JCS V13 I6

Volume 13 Issue 6

JOURNAL FOR

U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets

PEER REVIEWED

Querying the Queries An AI Approach to Manage Clinical Data Quality Deep Brain Stimulation Could Address Suicide Risk in Individuals Resistant to Treatment The Future of Healthcare Ecosystems The Real-World Impact of IDMP In-Home Services A Patient-Centric Approach to Improving Recruitment and Retention in Clinical Trials

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Contents

JOURNAL FOR

U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets MANAGING DIRECTOR Mark A. Barker BUSINESS DEVELOPMENT Clement Brown clement@senglobalcoms.com EDITORIAL MANAGER Beatriz Romao beatriz@senglobalcoms.com DESIGNER Jana Sukenikova www.fanahshapeless.com RESEARCH & CIRCULATION MANAGER Jessica Dean-Hill jessica@senglobalcoms.com ADMINISTRATOR Barbara Lasco FRONT COVER istockphoto PUBLISHED BY Senglobal Ltd. Unite 5.02, E1 Studios, 7 Whitechapel Road, E1 1DU, United Kingdom Tel: +44 (0) 2045417569 Email: info@senglobalcoms.com www.journalforclinicalstudies.com

4 FOREWORD TALKING POINT 6 Interview with Clinerion: Health Outcomes in Clinical Trials Clinerion is a company offering real-world data insights from their global hospital network covering over 36 million patients in almost 20 countries, online and refreshed daily. Senglobal talks with Douglas Drake at Clinerion to know more about the health outcomes in clinical trials.

WATCH PAGES 8 Integrated CDMO Growth Will Lead to Patients Seeing Record Number of Drugs Making it to Market It’s undoubtedly a very interesting time for the global CRO industry.

This is particularly true for CROs with locations across the world who have been able to leverage the talent available globally to support their customers’ projects. Ramesh Subramanian at Aragen talks about integrated CDMO growth will lead to patients seeing record number of drugs making it to market.

10 In-Home Services: A Patient-Centric Approach to Improving Recruitment and Retention in Clinical Trials Advances in wearables, telemedicine, and remote monitoring technology along with the convenience of in-home visits were bound to make decentralised and hybrid clinical trials standard with enough time. The adoption of in-home clinical services increased during the pandemic to reduce risks around bringing patients on site and it is likely that this approach is set to increase as sponsors see how it can support increased patient compliance, while also giving patients more flexibility in how they participate and increase recruitment and retention. Jodie Huddleston at ICON plc. explains the patient-centric approach to improve recruitment and retention in clinical trials.

12 Deep Brain Stimulation Could Address Suicide Risk in Individuals Resistant to Treatment

Journal by Clinical Studies – ISSN 1758-5678 is published bi-monthly by Senglobal Ltd.

Pharmaceutical and behavioural therapy treatments have successfully helped many patients manage symptoms of mental health conditions, such as major depressive disorder (MDD), posttraumatic stress disorder (PTSD), and schizophrenia, but patients who are refractory to those treatments have few options.

The COVID-19 pandemic has only underscored this treatment gap, prompting an increasing number of individuals to seek treatment for depression. Jaime Polychrones at Clarivate analyses deep brain stimulation that can address suicide risk in individuals resistant to treatment.

The opinions and views expressed by the authors in this magazine are not neccessarily those of the Editor or the Publisher. Please note that athough care is taken in preparaion of this publication, the Editor and the Publisher are not responsible for opinions, views and inccuracies in the articles.

Great care is taken with regards to artwork supplied the Publisher cannot be held responsible for any less or damaged incurred. This publication is protected by copyright.

REGULATORY

Volume 13 Issue 6 December 2021 Senglobal Ltd.

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14 Clinical Trials – Somewhere Between Tradition and Digital Modernity – A Wake-Up Call In the minds of young companies from the pharmaceutical or medical device sector, clinical trials lie somewhere in the future and are at best perceived as a necessary evil. Even the fact that clinical trials are part of the largest cost block of product development and take up a considerable part of the remaining patent term is acknowledged by the companies and their investors with a maximum shrug of the shoulders. Sven Engel at SynapCon Journal for Clinical Studies 1

Contents explains how clinical registration studies are not pharmacological phase I or phase II a studies in a 100 % controlled environment, but an organisational, highly complex and decentralised project with a large number of actors.

