the concept of “falsified medicine” not only to the product inside the package, but also to the package itself, both packaging and labelling. The outer packaging, in fact, must provide:

26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

“safety features enabling wholesale distributors and persons authorized or entitled to supply medicinal products to the public to verify the authenticity of the medicinal product and identify individual packs, as well as a device allowing verification of whether the outer packaging has been tampered with.2 .” According to the Directive, therefore, there are three essential and complementary requirements: • • •

The outer packaging must be genuine (authentication); The outer packaging must be identified (serialisation); The content must be that originally inserted (evidence of tampering).

If just one of these three elements is missing, it creates a leak, weakening the anti-counterfeiting action of the outer packaging. The focus of this white paper is the evidence of tampering. Although the Directive doesn’t require compliance with specific standards but focuses on defining theoretically the essential safety requirements for a medicine on the market, it does raise a legal obligation stemming from the definition of “antitampering device”. To be more precise, the anti-tampering device must allow a “verification of whether the outer packaging has been tampered with.” This means that a device that can be removed without leaving an evident trace of its removal couldn’t fulfill the definition of anti-tampering device because it won’t be able to allow a “verification of whether the outer packaging has been tampered with.” Tamper-evident Solutions: Costs and Effectiveness There are basically three tamper-evident solutions applied to the outer packaging of medicines: • •

Glue system; System with labels;

Systems with integrated mechanical solutions.

Regarding their effectiveness, some medicine agencies like FDA (Federal Drug Administration - USA) and TGA (Therapeutic Goods Administration Australia) have documented and defined the guidelines on tampering of medicine packaging. The above-mentioned agencies took a direct and accurate stand regarding the best methods to protect the outer packaging and the technical characteristics it must have. In particular, concerning the glue system, both FDA and TGA do not consider this a valid system, as is clear from the extracts below: •

FDA: “Paperboard cartons sealed by gluing the end flaps are not capable of meeting the Tamper resistant packaging requirements…”3 TGA: “Sealed paperboard cartons as currently available in the marketplace (e.g., cartons sealed by gluing the end flaps together) are unacceptable. However, future technological advances may provide sealed paperboard packages that meet the intent of the TEP requirements.”4

As well as the ineffectiveness of the “glue systems” can be added, furthermore, the increased costs to buy the material (glue and more use of cartonboard), the investments to modify the packaging machineries and the related costs of change and process management. The FDA and TGA have a very clear stance regarding the technical requirements of the tamper-evident systems using closing labels for the folding boxes. Below are the extracts from the related documents. •

FDA: “..adhesives which do not permit the removal and reapplication of tape seals. In addition, tape seals may contain a feature that makes it readily apparent if the seals have been removed and reapplied. Tape seals must employ an identifying characteristic that cannot be readily Winter 2015 Volume 7 Issue 4


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duplicated.” TGA: “Paper or foil with a distinctive design” … “Tape seals are acceptable only if they contain a unique feature that makes it apparent if the seals have been removed and reapplied, e.g., a permanent adhesive.”

As one can see, these stances are perfectly convergent to what is expressed in the European Directive. The same, indeed, refers to the outer packaging and, therefore, it is set forth that every element of it must answer to the requirements of authenticity and identification, beyond giving a clear signal in case of tampering. The label, as part of the outer packaging, must, therefore, be authenticated and identified and give evidence of tampering as required by the medicine agencies mentioned above (FDA and TGA). Hence, the tamper-evident systems are considered valid only under these conditions. However, that does make their application very expensive. Indeed, the labels configured in this way are particulary expensive. They also affect the process efficiency, as the application of the labels, in many cases, slows down the packaging process, causing a growth in the packaging cost. On the market there are also available mechanical solutions that integrate the tamper-evident mechanism inside the folding box. The mechanical systems, as integrated in the folding box, do not need authentication and identification. Indeed, once the folding box itself is authenticated and identified in compliance with Dir. 62/11/EU, the tamper-evident mechanism is, in turn, authenticated and identified. These solutions, thus, can fulfill the requirements of identification, authenticity and evidence of tampering postulated in the European Directive without an explosion in costs and investments. However, the integrated solutions have to provide very effective mechanisms of safety to avoid nullifying the anticounterfeit action. Many of the integrated mechanism systems have proved, indeed, to be inadequate to defend the integrity of the packaging. Igb then focused its research and development on a system that would be 28 INTERNATIONAL PHARMACEUTICAL INDUSTRY

both inexpensive and efficient. The Igb Tamper-evident System Tamper Evident folding box. The Igb tamper-evident folding box looks like a normal case but it is provided with a mechanism that allows an immediate confirmation of opening or tampering. The solution is made up of three elements: • Hook • Support • Seal (also in braille version) When it is first opened, indeed, a seal comes off, revealing a colour and shape change of the original package. Advantages of the Igb Solution The first main advantage of the use of the Igb solution is its simplicity: its use doesn’t modify or slow down the packaging process.

The end user can close the package like any other one

Social considerations: • Environmentally-friendly • Blind-friendly References 1. Fact sheet N°275 – May 2012 2. Dir. 62/2011/EU 3. CPG Sec. 450.500 Tamper-Resistant Packaging Requirements for Certain Over-the-Counter Human Drug Products. 4. Guideline for the TamperEvident Packaging of Medicines, Complementary Healthcare Products and Medical Devices 5. For more information about the patent proceedings please register at www.igbressan.it

Indeed, the folding box can be used in the packaging machinery without modification. Furthermore, the manual packaging is also quick, and doesn’t require tools or additional material. It is also important not to overlook the peculiar shape of this solution, which also allows blind people to easily identify if the package has been tampered with. Finally, the case is made with a single, recyclable material that can be branded FSC or PEFC, so it can be considered to all effects an ENVIRONMENTALLYFRIENDLY package. Summary of the Advantages: • Complies with Dir. 2011/62/EU, FDA and TGA requirements • Synergy with other anticounterfeiting systems Savings: • No modification and/or expansion of the machinery • No slowing down in production line • No modifications or complications in procedures and processes • No additional materials required (glue, labels or film) • No duplication of costs of authentication and identification Safety: • Inviolable • Breakage of the TE seal irreversibile

Alessio Bressan graduated magna cum laude at University Luigi Bocconi in Milan. Later, he gained a Masters in process innovation and another one in management of industrial companies. He worked with Ernst & Young as a consultant in industrial innovation projects. Since 2000 he has worked in Igb, and since 2003 has been part of the board of directors. In 2014 and 2015 he participated as speaker in the convention “Drug Packaging” in Milan. Winter 2015 Volume 7 Issue 4


Drug Discovery, Development & Delivery

High-quality, Fast Antibody Conjugates in Complete ELISA Kits Every immunoassay exploits the ability of an antibody (referred to as a primary antibody) to bind selectively to a particular target antigen, which is usually presented in a complex fluid such as serum, blood or urine, or in a solid matrix such as a slice of tissue, a cell monolayer, a nitrocellulose blot or a plastic microplate. The antibody, in conjunction with a label that provides measurability, allows the quantity and/ or distribution of the antigen to be determined. There are many types of labels but fluorescent proteins, enzymes, organic dyes or gold nanoparticles are the most common ones. Immunoassay applications in which labels are employed include, among others, ELISA, lateral flow assays, western blotting, flow cytometry, and immunohistochemistry. Immunoassays can be configured in many ways but there are two main categories of assays; ‘direct’ and ‘indirect’, these terms indicating whether the label is attached to the primary antibody or to a secondary reagent (often an anti-species antibody), respectively (Fig. 1). Ideally, when developing an immunoassay, a researcher has at his/ her disposal a wide selection of reagents to obtain the best possible assay performance. However the choice is often limited. First, the primary antibody conjugated to the required label may not be commercially available, as antibody companies offer only a small fraction of the antibody conjugates that could theoretically be made. In this situation the researcher has two options; (i) to develop an indirect assay, which requires more incubation and wash steps than a direct assay, and can give rise to false assay signals if the secondary reagent is not completely speciesspecific; or (ii) to create the required primary antibody conjugate in-house. A perceived barrier here is that antibody conjugation processes are complex and require specialist knowledge but, as we will see below, significant advances in conjugation technology now mean that anyone can create high-quality conjugates with ease. To facilitate one-step labelling of antibodies with a wide range of labels 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

including enzymes, biotin, streptavidin and fluorescent materials, we have created a technology and kits that create a stable covalent bond, resulting in conjugates that can be stored for up to 18 months. The technology works by activating the proprietary chemicals in the mixture upon dissolution of the lyophilised label with a solution of the antibody (or other biomolecule) to be labelled, resulting in a covalent attachment of the label in a gentle and controlled process at a near-neutral pH. No knowledge of chemistry, nor any expensive equipment, is required; the primary antibody is simply pipetted into a vial of lyophilised label. (Fig.2.) Although the antibody labelling procedure from a user’s perspective is incredibly easy, the chemistry is very sophisticated and allows the formation of high-quality antibody conjugates without the complexities associated with more traditional methods. Conjugation kits providing an analogous one-step covalent conjugation procedure for making antibody-gold conjugates are also available, using nanoparticles that have a unique surface coat which dramatically enhances colloidal stability. A number of functionalised coated materials are also available, e.g. a maleimide derivative to allow oriented attachment of antibody fragments terminating in a cysteine residue.

The conjugation kits are not speciesor sub-type-specific and can be used to conjugate any antibody, most proteins and many peptides, as the kits utilise amine groups (lysines) on the target biomolecule. With a collection of over fifty labels available in an easy conjugation format, researchers can create almost any primary antibody conjugate on demand. Labels presently available in a one-step format include fluorescein, other organic dyes (e.g., DyLight®, Cy®, and Atto dyes), fluorescent proteins, tandem dyes, enzymes, biotin, streptavidin, and gold nanoparticles (10nm, 20nm, 40nm, 60nm and 80nm diameters). The incubation time for the standard range is just three hours (although, sometimes more conveniently, reactions can be set up and left overnight with no detrimental effects), however other available lines have just a 15-minute incubation time. The hands-on time to set up reactions is just 30 seconds.

Winter 2015 Volume 7 Issue 4


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Drug Discovery, Development & Delivery These conjugation kits have been carefully optimised to ensure that all of the antibody is labelled. The by-products of the reaction are completely benign, and do not interfere in any applications. Importantly, no spin or separation steps are required either during or after the conjugation procedure, which means that antibody recovery is effectively 100%. The inherent simplicity of the conjugation process guarantees that immunoreagents will show excellent consistency from batch to batch and that conjugate performance will be identical at any scale. The kits can be used for in-antibody screening applications at just 10ug scale or used to produce bulk reagent at mg or gram scale. Regardless of the scale of operation, the hands-on time remains 30 seconds. The LightningLink approach utilises one chemistry for all labels, further simplifying assay development if a selection of different labels is to be evaluated. B.I.T.S. Immunoassays Scientists working on biomedical and bioscience research often need to identify and quantify tiny quantities of particular molecules in all sorts of biological fluids, especially blood (serum or plasma), and urine. These fluids are complex mixtures of many different molecules, some of which are in quite high concentrations, making it very difficult indeed to pick and measure the specific molecule of interest. This is the molecular equivalent of “searching for a needle in the haystack�. Immunoassays, exploiting the exquisite sensitivity and specificity of antibodies, have provided the answer, and have therefore become an essential tool for research and routine diagnosis in virtually all fields of medical science. In fact, medical science could not have progressed very far without the emergence of immunoassay technology over the past seven decades. Immunoassays have a number of particular strengths and advantages, leading to their widespread use, and a desire to constantly improve their performance has led to many technical advances within the field over the past few decades. The two general immunoassay techniques that have achieved the widest application are solid phase capture techniques, in which an antibody or antigen is attached to (immobilised on) a solid surface (such as a well of a microtitre plate or magnetic beads or the interstices of a cast nitrocellulose strip), 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

which is then exposed to a test sample suspected of containing an antibody or antigen capable of binding to the immobilised antibody or antigen. A typical sandwich immunoassay utilises two populations of polyclonal antibodies, each modified in a different way to capture or detect, respectively, an antigen analyte. One population is modified to carry a label, while the second one is linked to a solid surface, such as the inside walls of a test tube. The procedure must be carried out in a set sequence to organise the antibodyantigen interactions in an orderly way, allowing their binding properties to deliver a reliable assay result. If the sequence is not followed, antibodyantigen interaction will take place, but it will not be orchestrated into a detectable, quantifiable result.

For molecules too small to have two antibodies binding to them simultaneously, such as desmosine and small peptides such as fMLP, a different strategy is needed to make an immunoassay for these analytes – the socalled competitive assay. In competitive immunoassays, it is possible to utilise only one binding step, in contrast to the two-step sequence of sandwich assays. Competitive assays generally use a labelled antigen instead of a labelled antibody, but the capture antibody is still required. It is possible to reconfigure these assay components to allow the use of a labelled antibody together with an immobilised antigen, but the basic principles are the same. of

intrinsically robust, the fact is that different immunoassays for the same analyte usually vary enormously in their quality. This is because the antibodies on which they are built vary in their affinity and specificity, while the immobilisation and labelling procedures can be more or less efficient. For these reasons the B.I.T.S. immunoassays stand out from the crowd. The extremely high quality and consistency of the labelling and surface coating chemistry and procedures used in the development and manufacture of the B.I.T.S. products provide assurance of the best possible immunoassay performance. We develop and use numerous immunoassays in our studies on biomarkers of inflammation and infection, for eventual application in medical diagnostics. High-quality assays are absolutely essential for this work, and rigorous demands on specificity, accuracy and sensitivity are the norm. At present the B.I.T.S. kits range includes ELISAs for desmosine and fMLP. The unique desmosine ELISA has been tested against DPD and PYD for crossreactivity and validated against the exacting and rigorous reference assay of LC/MSMS. The LC/MS-MS method as described in the literature takes 24-48 hours, depending on how much sample preparation (mainly acid hydrolysis) is considered necessary. The B.I.T.S. desmosine ELISA needs no sample work-up and has an assay time of 1.5hr. The B.I.T.S. fMLP ELISA is unique, being the first commercially available ELISA for fMLP and, just like with the B.I.T.S. desmosine ELISA, no sample preparation is required. Mologic B.I.T.S. kits provide all the reagents and buffers necessary and the simple procedure makes it compatible with any research laboratory with basic EIA/ELISA instrumentation. In addition to ELISAs, the B.I.T.S. kits range also includes a lateral flow assay for A1AT with a 10-minute read time. Everything to run the assay is included in the kit and no additional equipment is required as a quantitative score card makes result interpretation a simple operation.

Although the general properties immunoassays are simple and Winter 2015 Volume 7 Issue 4


Drug Discovery, Development & Delivery

Dr Nick Gee, CEO/CSO of Innova Biosciences Nick is a biochemist with over 20 years’ experience in the pharmaceutical and biotechnology industry with Merck & Co., Amersham International, Warner-Lambert and Upstate Biotechnology. He joined Warner-Lambert's research facility in Cambridge, UK in 1991 and was Head of Protein Biochemistry and Assay Development from 1994-1999. Nick was VP of Scientific Operations at Upstate’s European base in Dundee from 1999-2002, after which he returned to Cambridge to set up Innova Biosciences Ltd., where he is presently Chief Executive Officer and Chief Scientific Officer.

Julie Thompson, Research scientist at Mologic Julie has many years' industrial experience, becoming a graduate of the Society of Biology and gaining an MSc from King's College, London both in immunology whilst working for Unilever Research. Along the way she has picked up many technical skills, including bacteriology, cell culture and protein purification which have all been put to good use since joining Mologic in 2005 as a research scientist. Julie now works in the lab, developing new ELISA and lateral flow assays.

Amy Adams, Technical Support and Customer Service Supervisor at Innova Biosciences Amy graduated from the University of the West of England in Bristol with a Bachelor’s Degree in Forensic Biology in 2012, and began work in the labs at Innova Biosciences Ltd shortly afterwards. After working mainly within the manufacturing department, she then moved towards an office-based role, coordinating the Manufacturing and Logistics departments before settling within the Marketing Team, contributing to the email marketing efforts of the company as well as supervising the technical support and customer service provided to customers.

Professor Paul Davis is a scientific innovator and entrepreneur, widely known for his work and expertise in diagnostics, antibody engineering and inflammation biomarkers – topics which are reflected in his work as a science leader in industry and his role as honorary professor at the University of Warwick, University of Kent, University College London and Cardiff University. He frequently delivers invited lectures on these topics at national and international meetings, and they are prominent in his >100 publications and >60 patents. Ten years ago he co-founded Mologic, where he is a director and Chief Scientific Officer. Earlier in his career, he was a Senior Scientist in Unilever Research, where he led research in immunology, including diagnostics, vaccines, allergy and antibody-engineering. He is best known for his early work in medical diagnostics, when he was one of the scientists who founded Unipath, maker of the “Clearblue” pregnancy test, and inventor of much of the underlying immunoassay technology for home diagnostic tests.

Product News

Sartorius Stedim Biotech launches Flexsafe® 3D Pre-Designed Solutions for storage and shipping applications • • •

New S80 film features consistent cell growth, robustness and high quality Flexsafe® 3D shipping solutions meet stringent ASTM D4169 Standard Practice Pre-designed Solutions (PDS) proven for every process step in biomanufacturing

Today, single-use bags are increasingly used in all process steps of biopharmaceutical manufacturing. Their robustness, performance and quality consistency are crucial for ensuring the safety and economy of bioprocesses. This is why Sartorius Stedim Biotech (SSB), an international leading

supplier for the biopharmaceutical industry, developed a new polyethylene film and the Flexsafe® family of bags that provide outstanding quality and significantly facilitate implementation of next-generation singleuse factories. The complete control of the resins, film, bags and their final assembly, as well as dedicated supply chain and quality management for critical fluid-contact components, provides assurance of supply, reliable performance and a consistent extractable/leachable profile of Flexsafe® across all process steps. Designed for storage and shipping of biopharmaceutical fluids, SSB’s new Flexsafe® 3D Pre-designed Solutions (PDS) meet all the functional and validation requirements of the biopharmaceutical industry. These solutions feature the appropriate components, functionalities and quality controls that meet the specific requirements of each step in upstream and downstream processing and in final filling. Fluid-contact components are available off the shelf and their availability is backed by at least 24-month change notification to provide the best delivery reliability and business continuity. The three-dimensional single-use bags are available in a range of sizes from 50L to 1,000L and are made of exceptionally

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robust, yet highly flexible, 400 µm thick coextruded film structure. The strength of this film reduces the risk of damage to the bag, and its flexibility ensures easy installation and self-deployment of bags in containers, such as SSB’s stainless steel or plastic Palletanks®. The outstanding robustness of Flexsafe® bags has been demonstrated by shipping tests conducted in both airplanes and trucks and by applying the most stringent ASTM D4169 Standard Practice for Performance Testing of Shipping Containers and Systems. This standard is designed to reflect worst-case conditions at several temperatures. “With our Flexsafe® PDS, customers can easily select and safely implement single-use solutions proven for each process step. They will fully benefit from excellent cell growth in upstream, robustness in downstream and a consistent extractable profile in final drug products,” stated Jean-Marc Cappia, Vice President of Marketing for Fluid Management Technologies at SSB. Contact: Sartorius Stedim Biotech GmbH Goettingen, Germany Phone: +49.(0)551.308.0 info@sartorius-stedim.com www.sartorius-stedim.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 33


Drug Discovery, Development & Delivery

The Use of Preclinical Models to Drive Immunotherapy Cancer Research and Combination Strategies The ideal treatment for any disease is one that can cure it or prevent spreading with minimal impact on the patient’s quality of life. In the case of cancer, therapeutic agents were initially designed to kill rapidly dividing cells. These traditional treatments, namely chemotherapy and radiotherapy, remain the backbone of current therapy. Although effective, these treatments are often associated with severe side-effects and the emergence of drug resistance. The discovery of crucial molecular pathways that promote tumour growth and maintenance together with the development of drugs that specifically inhibit these pathways has ushered in a new era of cancer medicine, giving rise to new treatment options, including the latest advances in cancer immunotherapy. Decades of research have finally culminated in an ever-increasing understanding of the mechanisms used by tumours to evade and suppress host immunity. With this understanding has come an evolution in cancer therapy as immunotherapeutic interventions that increase tumour-specific responses, and block suppressive pathways on which tumours depend to maintain their immune privilege, have shown increasing efficacy in the clinic. Combination therapies involving immunotherapy are perceived to be one of the most effective approaches for the treatment of cancer, potentially exerting additive effects on tumour growth inhibition and overcoming the issues facing single-agent therapies, such as resistance. To realise the full potential of the emerging innovative approaches to tackle cancer and reverse immune evasion, innovative preclinical models are needed. To do this, models with a functional immune system are required to drive forward immunotherapy research and to enable the successful transition of immunotherapeutics from the laboratory to the clinic. Immunotherapy Taking advantage of a patient’s own immune system has shown remarkable results. The three main types of 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

immunotherapy include: cell-based therapies, antibody (including the popular checkpoint inhibitors) and cytokines. Cell-based therapies, also know as ‘cancer vaccines’, usually involve the ex vivo expansion of immune cells from cancer patients, which will be activated and infused back, where they are expected to induce a strong immune response against cancer. The first and only therapeutic cancer vaccine approved by the FDA is Dendreon’s Provenge, used for the treatment of prostate cancer1. Cytokines are compounds produced during the inflammatory response and there has been evidence of anti-tumour effects. IL-2, for example, was shown to be able to stimulate T-cells proliferation, promoting their anti-tumour response. However the high dose required was associated with strong side-effects, and cytokines are nowadays rarely used as standalone treatment. Antibody therapies are currently the most successful form of immunotherapy, currently approved for the treatment of lung cancer and melanoma and in clinical trials for a range of cancer types. The most palpable issue surrounding the development and application of immunotherapy is the necessity to find a balance between the higher costs of immunotherapy versus standard therapies, and its superior efficacy. This is currently the most significant drawback of immunotherapy and one of the main reasons why there has been some hesitation around using immunotherapy as a first-line treatment. Nevertheless, combination therapies involving different checkpoint inhibitors are perceived to be among the most effective approaches for the treatment of some types of cancer. Although research in the field of immunotherapy is fast-moving, scientists are still looking into how to maximise the benefits from immunotherapeutic agents, as cancer is a complex disease with extremely diverse histopathology and heterogeneous pathogenic mechanisms. It is, for example, still unclear why some

patients benefit from these treatments and others do not. There is, therefore, a distinct need for appropriate preclinical models in which to investigate mechanism of action and compounds efficacy. Immunocompromised models, such as cell line-derived xenografts (CDX) or patient-derived xenografts (PDX) are extremely useful tools for studying the physiopathology of human tumours and investigate the response to anticancer agents in a live host. However, to study the effects of immunotherapy, it is necessary for the host to have a functional immune system. Experimental mouse tumour models have provided key mechanistic insights into host antitumour immune responses, and these have guided the development of novel treatment strategies. To accelerate the translation of these findings into clinical benefits, investigators need to gain a better understanding of the strengths and limitations of different mouse models as tools for deciphering human anti-tumour immune responses. Syngeneic Mouse Models for Immunotherapy Models with a functional immune system are required to drive forward immunotherapy research and to enable the successful transition of immunotherapeutics from the laboratory to the clinic, reducing attrition rates and bringing costs down. Syngeneic models are murine tumours grown in the same strain of mice in which the tumour originated. In these models, the recipient mouse has a fully functional immune system, which provides an effective approach for studying how immunotherapy performs. These models offer several undeniable advantages. They are relatively inexpensive and reproducible, there is a strong baseline of drug response data, and they come in a wide variety of tumour types. They are also readily available, so studies are easily conducted with statistically meaningful numbers of mice per group.

Winter 2015 Volume 7 Issue 4


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Drug Discovery, Development & Delivery Radiotherapy Together with the development of less toxic chemotherapy, recent technological advances have introduced a revolutionary method, the image-guided microirradiation (IGMI), for a more accurate targeting of tumours while patients undergo radiotherapy. IGMI spares normal tissue surrounding a cancerous lesion, which in turn is associated with a reduction in side-effects in the clinic. The availability of such an advanced platform opens up the opportunity for multiple combination strategies, prime amongst which is the combination of IGMI with immunotherapy. However, clinically relevant models to interrogate the efficacy of different combination strategies of immunotherapy and IGMI are required. The use of IGMI in the preclinical setting has been less common until now; traditional irradiation studies utilise simple single-beam techniques or wholebody irradiation with lead shielding to focus the radiation to a specific area. However, these settings are far more aggressive and no longer mimic treatment in the clinic as they deliver a much higher dose of irradiation. The image-guided small animal radiation research platform (SARRP) is a state-of-the-art preclinical system that mimics clinical IGMI treatment. Application of SARRP to a Syngeneic model is an innovative system in which to demonstrate the outcome of combination of irradiation and chemoor immunotherapy in preclinical models of cancer. Combination Therapy: How Does it Work? For some cancers, the best approach is a combination of surgery, radiotherapy, and chemotherapy. Surgery or radiotherapy treats cancer that is confined locally, while chemotherapy also kills cancer cells that have spread to distant sites. Radiotherapy or chemotherapy can be given before surgery to shrink a tumour, thereby improving the opportunity for complete surgical removal. Radiotherapy and low-dose chemotherapy after surgery help to destroy any remaining cancer cells Cancer growth relies on more than one driver mutation and is also dependent on its environment. Targeting one single oncogene at the time can produce rapid responses; however cancer cells can evolve to overcome the single oncogene 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

inhibition by activating alternative pathways. This generally results in the patient relapsing or developing drug-resistance. By using combination therapies, that target more than one driver mutation at the time, it is possible to achieve better and more durable results. These combinations can include not only immunotherapy drugs like checkpoint inhibitors, but also targeted therapies that act on specific signalling pathways, as well as standard chemotherapy and radiation. How do Combination Strategies Apply to Immunotherapy? Combination approaches targeting more than one regulatory node of the immune system at the time have a strong potential for immunotherapy-specific combination strategies. Moreover the new immunotherapies are also attractive combination partners for existing standard-of-care treatment options, including chemotherapy and radiation, which until recently were considered incompatible. It is now clear, however, that many standard-ofcare agents have positive effects on the tumour's immunological environment. For example, both chemotherapy and radiation, by inducing DNA damage, have been shown to render tumour cells more readily recognisable by the immune system. Targeting immune checkpoints such as programmed cell death protein 1 and its ligand (PD1/PDL-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have achieved noteworthy benefits in multiple cancers by blocking immunoinhibitory signals and enabling patients to produce an effective anti-tumour response. Anti PD-1/PDL-1 and CTLA-4 antibodies work by preventing the down-regulation of the immune system by tumour cells and were initially tested as monotherapy, showing promising results in clinical trials. However, a large, ongoing study on patients with advanced metastatic solid tumours (CHECKMATE-032) demonstrated the anti-tumour efficacy of these checkpoint inhibitors could be enhanced by combining their administration, as this allows targeting two different checkpoints at the same time. Lately, a combination of radiotherapy with immunotherapy showed some promising results. Radiotherapy alone may not be sufficient to trigger anti-

tumour immune responses, especially in poorly immunogenic cancers. Thus, the combination of radiotherapy with immune modulators may have the capability to escalate anti-tumour responses to a level that could suppress or eliminate cancer. Combination of an anti-CTLA-4 antibody with radiotherapy has been tested in the CA184-043 trial on patients with recurring metastatic prostate cancer, showing signs of activity that encourage further investigation. A recent study at Crown Bioscience UK led by Rajendra Kumari (Chief Scientific Officer) demonstrates the combination outcome of irradiation and immunotherapy in a preclinical model of syngeneic breast cancer. Tumourbearing mice were irradiated using the SARRP allowing a more accurate treatment schedule, with planned protocols similar to those utilised in the clinic. Radiotherapy was combined with the anti-CTLA-4 antibody to investigate the outcome of this combination strategy. While immunotherapy alone had no statistically significant impact on tumour growth, radiotherapy as a single agent did reduce tumour size. However the addition of immunotherapy to radiotherapy exerted an additive effect on tumour growth inhibition over single agent therapy alone and resulted in higher levels of tumour-infiltrating immune cells, which are generally associated with better prognosis in tumour-bearing mice undergoing this type of treatment. A range of syngeneic models available at Crown have been tested ex vivo for response to different checkpoint inhibitors and immune cells modulation to determine mechanism of the action underlying treatment response. The heterogeneity in preclinical response not only to immunotherapeutics, but also to other agents, offers opportunities to trial different combination strategies, including combinations of immunotherapeutics with chemotherapy, radiotherapy and other targeted agents. To tackle resistance and metastatic disease, Crown Bioscience UK is mastering the use of bioluminescence in syngeneic models. Progression of bioluminescent cancer cells to metastatic sites can be assessed by optical imaging following treatment with irradiation and immunotherapy. This enables the longterm assessment of the combination strategy which is critical in demonstrating clinical benefit as well as understanding abscopal effects of treatments.

Winter 2015 Volume 7 Issue 4


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Drug Discovery, Development & Delivery

Conclusion The recent clinical success of cancer immunotherapies has renewed interest in a field that holds great promise for transforming the treatment landscape by harnessing the patient's own immune system to fight cancer. Various immunotherapeutic strategies are being developed to elicit an anti-tumour immune response, the most successful being the blockage of immune cells inhibition by the tumour using specific antibodies. Interestingly, combination strategies utilising two antibodies targeting different inhibitory nodes have shown the most promising outcomes. Combining immunotherapy with conventional standard of care agents could also result in more stable and durable antitumour responses since chemotherapy and radiotherapy could sensitise cancer cells, making them more susceptible to immunotherapy. The use of immunocompetent models, such as Syngeneic models, is essential when studying the effect of immunotherapeutic agents. These models are driving immunotherapy research 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and are providing important insights into the efficacy of new compounds and the development of more effective combination strategies. Furthermore, the right preclinical models can open opportunities for repositioning agents that may have failed or where patients have relapsed. Immunology is forever seeking new and improved ways to offer patients a better quality of life and the end goal of potential cures. Models can potentially transform cancer treatment and perhaps provide cures for cancer forms that historically had very poor survival rates. Given the long-term response observed in relapsed melanoma or lung cancer patients treated with checkpoints inhibitors, immunotherapy seems to be able to solve the challenge of drug resistance and enable a stronger anti-cancer effect. Ultimately, combination approaches that integrate immunotherapy with conventional cancer treatment hold the promise of becoming the most effective strategy for improving cancer patient survival.

Reference 1. Wery, JP (2015) Immunotherapeutics: The coming of age of cancer immunotherapy as a treatment paradigm. Therapeutics. 9-14

Dr Jean Pierre Wery. Prior to joining CrownBio, Dr. Wery was Chief Scientific Officer at Monarch Life Sciences, a company dedicated to the discovery and development of protein biomarkers. Prior to joining Monarch, Dr. Wery spent three years at Vitae Pharmaceuticals, Inc. where he was VP of Computational Drug Discovery. Before joining Vitae he worked for 12 years at Eli Lilly and Company in various scientific and management positions. Dr. Wery received his B.S. and Ph.D. in Physics from the U. of Liege, Belgium. Following his Ph.D., he did postdoctoral studies at Purdue University with Prof. Jack Johnson. Dr. Wery has authored more than 50 abstracts and publications. Winter 2015 Volume 7 Issue 4


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Clinical Research Rare Diseases: Ethical Considerations in Clinical Development Abstract: The drugs used to treat rare diseases are known as “orphan drugs”. There are limited numbers of patients available for enrolment in clinical trials, so it is difficult to ascertain the safety and effectiveness of the product being tested for use. It is important, that the risk/benefit ratio is carefully weighed, and that trials be designed to systematically observe patients and attempt to collect adequate data to demonstrate effectiveness as well as to determine the optimal dosage. A researcher needs to consider local cultural values when it comes to the application of the ethical principles to individual autonomy and informed consent. In research on sensitive issues, this will have to be properly addressed in the research protocol to safeguard the human rights of the dependent or vulnerable persons and populations. Based on this review, it can be concluded that it should be followed strictly to protect the patient, and also this study is needed to create awareness about rare diseases. Key Words: Orphan drug, rare diseases, informed consent, ethical considerations   1. History: More than 30 years ago and after years of discussion and concern, a task force created by what is now the US Department of Health and Human Services (DHHS) issued a call for action in a report on what might be done to promote the development of drugs with limited commercial value. Although a particular focus was drugs aimed at small groups of patients affected by rare diseases, concern extended to drugs intended for larger populations that were, for various reasons (e.g., lack of patentability; need for long-term trials to demonstrate efficacy), not attractive development targets for pharmaceutical companies (e.g., Asbury, 1985). Creation of the interagency task force in 1978 came after hearings on the recommendations of a congressionally created Commission for the Control of Huntington's Disease and Its Consequences, calls for action from the Neurologic Drugs Advisory Committee of FDA, and pressure from other individuals and groups that were highlighting the 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

barriers to the development of therapies for rare conditions and proposing government action to overcome these barriers (Asbury, 1985). Important dates in the history of orphan drug regulation1: 1. 1983: The US introduces the Orphan Drug Act 2. 1985: Japan acknowledges the issue 3. 1993: Japanese regulation comes into effect 4. 1995: EU council resolution on orphan drugs 5. 1997: Australian orphan drug policy comes into effect 6. 1999: EU Regulation on orphan medicinal products published 7. 2010: The EU Regulation on orphan medicinal products establishes a centralised procedure 2. Introduction: With more than 25 million people affected in the United States and 50 million worldwide, rare disease research and treatment is an important medical necessity. Yet, little research has been done on many rare diseases, leaving both physicians and patients with a lack of treatment options, and, in some cases, with only a basic understanding of the disease itself. New studies focusing on rare diseases often face challenges related to small patient populations, the lifelong nature of the diseases, and variations among disease sub-types. Increasingly, researchers are turning to patient registries to fill some knowledge gaps, as registries offer an opportunity to learn much about the way patients are diagnosed and treated and about how they respond to various management approaches. Patient registries have considerable potential to help improve understanding of rare diseases and provide the knowledge base necessary to support development of effective treatments2. Rare Disease3: Rare disease = one affecting fewer than 200,000 people in the US. • 6000-8000 rare diseases

• •

affecting 7% of population 4 out of 5 have a genetic basis 70-75% have a prevalence of < 100,000 people

Orphan drug = one that has been developed to treat a rare disease • More than 2200 molecules designated as orphan drugs • 30-40% are for rare cancers • 362 approved drugs since 1983 3. Background: The US Food and Drug Administration (FDA) and the National Institutes of Health (NIH) define a rare or orphan disease as any disease that afflicts fewer than 200,000 people in the United States4. Over 6800 rare diseases, affecting 25 million Americans, have been identified to date. Rare diseases can cause a wide range of symptoms and may be chronic, progressive, disabling, and life-threatening. About 75 per cent of these diseases affect children, and about 80 per cent are related to genetic defects5. Some of the more well-known rare diseases include sickle cell anaemia, haemophilia, Tourette syndrome, and Tay-Sachs disease. Less well-known examples include Wilson’s disease, Turner Syndrome, and Gaucher disease. 4. Orphan Drug Development and Regulatory Challenges6: 1. Large heterogeneity in disease pathophysiology 2. Poorly understood natural histories and progression 3. Few patients are available conducting clinical trials 4. Uncertainty about the appropriate duration of treatment 5. Lack of appropriate endpoints that predict outcomes 6. Large heterogeneity in treatment effects 7. Require compromise, innovation and trade-offs 8. Make difficult decisions in absence of ideal information 5. Research Challenges: In general, little is known about most rare diseases. The small number of patients with a rare disease often results in limited clinical experience within individual Winter 2015 Volume 7 Issue 4


Clinical Research treatment centres. The clinical description of the disease may be incomplete or skewed, and the medical literature often consists of individual case reports or small case series, limiting understanding of the natural history of the disease. Both the lack of available treatments and the poor understanding of many rare diseases can be linked to the unique challenges that rare disease research poses. The challenges occur across the life cycle of a research study, affecting the study design, ethical considerations, and subject recruitment and retention. When designing a rare disease study, it may be impossible to find fundamental information on the disease on which to base the study protocol. For example, data on the disease prevalence and incidence may be unavailable, making it difficult to determine an appropriate study size. Diagnosis may be complex, particularly in cases where there is no definitive test. The development of the study data set may be hindered by a lack of information on the full range of disease symptoms or treatment practices7. Selecting appropriate study durations

may be difficult, particularly for diseases where new treatments are extending life spans. Ethical concerns may also arise in rare disease research. The majority of rare diseases affect children, who are considered a vulnerable population. Designing and conducting studies that enroll children may be more complex than designing studies for adults. For example, the International Conference on Harmonization (ICH) has released detailed operational guidelines for clinical trials in paediatric populations; these guidelines recommend, for example, that studies be performed in institutions with a paediatric infrastructure and appropriate personnel. Parents may be reluctant to consent to research, and there is ongoing debate about what age assent from the child, in addition to parental consent, is necessary for participation. Rare disease research may also focus on other vulnerable populations, such as cognitively impaired persons or pregnant women. Rare disease studies need to be sensitive to the needs of these populations.

Once a study has begun, it may face patient recruitment challenges. By definition, rare diseases have limited patient populations. Patient recruitment can become even more complicated if there are multiple, simultaneous studies of a rare disease, as enrolment in one trial may make a patient ineligible for another trial. Patients with the disease are likely to be widely scattered across the United States or globally. Recruitment may involve a large number of physician offices or speciality centres, and studies may need to include patients from several countries to obtain a sufficient study population. Lastly, retention of patients for the duration of the study is often extremely important, given the small study sizes. Studies generally need to devote significant effort to following up with patients who move or seek care at other locations to keep these patients enrolled in the study. 6. Challenges in Access to and Affordability of Medicines for Rare Diseases8: Despite the progress, no effective and safe treatment is available for many rare

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Clinical Research diseases. Furthermore, when treatments are available, obstacles are encountered that hinder access to and use of these drugs. 6.1 Challenges in assessing clinical relevance and cost-effectiveness The methodology for evaluating orphan drug treatments is often still in an experimental phase, hampering positioning in clinical practice. 6.2 Lack of knowledge and training For many rare diseases, available information is inadequate. Health professionals are often deficient in appropriate training and awareness to be able to diagnose and adequately treat these diseases. 6.3 Deficient diagnostic systems For many diseases, no diagnostic methods exist, or diagnostic facilities are unavailable. In these cases, diagnosis may be problematic. Consequently, validity, coding, and reproducibility are problems. Although the pace of gene discovery for rare genetic diseases has accelerated during the past decade, in part due to the success of the Human Genome Project, translation of these discoveries to clinical utility still lags behind. 6.4 High prices Prices of orphan drugs per treatment episode can be very high. For example, the cost of treatment with enzyme replacement therapies may reach more than US$150,000 per treatment year. The affordability of orphan drugs has become a major issue for payers and is thus a strong driver of tensions between the different stakeholders. Some companies have responded to this by developing programmes to facilitate access to orphan drugs. These obstacles to treating rare diseases with orphan drugs exemplify and mirror the global debate of deficiencies in bringing new drugs to patients who need them. Furthermore, advances in pharmacogenomics may lead to treatments benefiting a small subgroup of patients. 7. Case For Rare Disease and Orphan Drug Development9: Trends: • Licensing deals (ex: Pfizer and Protalix) • Mergers (ex: Sanofi and Genzyme) 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

• • •

Label extension strategies (ex: EPO for anaemia in CRF) Government roadmaps (ex: EMA and NIH) Dedicated industry units (ex: GSK and Pfizer)

7.1 Categories of Rare Diseases and Orphan Drugs: NME for as yet untreated people with rare disease • Example: alglucosidase alfa for Pompe disease (~ 1:40000?) • Exogenous source of lysosomal enzyme acid alpha-glucosidase (GAA) • Muscle weakness, enlarged hearts, difficulty walking Drug for common disease - Drug for rare disease (“re-purpose”) • Example: sildenafil for pulmonary hypertension (~ 1:50*?) • Selective inhibitor of phosphodiesterase type 5 (cardiac biomarkers) • SOB, chest pain, tachycardia, ankle/leg swelling

meets the annual reporting requirements of both the US and the EU for orphan designated products. The single annual report, much like separate agency reports, will provide information to both agencies on the development of orphan medical products, including a review and status of ongoing clinical studies, a description of the investigation plan for the coming year and anticipated or current problems in the process that may impact their designation as an orphan product. The single annual report submission to both regulatory agencies is voluntary and will apply only to sponsors who have obtained an orphan designation status for their product from both the FDA and EMA. Top players in the manufacture of orphan drugs and pipeline drugs in various pharmacological categories are illustrated in the given table. Companies involved in the manufacture of orphan drugs11:

Drug for rare disease - Drug for common disease • Example: canakinumab for Muckel-Wells syndrome (~ 1:2000?) • Anti-interleukin-1 beta monoclonal antibody (protein biomarkers) • Fever, rash, conjunctivitis, swollen joints, hearing loss, renal failure 8. Recent Developments in Regulating Orphan Drug Approval: The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have announced a more streamlined process to help regulators better identity and share information throughout the development process of orphan drug and biologic products, which are developed specifically to treat rare medical conditions10. Both agencies have agreed to accept the submission of a single annual report from sponsors of orphan drug and biological products designated by both the US and the EU. Currently, if an orphan product was granted designation on the exact same day in both the US and EU, the sponsors must submit separate reports to their respective regulatory agency. The use of one annual report will also benefit sponsors by eliminating the duplication of efforts and by simplifying the process that

List of biopharm and biotech companies 9. Growing Use in Healthcare: Patient registries are emerging as new tools with considerable potential for rare disease research. A patient registry can be defined as an organised system that uses observational study methods to collect uniform data (clinical and other) to evaluate specified outcomes for a population defined by a particular disease, condition, or exposure, and that serves one or more predetermined scientific, clinical, or policy purposes12. In recent years, patient registries have played an increasingly important role in medical research as stakeholders have emphasised the need for real-world data on patient outcomes and effectiveness from a broad range of patients. In 2007, the Agency for Healthcare Research and Winter 2015 Volume 7 Issue 4


Clinical Research

Figure 1: Orphan Drug pipeline Quality (AHRQ) published the landmark handbook, Registries for Evaluating Patient Outcomes, with a second edition released in September 2010. In the past year, the NIH and AHRQ have issued several new funding opportunities under the American Recovery and Reinvestment Act (ARRA) that specifically focus on registries13. The FDA already uses registries in assessing the safety and effectiveness of approved drugs and devices. Since 2005, the FDA Center for Devices and Radiological Health (CDRH) has called for some 120 post-approval studies, many of which use new or existing registries to study the real-world effectiveness of specific devices in community practice. 10. Key Highlights in EvaluatePharma's Orphan Drug Report 201414: • A record 260 orphan drug designations were granted in the US in 2013 • Orphan drug sales to grow 11% per year through 2020, compared to 5% for drugs (excluding generics) treating larger patient populations • Vertex’ VX-809 in combination with Kalydeco was 2013’s most valuable R&D orphan drug based on NPV, while Pharmacyclics’ Imbruvica ranked as the most promising new orphan drug approved by the FDA in 2013 • Bristol-Myers Squibb is set to leapfrog Novartis as the leader in orphan drug sales in 2020 thanks to cancer immunotherapeutic Opdivo • Phase III orphan drug development cost is half that of non-orphans but development time for orphans is not shorter than for non-orphan drugs • Anticipated return on investment for a Phase III/filed orphan drug is 1.89 times greater than for a non-orphan drug www.ipimedia.com