THERAPEUTICS

18 The Future of Healthcare Ecosystems: The Real-World Impact of IDMP

Ten years ago, our team published a commentary on what assuredly appeared to be the “Death of CNS Drug Development: Overstatement or Omen” after several large pharmaceutical companies abandoned or severely restricted neuropsychiatric drug development efforts citing costly and long development periods with relatively lower chances of successful drug applications. Christine K. Moore, Natalia E. Drosopoulou and Henry J. Riordan at Worldwide Clinical Trials talk about portending a renaissance in neuroscience drug development.

A lot of lip service has been paid by the IDMP software industry to the potential of data-driven processes beyond regulatory compliance.

But the opportunities are very real – and wide-ranging – and pharma companies and their software providers have an important role to play in enabling these advances, through their ambitions for and approach to data-driven information management and transparency. Biotechs, without legacy systems and processes to hold them back, might even lead the way. Frits Stulp at Iperion sets out the enhanced role that could be played by a standardised datadriven ecosystem that’s actively promoted by the pharma industry.

20 A Guide for Establishing and Governing Data Collection Standards Many data management teams report that their standards initiatives have stalled or failed because executives aren't bought-in, standards are over-proliferated, or they are stuffed with exploratory variables.

In this guide, leaders across pharmaceuticals, biotechnology, generics, and medtech will learn best practices to build and maintain an effective clinical data collection standards program while driving team adherence. Ami Dudzinski Mehr and Drew Garty at Veeva Systems show a guide that provides recommendations on defining specification and variable tables and when it is appropriate to develop internal standards versus using existing widely accepted standards.

MARKET REPORT 24 Unlocking the Business Benefits of Text Mining in Regulatory Operations As IDMP implementation advances in Europe, data is becoming a key asset for the life sciences industry. Currently, pharma companies are focusing on the heavy burden of initial data collection, but ultimately it is data maintenance that will become the prevalent challenge. This can only be tackled by paying continuous attention to the quality and integrity of data. Renato Rjavec at Amplexor explains advanced text mining technologies, applied in the context of end-to-end regulatory information management, can help considerably both with accurate data ingestion and ongoing data maintenance.

26 Medical Writing – Benefit of Good Medical Writing Knowledge is vital at every stage of a medicine’s lifecycle – from that first glint in the scientist’s eye at their origin, to the delivery of a medicine to patients with detailed instructions on their safe use.

And at each stage, this knowledge is passed on in writing. Medical writers are professionals with a broad expertise in communication, who are skilled at presenting complex information in a manner that is clear, logical, and attuned to the needs of a particular audience.

Tahseen Khan at Labcorp shows the benefit of good medical writing.

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32 Anticipating a Renaissance in Neuroscience Drug Development

36 Patient Engagement and Real-World Data Drive Innovation in Orphan Disease Drug Development An estimated one in 10 people are affected by a rare disease, and the cumulative economic burden of rare diseases surpasses that of common conditions like cancer or diabetes. Yet of the 7,000 known rare diseases, approximately 95% lack effective treatments.

Rare disease research is complicated by small and dispersed patient populations and often limited understanding of disease pathogenesis and progression. Caitlin Nichols and Kristina Cotter at AllStripes Research examine patient engagement and real-world data drive innovation in orphan disease drug development TECHNOLOGY 40 Querying the Queries – An AI Approach to Manage Clinical Data Quality High quality clinical trial data is essential for a successful clinical trial.

This data is the foundation for the analysis, submission, approval, labelling and marketing of a compound. A focus on data cleaning, an essential process in the collection and management of clinical data, ensures that the data collected is consistent and accurate. Jennifer Bradford and Sheelagh Aird at PHASTAR analyse AI approach to manage clinical data quality.

LOGISTICS & SUPPLY CHAIN 42 The Role of the Falsified Medicines Directive and Delegated Regulation in the Supply Chain of Clinical Trials Companies providing clinical trial supply services to sponsors and contract research organisations (CROs) need to comply with a complex framework of regulatory requirements and industry standards. To ensure that the integrity of the supply chain of pharmaceutical products remain intact in the European Union (EU), a series of regulatory measures have been adopted by the European institutions and the European Medicines Agency (EMA) in the last decade. Tibor KOVÁCS at PHARMAROAD KFT. exams the role of the falsified medicines directive and delegated regulation in the supply chain of clinical trials.