11. Market Exclusivity and Patents: The incentives provided by market exclusivity for orphan drugs need to be understood in the context of both patent law and other policies granting exclusivity for drug sponsors. Patent law provides an important means for innovators to protect their inventions or intellectual property from competitors16. It gives patent holders the exclusive right to produce, use, or sell the patented invention for a specified period (35 USC 271(a)). Patents are issued by the US Patent and Trademark Office and, under current law, extend for 20 years from the date of submission of the patent application. By the early 1980s, the research and development process for new drugs, combined with the time required for FDA review, had reduced the effective patent life for the average new drug to well below the 17 years then available under patent law. In the Drug Price Competition and Patent Term Restoration Act of 1984 (widely known as the HatchWaxman Act), Congress provided for the restoration of a portion of the patent term consumed by clinical studies and FDA review. In general, patent term restoration is limited to five years and an effective period of (post-approval) patent protection of 14 years15. The first exclusivity rule provides that truly innovative drugs — new chemical entities (also called new molecular entities) — receive a five-year period of data exclusivity, during which the sponsor of a generic drug must submit a full New Drug Application that relies on its own preclinical and clinical data. At the end of five years (four, if the generic drug applicant chooses to challenge the innovator's patents), the applicant can submit an ANDA that need only show that its product is the same as, and bioequivalent to, the innovator's product. The second exclusivity rule provides that other applications for approval that are supported by clinical data (e.g., those involving new formulations of the drug) receive three years of exclusivity. Again, during the period of exclusivity, generic versions can be approved only if sponsors provide their own clinical data on safety and efficacy. In 1997, Congress enacted the Best Pharmaceuticals for Children Act (as

part of the FDA Modernization Act) to encourage the testing of pharmaceuticals for children. If a company conducts paediatric studies in response to a written request from FDA and complies with various requirements relating to these studies, the law provides for an extension of six months to the exclusivity periods described above. Thus, for example, the five-year prohibition on the submission of an abbreviated application becomes five years and six months. The market exclusivity incentive for orphan drugs is broader than the various types of exclusivity which are discussed. During the period of exclusivity, FDA cannot approve an application from a different manufacturer for the same orphan drug and the same indication — even if that sponsor provides independent clinical data of safety and efficacy. An exception is available if the sponsor who has the orphan drug approval agrees to the additional approval or is found to be unable to supply sufficient quantities of the product. Orphan drug exclusivity applies to those vaccines and diagnostic or preventive drugs either designed to affect conditions that afflict a relatively small number of people, or for which there is no reasonable expectation of the recovery of research and development costs. The approval of an application for orphan designation is based upon the information submitted by the sponsor. A drug that has obtained orphan designation is said to have “orphan status.” Sponsors need to follow the “standard regulatory requirements and process for obtaining market approval.”A sponsor may request orphan drug designation for a previously unapproved drug or for an already marketed drug. More than one sponsor may receive orphan drug designation for the same drug for the same rare disease or condition. Drug with orphan status enjoys exclusive approval and market exclusivity. 12. Regulatory Requirements Orphan Drugs in US and EU:

for

1. Regulatory Requirements for Orphan Drugs in the US: The term ‘orphan drug’ refers to a drug or biologic that treats a rare disease affecting fewer than 200,000 of the US population. The Federal Government had to find a way to make it more attractive for drug manufacturers to develop drugs for INTERNATIONAL PHARMACEUTICAL INDUSTRY 43


Clinical Research this group of diseases. As a result, former President Ronald Reagan signed into law on January 4, 1983, the Orphan Drug Act (ODA).There are an estimated 7000 so-called orphan diseases identified around the world, and they occur in more than one out of ten people. These patients faced very limited treatment for these diseases and most had a poor prognosis. With the ODA in the United States and the implementation of the development of orphan drugs globally, approximately 1800 treatments have entered the research pipeline designated with orphan drug status and more than 300 products have been approved by FDA and other global agencies compared to a mere 10 products developed before 1983. Benefits for Developing Orphan Drugs in the United States: The ODA provides several development incentives: 1. It provides for the development of drugs for diseases that ordinarily would not generate enough revenue to make it worthwhile for a company, thus benefiting society. 2. It provides tax incentives: a tax credit of 50% of the cost of conducting human clinical trials. Final regulations on the tax credits were published in the Federal Register on October 3, 1988 (53 FR 38708), and the current version of these regulations are in Title 26, Code of Federal Regulations, Section 45c. 2. Regulatory Requirements for Orphan Drugs in the EU: A medicinal product is designated as an orphan medicinal product if: â&#x20AC;˘ It is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting no more than five in 10,000 persons in the European Union at the time of submission of the designation application (prevalence criterion), or; â&#x20AC;˘ It is intended for the diagnosis, prevention or treatment of a lifethreatening, seriously debilitating or serious and chronic condition, and without incentives it is unlikely that expected sales of the medicinal product would cover the investment in its development, and; â&#x20AC;˘ No satisfactory method of diagnosis, prevention or treatment of the 44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

condition concerned is authorised, or, if such method exists, the medicinal product will be of significant benefit to those affected by the condition.

fully apprised of the research and the impact and risk of such research on the research participant and others; and whereby the research participants retain the right to abstain from further participation in the research, irrespective of any legal or other obligation that may have been entered into by such human participants or someone on Fig: 3 Number of Orphan Drug Designation Requests by year their behalf, subject to only In the past decades there were only minimal restitutive obligations of any a few products developed for rare advance consideration received and diseases by pharmaceutical companies, outstanding. Cardinal principles to since rare diseases only affect small be observed throughout the research populations. Rare diseases need more and experiment; the ethics committee attention due to lack of proper diagnosis shall decide on the form of consent to and treatment; the return on investment be taken or its waiver based on the by pharmaceutical organisations was not degree of risk that may be involved. high. In order to boost the development of products, the FDA has initiated funding 3. Principles of Non-exploitation: (grants) for rare diseases. Whereby as a general rule, research participants are remunerated for 13. Principles for Research Using Human their involvement in the research or Beings as Participants: experiment; and, irrespective of the Statement of General Principles16: social and economic condition or status, or literacy or educational levels Any research using human beings as attained by the research participants, participants shall follow the principles are kept fully apprised of all the given below: dangers arising in and out of the research so that they can appreciate 1. Principles of Essentiality: all the physical and psychological Whereby the research entailing risks as well as moral implications of the use of human participants is the research, whether to themselves considered to be absolutely essential or others, including those yet to be after due consideration of all born. Such human participants should alternatives in the light of the existing be selected so that the burdens and knowledge in the proposed area of benefits of the research are distributed research; the proposed research has without arbitrariness, discrimination been duly vetted and considered or caprice. by an appropriate and responsible 4. Principles of Privacy and body of persons who are external Confidentiality: to the particular research and who, Whereby the identity and records of the after careful consideration, come to human participants of the research or the conclusion that the said research experiment are as far as possible kept is necessary for the advancement of confidential; and that no details about knowledge and for the benefit of all identity of said human participants, members of the human species and which would result in the disclosure for the ecological and environmental of their identity, are disclosed without wellbeing of the planet. valid scientific and legal reasons which may be essential for the purposes of 2. Principles of Voluntariness, therapeutics or other interventions, Informed Consent and Community without the specific consent in writing Agreement of the human participant concerned, Whereby research participants are or someone authorised on their behalf; Winter 2015 Volume 7 Issue 4


Clinical Research and after ensuring that the said human participant does not suffer from any form of hardship, discrimination or stigmatisation as a consequence of having participated in the research or experiment. 5. Principles of Precaution and Risk Minimisation: Due care and caution is taken at all stages. Research participants are put at minimum risk. No known irreversible adverse effects, and generally, benefits. Both professional and ethical reviews of the research are undertaken at appropriate stages. 6. Principles of Professional Competence Whereby the research is conducted at all times by competent and qualified persons who act with total integrity and impartiality and who have been made aware of, and are mindful of, preferably through training, the ethical considerations to be borne in mind in respect of such research or experiment. 7. Principles of Accountability and Transparency Experiment will be conducted in a fair, honest, impartial and transparent manner. Full and complete records of the research, inclusive of data and notes, are retained for the purposes of post-research monitoring, evaluation of the research, conducting further research scrutiny by the appropriate legal and administrative authority, if necessary. 8. Principles of the Maximisation of the Public Interest and of Distributive Justice Whereby the research or experiment and its subsequent applicative use are conducted and used to benefit all humankind and not just those who are socially better off, but also the least advantaged; and in particular, the research participants themselves and or the community from which they are drawn. 9. Principles of Institutional Arrangements Whereby there shall be a duty on all persons connected with the research to ensure that all the procedures required to be complied with and all institutional arrangements required to be made in respect of the research www.ipimedia.com

and its subsequent use or application are duly made in a bona fide and transparent manner; and to take all appropriate steps to ensure that research reports, materials and data connected with the research are duly preserved and archived. 10. Principles of Public Domain Whereby the research and any further research, experimentation or evaluation in response to, and emanating from such research is brought into the public domain, so that its results are generally made known through scientific and other publications, subject to such rights as are available to the researcher and those associated with the research under the law in force at that time. 11. Principles of Totality of Responsibility Professional and moral responsibility; the effect of the research is duly monitored and constantly subject to review and remedial action at all stages of the research and experiment and its future use. 12. Principles of Compliance General and positive duty on all persons conducting, associated or connected with any research to ensure that both the letter and the spirit of these guidelines, as well as any other norms, directions and guidelines, are followed. These 12 principles laid down under Statement on General Principles are common to all areas of biomedical research. Conclusion: Based on this review it can be concluded that orphan drugs may help pharma companies to reduce the impact of revenue loss caused by patent expiries of blockbuster drugs. The new business model of orphan drugs offers an integrated healthcare solution that enables pharma companies to develop newer areas. In the recent past, there has been development in drug approvals for orphan and rare diseases. USFDA has awarded 18 new research grants totalling more than $19 million to boost development of products for patients with rare diseases. The grants will trigger the orphan drug / rare disease pipeline, which may be a ray of hope for patients with orphan and rare diseases.

References: 3. https://www.google.co.in/search?q=history+of+orphan+drugshttp://www.ncbi.nlm.nih. gov/books/NBK56194/http://www.slideshare. net/patrickconneran/orphan-drugs 4. Michelle Leavy, Richard Gliklich, MD. Applied Clinical Trials., http://www.appliedclinicaltrialsonline.com/patient-registries-and-rare-diseases 5. http://www.fda.gov/downloads/AdvisoryCommittees/orPharmaceuticalScienceandClinicalPharmacology/UCM247635 6. National Institutes of Health, Office of Rare Disease Research, "Rare Diseases and Related Terms" http://rarediseases.info.nih.gov/ 7. http://www.genome.gov/27538160 8. www.ncbi.nlm.nih.gov/ 9. http://www.appliedclinicaltrialsonline.com/ 10. Aarti Sharma, J Pharm Bioallied Sciv. 2(4); OctDec 2010PMC2996062http://www.ncbi.nlm. nih.gov/pmc/pubmed/ 11. http://www.fda.gov/downloads/AdvisoryCommittees/orPharmaceuticalScienceandClinicalPharmacology/UCM247635 12. http://www.globalbusinessinsights.com/ content/rbhc0251m.pdf 13. http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm202300.htm 14. h t t p : / / w w w. f d a . g o v / M e d i c a l D e v i c e s / DeviceRegulationandGuidance/ PostmarketRequirements/PostApprovaStudies/ default.htm 15. h t t p : / / w w w. f d a . g o v / M e d i c a l D e v i c e s / DeviceRegulationandGuidance/ PostmarketRequirements/PostApprovaStudies/ default.htm. 16. http://www.evaluategroup.com/Public/Reports/ EvaluatePharma-Orphan-Drug-Report-2014. aspx 17. http://www.fda.gov/orphan/progovw.htm 18. http://icmr.nic.in/ethical_guidelines.pdf

Balamuralidhara V. Assistant Professor Regulatory Affairs Group, Department of Pharmaceutics, JSS College of Pharmacy, JSS University, Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India Email: baligowda@gmail.com

Lakshmi Triveni. Kolla Regulatory Affairs Group, Department of Pharmaceutics, JSS College of Pharmacy, JSS University, Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India Email : triveni2793@gmail.com

T.M. Pramod Kumar Professor, Regulatory Affairs Group, Department of Pharmaceutics, JSS College of Pharmacy, JSS University, Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India Email : tmpramod@yahoo.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 45


Clinical Research

Technology Advances in Feasibility, Recruitment and Retention Biopharmaceuticals are intensely focused on efficiency and time to market; however, the nature of clinical trials continues to present obstacles to attaining these goals. Today’s trials are still far too costly, and study cycle times remain too long to achieve a recoverable time to market. In response, many biopharmaceuticals are focused on reducing study cycle time by pinpointing the right countries, sites and patients. In tandem, they are turning to insights from clinical research organisations (CROs) to provide a comprehensive view of the competitive site landscape. Unfortunately, a lack of real-time standardised data still exists, causing genuine issues such as user distrust of the data, an inability to analyse data across studies, and critical data-driven decisions that cannot be made in a timely manner. Electronic clinical research organisations (eCROs), innovative CROs with a comprehensive in-house application services business, are addressing this deficiency with new offerings that deliver speed, simplicity and service above and beyond those of the traditional CRO. The need for faster study startup along with optimised country and site identification has created several approaches to data-driven feasibility through the use of advanced technology, utilising up-to-date data and analytics to aid in both patient- and site-centric feasibility. Additionally, after patient populations are located there are a variety of technologies being used to enhance recruitment and retention. Data-driven Feasibility The value of patient data has always been recognised, but true patient-centric organisations must also recognise the value of feedback of patients themselves. Social media is one route that has opened up a communication channel with patients. Although pharmaceutical companies may see the benefits of social media, they may resist its full potential because of uncertainty and an underlying fear about the legal risks. These risks are typically associated with privacy, adverse event reporting and unblinding. Regulatory guidance around use of social media is not yet fully developed 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and it is therefore recommended that companies engage their risk management departments to ensure the data being collected has meaningful purpose. A recent study1 tracked 224 pharmaceutical brands and analysed more than 257,000 associated posts across social media sites during a 30-day period. Some of the key findings include: • Only 0.3% of all posts contained an adverse event (AE) experience • Of those, only 14% of the posts that contained an AE (.04% overall) had an identifiable name and contact method • On average during the 30-day period, each brand received a total of three posts that met the requirements for AE reporting These results suggest that benefits and opportunities from engaging in online conversations far outweigh the risk of an occasional adverse event that would require reporting. The majority of communications involve one-way commercial promotion of a drug. Social media assists in study awareness, driving traffic to either a call centre or to a study website where the potential patient can learn more or pre-screen before referral to a site. This still requires initiative by the individual to act. New advancements in technology leverage web listening, which provides real-time analysis of publicly available social media to deliver insights into patient experiences, views and perceptions. Some eCROs can now analyse and assess social conversations, advise clients, engage patients and influencers, and understand sentiment. A critical objective of site-centric feasibility is providing a comprehensive overview of sites, primary investigators, centres, and subjects by geographical regions, therapeutic areas, indications, performance and quality factors. In order to optimise a study, an eCRO needs to aggregate, master and analyse site data from both internal and external sources. Disease prevalence and incidence data, demographic data, prescription and claims data need to be marshalled

along with historical site experience to ensure predictable outcomes and clinical study success. In an environment as multifaceted as the clinical research enterprise, it can be difficult to identify the signals from the noise. The eCRO in command of the dashboard bringing this complex site intelligence landscape into focus will be able to generate the insights needed to deliver the study on time and within budget. Most delays in clinical programmes occur at the site level. A big factor contributing to delay is the churn rate among investigators. In some estimates, over 50 per cent of investigators have only completed one study; therefore, the very basis of a successful trial – the research site environment – is in constant flux. Furthermore, undermining investigators’ ability to select the right trial site is a lack of coherent and compelling data. The previous performance of the investigator is the critical piece of information helping companies make the best site selection decisions; however, such information is fragmented and dispersed throughout the industry. The task of collating this data and gleaning insightful knowledge from it is a major technical challenge. “Selecting Sites: Using Data to Driven Decision Making,” examined which performance factors and site characteristics are correlated with enrolment. Findings from the analysis of over 38,500 global sites, with at least three trial instances in Phase II-IV, demonstrated that performance data and site characteristics are predictive of future success. Previous recruitment success, type of site, and hours per week dedicated to clinical research are good indicators. As they continue to build out the complex landscape site capabilities and performance, eCROs will find it increasingly difficult to identify the predictive signal from noise. More advanced eCROs can provide a combination of dynamic and sophisticated analysis of site data with best-in-class visualisations to generate key insights to optimise country and site identification. Aggregating and mastering investigators across both in-house and Winter 2015 Volume 7 Issue 4


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Clinical Research third-party databases produces a more comprehensive and therefore clearer picture of what sites have achieved in terms of recruitment rates in comparable studies. Various sources of site data can be aggregated, including: study pipeline, competitive landscape, performance data (e.g., randomisation and enrolment metrics), and quality metrics. These can come from lab data, electronic data capture (EDC), medical imaging and other central lab analyses such as ECGs and CTMS systems. eCROs that have created a complete view of site intelligence data are better positioned to understand site capabilities and in turn make more accurate datadriven decisions regarding country and site selection. A platform visualising the key drivers for country selection – medical, financial, regulatory, operational and clinical – allow for scenario-based country selection to confirm the suitability of countries proposed by sponsors for any given study. This enables the magnification of countries at higher risk of under-performing, ensuring that the study has an optimal mix of countries to deliver results on time and support a sponsor’s development strategy. Answers are rarely found in an algorithm; a detailed analysis reinforced with data will inform better decision-making. Clinical trials may seek to answer an important scientific question, but to be executable they need buyin from a number of constituencies: investigators, patients, family and friends of patients and patient support groups. Understanding what might motivate those stakeholders to take part, or conversely, what might cause them to reject the study, is an important part of determining the feasibility of a study. Web listening can reveal what patients and physicians really think about a therapy area, current treatments, a particular class of drugs, clinical research in general or even the reputation of the sponsor company. Because it is passive listening rather than active questioning, it can often reveal far more than surveys. The insights that it can bring can significantly impact how to position the study to investigators and patients, how to support the study better at the site level, and even how to adapt the study to better fit with a patient’s care pathway. This recognises the critical role investigators and patients play as active participants in the clinical trial process. 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

eCROs understand the patient profile in collaboration with internal patient recruitment, feasibility, and therapeutic area experts. With the appropriate technology, they can define desirable criteria for country and site selection, and communicate it to the global clinical operations teams to execute. Once sites are selected, the patient recruitment group should re-engage with field operations to create a local site patient cohort. From there, rapid enrolment for the study begins through chart review or EMR (if available). This approach can ultimately reduce the number of non-performing sites, increase the overall number of high enrolling sites and accelerate the enrolment period – reducing the overall study cost and cycle time. Recruitment and Retention Technology It is equally beneficial to use technology to ensure study participants complete all necessary procedures and visits. Several considerations determine the best approach for technology in recruitment and retention strategy, including: • • •

Are there regulations or legal requirements that prohibit the electronic tactics? Have the ethical tactics previously been accepted? Are the tactics acceptable from a cultural standpoint?

It is important to refine patient recruitment and retention strategies to the country level to better support patient enrollment, and it is critical to get input into which tactics will be most impactful and approved by ethics committees. Use of pre-built study websites can maximize recruitment, minimize attrition, and encourage compliance. Recruitment and pre-screening services, plus continual education throughout the course of the study are used to engage and retain patients by developing a sense of community and extending study support. Animation technology can improve education during the informed consent form (ICF) process by increasing patient understanding of clinical trials and protocol requirements. It can also include questions to evaluate patient apprehension. These best practices provide a consent process with the patient and family regardless of literacy or prior medical knowledge.

Video communication is another technology that can help maintain patient contact. Webcams and beamers (videophones) can be utilized to connect the patient with call center technology to provide for remote dosing or to address concerns. With their focus on and experience in technology, eCROs should be well-equipped to create these solutions aimed at replacing expensive traditional site visits with efficient remote communication. Study data collected in this manner was found to be more reliable and completed ahead of schedule. There are also many options in the mHealth field, which, through the use of mobile devices, can improve clinical study efficiencies in patient recruitment and retention. This includes the use of mobile applications for visit schedules, dosing, education, symptom tracking, and reminders. Most people have already acclimated to mobile devices into their daily lives; extending study contact via mobile technology is a natural way to increase patient interaction. Future Advancements in clinical trial technology as a means to build competitive patient strategies will continue to drive investment in this area. As pharmaceutical companies continue to explore the latest available tools, there is a scale of adoption to be expected, whereby key components will be outsourced to the leading technology service providers. Unlike traditional CROs or functional service providers (FSP), eCROs offer the most effective combination of technology, capability, and scientific and clinical knowledge within a single point of accountability. References 1. Kmetz, Jackie, Adverse event reporting: What pharmaceutical companies need to know, Cision. com: http://www.cision.com/ us/2013/12/adverse-eventreporting-pharma, 2013 2. Schultz, Joshua, “Selecting Sites: Using Data to Driven Decision Making,” DIA Annual Meeting, San Diego 2009. Paul Evans, PAREXEL Vice President, Global Head, Feasibility & Enrollment Solutions, Xavier Flinois, President of PAREXEL Informatics.

Winter 2015 Volume 7 Issue 4


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Technology

Healthware – Beyond Bracelets and Watches

Norman J. Holter, regarded as the “father of mobile ECG monitoring”, developed the world’s first ambulatory cardiology monitor, and arguably the world’s first wearable device, in 1954. The device weighed 85 pounds and had to be strapped to the patient like a bulky backpack. For the very first time, the patient’s cardiac wellbeing could be tested in his natural state, at any point during the day. No longer did the physician wait by the patient’s bedside to detect an arrhythmia, nor did the testing have to happen in a controlled clinical environment. However, Holter himself was the first person to acknowledge the practical difficulties associated with the device’s form factor. After a lifetime dedicated to miniaturising the monitor, he successfully managed to shrink the device to the size of a briefcase. However, even a visionary like Holter, who dreamt of a device that would measure cardiac activity on “skiers, parachute jumpers and runners”, would be no doubt be surprised to learn that his efforts have led to a multi-billion dollar industry, whose latest offerings include wearable devices that can be printed onto the patient’s skin. Healthwear: Wearable Devices used in Healthcare The popularity of wearable devices, such as smart watches, bracelets and glasses is evident from the numerous products that consumer electronics companies like Apple, Samsung and Sony roll out every year. In fact, wearable devices have become synonymous in the minds of the users - and perhaps developers as well - with activity trackers. Wearables are indeed a great tool for tracking physical activity (FitBit, Misfit, Moov) and sleep patterns (Pebble, Jawbone). However, the utility of these devices goes far beyond tracking fitness and offering notifications on-the-go. One of the biggest market opportunities for these devices lies in healthcare, specifically, in the fields of diagnosis, patient monitoring and therapeutics. There is a considerable overlap between diagnosis and patient monitoring, as far as wearable devices 50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

are concerned. Diagnostic devices are used to confirm or rule out health conditions, such as a cardiac arrhythmia, or seizures; whereas monitoring devices are used for passive, precautionary and often remote monitoring of a patient’s health conditions. Growth Drivers and Challenges Figure 1 illustrates some of the most impactful market factors that are expected to drive the wearable devices industry. The technical advances in wearable devices, such as longer battery life, better sensing capabilities, miniature form factor, and so on, are made possible by the rapid advances in the enabling technology platforms supplied by the sensors and electronics industries. Similarly, the advances in cloud computing, the foundation for online data storage, data sharing and remote monitoring, is another technical driver of the wearables space. On the demand side, there is a growing need for round-the-clock monitoring of patients, particularly the elderly and the chronically ill. There is also a pressing market need for non-invasive diagnosis and therapeutics, which is a major driver of innovations in wearable biosensors. All these needs point towards a class of non-invasive, wearable devices that can monitor patient health parameters, so that the patient’s wellbeing can be monitored, and the caregiver can be alerted in case of any emergency.

Figure 1: Key drivers of market growth However, the healthwear market also has its fair share of technological and market challenges. One of the biggest technical challenges is the difficulty in accurately capturing physiological data. The sensitivity of the device is the fulcrum around which the diagnostic or therapeutic capabilities of the device can be showcased. Moderate sensitivity is

sufficient for activity tracking or caloriescounting for fitness and recreational purposes; however, for clinical use, the device must house a sensor whose sensitivity is on par with clinical testing. Some of the other technical challenges to market growth and adoption are: patient data safety, and the lack of seamless integration with existing clinical information systems and practices. Figure 2 captures some of the key market challenges that wearable devices face.

Figure 2: Key challenges to market growth Through the course of its industry research, TechVision has studied and profiled a number of wearable devices that have been used for healthcare applications. Provided below is a snapshot of the key diagnostic and therapeutic applications of healthwear devices. Health Diagnostics Monitoring

and

Wellness

EEG Headsets A particularly interesting wearable device that is on the cusp of mass adoption is the wearable EEG device. At least a dozen companies (Emotiv Lifesciences, Neurosky, Interaxon, Advanced Brain Monitoring and Thync, to name a few) are developing lightweight, wireless and portable EEG headsets. Designed as simple headbands or helmets, these devices can record brain activity and wirelessly transmit the readings to a smartphone or a computer. Continuous monitoring of brain activity can provide information about the quality of sleep. Additionally, it can warn users and caregivers of impending seizures and give insights into mood swings, cognition and emotional states of the user. Given the growing awareness of mental health, brain activity monitors Winter 2015 Volume 7 Issue 4


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Technology can play an important role in the years to come. Wearable EEG headsets are the foundation on which the promising and much-researched field of brain-computer interfaces rests. eLens Around 2013, just as critics were panning the Google Glass for being too “gimmicky”, news tricked out that Google was developing a far more cutting-edge wearable eye device - a smart contact lens or an electronic lens. The lens was lined with electronic sensors that measured the level of glucose in the wearer’s tears and transmitted it to a receiver. In rapid succession, companies such as Sensimed and Johnson and Johnson and a host of university research groups revealed that they too were working on electronic lenses. Electronic contact lenses are in the prototype stage, and make take a few years to be commercialised for clinical applications, but their potential is undeniable. From monitoring glucose levels without drawing blood, measuring the intra-ocular pressure, performing routine eye tests and augmenting vision, their applications are myriad, based only on the sensors that form the lens architecture. Smart Fabrics One of the disappointments with the current generation of wearable devices is that they are bulky, conspicuous and not always fashionable. The most intuitive solution to these concerns is therefore, to completely integrate the electronics and sensing capabilities into the wearer’s fabric. Smart fabrics are a class of textiles that can, among other functions, communicate, monitor, transform and even conduct energy. The variety of players who are investing in and actively researching the smart fabrics landscape is staggering and speaks to the potential of the technology. Sportswear experts such as Nike and Adidas, sensor companies such as BeBop Sensors and clothing companies such as AiQ Smart Clothing, Levis and many more along the technology chain are working on intelligent, interactive and functional fabrics. eTattoo Perhaps the ultimate form of technology integration would be to have the wearable devices embedded on to the skin of the user – sort of an electronic tattoo. Firmly in the realm of academic research, these “devices” are actually stretchable skinwww.ipimedia.com

Chapter Title like material with electronic Okcircuits and sensors printed on them. These “tattoos” can sense electromyographic signals, measure blood toxicity levels, pick up the precise electrical data from the heart or brain, accurately measure core body temperature and so on. Aided in no small part by the rapid innovations in flexible electronics and ultrathin sensor systems, these skin-hugging wearables may be the final destination that began with an 80-pound wearable device.

Figure 3: The roadmap of diagnostic healthwear products Therapeutics Drug Pumps There are certain classes of drugs, monoclonal antibodies, immunoglobulins and biologics, which cannot be administered orally due to pharmacokinetic complications. They have to be injected subcutaneously or intravenously. Wearable devices that are designed as body-worn cartridges or reservoirs of essential drugs can administer the drugs in an effective and automated manner. The devices can further be programmed to deliver specific quantities at specific times, so that there are no issues of over-dosage or forgetfulness by the patient or caregiver. Such devices would greatly benefit patients on chronic medications, such as insulin, and patients with a propensity to forget medications, ensuring compliance to prescribed medication. Companies such as Amgen MedImmune and Unilife have wearable drug injectors. Wearable injectors are in the interest of the multibillion dollar biologics market, and hence, they are an area to watch out for in the near future. Neurostimulation Electrical stimulation of the brain and the peripheral nervous system has been a clinical practice for several decades now.

This involves the use of wired electrodes supplying mild electrical impulses to manage pain, restore hearing, manage and control seizures and tremors, and so on. With the advent of wearables, neurostimulation can be made available for over-the-counter use, outside the clinical setting. Belgium-based Cefaly Technology has developed portable headbands that supply micro-impulses that stimulate the trigeminal nerve, as a way of compensating for electrical activity that leads to migraine headaches. Massachusetts-based NeuroMetrix has two wearable products that are designed to provide non-invasive neurostimulation to provide relief from chronic pain caused by diabetes, sciatica, fibromyalgia, and other conditions. Beyond Quantified Self Quantified self is the practice of recording personal activities such as eating, physical exercise, emotional state and so on, on to a digital platform. Wearable devices have been the foremost enabler of this movement. However, as we have seen, the utility of wearable devices has expanded from this, to more professional applications such as diagnostics and monitoring. However, even the applications mentioned in this article do not accurately capture the potential of wearable devices in healthcare. Every aspect of healthcare – surgery, medical imaging, wound care, mental health, rehabilitation, medication compliance, clinical diagnostics, health informatics, and population health management – stands to benefit from wearable devices. It would not be an exaggeration to view healthwear as the single biggest technology enabler of the concept of personalised medicine, or providing personalised health service to patients.

Bhargav Rajan is a senior research analyst working with TechVision, the technology consulting arm of Frost & Sullivan. He tracks innovations in medical devices, medical imaging, clinical diagnostics and healthcare practices. He can be reached at bhargavr@frost.com. INTERNATIONAL PHARMACEUTICAL INDUSTRY 52


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 53


Technology Leveraging Cloud-based EDC for Data Acquisition and Sharing A primary challenge faced by clinical trial professionals around the world is the means by which data is collected and logged for their studies. There are three principle ways of recording this data: pen and paper, traditional computerised data-capturing applications, and more recently, cloud-based electronic data capture (EDC). Pen and Paper Though pen and paper seem inexpensive on the surface, it is prone to unnecessary issues based in human error, resulting in significant hidden costs including double data entry, unnecessary data cleaning costs, and time-consuming data analysis and reporting, and ultimately this is the most expensive form of data capture for clinical trials. In one case, Novartis reported spending $17 million1 simply on the cost of printing CRFs on NCR paper for 400 clinical trials. This is money that small organisations simply cannot afford to waste. Moreover, the cost of the paper is trivial compared to the costs of addressing the additional errors introduced using paper capture methods. There are also numerous issues in getting the collected hard-copy information to other parties for auditing and submission purposes. Scanning, paper handling and shipping, and double data entry in Excel all end up taking valuable time that could be allotted to more meaningful tasks pertinent to the clinical trial. While it is widely understood that this method is less effective as compared to EDC options, transition away from pen and paper has been cripplingly slow in many areas of the clinical trial, even here in the US. The time, effort and expense of migrating from paper to EDC have been strong barriers for many companies, but in the long term, staying with paper capture severely hinders productivity for the organisation executing the clinical trial. Traditional EDC Traditional EDC applications drastically reduce the probability of human error; however, these applications also 54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

traditionally require a great deal of customised programing to meet the specific needs of a particular trial, which can add substantial startup costs, cutting into funds that could be better spent carrying out the clinical trial itself. The use of EDC applications does improve the quality and aggregation of acquired data, as well as providing a faster means of entering the data (think typing versus writing by hand). EDC systems provide real-time data edits against rules defined for the type of data being collected, preventing most data entry mistakes. Sophisticated systems also provide field comparison edits, even across multiple forms, alerting the user to potential data issues before they are saved. Furthermore, a computerintegrated platform makes information recall more effective via a quick, searchable database. This represents a vast improvement over manually searching hand-written materials time after time for needed information along the way. However, even with all of the benefits that accompany traditional EDC solutions, there are still a number of drawbacks. To start, they can be very expensive. Traditionally, EDC systems have been available for hundreds of thousands of dollars in licence fees, followed by the costs associated with professional services for the software build out and setup, as well as IT support. Furthermore, it is necessary to train and certify each of the professionals that will be using the software â&#x20AC;&#x201C; more time and money expended in the prepping phase. Traditional EDCs can be ineffective at getting the necessary information to external parties that need to evaluate and audit the findings. Consequently, information has to be exported, transformed and loaded into a common format before being shared with other groups or systems. Cloud-based EDC Cloud-based EDC is the final option. This method takes advantage of the shortterm cost efficacy of pen and paper and the pinpointed accuracy of traditional

EDC and combines them with numerous other added benefits that translate to lower costs and significant time-savings. One of the core benefits of a cloud-based EDC lies in its capability to mitigate human error, while also diminishing the need for IT professionals as compared to traditional EDC systems. Additionally, cloud systems are more scalable and accessible to necessary parties from any computer, any time. Certain cloudbased EDC systems can make providing a 21 CRF part 11 validated environment simple, cost-effective and instantaneous. Complying with regulatory bodies, such as the FDA, with regard to the hardware and software environment has never been easier. Finally, another added benefit of cloud-based EDC is the ease of operation for the end user. Every step is conducted in an online environment. They can design the forms, which in some cases can be enabled in a do-it-yourself, cloud-based application. With this type of system, the end user would sign up for a service and begin creating forms with a few clicks of a mouse, which would have previously taken several weeks to accomplish when creating the forms from scratch. The work is performed by clinical trial professionals, not programmers, reducing review time and acceptance testing cycles. A 2011 study2 entitled Comparison of Electronic Data Capture (EDC) with the Standard Data Capture Method for Clinical Trial Data found that, â&#x20AC;&#x153;given the considerable reduction in the time from data collection to database lock, EDC holds the promise to reduce researchassociated costs.â&#x20AC;? The natural choice should be cloudbased EDC, however only 20 per cent3 of worldwide clinical trials are using this method. With other computer-based options, the user must download any information to be transferred and send it to the various receiving parties. In the cloud, receiving parties and authorised third-party applications can access results in real time without time-consuming and risky transfers of data.

Winter 2015 Volume 7 Issue 4


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Technology Summary The clear choice of optimal clinical trial productivity is cloud-based EDC. This method has toppled the barriers by addressing regulatory issues as well as the need for system validation. Programmers and IT staff are being relegated to other purposes and the tech sphere, medical tech included, is quickly heading straight for the cloud.

Paper-based and traditional EDC methods are labour-intensive and generally involve numerous people putting in time, adding the likelihood of even more human error. The Importance of Real-time Data Acquisition With real-time data acquisition, the user can make much faster informed decisions. They know virtually up to the minute if their trial is safe and not delivering adverse effects. There are few cost savings more substantial than stopping a trial earlier because it is being shown to be failing. With pen and paper, the process of waiting for a site to send data can take weeks or even months to know a clinical trial is deemed a failure, potentially putting test subjects in unnecessary danger. In real time, the user knows whether adverse effects are taking place and whether action needs to be taken to change the course of the study or completely drop the study altogether. Ease of FDA and Auditing Submission Auditing and submitting a study have become infinitely easier with cloud-based systems on the market, because the programs can track exactly what actions have been taken, when and by whom, thanks to timestamps and traceable 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

queries. This also ensures that the data has gone through the proper processes. With paper, it is difficult to prove, but with EDC, one can look at specific data points to ensure the data is correct and unaltered. This leaves a precise, accurate real-time audit trail that would be nearly impossible to achieve through any other means. Furthermore, EDC can integrate with algorithms that detect site frauds â&#x20AC;&#x201C; e.g. fake patient enrolments rates, etc. In doing this, risk and error are dramatically reduced. Most cloud-based EDC systems can allow only certain individuals with the necessary credentials to make edits to the study. This helps with compliance, eventually easing the process of FDA and other third-party approval in later steps. Why Resistance? Change can be a challenge for many organisations. Adopting newer, more efficient technologies often gives medical professionals the false assumption that the sometimes steep learning curve equates to an unnecessary waste of time, when, in fact, the opposite is true. For the purposes of EDC, the ability to adopt and adapt to the change will immediately give rise to more saved time and money as compared to previous, outdated methods.

References 1. Keet, G. Data Values. International Clinical Trials. (Sept. 2015). ht t p ://www.sa med a nl t d. c o m/ magazine/13/issue/238/ article/4157 2. Walther, B., Hossin, S., Townend, J. et al. Comparison of Electronic Data Capture (EDC) with the Standard Data Capture Method for Clinical Trial Data. (Sep. 23, 2011,). PLOS. http://journals.plos.org/plosone/ article?id=10.1371/journal. pone.0025348 3. Miseta, E. Clinical Leader Interviews Clinovo on Trends, Benefits and Strategies in the Adoption of Electronic Data Capture (EDC) Systems. (2014, Dec. 10). http:// www.clinovo.com/news/clinicalleader-interviews-clinovo-trendsbenefits-and-strategies-adoptionelectronic-data

Glenn Keet has been in healthcare IT for three decades and is the Chief Executive Officer of Clinovo, a cloud-based SaaS software vendor focusing on electronic data capture (EDC) solutions for the clinical trial industry. Prior to Clinovo, Glenn was the head of business development for Optum's Health Care Cloud, focusing on developing the ecosystem of providers, developers and consumers. Mr Keet became part of Optum via the acquisition of Axolotl Corp., where he was President. He has previously held the role of VP of Business Development, and has also served as VP of Professional Services. Glenn Keet graduated from Lehigh University in 1986 with a BS in Mechanical Engineering and BA in Applied Sciences. Email: glenn.keet@clinovo.com Winter 2015 Volume 7 Issue 4


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Logistics and Supply Chain

Effecting Change in the R&D Supply Chain to Deliver Value in the Industry As we enter a new phase of growth by 2020, some key decisions need to be taken to ensure that the pharmaceutical industry remains stable and continues to take advantage of growth and profit opportunities offered to it in the coming years. Whilst pharma development in the bid to advance human health is seen as one of the most research-intensive activities cross-industries, the pace of change is slow and the timely adoption of new technologies and ideas is potentially one of its biggest opportunities to counteract some of the challenges it faces. It is not all doom and gloom, as the industry is set to reach levels of approximately $1.6trillion by 2020. We know this is driven by the increased consumer demand as the global population grows, ages increase and the western world suffers from the health effects of a more sedentary lifestyle. However, one of the challenges that cannot be ignored is the commercial environment pharma now operates in. Companies are experiencing harsher conditions as healthcare payers impose new constraints on providers and are questioning and scrutinising the value of medicines. The fact is that key stakeholders are looking for better therapies from a clinical and economic perspective. However, we have seen stagnation in the output of pharma over the past 8-10 years, and it has not really adapted its processes or made decisions to truly reshape product development processes. So how can it remain viable and retain the interest of its investors with acceptable levels of return? In order to ensure shareholder value during the foreseen growth, the R&D process must make some changes. These changes need to be addressed, not only in manufacturing but also within the distribution models. It is quite simple: new drug pipelines must be fuelled to drive growth strategies, but in an effort to deliver on this plan the R&D costs must come down! The current levels of spend and waste in the process cannot be sustained as the ratio of research to successful drug compounds on the market reduces.

58 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Even with a successful pipeline of development, the ever-growing question is how you can adopt changes to drive efficiencies whilst maintaining quality. The continuous “elephant in the room”, between the quality owners of large pharma and the business stakeholders, is the delicate balancing of cost reduction and product integrity. Good-quality global data will reduce risk, reduce time to market and increase the likelihood of a compound being approved and successfully patented and marketed. However, that quality security can sometimes come at a price that is too high, and this is now coming more and more into question. The answer is not simple and if we take the ever-increasing regulatory challenges surrounding new drug development and finished pharmaceutical distribution it becomes more complex. Logistics is becoming more and more of a concern within R&D as it becomes one of the biggest areas driving budget issues. New GDP regulations particularly affecting Europe today have delivered another conundrum to the industry, as now more and more medicines require investment in temperature-controlled supply chain solutions. So one obvious answer is to innovate within the overall supply chain Innovations within Temperaturecontrolled Packaging: There is a significant growth in the developments of innovative solutions across passive and active cold chain solution providers. Many logistics partners recommend myriad solutions depending on the geographical scope, the required temperature bandwidth and of course the value of the drug being distributed. It is perhaps this “choice” of solution, where cost is the main decision driver, which is delaying the move to a standardised model to maintain the integrity of all drugs requiring control at a sustainable price. TNT has looked at this issue of “choice” and finds itself assessing whether there is in fact a need for a more straightforward approach to secure quality but at the

right price. Low Cost for 24-48-hour Transport Polystyrene and Polyurethane Whilst a viable option at times, as the growth in biologics continues and as companies want to outsource non-core activities, this solution is becoming a dinosaur. Having pharma companies or even their contracted third parties having to invest in polystyrene packaging storage and conditioning, managing various SOPs for temperature bandwidths and seasonal changeovers is by no means the ideal supply chain model. It is open to human error and is an unstable solution for many temperature bandwidths, product types and shipping lanes you may have to service. Whilst it still has its place in the supply chain, this is purely due to the cost barrier of other solutions. Furthermore, this is not a sustainable solution in a world where the environmental knock-on needs to play a role. This is high on the agenda of most global companies, as well as a key topic for governmental healthcare owners as public spending continues to be in focus. Phase Change Shippers – Expensive but Stable Solutions for Multiple Temperature Bandwidths PCMs have become a much more favoured solution over the past number of years due to the effectiveness of the insulation technology. The stability and reliability, even for intercontinental movements, was welcomed within the industry. The ability for the technology to store and release energy based on the external temperatures, and the limits to changeover scenarios, mean that the simplified procedures around the fulfilment and conditioning position this solution as a more viable and longterm option than its older cousin, the polyurethane with water gel-packs. Using PCM with vacuum insulation panels is the crème de la crème of temperature-controlled packaging options, as VIP insulates 10 times better Winter 2015 Volume 7 Issue 4


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Logistics and Supply Chain

than conventional materials. This is also space-efficient and therefore allows for larger payload capacities whilst still delivering a lighter technology. However, the issue here is that this is not a viable alternative for many distribution lanes and for many products due to the cost issue. This is an expensive option which many companies cannot justify for their less valuable drugs and certainly cannot justify for flows within Europe or within other regions. Whilst it is a lighter technology than polyurethane and therefore the freight costs are lower, it is still seen as more expensive as the real value drivers are still not accepted by the industry. These value drivers can be worked out even in Euros if the industry is willing to take time to consider the benefit overall in driving out direct and indirect costs. This solution removes issues with excursions in temperature therefore removing quality investigation costs, product deletions and wastage of drug along with any reshipping costs. If this solution became standard and fulfilment of the service no longer needed to be in60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

house, companies would save significant costs on direct labour and warehousing of empty boxes. The packaging industry has looked to address this and many of the PCM providers and specialist logistics companies have now adopted a fulfilment and rental option. The packaging can be cleaned and reused, offering pharma some savings, although one suspects overall offering the providers higher returns.

servicing more globalised supply chains. As with all advances, less stable biologics will continue to increase in availability and as it does, cold chain technology will need to keep up. Making PCM the new standard is the first step in this process.

Notwithstanding this development, there is still a significant barrier to standardising this as the “hoover” or “Nespresso” of the industry, as it is missing a stable supply chain process at the receiver location as well as a fundamental overhaul of the commercial model surrounding one-way rental.

Firstly, there is a need for packaging suppliers to continue to add size options to allow for smaller, more efficient drug volume deliveries, or indeed as the distribution model changes, move heavier bulk and make this an option not only for high-value drugs and R&D product but also commercial drugs.

What might the overall model look like if a solution could be standardised delivering quality and cost savings? Ultimately, right now the technology is likely to be PCM with vacuum insulation panels, as the best-in-class offering on the market. The control that this technology offers is what is needed to meet the ever-increasing challenge around temperature stability as well as

Even those specialist logistics carriers already offering PCM rental solutions cannot offer a sustainable model due to their inability to truly control the supply chain, as they do not own an end-to-end network. Their solutions are therefore still costly and only used for very specific product lines or for specific longhaul distribution lanes. Therefore the commercial model must be looked at as

However, to break down the barrier, it will require innovation not only in the cold chain solution, but also in the overall supply chain concept.