45 Intricacies and Future Considerations for the Cell and Gene Therapy Cold Chain The rapidly growing field of cell and gene therapy is both exciting and confusing to many, including those who work in the medical community and on the periphery. Advancements of therapies happen at a feverish pace. The number of clinical trials increases exponentially in a short time. And bringing therapies to commercialisation remains a hurdle. Vince Paolizzi at Peli BioThermal highlights the Intricacies and Future Considerations for the Cell and Gene Therapy Cold Chain.

Volume 13 Issue 6

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Our Spotlight Services Include: - Assay Development - Kit Building - Biomarkers - Preclinical Services - Histology and Digital Imaging - Sample Management and Storage Learn what keeps #MLMinMotion at www.mlm-labs.com

Foreword The festive season is drawing ever closer and here at JCS, we are thrilled to bring you our sixth and final issue of the year!

Artificial intelligence is now affecting every area of our lives. From the self-driving cars, that increasingly populate our roads, to the virtual assistants that live in our phones (and have spelt the end of anyone naming their child Siri or Alexa ever again). Nobody can question that, so far, AI has yielded a positive and far less apocalyptic effect on humanity than the killer robots of Hollywood initially had us believe.

One industry looking to capitalise on the benefits of AI is pharmaceuticals, where its uses and possible implementation almost seem unlimited.

Artificial intelligence and machine learning have been playing a critical role in the pharmaceutical industry and consumer healthcare business. From augmented intelligence applications such as disease identification and diagnosis, and helping identify patients for clinical trials, to drug manufacturing, and predictive forecasting, these technologies have proven critical.

The COVID-19 pandemic has shown itself to be an unexpected testing ground for AI to prove its present-day capabilities in the pharmaceutical industry. The hunt for new compounds to develop a vaccine, and mapping of the virus’ genetic sequence so we can understand it better are all tasks that AI is well-purposed for: large amounts of information that need swift, iterative processing as well as the ability to discern particular patterns from the data.

High-quality clinical trial data is essential for a successful clinical trial. This data is the foundation for the analysis, submission, approval, labelling and marketing of a compound. A focus on data cleaning, an essential process in the collection and management of clinical data, ensures that the data collected is consistent and accurate. Jennifer Bradford and Sheelagh Aird at PHASTAR analyse the AI approach to manage clinical data quality.

posttraumatic stress disorder (PTSD), and schizophrenia, but patients who are refractory to those treatments have few options.

The COVID-19 pandemic has only underscored this treatment gap, prompting an increasing number of individuals to seek treatment for depression. Jaime Polychrones at Clarivate analyses deep brain stimulation that can address suicide risk in individuals resistant to treatment.

Knowledge is vital at every stage of a medicine’s lifecycle – from that first glint in the scientist’s eye at their origin to the delivery of medicine, to patients with detailed instructions on their safe use. And at each stage, this knowledge is passed on in writing. Medical writers are professionals with broad expertise in communication, who are skilled at presenting complex information in a manner that is clear, logical, and attuned to the needs of a particular audience. Tahseen Khan at Labcorp shows the benefit of good medical writing.

As IDMP implementation advances in Europe, data is becoming a key asset for the life sciences industry. Currently, pharma companies are focusing on the heavy burden of initial data collection, but ultimately it is data maintenance that will become the prevalent challenge. This can only be tackled by paying continuous attention to the quality and integrity of data. Renato Rjavec at Amplexor explains advanced text mining technologies, applied in the context of end-to-end regulatory information management, can help considerably with both accurate data ingestion and ongoing data maintenance.

I hope you all enjoy your festive season and I look forward to welcoming you back in the new year, with more enthralling articles to be included in JCS. Beatriz Romao, Editorial Manager Journal for Clinical Studies

Pharmaceutical and behavioural therapy treatments have successfully helped many patients manage symptoms of mental health conditions, such as major depressive disorder (MDD), JCS – Editorial Advisory Board

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Hermann Schulz, MD, Founder, PresseKontext

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Ashok K. Ghone, PhD, VP, Global Services MakroCare, USA

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Jeffrey W. Sherman, Chief Medical Officer and Senior Vice President, IDM Pharma.

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Bakhyt Sarymsakova – Head of Department of International Cooperation, National Research Center of MCH, Astana, Kazakhstan

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Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

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Catherine Lund, Vice Chairman, OnQ Consulting

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Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

Cellia K. Habita, President & CEO, Arianne Corporation

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Maha Al-Farhan, Chair of the GCC Chapter of the ACRP

Chris Tait, Life Science Account Manager, CHUBB Insurance Company of Europe

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Deborah A. Komlos, Senior Medical & Regulatory Writer, Clarivate Analytics

Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmacy

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Robert Reekie, Snr. Executive Vice President Operations, Europe, AsiaPacific at PharmaNet Development Group

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Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai)

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Stefan Astrom, Founder and CEO of Astrom Research International HB

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Steve Heath, Head of EMEA – Medidata Solutions, Inc

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Elizabeth Moench, President and CEO of Bioclinica – Patient Recruitment & Retention

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Francis Crawley, Executive Director of the Good Clinical Practice Alliance – Europe (GCPA) and a World Health Organization (WHO) Expert in ethics

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Georg Mathis, Founder and Managing Director, Appletree AG

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Volume 13 Issue 6

Insights from the real world, in real time Clinerion enables faster access to innovative medical treatments for patients and physicians by unlocking the full scope of longitudinal information from patient electronic health records to generate productive real-world data.

Develop cohort models to understand and map patient risk factors, follow individual treatment paths or demographic groupings.

Enable metrics for personalized patient care and stratification, with instantaneous access to live data on patient journey and outcomes.

Image by Bill Oxford, on Unsplash

Understand pandemic epidemiology: follow infection rates and treatment patterns in near-real-time, as well as identify patient risk factors.

www.journalforclinicalstudies.com

Journal for Clinical Studies 5

Talking Point

Interview with Clinerion: Health Outcomes in Clinical Trials Q1. Can you start by explaining a little bit about Clinerion and What are Clinerion’s ambitions for the future?

Clinerion is a company offering real-world data insights from our global hospital network covering over 36 million patients in almost 20 countries, online and refreshed daily. The Clinerion Patient Network Explorer can be used to query real-time, anonymized EHR data that can be used for study feasibility, as well as to follow patient journey and outcomes. Our network contains significant longitudinal data of between 5 to 7 years, on average. Partner hospitals can use our Patient Finder internally for their own patient care, stratification and outreach for clinical research and trial recruitment.

Our goal is to better enable digital healthcare data, not just for care reimbursement but for actual patient care, and better patient outcomes. Digital data is now at the forefront of better patient engagement, diagnosis and monitoring and Clinerion’s technology enables hospitals, care givers and clinical research partners to use the digital resources already within the hospital better.

Q2. What is real-world data (RWD) solutions and How does it enable Pharma to achieve its goals?

Real World Data is entirely about perspective. What health data is needed to answer your question? RWD now encompasses the entire pharmaceutical process from discovery and development into clinical research and commercialization. The specific question requires a specific answer and thereby a specific data capability to answer. EHR data, such as Clinerion´s, help in pre-clinical and clinical understanding of patient journey and outcomes and improving outcomes.

Q3. How does Clinerion use RWD to improve clinical trials and thus health outcomes?

Clinerion is unique in our relationship with our hospitals within our network in that we provide at no charge, a first-ever interface for many member hospitals to see and use their own health information system (HIS) data for their own patient care and stratification. Often this data is used for care reimbursement and not able to be queried by physicians and care givers. However, as part of the digital ecosystem within the hospital, making this data available for actual healthcare is part of Clinerion´s mission of “SMART hospital” enablement and democratization of healthcare data, globally.

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To the specific question of how we improve clinical trials, the unique configuration of the Patient Network Explorer, outside the hospital, and Patient Finder, inside the hospital, allows the hospital staff, with appropriate permissions, to re-identify patients from trial criteria, enabling faster patient screening for outreach and potential clinical trial recruitment. This supports better healthcare outcomes, especially in rare diseases, where this framework can be used phenotypically to identify patients that have never yet been correctly diagnosed. By highlighting potential patients with by disease phenotypes, a hospital with study approval can create an outreach program, run diagnostic screening and thereby correct misdiagnoses and medication.

Q4. Patient Network Explorer – how does it work in respect to clinical trials?

In a clinical trial, a query is generated on anonymized patient data in Patient Network Explorer. This query can be accessed by the Patient Finder inside the hospital, allowing the clinical research team to screen patients for potential clinical trial inclusion. They can re-identify and recruit candidates directly from their patient records. This is unique and a singular hybrid technology that allows immediate and real time metrics on patient, patient care and patient feasibility toward clinical trial inclusion.