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a key step change. Distribution network providers seem to be best placed to drive key change and support a change in the commercial model. We saw in the late 1990s that the integrators entered the clinical market by offering network-based services around the fulfilment of dry ice shippers and return of biological samples to labs. This changed the industry and drove cost out of the supply chain over a 2-3 year period. Today, samples are moved within these networks in large volumes and with adopted processes to secure quality and performance. The quality is thus maintained but the prices are adjusted to more sustainable levels for the industry. Using these networks, which today deliver and return samples from similar healthcare locations, to support a reusable PCM network service, has to be considered as a justifiable alternative and an obvious next step in supply chain reform for R&D. This move in the industry will allow large, mid-size and small pharma and biotech to focus on quality of drug development and production, and completely outsource activities around packaging fulfilment, sourcing, www.ipimedia.com

temperature management and returns management. It removes waste in the supply chain by ensuring product integrity, and with the adoption of reusable packaging as the standard method of this type of temperature-controlled distribution, wastage of packaging material becomes a distant memory and a small positive development in healthcare budget reform. With a standard temperature-controlled shipping solution such as PCM, quality management can focus on core activities around drug development processes and data rather than on inspecting and reviewing multiple logistics solutions and excursion issues. Finally, it will drive out significant cost in the industry due to both the smaller transportation footprint and the full outsourcing of packaging inventory management. Freeing up much-needed warehouse space for core activities and to support capacity efficiencies must be seen as another positive and valuable effect of such a service. At TNT we believe that using existing distribution capabilities to add on a reusable PCM network service for pharma is a bold next step. The cost

viability of the service opens up the market and allows for the use of best-inclass technology, supported by the best of networks to deliver quality to the industry. The challenge will be in convincing the industry to look at the true value created and also change the processes within investigator sites. But the journey has started and perhaps we will look back in years to come and wonder how it took so long to get here. Cathy O'Brien is Industry Director Healthcare at TNT. Working within healthcare since 2003 in the clinical research sector and pharma industry, Cathy was active in positioning TNT's Clinical Express service as one of the first integrator services for global lab's distribution needs within the R&D supply chain. Today, Cathy is working with global companies identifying further developments TNT can bring to market to help drive positive change in distribution models specifically around temperature controlled distribution. Currently, TNT are working on the first reusable PCM network service, which is being launched at IQPC and is currently being implemented for one of the global players in clinical trial supplies. Cathy will talk more about this service during the conference.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 62


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Logistics and Supply Chain How Do Kelvin Hours Help with Assessing the “Thermal Challenge” to Create a Standard Version of Performance in Temperature-Controlled Packaging? With the ever-evolving developments in the biopharmaceutical industry, there has never been a greater need for assured reliability when it comes to the transportation of pharmaceutical payloads, and the guaranteed robustness of temperature-controlled packaging is proving ever more vital. The continuing growth of, and increasing move to, the implementation of large-molecule medicines naturally calls for greater reassurance of temperaturecontrolled packaging reliability, and the life sciences industry, as well as the packaging industry, would benefit from an all-encompassing, standardised measure of performance when it comes to temperature-controlled systems adopted to transport often high-value assets. There needs to be a more universal approach for a standardised measure of performance. Currently many vendors demonstrate the performance of temperature-controlled packaging by showing an example of performance, most often carried out with an ambient profile that shows how the temperaturecontrolled packaging will respond to a particular simulated shipment route. However, this method has its drawbacks. Currently the go-to industry standard for performance regularity is mainly via the International Safe Transit Association (ISTA) which represents a collaboration of manufacturers, packaging suppliers, testing laboratories and carriers working together to try and ensure responsible packaging. ISTA’s initial focus was on the mechanical testing sequences, used to prove the robustness of over-packaging for everyday products such as ovens and washing machines. More recently, ISTA developed thermal test procedures for insulated packaging and one of the profiles widely adopted in standard qualification, ISTA 7D, and more recently ISTA 7E is seen by some as an industry standard. Previously, organisations like ISTA have tried to create a standard profile that they say captures in essence the worst-case 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

scenario of what could happen in any given transport situation; however, what that ends up doing is further widening the possibilities of creating packaging that might not always be fit for purpose. The problem is companies might then end up with packaging that is overdesigned for the actual challenge of what the customer actually wants to use it for. With the emergence of the new generation of biopharmaceutical medicinal products, coupled with the emergence of new, remote and logistically challenging markets, the issue of being able to deploy reliable, high-performing shipping systems is paramount. This rapid rise in biopharmaceuticals, generating global revenues of $163 billion, equates to somewhere in the region of 20 per cent of the pharma market, making it by far the fastest growing part of the industry. Having to transport pharmaceutical products via challenging shipping routes, further facing the likelihood of being exposed to greater temperature stresses or unplanned hold periods (such as customs clearance), makes the introduction of a new industry-wide standard performance measurement something that should be at the forefront for decision-makers. There needs to be a collaborative call for a new industry standardised measurement system that is easy to implement and can be adopted worldwide within the sector. There is an even greater urgency to address the situation, especially with the new-generation growth of biopharmaceutical products that are highly temperature-sensitive and must be stored and transported within the specified temperature range. Why not implement a thermal stress score, a standardised procedure, calculated by stress-testing with universal acceptance? For greater reliability, the industry is calling out for a standardised method such as Kelvin Hours (KH), which could be universally adopted and recognised as a new industry standard for the global temperature-controlled packaging industry. It brings to the fore the shipping

system’s performance capabilities. The benefits of adopting Kelvin Hours as a standard performance measure is that it doesn’t tie itself to a particular ambient test profile. Rather it is centred on what the specific selected shipping system is capable of doing and therefore you can say against ambient profile X, Y or Z, that particular shipping system will perform for a specific number of hours for those different challenges, so it makes it less subjective and more of a measured approach. With this proposed KH principle you could collate your Kelvin Hours via a simple equation - average thermal stress (K) x control duration (hrs) = K.Hrs. Adopting this calculated stress testing, using vendor qualification data, enables easy fit-for-purpose evaluations. Kelvin Hours could easily be adopted as a tool to select the most appropriate level of performance of packaging, and this can be used across the board with a broad range of performance points for the newer-style phase change material (PCM) systems, which is where the Kelvin Hours measure works particularly well. A company using temperaturecontrolled packaging can assess shipping lane data using Kelvin Hours and select a packaging system which satisfies the minimum performance requirement. Essentially what you have done is you have matched the shipping system to the challenges it is going to face, as opposed to having one shipper option and then finding out that you’ve used only half of its potential performance in your particular shipping lane. The need for a new, standardised measure of performance was not so pronounced previously when it came to the shipping of the small molecule pharmaceutical products, which were potentially less temperature-sensitive. The new generation of large-molecule biopharmaceutical products, which are being developed for relatively rare conditions, such as the various cancer treatments, rely on high-performance packaging systems to avoid their complex, Winter 2015 Volume 7 Issue 4


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Logistics and Supply Chain fragile structures being destroyed. These more sophisticated pharmaceutical medicines being developed to help people overcome, or live with, certain diseases, are a vital lifeline for patients who are reliant on them, which is why it is paramount these drugs arrive intact and perform properly. For pharmaceutical companies developing products to treat such conditions, reliability in shipper performance is equally critical within the clinical trials industry, where the materials that are being shipped are designed to be tested on “in-human” Phase I clinical trials. It is at that fragile stage where pharma companies do not have any stability data for the medicines being trialled, so they cannot afford to let them go outside of a temperature window, and what is required is a more robust shipping system. These systems are crucial, not just for the safe transportation of the medicines being trialled, but also when it comes to shipping the comparator drugs. When it comes to clinical trials, and the development of a new pharma product, it has to be trialled against drugs similar in the market most usually being sold and manufactured by a competitor, so pharma companies have to buy these products at market value, which is often extremely expensive. Coupled with the fact these companies have no access to any stability data, they have to ship the payload within a strict temperature range to know it is going to be as effective as it should be, and therefore prove its worth against its competitors. The cost implications related to comparator drugs testing can be extremely high and can constitute up to half of the clinical trial’s total budget allocation. Therefore if that comparator drug goes to waste because the packaging selected for the transportation fails to meet the high standards necessary, and is substandard as it has no well-defined performance measure, the costs can be unbelievably high with, for example, a 10ml vial costing tens of thousands of euros for a single dose. Acting as one of the drivers for the introduction of an industry-wide standardised measure of performance www.ipimedia.com

such as the Kelvin Hours, is the development of these large-molecule products. This is an example of where a standardised and globally adopted performance measure such as Kelvin Hours will become increasingly relevant in the future, when people cannot take the chance on something not working. They need that reassurance that the packaging has been specified well and it will deliver for them.

This could revolutionise the packaging industry, and rather than selecting a shipper for a particular duration it would be a case of selecting the appropriate shipper with the relevant Kelvin Hours score (KHS) attached to it. For further ease of use, a customer could describe the challenges of their specific shipping lane and receive a score that would help them choose the best packaging product for their needs.

The growth of gene therapies, and manipulating proteins in research into certain conditions like cystic fibrosis, are also proving to be strong drivers in a suggested shake-up of the current systems.

This would also have great costeffective repercussions as it would help prevent picking a product that has been over-engineered for the challenge or job it is actually required for.

The introduction of a more standardised measurement system would have industry-wide relevance. Especially so in the clinical trials market, where large, global pharmaceutical companies are focusing their research and development increasingly in the high-value niche application products. If this new Kelvin Hours approach was adopted across the industry, there would be different levels/points of performance so you end up with different Kelvin Hours scores, which in turn would make it easier to match that with the appropriate shipping system required. Technically speaking, the industry could use a Kelvin Hours scoring system which appraises performance at the actual stage of preparing the packaging.

The wider this suggested system was adopted in the future, the easier it would be to compare one set of products against another. It means you can really compare ‘apples with apples’ whereas at the moment, because there are all these very different ambient profiles being used in the industry, performance – or the appreciation or perception of performance – can be skewed. The KHP works extremely well with newer PCM systems and where it probably needs a little more development is when trying to use that same performance measure for the older technology, water-based systems. In a bid to make the KHP measure a bit more robust, it would require trying to build in an additional aspect that takes into account the inefficiencies of the old technology systems to make it truly allencompassing. INTERNATIONAL PHARMACEUTICAL INDUSTRY 66


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Logistics and Supply Chain Therefore a new, industry-wide performance measurement would benefit not just packaging suppliers but also those who have to specify the packaging. It could be a performance measure which, as long as they have visibility of the temperature challenges they expect to see in a shipping lane, they can use it to create this stress score, this KHS, and then simply go into the marketplace requiring a box capable of a certain KHS. In theory, whichever suppliers have packaging tested to the standardised KHS should have the shipper most appropriate for the job.

Most of the new product development we are seeing in the temperaturecontrolled packaging industry incorporates the newer, more advanced materials, but there is still a significant proportion of the market using the older, water-based systems purely due to the cost restraints. There are packaging suppliers who might have their own set of ambient profiles they qualify their packaging against. What we also see is that some customers will request packaging suppliers to qualify against their own

ambient profiles, which they see as being indicative of what they would expect during distribution of their product from one location to another. The issue is every single customer will have a different view on what that looks like. So you have not simply different vendor profiles, but also different customer profiles and ideally, because the whole qualification process is extremely time-consuming, it would be beneficial to make the process simple and quick.

Over the last five years there has been a notable rise in the temperature monitoring of pharmaceutical products. Depending on which region a product is being shipped to â&#x20AC;&#x201C; for example emerging markets such as the Middle East â&#x20AC;&#x201C; when that package reaches customs control, if they see it is a temperature-sensitive package with a data logger inside it, they may have to open the package to inspect the data logger and make sure it is still within temperature. If it has not been maintained at the correct temperature up to that point, the package could be sent back. The industry needs change, especially the pharma industry, for these ever more sophisticated medicines to be effective. If they are protein-based, the proteins can denature so that medicine, which is potentially going to help to cure a patient or help relieve their symptoms, could, if exposed to too high or cold temperatures for too long, lose efficacy.

Richard Wood, Design Manager at Peli BioThermal, has worked in various design and manufacture engineering functions during his career. He has been part of the company since 2005 and has been involved in hundreds of cold chain packaging projects. Richardâ&#x20AC;&#x2122;s current role is focused on standardising development, qualification and manufacturing practices across the Peli BioThermal network, supporting its global customer base and leading the new product development programme. Email: richard.wood@peli.com 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Winter 2015 Volume 7 Issue 4


Advertorial Temperature-safe Airfreight Packaging for Euro Pallets Minimising the Risk for a Full Euro Pallet of your Thermo Labile Products at a Reasonable Price Do you want to transport pallets with valuable pharmaceutical products at a stable temperature? Reliably and without power supply from outside? Many products that are shipped for pharma companies, importers and wholesalers can quickly be damaged if the correct temperature is not ensured during the entire transport. Substantial values are at stake. If the products are affected by warmth or freezing cold, the quality of the product decreases, gets ineffective or even becomes dangerous when used. In the last two years, there has been an increasing focus on temperature-safe transport, since the European Guidelines on Good Distribution Practice of Medicinal Products for Human Use (GDP) read: “The required storage conditions for medicinal products should be maintained during transportation within the defined limits as described by the manufacturers or on the outer packaging.” While cold chain 2°C to 8°C is well known in the logistics community, controlled room temperature (CRT) covers a large proportion of pharmaceutical products. The most common temperature ranges shown on pharmaceuticals are 2°C to 8°C, 15°C to 25°C and 2°C to 25°C. There is still a need for more safety, but there are cost restrictions. While thermo covers are not able to hold the temperature long enough in this range, active cooling systems are expensive; well-insulated packaging large enough for the pallet is the solution. How to Find a System that Works The logistics manager needs to find a suitable way to transport valuable goods from A to B. To find the right cost-effective and temperature-safe packaging, it is necessary to analyse the risks involved. There are a number of known problems in temperature-safe transport. If there are many companies involved and your product changes hands during transport, the task is complex and riskier. A huge problem is temperature www.ipimedia.com

For a small number of elements this process takes 48 hours. Once the elements are solid you can start the packaging. First, the pallet of goods must be placed on the bottom part, and the delta T Fluid elements must be placed around the goods. Now close the pallet shipper with its four side panels. Finally put the Accu lid on top and, after wrapping with stretch foil, the system is ready to go. The whole procedure takes no more than 15 minutes. Now the freight can be transported from door to door, without the risk of leaving the pallet in an unprotected environment.

excursions, when the freight is outside protected environments. While the pallet is on a ramp waiting for loading or on the tarmac of an airport, temperatures can reach up to 60°C in Middle East countries, or fall far beyond freezing level in Scandinavian airports. Protecting your pallet of products from the beginning to the end will provide a significant improvement to avoid the described temperature excursions. delta T GmbH offers an insulated EPS Pallet Shipper with passive temperaturestabilising delta T fluid elements, that meets this criterion. The temperaturestabilising elements contain delta T fluid and absorb heat by their crystalline structure. The temperature inside the EPS Pallet Shipper stays in the selected range until the melting process is over.

How Long Will the Temperature Stay Constant? As long as desired. 120 hours is the standard run time, but the duration depends on the combination of the insulation and the number of delta T fluid elements, as well as the outer temperature. For one-stop airfreight routes, a 72-hour system without vacuum panel insulation is sufficient. By doubling the amount of fluid elements, the temperature will hold twice as long. Due to the construction of the lid-system, a patent of delta T GmbH, transport time could also be easily increased by changing cooling elements in the lid cavities during transport, or when encountering unexpected delays. Contact sales@deltaT.de delta T GmbH Industriestrasse 13 35463 Fernwald Germany www.deltaT.info

Using the EPS Pallet Shipper 1200L for a 2°C to 8°C Airfreight Transport First the delta T fluid elements must be precooled for a certain period of time until the fluid is solid. This will occur when the temperature is at least 2 degrees below the fluid´s melting point. The pre-cooling time depends on the number of fluid elements. INTERNATIONAL PHARMACEUTICAL INDUSTRY 69


Logistics and Supply Chain

An Interview with va-Q-Tec AG A Leader in Thermal Packaging Products By Orsolya Balogh, Managing Editor at Pharma Publications 1. Tell us a little bit about va-Q-tec. What are your key offerings to the industry? va-Q-tec is a producer of vacuum insulation panels (VIPs) and phase change material (PCM) that serves the pharmaceutical packaging, domestic appliance, automotive and buildings industries. Within the pharmaceutical sector, va-Q-tec has vertically integrated its technology to produce a range of high-performance thermal packaging. The product range comprises both single and multiple use systems for clinical trials and the volume distribution of finished pharmaceuticals. Our clinical trials and direct-to-patient boxes are designed to deliver the highest performance at the lowest cost and vaQ-tec is able to achieve this by holding all aspects of development, qualification and production in-house. Most recently, the clinical offering has been further extended to provide the shipper with a pay-per-use option that is provided hand-in-hand with our logistics partners. A shipper-focused service that simplifies operations while delivering return logistics and qualified fulfilment services that has had a successful launch this year and will be significantly expanded in 2016. For the volume distribution of pharmaceuticals, va-Q-tec developed the va-Q-tainer single and multiple pallet shippers. Understanding that pharmaceutical shippers do not want the complexity of reverse logistics, vaQ-tec established the va-Q-tec Global Rental Service in 2011. Since its launch, the Load & Go™ service has expanded globally with a strong partner network of airlines, freight forwarders, integrators and specialist couriers. Today the fleet of just over 1000 containers is delivered from 21 network stations and is available for one-way rental trips to over 500 destinations worldwide. The network will be further developed in 2016 and vaQ-tec will continue to expand its fleet at a rate of 40 containers per month from a new, dedicated production facility in Germany that opened this year. 70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

2. How do you see the temperaturecontrolled logistics industry moving forward? What are the key changes / (challenges) you see within the industry? As a technology-based company with firm foundations in the Physics Department of Wuerzburg University, va-Q-tec has embraced the evolving technical requirements of pharmaceutical shippers. While our main activities are in the established temperature ranges of -25 to -15 °C, +2 to +8 °C and +15 to +25 °C, our physicists and product engineers have been particularly busy most recently with the evolving requirements of the bio pharma segment. This has resulted in our standard container service being supplemented with qualified solutions for pallet shipping at <-60 °C, -50 to -40 °C and -40 to -30 °C. As with all our Load & Go™ products, these rental solutions are qualified with at least 120 hours’ performance. A remarkable achievement given that there is over 80 °C difference between the ambient environment and the shipment temperature. With high growth within the bio pharma segment and the volume of API shipments increasing month on month, our challenge today is to further expand the global availability of these solutions while keeping abreast of further developments in shipper requirements. 3. The revised EU GDP guidelines has been extended to cover CRT products. What challenges has this created for your company & the industry? Without doubt the revised EU GDP guidelines has been the defining feature of our year. The revision precipitated a huge increase in demand that has touched all corners of our business. Container production was doubled with the opening of a new manufacturing facility that also has the capacity for further increases in production rate. This enabled us to more than double the size of our container fleet during the course of the year and has been key to securing container availability for our shippers. In our Load & Go™ service, the containers are delivered pre-conditioned and ready

to use. As such, we have had to work hard with our network station providers to increase the capacity of our qualified pre-conditioning facilities, training more operators and introducing new technologies to improve our operational efficiency. With turnover increasing more than 300% this year we have also had the pleasure of welcoming many new faces to the va-Q-tec family, with most joining our Customer Services and Operations Departments. They have brought with them a new energy and enthusiasm as well as valuable experience and new perspectives. The industry has been challenged with available capacity this year as a result of the revised guidelines, but from our vantage point it has stepped up and delivered just as we have done and is finishing the year stronger and more able to meet the next challenge as a result. 4. What process / products do you have in place to mitigate risk? At the heart of every va-Q-tec thermal packaging product is the company’s vacuum insulation and phase change material. va-Q-tec’s vacuum insulation panels are unique in that every panel has an embedded, patented device that enables the strength of the vacuum to be quickly and efficiently measured. Within our rental services, the pressure within every vacuum insulation panel is measured as part of the release procedure to verify that the containers’ insulation conforms to that with which it was qualified by the shipper. Within our network stations, the pre-conditioning of the phase change material is monitored and logged, with calibrated devices, at the shipset level to guarantee that it is prepared perfectly and every aspect of the containers’ condition is rigorously inspected by our trained operators. These measures ensure that the released containers conform to qualification every time and the data from all of these checks and measures Winter 2015 Volume 7 Issue 4


Your Expert

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PDP is a truly global specialist courier with over 20 yearsâ&#x20AC;&#x2122; experience dedicated to Clinical Research and Lifescience Logistics, Cold Chain Management and Pharmaceutical Distribution. Right Time Contact Us sales@pdpcouriers.com www.pdpcouriers.com

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Korea t. +82 (0) 2 333 4461


Logistics and Supply Chain is collated into an audit trail that is then maintained for 10 years. The va-Q-tainers are fitted with a monitoring and logging system that records the internal and ambient temperature throughout the transportation cycle. On return to our network station, the data is uploaded from the container and every single shipment is scrutinised by our QA department in the UK before being delivered in a report to the rental party as part of our standard service. Furthermore, the temperature data is added to the audit trail and also examined by our TCS Team (thermal customer support) who have responsibility for performing a longer-range analysis to ensure that the shippers’ assumptions remain valid across all trade-lanes and seasonal variations. All these measures, combined with the high performance of the advanced passive containers ensure that there are no temperature excursions within our container rental service. 5. You are one of the nominees for the Supply Chain Innovation Award at the IQPC Cool Chain Conference. Can you explain your innovations and uniqueness?

KLM Martinair (AFKLMP) Cargo for its joint Supply Chain Innovation. The hasslefree AFKLMP Cargo rental arrangement of advanced passive va-Q-tainer containers enables reliable Closed Cool Chain Solutions© for global shipments. Unique temperature ranges from -60°C to +40°C to over 500 AFKL network points are provided in a container fleet of over 1000 containers in five sizes. The va-Qtainer container is an advanced passive container. It is available in a full service one-way rental service around the world enabling low-risk, closed cool chain shipments from origin to destination. In the hassle-free AFKL rental arrangement, the va-Q-tainer container is delivered preconditioned to the shipment origin, ready to “Load & Go” without any additional handling required. With the widest temperature ranges available on the market and costsaving packaging sizes, the va-Q-tec AFKL Closed Cool Chain solutions© provide an innovative cool chain service offer to clinical, pharmaceutical, and biotechnological shippers. The va-Qtec Air France KLM Martinair Cargo Supply Chain Innovation has a great positive impact on industry and patients worldwide, with thousands of shipments, deviation-free.

Dominic Hyde, Managing Director at va-Q-tec Ltd. Originally a software and systems engineer, Dominic Hyde entered the global cold-chain logistics field in 2001. Since 2011 he has been the Managing Director of va-Q-tec Limited, a subsidiary dedicated to the global rental of containers and the provision of fulfilment services to the clinical trials and pharmaceutical distribution segments. This extension of the va-Q-tec business into the rental of its vacuum insulated containers marks a major success for the company. Together with his team, Dominic is meeting the significant global demand for rented thermal containers as this represents a reliable and cost-effective alternative to purchasing and owner operation for customers. New airline, freight forwarder and integrator partnerships have realised a significant step forward in securing the transportation of temperature-sensitive pharmaceuticals and have played a significant role in enabling the strong growth of the business.

va-Q-tec is nominated for the IQPC Cool Chain Award together with Air France

www.ipimedia.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 72


One Detection Technology. Three Applications. One Automated Platform.

— Automated Microbial Enumeration and Reporting — Non-Destructive Test Uses No Reagents — Positive Results in Hours — Single or Concurrent Testing

The Growth Direct TM System revolutionizes microbial testing. By providing a single technology to perform all key microbial quality control tests, the Growth Direct TM System automates and accelerates testing with positive results in hours and final CFU counts in about half the time of traditional methods, eliminating error-prone manual steps and saving labor.

To learn more about automating your microbial QC lab, visit www.rapidmicrobio.com


Manufacturing Reducing Particulate from Metal Products in Medical Devices As the medical device market evolves to become highly sophisticated and advanced, metal part manufacturers face constant pressures in being able to reduce particulate in the production and assembly of components. For medical device component manufacturers, developing new methods to reduce particulate is becoming increasingly important.

"bought-off-the shelf" machinery which is very versatile and can make a huge variety of products. Traditional spring coilers form springs by continuously pushing wire against an inclined tool which forces the wire to bend and form a coil. This generates high levels of friction, requires lubrication (usually in the form of soap coated wire), and greatly restricts the rate at which the coil can be formed.

Over the years our design and engineering teams have been working in collaboration with some of the world’s leading medical device manufacturers to develop techniques for reducing particulate.