Q5. How does Patient Network Explorer’s hybrid technology benefit Health Outcomes?

Simply put, digital enablement is immediate, real time, and therefore more enabling to patients in need where time is critical and time-to-diagnosis, time-to-treatment, time-to-care is critical to outcome and therefore to better treatment metrics.

Q6. Although mHealth devices and sensors are continuing to evolve, and it is now possible to capture a vast array of physiological data, the operationalization of digital trial is not without challenges. Can you explain the benefits of integrating digital health effectively and efficiently?

Although there is increasing more digital data available, it is also increasingly a question of whether the data is fit-for-purpose and ensuring that the data available is appropriate to the scope and intent of the research. Increasingly, with the Internet of Things and digital metrics, Volume 13 Issue 6

Talking Point

there are more and more mechanisms to derive behaviour tracking and human physiological metrics. These must, as in any clinical research, have purpose and ethical intent.

Q7. Decision makers in health care are increasingly interested in using high-quality scientific evidence to support clinical and health policy choices; however, the quality of available scientific evidence is often found to be inadequate. How does Clinerion plug the hole in research data analysis?

Electronic health records are high quality clinical data as they are a record of patient care and the patient journey over the course of diagnosis and treatment within the hospital care setting. It is, however, one vector of data within an increasing array of healthcare data resources and metric outputs. Increasingly, the question is having the right tool, or data which is fit-for-purpose for the intent or question intended. Much like carpentry, the type of tools needed are specific to the type of wood you have and to what piece of furniture you want to make with it. So,

the first question is: what the research goal is, from which one can then scope the data and resources needed.

Q8. What are Clinerion’s plans for the clinical trials sector in 2022?

The need is always in the direction of more data, so Clinerion has strategic plans and efforts ongoing toward natural language processing to begin to incorporate unstructured data from physicians’ charts and gather interpreted diagnosis and care. In a further step, Clinerion is also developing the capability to apply artificial intelligence and machine learning models and learning metrics across our federated network in a federated learning model. Our model is always to work with the data in situ within the hospital, and not move care data outside the hospital firewall. This is critical to data privacy and regulatory compliance (e.g., GDPR). We only bring healthcare insights and model outputs outside without compromising primary patient data.

Douglas Drake Douglas Drake, MS, MBA, is originally a life science researcher with a passion for digital enablement of better patient care. For over 30 years, Douglas has worked in various aspects of diagnostics, therapeutic research, drug discovery and global business development. He has broad experience in transformative technologies, data sciences, digital healthcare and applying these to improving patient engagement and the patient journey.

www.journalforclinicalstudies.com

Journal for Clinical Studies 7

Watch Pages

Integrated CDMO Growth Will Lead to Patients Seeing Record Number of Drugs Making it to Market It’s undoubtedly a very interesting time for the global CRO industry. This is particularly true for CROs with locations across the world who have been able to leverage the talent available globally to support their customers’ projects.

Leveraging on the macro changes in outsourcing in the last year, there has been significant capital flowing into life sciences industry, and every company, whether a large pharma or a young biotech company, has externalisation as a key element of its core growth plan. In 2020 alone, the industry attracted over $23B in venture investments. India has come a long way in creating world class infrastructure and offering cutting edge research; and is now seen as an attractive destination for companies in US/EU to outsource their outsourcing needs required to drive their discovery, development, and manufacturing projects.

Demand for outsourcing discovery is rapidly increasing driven by two complementary factors. Firstly, the rise in the number of R&D projects from small biotechs who contribute a significant potion to the growing product pipeline. Secondly, the global trend in de-risking the over dependence on China by big pharma companies.

They see India as an alternate option which benefits the India CRO companies.

While it is true that some clinical and commercial manufacturing of APIs move back into the West, overall, there is not enough capacity within American and European contract providers to manufacture all steps of the APIs. This leads to two scenarios - one where all the synthesis steps of an API is made in India and the second approach where we see starting materials, intermediates, advanced intermediates, and regulated starting materials being supplied from Asia with final steps carried out in America or Europe. In summary, we expect India to grow and benefit from the expected growth in needs for discovery, development, API and Drug Product manufacturing.