In many cases, coil springs are formed by wrapping the wire around a rotating mandrel which generates much lower levels of friction, does not require soap coated wire and can produce springs at much higher production rates. Mandrel coiling is not as versatile as traditional coiling methods and bespoke sized tooling will be required for each product. If the required quantities are high enough this method can be very economical.

What Are Particulates? Particulates are minute, separate particles of organic or non-organic matter that contaminate components. Particulate can be generated during the coiling or forming process by friction between the raw material and the tooling, and from foreign bodies such as lubricants that are picked up by contact during manufacturing. What Produces Particulates? Components can also be contaminated by airborne particulate present in the atmosphere surrounding the process, and contact with operators, equipment, packaging materials etc., during manufacturing. Some coiling processes require the raw material to be coated with coiling soap to reduce the effects of friction during the coiling and forming process. Usually these contaminants are removed by secondary processes. Processes to Remove Particulate Prevention by Design
 In some circumstances particulate can be reduced by prevention. For some applications, bespoke processes have been designed that do not require soap coated wire and design tooling to reduce frictional effects as far as possible. Designing and building bespoke manufacturing equipment can provide an advantage for customers as the process can be optimised for the product. Most spring manufacturers use 74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The versatility associated with general purpose spring coiling equipment for high-volume mass production requires a relatively large amount of equipment and tooling, some of which is redundant for manufacture of any individual product. All the machine components provide opportunities for generation of particulate. Bespoke manufacturing equipment is better designed to fit the product so that all components used in the machine construction are critical to the manufacturing process, and there is no redundant equipment. The design of each machine component and its potential for generating particulate is carefully considered. Sharp edges and situations where high levels of friction can occur are generally avoided. Materials which reduce friction and have high wear resistance such as carbide, polished stainless steel, hard eloxated/hard anodised aluminium, and other FDA-approved materials, can be employed. Opportunities for particulate to collect such as blind holes and internal corners are avoided wherever possible. Vibratory Deburring
 This is the process of removing burrs from components in order to smooth surfaces and edges. During the manufacturing

process, operations such as cutting can leave raised edges or small pieces of material known as burrs that can become detached from the parent component. These can be removed by deburring using centrifugal, vibratory bowls and high-density ceramic or synthetic media. Laser Deburring
 Cutting round section wire can often leave burrs where the wire has been cut. For some components, laser deburring, which provides a “dome”-shaped end to the wire by firing a high-powered laser beam directly onto the end of the wire is being offered. Sieving
 Sieving is a vibratory process that removes particulate by gentle abrasion while supported on a mesh or gauze. The particulate is separated from the components by dropping through the mesh. The size of the mesh is critical to the success of the sieving operation. Solvent and Aqueous Cleaning
 Solvent and aqueous cleaning are dedicated washing processes and are suitable for most metallic materials. These both require the component to be immersed in a heated liquid media, either solvent- or water-based, for a period of time. The components are usually tumbled within the media or the media agitated during the process. Particulate is washed from the components and removed by filtration of the media. Aqueous cleaning is generally more environmentally friendly than solventbased cleaning processes. Ultrasonic Cleaning
 Ultrasonic cleaning is carried out in conjunction with either solvent- or aqueous-based cleaning processes. This involves using an ultrasound-generating transducer immersed within the media that creates bubbles using high-frequency (20-400 kHz) sound waves to agitate the media. This “cavitation” process removes contaminants that are adhered to, or embedded into, the surfaces of materials such as metals, plastics and ceramics, etc.

Winter 2015 Volume 7 Issue 4


For

perfect

production

methods Handling equipment

– Lifting, weighing, blending, pallet transfer – Mobile or stationary – Manual or fully automatic – Loads up to 2500 kg handled – Hygienic stainless steel – GMP-compliant design – ATEX conformity

Müller GmbH - 79618 Rheinfelden (Germany) Industrieweg 5 - Phone: +49(0)7623/969 -0 - Fax: +49(0)7623/969-69 A company of the Müller group info@mueller-gmbh.com - www.mueller-gmbh.com


SWEDISH PLASTICS EXPERTISE At Modulpac we put more than 30 years experience into the development of our products. We manufacture a wide range of plastic closures for the pharmaceutical market as well as the food industry. Through flexibility and know-how we find the most efficient solution for your particular needs.

• Closures for all applications • Clean room production • Flexible profiling possibilities • Client customized solutions • Extensive series as well as small batches

Acid Cleaning (Pickling) Pickling is usually performed in citric or hydrochloric acid solution, and removes a thin, surface layer of the material, taking the embedded particulate and other contaminants with it. It is often performed as a pre-treatment prior to passivation of stainless steels. Clean Manufacturing Areas
 Some spring-making processes, such as traditional coiling methods that require soap coated wire, generate large amounts of particulate. Other methods such as mandrel coiling with bright wire are inherently cleaner, but still generate particulate to a lesser degree. The amount of residual particulate that is acceptable to the customer will largely depend upon the application of the product. Manufacturing areas which are clean and dedicated to the customer's product, and isolated from other processes, need to be designed to match the process and the product specification, with the aim of reducing foreign matter introduced by operators and the surrounding environment contaminating the product. Depending on the process and customer requirements, some clean areas will only require the operators to wear protective clothing, while others have interlocking doors and maintain a positive air pressure etc. Manufacturing within these areas can maintain particulate to levels where the cleaning burden on the component can be dramatically reduced without the high costs and limitations imposed by "cleanroom" manufacture. Cleanrooms
 Cleanrooms are graded by the number and size of allowed particles per unit of volume. A Class 100,000 cleanroom, for example, can have up to 100,000 per cubic foot of air. Where springs are ultimately to be assembled into devices within cleanrooms, customers will need the component parts to be free from biological contamination, as well as particulate. Class 10,000 (ISO 7) cleanrooms can be installed so that parts can be cleaned in-house. This allows product to be passed into the cleanroom via an airlock ‘pass-through’, directly from the clean manufacturing area. Once inside the cleanroom, the parts are ultrasonically cleaned to remove any contamination, double-bagged within the cleanroom, and passed out through a further airlock to await despatch. The parts can then go into the customer’s cleanroom, with the outer bag removed, so that no contamination is taken in via the outer packaging. Control of the efficacy of the cleanroom can be achieved by performing regular bioburden tests on cleaned parts. This will give assurance that the parts meet the prescribed microbial limit for the number of bacteria present.

Please contact us to learn more about how we can help your business. We might be your future partner.

Västergatan 16, 341 50 Lagan, Sweden Phone +46 (0)372 – 255 00 Fax +46 (0)372 – 255 01 E-mail sales@modulpac.se Website www.modulpac.se 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Graham Perkins, Medical Sales Manager, has worked on numerous successful development programmes for ADVANEX and introduced various mechanical innovations to medical device companies and design houses for over 20 years He is a technically trained business development professional with a depth of knowledge of metal forming and component supply Email: graham.perkins@advanexeurope.co.uk Winter 2015 Volume 7 Issue 4


Chapter Title

Providing custom-made support to drug product development Specialist for pharmaceutical development of solid oral forms, Synerlab Développement is your partner from labscale to industrial transfer. Thanks to a highly qualified team and a large range of technologies, Synerlab Développement handles the entire product development process from preformulation to industrial scale-up, including clinical batches as well as analytical development and stability studies.

Pharmaceutical Development Center GMP site

At Synerlab Développement, our specificity is to take on full development projects, but we can also meet your specific requirements for project sections with our range of analytical and galenical studies. We are committed to responsive, flexible, high quality services and products delivered with a focus on continuous process improvement.

Groupe SYNERLAB • ZI de Krafft • 67150 ERSTEIN - FRANCE - sales@synerlab.com 77 INTERNATIONAL PHARMACEUTICAL INDUSTRY

www.synerlab.com

Winter 2015 Volume 7 Issue 4


Manufacturing

A Quality-by-design Approach to Upstream Bioprocess Interrogation and Intensification Efficient biopharmaceutical process development relies on the quality-bydesign (QbD) paradigm. QbD is a scientific, risk-based proactive approach to drug development that aims to have a full understanding of how the process and product are related. This knowledge is gained by process analytical technology (PAT). In this case study the Applied Process Company (APC) integrated external PAT and an APC-developed controller with a parallel bioreactor system. Online PAT measurement and control of the identified critical process parameters led to greater understanding and the streamlined optimisation of a mammalian cell bioprocess. The study exemplifies the value of flexible bioreactor systems which allow ease of integration of third-party technology. Introduction Biopharmaceuticals represent a significant and growing sector of the pharmaceutical industry. The global biopharmaceutical industry is currently worth over 107 billion euros, according to research conducted by BioPlan Associates1. However, a lack of understanding of the process and product interdependencies potentially results in manufacturing challenges. Optimisation of protein production based on empirical experimentation and quality testing of the end product often results in bioprocesses operating under suboptimal conditions and hence in extended cycle times, excessive raw material and utility requirements, and elevated numbers of process or product failures, which together culminate in a high cost of manufacturing. To ensure consistent drug quality and reduce batch-to-batch variability, pharmaceutical companies and regulatory authorities aim to replace the “quality-by-testing” with a “quality-bydesign” strategy. In a QbD approach, critical quality attributes of the end product are defined and subsequently a production process is developed which aims at meeting those attributes. This involves identification of a design space, a range of experimental conditions within which variations in process parameters do not affect product quality. 78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Prerequisite is the identification of critical process parameters by PAT that in the course of protein manufacturing are then monitored and, if needed, controlled. The PAT required to support a QbD product may be simple or complex, depending on the nature of the product and process used for its manufacture. Generally speaking, mammalian cell culture processes and the products which they produce are complex and hence, there are many challenges to implementing a PAT/QbD strategy. However, the potential benefits coupled with regulatory pressures are driving a strong interest in and an increased level of adoption in the biopharmaceutical industry. Biological processes are known to have a much higher level of variability than their chemical counterparts. PAT and QbD offer an avenue to better understand and control this variability, which has implications for the process economics, control and final product quality. Traditionally, temperature, pH, and dissolved oxygen are the main parameters measured and controlled online due to the availability of traditional, robust sensors. However, as technology advances, other process parameters such as cell density, cell viability, substrates concentrations, product and by-product concentration, dissolved carbon dioxide and biomarkers can now be measured and analysed in real time in an automated manner, although not yet routinely. The availability of realtime process information is of particular value in addressing the variability and unpredictability of animal cell cultures as it opens up the possibility of implementing advanced control strategies capable of directly impacting critical process parameters and critical quality attributes.

APC delivers chemical and bioprocess engineering solutions and technologies to enable streamlined development, optimisation, and supply of new and existing chemical and biological entities. APC’s process development technology platform (BioACHIEVE™) combines PAT technology, multivariate data analysis, process modelling, and advanced control strategies2. This article describes the successful integration of external PAT with a parallel bioreactor system using an object linking and embedding for process control (OPC) communication protocol. The aim was to optimise the performance of a Chinese hamster ovary (CHO) mammalian cell bioprocess. In a previous study the glucose concentration was identified as a critical process parameter3. The objective of the following case study was to improve process performance by optimising the glucose feed profile. By moving from the traditional bolus fed-batch to a continuous feeding fed-batch strategy, nutrient depletion should be prevented and a stable macro-environment for the cells should be established. Material and Methods Cell Culture CHO cells were cultivated in a glucosefree formulation of EX-CELL® CHO DHFRmedium (Sigma-Aldrich® Co., LLC, USA) supplemented with 20 mM glucose, 4 mM glutamine, 1 µM methotrexate, 0.1% (v/v) Pluronic® F-68 (SigmaAldrich Co., LLC, USA) and 10 mL/L penicillin-streptomycin (Sigma-Aldrich Co., LCC, USA). Cells were cultivated for 7 to 9 days at 37°C using a four-fold DASGIP® Parallel Bioreactor System for

Fig. 1: Eppendorf DASGIP Parallel Bioreactor System for cell culture. Winter 2015 Volume 7 Issue 4


Comprehensive bioprocess software solutions: BioCommand®, DASware® control and DASware®

More than Expected Eppendorf bioprocess software — Much more than bioprocess control > Intuitive user interfaces and graphical displays > Superior process monitoring, control and data logging > Advanced programming, process information and DoE functionality > OPC compliance and remote control > 21 CFR Part 11 compatible > Applicable to third-party bioreactor units

With BioCommand and DASware control Eppendorf offers Supervisory Control and Data Acquisition (SCADA) software packages for advanced bioprocess control. The comprehensive DASware software suite provides next generation bioprocess information management.

www.eppendorf.com Eppendorf ® and the Eppendorf logo are registered trademarks of Eppendorf AG, Germany. New Brunswick™ is a trademark of Eppendorf AG, Hamburg, Germany. DASware ® is a registered trademark of DASGIP Information and Process Technology GmbH, Germany. BioCommand® is a registered trademark of Eppendorf, Inc., USA. U.S. Design Patents are listed on www.eppendorf.com/ip. All rights reserved, including graphics and images. Copyright ©2015 by Eppendorf AG.


Manufacturing

80 INTERNATIONAL PHARMACEUTICAL INDUSTRY

with an Eppendorf DASGIP Parallel Bioreactor System. The glucose concentration in the CHO mammalian cell culture was determined online using Raman spectroscopy coupled with chemometric partial least squared modelling. The offline results determined via an enzymatic assay were highly comparable to the results obtained online by Raman spectroscopy (Figures 3A, 3B). Overall, the continuous feeding fed-batch bioprocess resulted in an increase in peak viable cell density and the integral of the viable cell density (Figures 3C, 3D) which is directly related to increased titre. A Glucose concentration (mM)

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D Cell density (cells/mL)

close to the setpoint, an APCdeveloped model Eppendorf Eppendorf predictive controller DASGIP MP8 DASware control Multi Pump Module (MPC) algorithm Adding glucose was integrated via Calculation of feed rate bidirectional OPC Feedback communication. Loop The essence of Eppendorf MPC is to optimise APC-developed DASGIP Model Predictive Controller Bioreactor forecasts of process Algorithm behaviour. This Quantification of forecasting is Raman measurement glucose concentration Kaiser Optical Systems accomplished with RamanRxn2 Multi-channel Raman analyzer a process model, and, therefore, Fig. 2: Integration of external PAT with an Eppendorf DASGIP the model is an Parallel Bioreactor System. essential element of an MPC controller. cell culture equipped with 2.5 L (working Based on online volume) DASGIP® Benchtop Bioreactors readings of the identified critical process (Eppendorf AG, Germany) (Figure 1). parameters, the model is used to Cultures were agitated at 120 rpm. The calculate optimal feed rates for set-point pH was controlled at 7.2 using 1 M maintenance. MPC facilitates the ability NaOH and CO2 gas, respectively. Air to proactively counteract deviations saturation was set to 50 % and controlled from the set-point and to simultaneously using air and oxygen supplied via a control multiple process parameters, sparger. and is hence especially suited to ensure constant culture conditions in multivariate Offline Measurement of Process bioprocesses. Parameters The MPC actuated a DASGIP MP8 multiCell density and cell viability were pump module to execute continuous determined offline using a Cedex® HiRes glucose feeding. system (Roche Diagnostics® GmbH, Germany). Bolus Fed-batch and Continuous FedOffline measurements of glucose batch Glucose Feeding concentrations were performed using The glucose concentration was adjusted an enzymatic assay kit (Megazyme® using a feed medium consisting of International Ireland Ltd). 653.6 mM glucose, 58.8 mM glutamine and 58.8 g/L soy protein hydrolysate Integration of External PAT and In-house dissolved in glucose-free EX-CELL CHO Developed Controllers DHFR- medium. Figure 2 illustrates the integration of external PAT and an in-house developed Two fed-batch feeding strategies were controller with a parallel bioreactor investigated in the study. The first was a system. Online measurements of glucose fed-batch culture manually fed with bolus concentration were performed by Raman additions, at 24 h intervals, the volume spectroscopy. A RamanRxn2 Multi- of which was proportional to offline channel Raman analyser (Kaiser Optical integral viable cell density measurements Systems. Inc., USA) was integrated with for the previous 24 h interval. The second the bioreactor system using DASware regime was a continuous feed, the rate analyze software. DASware analyze of which was determined and adjusted utilises an OPC communication protocol, automatically using a model predictive an industry standard which facilitates the controller and Raman-determined communication of devices from different glucose values to keep the glucose manufacturers. To translate the Raman concentration in the bioreactor at a setspectra into concentration information, point of 11 mM throughout the culture. chemometric partial least squared calibration models were developed using Results and Discussion the SIMCA® multivariate data analysis Using the DASware analyze software package (MKS Umetrics AB, Sweden). a RamanRxn2 Multi-channel Raman analyser and an APC-developed MPC To maintain the glucose concentration algorithm were successfully integrated Flowrate control

40 30

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Fig. 3: Glucose set-point control via a model predictive controller algorithm resulted in an increase in cell densities. A, B: Glucose concentration was measured online and offline, respectively. (A) Glucose concentration was adjusted via a bolus fed-batch feeding strategy. (B) The glucose set-point was maintained in a continuous feeding fed-batch strategy using MPC. C, D: Total cell densities (TCD), viable cell densities (VCD), and viability were determined for the bolus fed-batch culture (C) and the continuous feeding fed-batch culture (D). Winter 2015 Volume 7 Issue 4


Manufacturing Conclusion The parallel bioreactor system used was a suitable host for APCâ&#x20AC;&#x2122;s BIOACHIEVE process development technology platform, which APC applies to upstream bioprocesses. The DASGIP system facilitated the ease of integration of external PAT and transfer of this information to and from APC-developed controllers. This allowed optimisation of the process performance based on greater process understanding, ultimately delivering improvements in cell growth. This case study exemplifies the value of increased process understanding and control in biopharmaceutical manufacturing. Advancements in sensor technology and data analysis facilitate the ability to control the identified critical process parameters to their respective target levels and thus optimise the critical quality attribute design space. To apply the QbD approach to upstream bioprocess development, bioreactor systems which allow smooth integration of external sensors and controllers are crucial.

Are your plants ready

References 1. BioPlan Associates Inc. 11th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production. ISBN 978-1-934106-24-2 (2014) 2. APC Ltd. Bioprocess development and optimization: A technology enabled approach to process development. APC White Paper (2013) 3. Craven, S. A quality-by-design approach to upstream bioprocess development. The Engineers Journal (2014)

to swiftly respond to changing markets and production needs, reliably provide top quality drugs while meeting regulatory compliance?

Stephen Craven, APC Ltd, Dublin, Ireland Dr Stephen Craven earned his PhD from the School of Chemical and Bioprocess Engineering, University College Dublin, where he developed bioprocess models for mammalian cell fermentations and also developed and applied advanced control strategies to PAT-enabled bioprocesses. Dr Craven currently works as the life sciences team leader within APC

We can help you to have them. Contact us.

Ltd, Dublin. Email: stephen.craven@approcess.com

Ulrike Becken, Eppendorf AG Bioprocess Center, Juelich, Germany Dr Ulrike Becken works as a Scientific Communication Manager at the Eppendorf AG Bioprocess Center in Juelich, Germany. Amongst others she is responsible for authoring application notes in cooperation with customers. Dr Becken earned her PhD from the Rheinische-FriedrichWilhelms University, Bonn, in the field of cell biology. Email: becken.u@eppendorf.com 81 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Winter 2015 Volume 7 Issue 4

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Packaging

Redefining Value in the Pharmaceutical Industry and the Role of Packaging Providing safe and efficacious treatment of disease is no longer sufficient for new drug products. Today’s medicines must address an unmet need or be a much better solution than existing products. They need to increase patient adherence, be easy to use, prevent counterfeiting and tampering, be traceable and of course be cost-effective. Advances in pharmaceutical packaging technology are making it possible for drug manufacturers to meet these increasingly challenging requirements. New Concept of Value Healthcare costs have risen dramatically over the last two decades due to the aging of the global population, the increasing prevalence of chronic diseases, the shift to more expensive biologic drugs, and poor patient adherence. Simultaneously, the quantity of data on the effectiveness of different drugs in different patient populations that is readily available to providers, payers, and governments has increased significantly. Patients and general consumers also have much greater access to information on treatment choices. The result: the value of medicines is no longer determined solely by their efficacy and safety. Evidencebased medicine (EBM) is on the rise, and comparative effectiveness research (CER), or patient-centred outcomes research (PCOR), studies abound. Outcome-based insurance payments (payments linked to performance, value-based pricing) are slowly replacing unit-priced payment approaches. Under this scenario, new drugs must provide real and measurable value to all stakeholders, and drug prices are linked to the level of value that is provided rather than volume. However, agreement on how to determine that value has not been reached, and many different methods and systems are vying for recognition within the industry. Some factors that have been proposed include: • • • •

Treatment success level/impact on patient health Cost-effectiveness Improvement in patient quality of life Ease of use for the patient (or nurse/ caregiver/physician if not self-

82 INTERNATIONAL PHARMACEUTICAL INDUSTRY

• • • •

administered) Convenience for patient lifestyles Patient adherence Patient satisfaction Performance compared to other drugs (prescription/nonprescription) and/or disease management (diet, exercise, etc.) options Effect on overall required level of care.

While each insurance company uses different combinations of these and other metrics, a new drug will be listed on their formularies only if the drug manufacturer has demonstrated its value-add compared to existing treatments. Many of the factors listed above (ease of use, convenience, patient adherence, patient satisfaction, and even cost-effectiveness) are often determined through the choice of packaging/delivery method. Growing Importance of Packaging Pharmaceutical packaging today does far more than ensure product integrity. It serves as a platform for key labelling information and marketing communications. Track-and-trace, serialisation, and anti-counterfeiting technologies, which are becoming regulatory requirements around the world, are made possible through packaging. Special packaging designs prevent child tampering while still enabling easy access to medicines for seniors. Adherence is also improved through the use of unit-dose packaging (blister packs, stick-packs, blow-fill-seal ampoules and vials for parenterals, etc.), and new packaging designs that can be easily transported are meeting the needs of patients who are always on the move. Insulated packaging also helps manufacturers ensure the stability of biologics throughout the cold chain. Indeed, the pharmaceutical industry has come to recognise the value of thoughtful packaging design. Both the small-molecule and biologic drug markets are highly competitive today, with many products losing patent protection and generics and biosimilar producers aggressively pursuing all opportunities. Rising cost pressures and the shift to EBM

are additional factors influencing the choice of packaging for a given drug. Manufacturers are increasingly turning to outsourcing providers with expertise in and access to innovative drug delivery and packaging technologies to develop unique solutions. For new medicines, the goal with packaging is to address patient convenience and adherence concerns and add measurable value compared to the potential competition, and do so beginning at the earliest stages of the drug development cycle. For existing drugs, novel drug delivery and packaging technologies can provide the crucial competitive differentiation needed to extend product lifetimes and their associated revenue streams. Consequently, the pharmaceutical packaging market is projected to increase at a compound annual growth rate (CAGR) of approximately 8% between 2015 and 2020 to surpass $80 billion by 2020, according to Markets and Markets. The Freedonia Group pegs the growth rate at 6.5% and the value at over $100 billion (growing from $74 billion in 2014) in 2019. Mordor Intelligence is a mix of these two, with a CAGR of 8.38% and values of $57.9 and $93.84 billion in 2014 and 2020, respectively. Regionally, the mature markets of North America and Europe account for approximately 70% of the global pharmaceutical packaging market, according to Markets and Markets, but demand is increasing in emerging regions as consumer spending capacity increases, and the highest growth will occur in Asia-Pacific over the forecasting period. Freedonia predicts the greatest growth will occur in the Africa/Mideast region, followed by the Asia/Pacific region and Central and South America. Getting Personal… Several megatrends in the pharmaceutical industry are pointing to greater personalisation and the development of more targeted therapies. First, blockbusters are no longer the norm; rather, with access to cost-efficient, smaller, modular, single-use, flexible Winter 2015 Volume 7 Issue 4


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Packaging multiproduct manufacturing facilities, it is now economically viable for drug companies to develop and produce smaller-volume products for much smaller patient populations. New chemistries, such as antibody-drug conjugates (ADCs), are also allowing the very targeted delivery of very small quantities of highly potent drug substances, providing greater efficacy and reduced side-effects. The increase in the number of drug candidates with orphan drug status over the past several years reflects these new capabilities. Second, with the advent of inexpensive DNA analysis, physicians now have access to detailed information about the genetic makeup of their patients, allowing for very personalised treatment. Databases with comparative treatment results also provide physicians with information about which medicines should work best for any given patient based on his/her medical and genetic history and lifestyle. Third, many of those patients have very busy lifestyles and prefer the convenience of medicines that can be self-administered. Seniors and others with chronic diseases often prefer self-administration because it reduces the need for difficult and expensive office visits. Patient adherence is a real concern, however. Fourth, ease of use of medicines is a big priority for pharmaceutical manufacturers, and different segments of the population have very different needs. Access to the actual medicine, ergonomics, print size, and even packaging materials are being tailored to the preferences of seniors and young children, for example.

the potential to optimise supply chain activities and interact more directly with consumers and ultimately reduce overall costs. Numerous manufacturers of packaging equipment and systems have responded with operational software and hardware developments that are designed to integrate the application of barcodes and anti-tampering devices into packaging line production equipment and processes, and then track individual package units as they are aggregated, distributed and ultimately delivered to physicians and/or patients. Integration of robotics into packaging lines and increased automation often accompany the implementation of serialisation solutions. Further interaction with patients is another expected consequence. Packaging with barcodes provides a link to patients that can be used for many types of communications. For instance, patients can report health responses and gain access to tools designed to improve adherence, all linked to the specific product, and manufacturers can provide direct notifications of recalls. There is even the possibility to link specific products to individual patients through mobile applications, which enables direct provision of support and targeted messaging, provides a means for gathering detailed data regarding the level of value provided and may also help improve patient compliance.

â&#x20AC;Ś and Traceable

Advanced packaging technologies that facilitate the integration of serialisation and incorporate various avenues for such customer communication will clearly provide a competitive advantage. Those that combine this capability with additional patient-centric solutions will be even more successful at helping drug manufacturers demonstrate the value of their products. In addition to barcodes, other technologies that are finding use in track-and-trace applications include security inks, holograms, RFID tags, and specially designed labels.

Regulations for the prevention of drug counterfeiting including requirements for serialisation throughout the pharmaceutical supply chain will also be met through the modification of pharmaceutical packaging. While these new expectations add complexity and cost, they also offer the industry

The Attraction of Single-dose Delivery Systems In addition to poor patient adherence, medication errors (wrong medicine, insufficient or too large a dose, medicine taken too frequently or not often enough, etc.) can lead to further problems and additional visits to the emergency

All of these trends are driving the use of innovative packaging solutions. Today, patient needs often receive the same level of focus as product safety and efficacy, and innovative drug delivery and packaging technologies are helping branded, generic and biosimilar manufacturers meet all three requirements.

84 INTERNATIONAL PHARMACEUTICAL INDUSTRY

room, which add to the overall cost of healthcare. Single-dose packaging is an attractive solution that helps eliminate errors and can even increase patient compliance. Single-unit packages contain the correct dose and are meant to be used only once. With clear product labelling and lot numbers, they can be easily tracked. Many forms can be easily transported for patients that are often away from home. There are additional benefits for manufacturers, including controlled dose delivery and a reduced likelihood of contamination, which contribute to more consistent clinical trial results. Many hospitals also prefer single-dose technologies because they facilitate the management of medicationdispensing operations. Different single-unit packaging technologies have been developed for oral, topical and parenteral medications. Blister packaging is increasingly popular for tablets, capsules and other oral solid formulations because it has been shown to improve patient compliance and is easily customisable for different drug products, with many choices of materials and configurations. According to Freedonia, blister packaging will comprise the second-largest selling group of primary pharmaceutical containers due to its adaptability to unit-dose and clinicaltrial-dosage formats with expanded label content, high visibility, and built-in trackand-trace features. Pouch packaging is another option for solid dosage drugs. For injectable products, single-dose, prefilled syringes are very popular, with demand growing at above average rates due to the fact that more new drug products are based on biologic actives, according to Freedonia. Advances in the materials used for these packaging solutions are helping to eliminate concerns over contamination from extractables and leachables in plastic syringes, or due to the reaction of sensitive ingredients with glass. Auto-injectors are important packaging elements that increase the ease of self-administration of parenteral products offered in prefilled syringes. Prefillable inhalers are also experiencing increased demand due to the increasing number of chronic asthma, allergy, and migraine patients treated with inhalation drugs. Even oral liquids are offered in single-dose packaging, including plastic syringes with rubber tips, squeeze tubes and stick-packs. The latter are useful for solutions, suspensions and gels for oral Winter 2015 Volume 7 Issue 4


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Packaging and topical administration. Managing the Cold Chain with Appropriate Packaging Solutions In addition to driving the growth of prefilled syringes, the growing percentage of biologic drugs on the market has created a need for advanced packaging solutions that help ensure appropriate temperature control during shipment. Because many biopharmaceuticals are only stable at low temperatures, even minor temperature excursions can result in compromised product efficacy and patient safety and product losses, among other issues. Temperature control is therefore crucial, and regulations require extensive safety/stability testing if the correct temperature is not maintained. Careful selection of the right packaging solution from a highly experienced packaging provider is necessary to meet these stringent regulatory requirements and ensure reliable and safe product delivery. Of 200 representatives of companies who annually spend some degree of budget on insulated packaging recently surveyed by Nice Insight, 30% indicated that they experience frequent temperature excursions, and 87% experience some. Their biggest concern is the loss of irreplaceable and high-value products. They are looking for packaging solutions that not only provide temperature protection for an appropriate duration, but that can help them lower their packaging and shipping costs through re-usability, the incorporation of temperature loggers and the use of modular components. The most common packaging materials are polystyrene and polyurethane, but they are the least effective. Phase change materials can be useful, but most often are based on water and gel packs, that are only good for maintaining temperatures near 0°C. Packaging based on highperformance insulation carries the highest upfront costs, but if appropriately constructed and designed, can be the most effective and provide the lowest overall cost of ownership. Rental and reuse programmes are also available from some packaging suppliers. Increasing Role for Contract Manufacturers As the demands placed on pharmaceutical packaging have increased, from temperature control to 86 INTERNATIONAL PHARMACEUTICAL INDUSTRY

serialisation to personalisation and differentiation for competitive advantage, the technologies needed to meet these requirements have become more advanced. Not surprisingly, many drug manufacturers have elected to outsource packaging design and operations to contract manufacturing organisations (CMOs) and focus on their core competencies. CMOs with demonstrated experience and expertise in pharmaceutical packaging, and particularly those that have a history of developing innovative solutions, are seen as important partners in the development and lifecycle management of drug products. Despite the growing use of outsourcing providers and the greater emphasis that companies are placing on packaging, however, the competition among packaging CMOs is pretty stiff. Ongoing consolidation in the pharmaceutical industry and the need for cost control has led many manufacturers to identify fewer, strategic partners with strong track records of success. Those strategic partnerships can pay off, however; collaborations that incorporate packaging design early on in the development cycle often experience smoother technology transfer and can ultimately lead to simplification of the supply chain. The ability to provide cost-savings through innovative designs and material choices is a differentiator. Packaging CMOs with systems in place and the experience to handle highly-potent compounds such as antibody-drug conjugates also set themselves apart. Serialisation capabilities have become a must, which may be challenging for smaller packaging CMOs. Of 400+ buyers of outsourcing services recently surveyed by Nice Insight, 62% indicated that they outsource packaging services (second behind lab services (66%) and ahead of manufacturing (60%), storage/distribution/logistics (59%) and clinical trials support (57%)). Primary and secondary packaging for clinical trials (57% and 48%, respectively) and commercial scale production (47% and 46%, respectively) were the services most used, followed by packaging design and development (41%) and labelling (40%). When selecting contract packaging partners, quality was the most important

factor for survey participants. Secondtier attributes included reliability, innovation and affordability. For those respondents that expect to increase their outsourcing activities, key drivers include the need to address patent life issues and gaining access to new delivery forms and specialised technologies. Conclusion: Innovative Packaging Technologies Fundamental to Offering Real Value Pharmaceutical packaging is no longer only about protecting the integrity of drug products. It is now a crucial component of every final drug product delivered to patients. The design of, and materials used in, pharmaceutical packaging not only help maintain the safety and efficacy of therapeutics, they provide a means for tracking products to individual patients and make it easier for those patients and their caregivers to use them. They can help improve adherence with customised solutions for different patient populations. Most importantly, pharmaceutical packaging, when considered from the earliest stages of drug development, can provide competitive advantage and contribute to the value of a drug product, which are crucial factors for success in the face of evidenced-based medicine value-based pricing.

Guy Tiene MA, Director of Strategic Content, That’s Nice LLC - Nice Insight. Having worked at That’s Nice for many life science accounts, Guy's role involves the creation and deployment of researchbased content for Nice Insight, the research arm of That’s Nice LLC, a science agency. Guy oversees Nice Insight and brings a breadth of market research data to clients and the market on a regular basis. Prior to his return to the agency, Guy headed global marketing and communications for a large corporate business group contract manufacturing organisation (CMO) in pharmaceutical manufacturing. Guy holds a masters degree from Columbia University in New York City. Email: guy@thatsnice.com Winter 2015 Volume 7 Issue 4


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Packaging Relating Tamper Evident Technology to Market and Product Fraud Risk The goals of such tampering can be to remove content from the original box, or replace the content, without notice.

only identify the codes, but also help the user to understand the labels’ visual appearance and overt security features.

Tamper attack by liquid, heat and deep freeze More commonly, however, if so much effort is undertaken, criminals harvest intact security sealing labels from used boxes, to then reuse them on newly printed boxes on a larger, criminal scale2. Such types of fraud may lead to Individual fraudsters Small groups General criminal enterprise Organized crime members Terrorist Organizations Foreign government offenders

Type of product fraudsters

To make a pharmaceutical folding box tamper-evident may be as simple as taping the flaps. This method will reduce some less severe types of fraud, such as taking a blister out of the box, at a shop or warehouse, without notice. However, in high-risk environments, fraudsters may elaborate fancy methods to harvest even security sealing labels on original packaging for reuse. Dr Marietta UlrichHorn, together with devoted clients, works on a systematic approach to close the loopholes in tamper-evident technology. When evaluating a pharmaceutical product’s risk of being compromised, the surrounding market as well as the risk of the product shall be considered. The following table shows categories of illegal activities from smaller fraud to organised crime. Use this table1 to evaluate in each single case the tampering risk of a particular pharmaceutical product in a particular market.

For all of the removal attacks from 2 to 5, tamper-evident technology is key. For low-risk products and markets, a strong adhesive in conjunction with break cuts may suffice to make up for a simple seal, which will ward off fraud of lower probability and impact. A balance needs to be kept between breakage of cuts and adhesion. The often-targeted carton fibre tear is not always as safe as it seems. When uncoated carton is torn completely, this leads to the opportunity to glue the carton underneath the label without notice.

Type of product fraud

There are several ways that fraudsters get hold of security sealing labels, such as 1. Mimicking or copying the security sealing labels by printing, 2. Skillfully peeling the labels without destroying them, 3. Helping this peel by heat – e.g. with a hair dryer – and thus weakening the adhesive, 4. Weakening the adhesive by deep freeze temperatures, 5. Soaking the whole box in a liquid such as water or solvent, to weaken the adhesive from underneath, whereas the folding box typically cannot be reused and would be reprinted. 88 INTERNATIONAL PHARMACEUTICAL INDUSTRY

human harm and death, as illegally produced counterfeit products may be contaminated, ineffective or have other properties than expected. Brand value perception will be negatively affected, and liability claims may further damage the right holders of genuine product. How to cope with these fraud challenges? First of all, in order that security seals cannot be mimicked and massreproduced, they should be identifiable as what they are, by overt and covert security features, which are recognisable and difficult or impossible to copy. Nowadays identification codes – unique identifiers – are an efficient additional means for this recognition, as apps not

Too much fiber tear may permit re-gluing of the broken board, without damaging the label. When it gets to higher risk, void technology proves to be more efficient. As opposed to relying on a high adhesion and cohesion of the adhesive, balanced with the carton, the void technology provides a reliable weakness among its ink layers. Winter 2015 Volume 7 Issue 4


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Packaging This makes it a robust technology. It leads to breakage and display of symbols such as “VOID” under all standard ways of peeling. To resist cold spray attacks, it is recommended to use adhesives that also work under below-zero environments, once they have been stuck for 24 hours. The patterns displayed by this so called void-effect can be fully customised, using e.g. a lock symbol or language, and it can be in register with the security sealing label design and shape. These labels can be in different colour shades, and can be highly translucent to leave text and barcodes underneath readable.

How about soaking used pharmaceutical folding boxes for harvesting? A new void-technology has been recently developed to cover the wash-off gap. So void labels that resist the hardest of tampering attacks, thus resisting the harshest fraudster and criminal environment, are recommended to have several different void zones: • • •

Void zones made up of weak ink layers, for normal release by users to indicate the opening, void zones which indicate heatbased tampering, void zones which indicate soaking the seals together with the boxes, where they are on.

Void labels and how they work – before, after - This “void” technology separates several ink layers to a specific “OPEN” pattern upon removal and works on many surfaces, such as varnished and UV varnished boxes.

Translucent void label on top of 2D codes Translucent “void” technology leaves underlying text and codes readable. It becomes tricky when fraudsters use heat to remove labels. The use of heatreactive ink, which appears irreversibly around a temperature of e.g. 80 degrees Celsius, covers that heat gap.

VOID label on pharma Packing: “Do not use if tamper seal is missing or broken” may be an important message to users such as patients or health care professionals. 90 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Drawing of a prototype of such a seal, comprising of several void zones It is also important to communicate what is being used with those that are using the products. Examples include communicating the tamper-evident feature being present on the package, and statements such as “Do Not Use if Tamper Seal is Missing or Broken” can help consumers to know what should be present and how to check for its presence. Combined with a robust and well-constructed and tested tamper seal, communicating your features can further demonstrate your interest in helping your customers be assured they are buying genuine goods. When it comes to protecting patients against the ever-increasing professionalism of criminals, proactive measures must be even more professional.

Risk analysis and a solid risk mitigation plan lead decision-makers to take the right track in tamper-evident sealing. References 1. Table derived from a standard in progress, under ISO TC292 “Security and Resilience”. 2. Similarly, in the spirits industry, criminal efforts as described aim at refill of bottles with fake alcoholics or at reimbursement or consumer incentive fraud.

Dr Marietta Ulrich-Horn, Securikett. Marietta holds a PhD in philosophy from the University of Vienna, and has graduated as a Master of Business Administration from the Wirtschaftsuniversität Wien and the Carlson School of Management, Minnesota. Together with Werner Horn she is co-founder and CEO of Securikett, a company providing both security label and track and trace solutions in global applications. Marietta has been delegated by the Austrian Standards Institute to actively contribute to the emergence of European and International standards on authentication, traceability by unique identifiers, tax bands and tamperevidence. Marietta Ulrich-Horn is project leader of ISO WD 16678 part 2, where interoperability of track and trace systems is being shaped. Email: marietta.ulrich-horn@securikett.com

David Howard is the President of Global Brand Integrity Services, Inc., a Pennsylvania Consultancy Company formed in March, 2014. David recently retired as Director of Product Protection for the Global Brand Protection Group of Johnson & Johnson where he served for just over 20 years. David’s responsibilities included product and package protection through the use of process and technology advancements for the Medical Devices and Diagnostics; Consumer; OTC; and Pharmaceutical divisions of Johnson and Johnson. David is a 1981 graduate of Michigan State University with a BS degree in Packaging Engineering. David also holds a Masters of Business Administration (MBA) degree in Global Management. Email:dshoward@brandintegrityservices.com

Winter 2015 Volume 7 Issue 4


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Packaging Serialisation â&#x20AC;&#x201C; Commercial versus Clinical Perspectives There is a significant amount of activity in the pharmaceutical industry in mobilising to meet the requirements of recent Drug Quality and Safety Act (DQSA) legislation, passed by the United States Congress with the intention of limiting the spread of counterfeit or otherwise falsified medicines to patients for prescription drug products. This US requirement is aligned to the spirit of the Falsified Medicines Directive (FMD) passed in the European Union. Reports suggest approximately 61% of all global spending on pharmaceuticals happens in the continents of North America and Europe1. Estimates vary widely, however, the World Health Organisation (WHO) estimates between 1 and 10% of all global pharmaceuticals are counterfeit, with rates in developing countries being as high as 50%2. Many of these products find their way into the US and Europe through illegitimate or sometimes legitimate channels. In Mexico for example, WHO reports from more than a decade ago suggest that up to 10% of pharmaceutical products may be counterfeit or illegitimate and the illegal trade has certainly not slowed, but decidedly accelerated3. With the rise in access to internet-based pharmacies, which may or may not be legitimate, and licensed pharmacies, the lines are being further blurred in the traditional healthcare supply chain. Pfizer has recently undertaken a campaign to call attention to the proliferation of counterfeit Viagra from internet pharmacies, citing their own investigations that proved the Viagra supplied by 22 top internet sellers was counterfeit, and in fact the pills examined contained dangerous ingredients such as amphetamines, drywall, and blue printer ink4. The genesis of the DQSA was rooted in a rash of high-profile incidents where counterfeit or adulterated drug products significantly sickened or ultimately led to the death of unsuspecting patients in the US, many of whom were particularly susceptible due to compromised immune systems as a condition of their cancer treatment or otherwise. An investigative book titled Dangerous Doses highlighted how these falsified medicines found their 92 INTERNATIONAL PHARMACEUTICAL INDUSTRY

way into the legitimate pharmaceutical supply chain in the US, and the book pointedly called attention to the poorly regulated wholesaler licensing structure in the state of Florida. Reaction to the public outcry and scandal led to a patchwork of state laws and regulations across the US, with Florida enacting a requirement for drug pedigree to outline each transaction through the complicated supply chain. At the time this allowed for a paper-based pedigree trail, an amazingly antiquated system even for the times. As is often the case in the United States, the state of California led the way to more progressive action. The Board of Pharmacy in California pushed firmly for a system whereby a unique identifier would be created for each drug package sold in the state and tracked throughout the entirety of the supply chain, implemented by the pharmaceutical companies and drug wholesalers, generally referred to as â&#x20AC;&#x153;Track & Traceâ&#x20AC;?. This was met with stiff resistance from the pharmaceutical industry and its associated lobbying organisations. Despite several mandated deadlines and postponements, the California Board of Pharmacy ultimately forced the hand of the national government in creating and passing the DQSA legislation, unifying a vague but firm national standard to take effect in 2017. Legislation in the European Union followed a similar path with varying national standards amongst EU member countries, although recent changes have moved back a unified implementation standard to 2018. Much of the initial resistance to an industrywide Track & Trace system was the expectation that RFID chips would be the technological platform for implementation. While effectively established in many industries including automotive and aerospace, RFID showed a promising but perhaps premature path in the pharmaceutical industry. The high cost of individual RFID chips, the significant cost of technological infrastructure to support portals and IT architecture, and the technological limitations due to interference with certain product types ultimately led the industry to look to a scaled-down solution to meet the industry requirements. Where the governmental legislation and expectation ultimately settled was the application

of a combination of two-dimensional barcodes and human-readable text, such that each saleable package featured a unique serialised identifier code applied in the manufacturing process and also confirmed to be valid at the time of packaging. This code would also reflect the legitimate factory in which the medicine had been packaged. Physical packages and accumulated code data would then travel through the supply chain in parallel to the ultimate destination of hospital, clinic or pharmacy. In theory, a patient, pharmacist or practitioner could scan and verify this code to authenticate it as legitimate product fit for use. A substantial amount of work remains to establish the end authentication process and methodology. The passage of the DQSA and FMD legislation has significantly ramped up activity and investment within the industry to meet the rapidly approaching deadline for implementation. Pharmaceutical companies and outsourced partners, including the vast network of global CMOs, are scrambling to invest in both the manufacturing technologies for code application and verification, as well as the IT infrastructure to enable data transactions for inbound and outbound codes between businesses and within their own manufacturing networks and plant systems. Investment is funded exclusively by the manufacturers, with no provision in the DQSA legislation for the capital and resource expense. The integration of IT data exchange to manufacturing processes marks a significant turn for the industry. Taking a Page from Clinical Trials Clinical trial professionals may be asking what all the fuss is about. Clinical trials have been utilising serialised codes for decades in the form of randomised identifiers for individual investigational study kits. The use of randomised codes is essential in the blinding of study materials and ensuring the integrity of study results. At the onset of a study a series of randomised codes are established that are ultimately assigned to individual packages in the packaging and labelling operation for the investigational materials. The use of Winter 2015 Volume 7 Issue 4