As a CRO who has seen the dynamics of the market over the years, what have you chosen to focus on and what have you chosen not to cater to, as sometimes clarity on what not to do will take us closer to the goal faster?

It is an interesting question. We have been in the Indian CRO space for over two decades now. From offering stand-alone discovery chemistry services in our early days, we now offer comprehensive integrated discovery, development and manufacturing solutions for small molecules and biologics. We will continue to broaden our capacities in this space while creating niche differentiators in some of the expertise in discovery and development. We have identified those areas and will continue to invest in infrastructure and talent to retain our market leadership position. We also leverage with Aragen Biosciences to offer discovery, development solutions for 8 Journal for Clinical Studies

large molecules. Our growth strategy will include both inorganic and organic growth.

We have built our capabilities and infrastructure over the years listening to our customers’ future needs and backed with the industry best talent to provide cutting edge solutions.

In the last few years, we are also seeing the growth in the outsourcing of services to support biologics. We were the first Indian CRO to acquire a US CRO - Aragen Bioscience Inc. in 2014 to cater to the needs of companies in large molecules space and in development and manufacturing. We recently invested significantly in expansions, and now have the capacity to meet our customers’ immediate future needs. In biologics, we are advancing downstream, and investing in a manufacturing facility in the US to offer a single seamless solution to our customers that want to develop and manufacture at one place.

We have consciously chosen not to run our own internal drug discovery programs which can be a potential conflict to our business model. We also will not manufacture and market our own generic products.

What are the current trends to look out for in the CDMO market?

In a few words, it is being driven by the desire to find the scientific solutions to the most complex of problems. The science of biology and chemistry need to be completely integrated leverage on the power of AI to advance assets from concept to clinic. At the same time, we are seeing an increasing number of biotechs and the access to global talent to drive innovation. So, what we now have is a situation where R&D outsourcing has become a must have rather than a good to have strategy.

With the diversity of potential targets proliferating, it means that large pharma companies and biotechs need to have externalisation as a core part of their growth parts. The encouraging thing not just for ourselves, but for the wider contract research industry, is that this growth is accelerating, not abating. For example, in 2020 alone, we saw $23B in venture investments and the pandemic has attracted new venture capital partners into the industry at the same moment as there is a potential explosion of drug targets. What we anticipate over the next few years is that this will supercharge demand for discovery-into-development services, and we anticipate that the choice of CDMO will be a key factor in meeting development milestones.

How has the CDMO market evolved during the COVID pandemic?

One of the knock-on effects of the pandemic is that it has accelerated the growth and consolidation of the CDMO market, with a number of prominent deals in the last twelve months. In fact, even VCs [Bob Nelsen’s venture partner’s launch of resilience] that have traditionally only invested in innovative companies now looking to secure their supply chains with a CDMO in their portfolio of companies.

Volume 13 Issue 6

Watch Pages

For instance, what we saw that highlighted the need was that many of the pharma companies’ R&D/manufacturing sites were shut down for an extended period. But it’s also why CRDMOs (Contract Research Development Manufacturing Organisations) like ourselves realise the importance of being able to provide flexibility in supply chains in how we work with customers. To offer truly comprehensive services, you need facilities in different parts of the world where the expertise the clients need lie. Speaking of our customers, there is a significant demand for biological services, and we’ve aligned our facilities in regional bio hubs so that we can attract the best possible talent to join our discovery and development teams. Similarly, it is also important that CDMOs are able to provide security of supply chains by using a number of different sites.

More generally, what we have seen is a transition to remote monitoring and as an industry, we have increasingly innovated and used new technologies to provide real time reporting and longer time resilience planning. What we are undoubtedly going to see is that the larger, more integrated and global CDMOs are going to pick up the majority of the growth in the next few years. So, what you are going to see maybe five years from now is a much larger industry but also a much top-heavier contract services players. Companies like ourselves have both strategic alliances with big pharma and deeply integrated relationships with the biggest biotech hubs, especially those in the US. For example, in the past two years, Aragen has www.journalforclinicalstudies.com

grown by 19%, with our US Biologics arm doing phenomenally well (26% growth) – it is potentially a golden era not only for our company, but for the contract services industry as a whole. Most importantly, what we have not spoken about enough today, is the direct consequence of this – patients globally will see an increasing number of life-improving products making it to market.