Packaging these unique identifiers is intended to mask whether the drug product is active or placebo, one strength to another, or potentially disguising the investigation of the experimental product versus the established therapy (the “comparator”). The use of randomised codes is an established and fundamental tool in ensuring unbiased results in blinded clinical study. In principle, the application and use of randomised codes in clinical studies draws many parallels to the systems and architecture of commercial serialisation. The initiating party, either the sponsor company or a CRO, establishes a listing of codes that they apply to a specific subset of the drug product. The packager receives those codes as a highly protected list and utilises those codes in the labelling operation to create a unique identifier on each individual package. The packager then verifies back to the initiator which codes were utilised and which were not. As in many manufacturing processes, there are marginal waste products generated, therefore some codes may be scrapped through manufacturing inefficiencies or procedural activities. Ultimately the packager creates an inventory of packages with proper unique codes for use in the investigational study, typically communicated through a centralised IVR/IWR computer-based system with protected and restricted access granted to multiple parties engaged in the clinical supply chain. Commercial Implementation – Eating the Elephant The most pressing concern in the commercial side of the pharmaceutical supply chain is the scale of implementation for enabling commercial serialisation. Billions of drugs are created and consumed each year in the United States alone, never mind the broader global healthcare system. Traditionally in the US, the only identifier on a commercial prescription other than the manufacturer’s name is the lot or batch code. A typical commercial batch could contain hundreds of thousands of packages, with no differentiation among them, and no distinguishable feature that would indicate where the product was made or packaged. This often causes sizeable and very costly challenges when drug products need to be recalled by the manufacturer, as the drugs have travelled through an amazingly complicated 94 INTERNATIONAL PHARMACEUTICAL INDUSTRY

supply chain in reaching the end consumers. In theory, the implementation of unique serialised codes for each package would provide infinitely more visibility as compared to the current practice of recalling commercially distributed medicines. The other primary concern for the pharmaceutical industry is the scope and infrastructure to support the data generated in the serialisation process, as well as the transactional nature of the supply chain. In addition to the billions of serialised codes that will be created and tracked, the concept of aggregation exacerbates the scope of the challenge. In aggregation, the packager ties together the parent-child relationship of the individual drug package to its tertiary and ancillary packaging, up to and commonly including the pallet. For example, a bottle may be the unit of sale and therefore receive the primary serialised code. Twelve bottles then would be bundled with shrink film to unitise them. Those 12 individual codes would be married to a serialised code for the bundle. Four bundles would then be loaded into a corrugated shipper, which in turn would have its own serialised code. Shipping cases would then be loaded on the pallet and the pallet would have its own serialised code. What is ultimately created is a family of interrelated and structured codes identifying the inventory of the pallet. If in the course of distribution any product is removed or damaged, the data would need to be properly updated to reflect the change in connectivity. Taking this concept and extrapolating it across the scope of the global pharmaceutical supply chain can make one’s head swim. The deadline of 2017 looms large over the industry. Progressive-minded pharmaceutical companies have accepted their fate and moved forward with pilot studies or broader adoption ahead of the established deadline. A large proportion of the industry quite simply has not, and will be hard pressed to meet the deadline. What ultimately will happen with regard to enforcement is a topic of debate, but many believe that the FDA will impose fines for those companies not complying with the requirement. Serialisation equipment manufacturers and integrators, IT developers, and supply chain consultants are working feverishly to address the considerable demand today and anticipated mad rush of orders for the numerous pharmaceutical companies which have procrastinated in

their implementation plans and sizeable capital expenditure requirements. Select CMOs have positioned themselves to aid pharmaceutical companies in meeting the requirement, and the demand on CMOs will be substantial. PCI has been leading the effort to add serialisation capacity in support of the need, with millions of dollars invested across its global supply network adding equipment, infrastructure, and dedicated serialisation staff. Having supported commercially serialised products for many years has provided a profound working knowledge of the watchouts and best practices, but even our own rapid scale-up has yielded new learnings and considerations as we engage our broad customer base in their serialisation adoption. The industry will ultimately be transformed in the drive to meet serialisation legislation. The pace with which the industry adopts serialisation and anti-counterfeiting technologies will be crucial in keeping pace with the global bad actors to combat fake drugs reaching patients in need. References 1. h t t p : / / w w w. i m s h e a l t h . c o m / portal/site/imshealth/menuitem.762a961826aad98f53c753c71ad8c22a/?vgnextoid=26 6e05267aea9410VgnVCM1000 0076192ca2RCRD&vgnextchannel=a64de5fda6370410VgnVCM10000076192ca2RCRD&vgnextfmt=default 2. http://www.pbs.org/wgbh/nova/ next/body/uncovering-counterfeitmedicines/ 3. http://www.who.int/medicines/ ser vices/counterfeit/impact/ ImpactF_S/en/index1.html 4. https://www.viagra.com/getting/ avoid-counterfeits Justin Schroeder, Executive Director, Marketing, Business Development & Design at PCI Pharma Services (PCI). Mr Schroeder is responsible for new account development, global marketing, and creative package design with a focus on the development and commercialisation of unit dose and compliance-prompting packaging. At PCI/Anderson since 2000, Mr Schroeder previously worked with Hershey Foods Corp and J.M. Smucker Co. (Smucker’s), and is a Certified Packaging Professional, Institute of Packaging Professionals (IoPP) and Vice Chairman of the US Healthcare Compliance Packaging Council (HCPC). Email: info@pciservices.com Winter 2015 Volume 7 Issue 4


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Packaging Pharmapack Europe 2016: Delivering Success in Pharma Packing and Development Pharmapack Europe 2016 – held at the Paris Expo Porte de Versailles (10-11th February 2016) – is widely acknowledged as "the place to be" in the pharmaceutical and drug delivery supply chain. The event gathers key industry players together to meet with leading suppliers and discover the latest innovations in pharmaceutical packaging and drug delivery. Since its launch in 1997, Pharmapack Europe has nurtured a great reputation thanks to its unique concept, and continues to draw major companies from all over the world – with the 2015 event attracting 370 exhibitors and 3040 visitors. According to Pharmapack Event Director Anne Schumacher, Pharmapack attracts new exhibitors every year from start-ups through to CMOs and CMDOs, but also suppliers from emerging markets. In 2016, the event will gather 380 exhibitors from 31 countries and Anne commented: “This increase in exhibition scale is driven by organic growth within the market, but also by our efforts to continually adapt our platform to present the latest innovations and insights for decision-makers seeking specific packaging solutions in new therapies and drugs.” At this year’s Pharmapack, a series of conference sessions will take place, including: •

Trends and Challenges in Packaging Materials, chaired by Dr Joel Richard, Senior Vice President, Peptides, CMC & Engineering, IPSEN and Peter J. Schmitt, Managing Director, Montesino Medical Devices and Combination Products Development, chaired by Lionel Jeannin, Device & Packaging Development, Novartis Pharma AG and Andy Walker, Head of Device Technology, GSK New Packaging Insights to Better Serve Patients, chaired by Pr Philippe Arnaud, Chief of Pharmacy Department - Hospital Bichat-Claude Bernard AP-HP, ANSM Expert and David Dronneau, Technology, Innovation, Process & Solution Head

96 INTERNATIONAL PHARMACEUTICAL INDUSTRY

in R&D Clinical Supplies, Sanofi Roundtable on ‘emerging technologies and innovation forecast’

To help stay up to date on the latest issues across Serialisation and Track & Trace, the Symposium returns in 2016 and will provide in-depth analysis on ‘how to implement a successful and compliant solution in line with the EU Falsified Medicines Directive (FMD) Delegated Act’. First-hand answers and discussion will be provided from industry experts across CIP, Teva Pharmaceuticals, and other leading solutions suppliers. On the exhibition floor, visitors are encouraged to spend time exploring some of the many free sessions, powered by industrial experts in the Learning Lab. Topics for 2016 include “Biosimilar Packaging and Device Technologies to Shorten the Time to Market”; “Innovative Materials: Choices for Next Generation Medical Devices”; and “Intelligent subcutaneous delivery: moving beyond the bolus”. Positioned at the heart of the event, newly launched products will be showcased through the Innovation Gallery, which offers visitors an overview of some of most exciting developments. This year’s most significant innovations will be revealed during the Pharmapack Awards ceremonies. In 2015, an independent jury panel, composed of pharmacists from hospitals, academic researchers and pharma R&D experts,

awarded three winners in the health product category: RebiSmart® by Merck Serono; Easybox® by Teva Laboratories; and Bucomax by Pierre Fabre Médicaments laboratories. The winners in the exhibitor category were: Safety Syringe System from Credence MedSystems; the Datapen from Biocorp; and the tamper-evident folding box from Igb. And finally, visitors voted Press&Take from Stiplastics, a dispenser system for granules, capsules and micro-tablets, as their winner. A new addition for 2016, the Innovation Tour presents a unique opportunity for companies already enrolled in the Innovation Gallery to have their technologies championed by an industry expert to potential customers. Pharmapack Europe 2016 is the essential event for anyone looking to do business in, or learn more about innovations in, drug delivery and packaging – the trends and partnerships emerging here will push boundaries, create new revenue streams and drive the industry forward. So please, explore more about the event on www.pharmapackeurope.com “It is the essence of pharmaceutical packaging in Europe, all in one place” Helen Marshall, Global Category Manager, Astra Zeneca

Winter 2015 Volume 7 Issue 4


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PHARMACONEX 2016 About PHARMACONEX: Pharmaconex is the leading industrial pharmaceutical event in North Africa and the Middle East. The exhibition and conference has successfully run for the past three years and expanded year on year. We are excited to announce the launch of the 4th edition of this event, “PHARMACONEX 2016”, which will be held in Cairo International Convention Center (CICC), Cairo, Egypt, April 19-21, 2016. Pharmaconex hosts a vast exhibition area, which allows worldwide industrial pharmaceutical companies to showcase the latest products, services and technologies in drug manufacturing, with a unique scientific educational conference which brings together academic and industrial professionals from around the globe to introduce and share their knowledge and experiences to keep pace with rapid developments in the pharmaceutical industry. Pharmaconex 2015 Facts and Figures Exhibition: over 7500 sq. metres represented more than 150 international and local exhibitors specialised in manufacturing machinery, raw materials, packaging and consultation services to introduce to the Egyptian and neighbouring countries the latest technologies in production techniques and raw materials sources from all over the world. Visitors: More than 3570 visitors representing decision-makers in the pharmaceutical industry; CEOs, general managers, production managers, production engineers, laboratory specialists, IT engineers, QA & QC, cGMP and auditing consultants. Conference: Pharmaconex 2015 International Conference on Pharmaceutical Technologies brought together more than 50 academics and industrial professionals from Australia, Belgium, Egypt, England, France, Germany, Italy, Saudi Arabia, Switzerland and the USA. Eight parallel workshops/symposia cover tablets & capsules manufacturing technologies, sterile products advances technologies, advanced drug delivery systems, cleanroom technology and cGMP. Last year, the number of conference attendees reached 500 participants representing different departments from all pharmaceutical companies in Egypt. 98 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Alongside exhibition activities: B2B meetings with CEOs, CFOs and consultants of pharmaceutical factories with a selection of African hosted buyers. Participating Entities: Ministry of Health, Ministry of Trade and Industry, Arab League, Industrial Chamber of Pharmaceuticals, The Pharmaceuticals Export Promotion Council Of India (Pharmaexcil). Why Egypt? According to BMI Industry View © Business Monitor International Ltd BMI View: Egypt's pharmaceutical market presents one of the most attractive investment destinations for multinational drug-makers in the MENA region. A large market size and population coupled with an improved political and economic outlook support our positive outlook for Egypt. Headline Expenditure Projections • Pharmaceuticals: EGP29.50bn (USD4.17bn) in 2014 to EGP33.08bn (USD4.24bn) in 2015; +12.1% in local currency terms and 1.7% in US dollar terms. Forecast upgraded from Q315. • Healthcare: EGP98.31bn (USD13.88bn) in 2014 to EGP109.66bn (USD14.04bn) in 2015; +11.6% in local currency terms and 1.2% in US dollar terms. Forecast in line with Q315. Why Exhibit Exhibit at Pharmaconex to: • Launch new products. • Develop international networking and meet quality contacts. • Promote skills including innovative product solutions tailored to the decision-maker’s needs. • Propose your solutions to the decisionmakers of the industry. • Join the international manufacturers and suppliers in your area. • Enter new markets and/or develop your business. • Maintain contact with existing customers. • Meet your prospects and generate new leads. • Share on concrete projects. • Expand your network and meet your peers within the local and international platform. • Benefit from international media coverage.

Exhibitor & Visitor Profiles Exhibitor Profile • Raw materials pharmaceuticals • Production equipment • Disposables • Control and instrumentation equipment • Clinical research • Packaging materials and containers • Turnkey projects • Engineering, re-engineering & designing companies • Individual safety devices • IT for pharmaceutical industry, professional publications • Contract manufacturing • Pharma logistics • Financial institutions • Laboratory equipment • R&D equipment • Manufacturing accessories • Utilities • Consultancy Visitor Profile • Pharmaceutical manufacturers • Cosmetic manufacturers • Chemical manufacturers • Food and beverage manufacturers • Educational institutions • Engineering companies • Research institutions • Government • Trading agents Promotional Activities • Email campaign • Direct marketing • Social media campaign • SMS campaign • E-invitation system • Media coverage • Website • Newspaper advertisements Contact us Egypt Office Arab African Conferences and Exhibitions Samar Awad Exhibition Manager Email: samar.awad@pharmaconex.net Mobile: +2 010 24445031 Dubai Office Informa Life Sciences Exhibitions Grace Brown Email: grace.brown@informa.com Mob: +971 5 51528369 www.pharmaconex.net pharmaconex@informa.com

Winter 2015 Volume 7 Issue 4


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 101


Chapter Title News AZ announces $4-billion deal for majority stake in Acerta AstraZeneca how has confirmed that it intends to take a majority stage in privately held US/Dutch clinical stage biopharma Acerta Pharma in a deal valued at $4 billion.

Morquio A syndrome), which affects just 88 people in England, under a managed access agreement between the drugmaker and NHS England.

The drugs giant said it will pay Acerta $2.5 billion upfront, plus an unconditional $1.5 billion either on receipt of the first regulatory approval for cancer drug acalabrutinib in the US, or the end of 2018, depending on which comes first.

People born with the disease lack an enzyme that breaks down large sugar molecules the body can’t utilise, leading to their accumulation in tissues and organs causing a wide range of symptoms such as joint and skeletal abnormalities, hearing and vision loss, heart valve disease and pain.

The agreement also provides Acerta’s shareholders the opportunity to sell, and AZ to buy, the remaining 45% of the firm’s shares. These options can be exercised at various points in time, conditional on the first approval of acalabrutinib in both the US and Europe and when the extent of the commercial opportunity has been fully established, at a price of around $3 billion net of certain costs and payments incurred by AZ.

Vimizim replaces this enzyme, offering the first treatment that targets the underlying cause of the disease, at a cost of around £395,000 per patient, per year. But under the agreed managed access arrangement, all clinically suitable patients in England will be allowed treatment with the drug over the next five years, while clinical data on its use is collected for future evaluation of provision.

Acalabrutinib is being tested in a variety of leukaemia’s, lymphomas and other cancers, and alongside Merck & Co’s immunotherapy Keytruda (pembrolizumab). The drug is a BTK inhibitor with a mode of action similar to AbbVie/Johnson & Johnson’s blood cancer drug Imbruvica (ibrutinib), which is widely expected to rake in peak sales in excess of $5 billion.

“The Committee concluded that the combined funding arrangements specified in the managed access agreement offered acceptable value for money in the context of the uncertainty of the clinical benefits and will be used to inform a future review of this guidance,” said Meindert Boysen, Technology Appraisals Programme Director at NICE.

Early clinical data looks promising; results from a Phase I/ II study recently published in the New England Journal of Medicine showed a 95 percent response rate in patients with relapsed chronic lymphocytic leukaemia, the most prevalent form of adult leukaemia.

Vimizim was rejected by the Scottish Medicines Consortium back in September despite a “powerful testimony” from patients about the impact of the disease. “While elosulfase alfa has the potential to improve quality of life in the short term, the case presented by the company was not robust enough to convince the Committee about the longer-term benefits when balanced against its extremely high cost,” the SMC said at the time.

“Acalabrutinib provides us with a small molecule presence in blood cancers to complement our existing immunotherapy approach, in collaboration with Celgene in haematological malignancies,” said AZ’ chief executive Pascal Soriot. “Furthermore, we look forward to working closely with the Acerta team and benefiting from the considerable clinical expertise they bring in this complex area of medicine”. The move falls in line with AZ’ strategy of focusing acquisitions to boost its long-term growth prospects. Just last month, the company announced plans to buy US biotech ZS Pharma for $2.7 billion, gaining access to its flagship cardiovascular compound, a potential best-in-class treatment for hyperkalaemia - a condition characterised by elevated levels of potassium in the blood linked with increased mortality in chronic kidney disease and coronary heart failure. The transaction with Acerta is expected to complete by the end of the first quarter of 2016, subject to customary closing conditions, and be moderately dilutive to AZ’ core earnings in the near term. Final NICE OK for Biomarin's Vimizim Patients with a very rare inherited lysosomal storage disease will now get treatment with Biomarin’s Vimizim funded on the National Health Service in England and Wales after cost regulators issued a final nod for the drug. As part of its Highly Specialised Technologies Programme, NICE has recommended Vimizim (elosulfase alfa) for the treatment of mucopolysaccharidosis type IVa (also known as MPS IVa and 102 INTERNATIONAL PHARMACEUTICAL INDUSTRY

GSK/Janssen RA drug on track for filing next year A new therapy being developed by GlaxoSmithKline and Janssen as a treatment for rheumatoid arthritis has passed late-stage clinical safety and efficacy tests, paving the way for regulatory filings next year. The UK drugs giant said it has banked positive top-line results from the Phase III programme investigating the human antiinterleukin 6 monoclonal antibody sirukumab for the treatment of patients with moderately to severely active rheumatoid arthritis. The programme consists of three studies, the first of which, SIRROUND-T, includes patients with active RA despite antitumor necrosis factor (TNF)-alpha therapy. The second, SIRROUND-D, involves patients with active RA despite taking disease modifying anti-rheumatic drugs (DMARDs), and the third, SIRROUND-H, compared subcutaneous sirukumab with adalimumab (an anti-TNF monoclonal antibody), in biologic naïve patients intolerant, unable to take, or unresponsive to methotrexate. Full results from these three pivotal studies will be presented at forthcoming scientific conferences and submitted for publication in peer-reviewed journals, GSK said, but also stressed that there were no unexpected safety findings relative to the known effects of anti-IL-6 inhibitors. Janssen and GSK formed a co-development and coWinter 2015 Volume 7 Issue 4


ChapterNews Title commercialisation pact for sirukumab in RA back in 2011. The agreement allows both companies the option to investigate the drug for other indications beyond RA; GSK is also testing sirukumab in a Phase III trial involving patients with Giant Cell Arteritis. FDA approves Lilly's diabetes drug Basaglar Eli Lilly and Boehringer Ingelheim’s insulin Basaglar has now been awarded full clearance by US regulators, following a tentative approval in 2014, offering the first “follow-on” insulin glargine product to treat diabetes. Basaglar, which is considered a biosimilar of Sanofi’s blockbuster diabetes drug Lantus in the EU but not the US, has the same amino acid sequence as the currently marketed insulin glargine product. The product was assigned a tentative approval for controlling high blood sugar in adults and children with type I diabetes and adults with type II diabetes because, while it ticked all the regulatory boxes for approval, it remained the subject of a patent infringement suit filed by Sanofi. Sanofi and Lilly finally settled the US patent infringement lawsuit relating to Lantus SoloSTAR (insulin glargine) in September. The once-daily injectable was approved by regulators in Europe in 2014, where it is marketed as Abasria, after clinical studies showed the product to have a comparable quality, safety and efficacy profile to Lantus. NHS finances to continue downward spiral, warns NAO The financial state of acute NHS hospital trusts significantly declined in the last year and is still on a downward spiral, according to a report by the National Audit Office. The “severe deterioration” in the financial position of NHS trusts and foundation trusts (FT) was worse than expected, as debts of £843 million were racked up - a far cry from the £91 million shortfall booked in 2013/14 - and net deficit for the current year is now on track to hit £2.2 billion. Overall, NHS bodies - NHS England, clinical commissioning groups, NHS trusts and NHS FT - swung from a surplus of £722 million in 2013/14 to a deficit of £471 million in last year, but this includes an underspend of £190 million by NHS England of £182 million by CCGs. The Department of Health has already put in place some measures to curb trust spending, but the public spending watchdog is warning that the response by the Department, Monitor and the NHS Trust Development Authority might come too late to improve the 2015-16 financial position.

pressure on acute trusts will not go away. Until there is a clear pathway for trusts to get back to financial stability, we cannot be confident that value for money will be achieved,” said NAO head Amyas Morse. Meg Hillier, chair of the Committee of Public Accounts, told the Telegraph: “It is simply unacceptable that the finances of acute hospital trusts have deteriorated at such a severe and rapid pace. Some NHS and foundation trusts are only getting by on handouts, costing the taxpayer £1.8 billion in 2014-15.” The NAO is recommending that all NHS bodies work together to improve the trust planning process and their oversight of financial risk, that the DH fully considers how any proposed cost containment measures will be implemented successfully in practice, and that it moves “ambitiously and more thoroughly’ to set savings goals and secure financial sustainability. First Clinical Commissioning Group in special measures In an unprecedented move, NHS England has now placed NHS Shropshire Clinical Commissioning Group in special measures, indicating that it has grave concerns across the breadth of the Group’s operations. The special measures regime, which forms part of the CCG Assurance Framework, is designed to offer a structure for measured performance improvement overseen by NHS England while allowing the CCG to remain accountable for its functions. As such, a ‘turnaround team’ was recently sent into the Group to help address some of the core challenges it faces and improve its financial position, which is on track for an in-year deficit of some £10.6 million. Now the CCG is officially in special measures the initial focus will be on: producing a financial recovery plan’ setting up an external capacity and capability review, which will feed an overall improvement plan; and recruitment of a turnaround team. Weekly financial review meetings with the NHS England Director of Commissioning Operations for North Midlands and monthly meetings with the Regional Director are also to take place, the CCG was told in a letter from NHS England. But Gill George, chair of the Group, recently told local publication the Evesham Journal: “The real problem is that there isn’t enough money coming into Shropshire’s NHS in the first place”. “Funding policy discriminates against rural areas and discriminates against areas with an older population. This means that Shropshire loses out twice”.

The auditor is also questioning whether a coherent plan in is place for the extra £8.4 billion promised by the government for the NHS and how to get trusts’ finances back on track “to close their estimated £22 billion gap between resources and patients’ needs by 2020/21”, and reiterated its warning that the trend of declining financial performance is not sustainable. Pressure 'will not go away' “Continued demand for healthcare services means that the www.ipimedia.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 103


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104 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Winter 2015 Volume 7 Issue 4


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IPI - Volume 7 Issue 4  
IPI - Volume 7 Issue 4  
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