Ramesh Subramanian Ramesh Subramanian is responsible for global business growth, leading sales, marketing, strategy and the corporate development function. With over 20 years of experience in leadership roles, Ramesh has built global businesses in Asia and Europe, raised venture capital, established transformational strategies, driven M&A, negotiated cross-border deals and managed alliances. Prior to Aragen, he served as Senior Vice President and was part of the management team at Piramal Pharma Solutions. Ramesh was previously a part of management teams at Chemizon, a firm he led from start-up to successful entry into the equity market; and Jubilant Life Sciences. He has also held leadership positions at SK Capital Partners/Ascend Performance Materials and Johnson Matthey.

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Watch Pages

In-Home Services: A Patient-Centric Approach to Improving Recruitment and Retention in Clinical Trials The Future of Clinical Trials Advances in wearables, telemedicine and remote monitoring technology along with the convenience of in-home visits were bound to make decentralised and hybrid clinical trials standard with enough time. However, the COVID-19 pandemic accelerated their adoption and now, even with the hope that the pandemic will soon be behind us, hybrid and decentralised models are poised to become viable solutions in clinical trial design because of their inherent agility, inclusivity and most importantly, patient centricity.

The adoption of in-home clinical services increased during the pandemic to reduce risks around bringing patients on site and it is likely that this approach is set to increase as sponsors see how it can support increased patient compliance, while also giving patients more flexibility in how they participate and increasing recruitment and retention.

To Include or Not Include – That is the Question…

In-home clinical trial services are beneficial in a wide range of studies across all trial phases and therapeutic areas, and can also be used as a strategy to rescue studies that are struggling to reach enrolment targets. However, there are certain study types that are particularly

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suitable for in-home trial visits. For instance, including in-home visits in a study that requires frequent assessments over a long period will reduce the overall patient burden, making it easier for them to continue in the trial.

The inclusion of in-home services also expands the geographical patient outreach of any single site. This approach can be particularly advantageous for both patient recruitment and retention in rare disease studies, where patients are more likely to be geographically dispersed.

A wide range of services can be performed in a home setting by licensed healthcare professionals including: • Administration of investigational product and comparator drugs (IV, injection, oral, nasal, or topical routes) • Biological specimen collection and processing • Body systems assessments • Measuring and recording vital signs which can also be supported by wearables and data-collection sensors • Adverse event and concomitant medication reconciliation.

These activities can also be performed at an alternative location designated by the patient, for instance in suitable room at a workplace, at school or while on vacation, making trial participation less disruptive for the patient.

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Watch Pages

What does the participant think?

In a recent survey conducted by ICON to gauge the willingness of respondents to participate in clinical trials featuring this and other components of decentralised and hybrid clinical trials, 33% indicated that they would opt for a hybrid of locations (in-home and in-site) for assessments and 30% had no preference for location. While not a unanimous vote for in-home services it does reflect the patient preference for options and convenience.

And as for the experience it seems like when conducted correctly in-home services can improve patient experience. In one study when 57 rare disease patients were asked about their experience, they collectively rated in-home clinical trial experience to be 9.5 out of 10.

Moreover, 75 percent of the respondents indicated that having inhome services available was a major factor in choosing to participate in the clinical trial in the first place, while 81 percent cited it as a factor for their ongoing participation in the study.

Regulatory, Logistical and Training Considerations It’s important to be aware that if you are planning to incorporate in-home visits, it must be stated in the protocol, submitted for institutional review board and ethics committee approval and included in the patient’s informed consent form. Additionally, adding in-home services mid-study is considered a protocol change and, therefore, must be reviewed and documented appropriately.

Therefore, making an early decision to include in-home clinical services can help minimise costly and time-consuming protocol changes down the road. The lead time to set up in-home services usually takes six to eight weeks. However, with upfront planning and consultation from an experienced in-home services provider, this initiation can be done efficiently without greatly affecting study start-up timelines.

In addition to the regulatory requirements for in-home patient visits, you also need to consider additional logistical and operational elements. This includes specialised training for nurses who will be meeting with patients in their homes (or other preferred locations); procuring and delivering clinical supplies and equipment and ensuring that a reliable digital and data collection framework is in place. Selecting the right sites is also essential, since they will always perform a critical role in the medical oversight of in-home services.

What Benefits the Patient, Benefits the Sponsor For patients, in-home services add flexibility in how they participate, empowering the patient to enrol in the study without the risk of compromising their lifestyle and making it easy to stay the course. www.journalforclinicalstudies.com

For sponsors, in-home clinical services can increase protocol compliance, expand the geographic reach of a clinical trial, and ultimately accelerate patient recruitment and enhance patient engagement.

It is important to assess the suitability of in-home services for the study in upfront study planning to ensure inclusion in the protocol and that the appropriate logistics are in place. With the support of an experienced partner, patient assessments can be conducted efficiently in-home and this can positively impact patient recruitment and retention targets.

Read more about the best ways to operationalise decentralised and hybrid clinical trials in our whitepaper.1 For additional information on Accellacare In-Home Services and their role in decentralised clinical trials, please visit accellacare.com/in-home.

REFERENCES 1.

https://iconplc.com/insights/transforming-trials/decentralised-and-hybridclinical-trials/practical-considerations-in-transitioning-to-dct/index.xml

Jodie Huddleston Jodie Huddleston is the Vice President of Accellacare In-Home Services, part of ICON plc. She has over 25 years of leadership experience in clinical research, including translational research, clinical strategy, business development and clinical operations. Prior to joining Accellacare, Jodie was the Senior Director, Mobile Research Solutions for IQVIA, where she built a new division within IQVIA’S Decentralized Trials division specialising in mobile research nursing and phlebotomy services to support clinical trial visits in the home.

Jodie also built homecare clinical trials strategy and operations as the Principal of Huddleston Consultancy and worked as the Director of Clinical Trials for CVS/Coram Specialty Infusion, leading their direct-to-patient clinical trials division. Throughout her career, she has also built new service offerings for several large organisations in academia, community hospitals, and clinical trial support organisations. Jodie received her BS in Nutrition and Exercise Physiology from Miami University and has completed graduate work in Pharmaceutical Management and Healthcare Administration from the University of Colorado.

Journal for Clinical Studies 11

Watch Pages

Deep Brain Stimulation Could Address Suicide Risk in Individuals Resistant to Treatment Between 1999 and 2016, the number of suicide attempts in the US increased in most states. According to the Substance Abuse and Mental Health Services Administration, 25 states experienced a >30% increase.1 In 2018, the US saw 48,344 deaths from suicide, 46,510 of which were adults.

Pharmaceutical and behavioural therapy treatments have successfully helped many patients manage symptoms of mental health conditions, such as major depressive disorder (MDD), posttraumatic stress disorder (PTSD), and schizophrenia, but patients who are refractory to those treatments have few options.

The COVID-19 pandemic has only underscored this treatment gap, prompting an increasing number of individuals to seek treatment for depression. Deep brain stimulation (DBS), a treatment that relies on a device and accompanying wires to target certain areas of the brain, may be a solution for some of these individuals.

The Current DBS Landscape The National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH) defines DBS as “a surgical procedure used to treat several disabling neurological symptoms” that “uses electrical stimulation to regulate electrical signals in neural circuits to and from identified areas in the brain to improve movement symptoms.”2 Multiple treatment sites in the brain have been proposed for refractory depression, according to Johns Hopkins University (JHU).3 The US Food and Drug Administration (FDA) approved the first DBS device in 1997 for the suppression of tremors in certain patients.

Since then, multiple device companies have developed and launched DBS devices for various indications. While DBS is currently only approved in the US to treat Parkinson’s disease, essential tremor, dystonia, obsessive-compulsive disorder (OCD), and, most recently, epilepsy, research continues on the use of DBS to treat mental health conditions. OCD was the first – and remains the only – psychiatric indication approved by the FDA for DBS.

Making Untreatable Depression Treatable MDD affects 15–17% of individuals in the US.4 The frequency of treatment-resistant depression (TRD) is difficult to quantify due to a lack of standard definitions and criteria, but the incidence of TRD in the literature is reported as 12–55%.5 In the US, approximately 30% of individuals with TRD have attempted suicide at least once.

FDA-approved drug treatment options for TRD include Eli Lilly and Company’s Symbyax (olanzapine/fluoxetine; capsule) and Janssen Pharmaceuticals, Inc’s Spravato (esketamine; nasal spray). Research is also ongoing into the use of psychedelics (e.g., psilocybin, 3,4-methyl​enedioxy​methamphetamine [MDMA]) to treat TRD.6 Eye movement desensitisation and reprocessing (EMDR) can also be used to treat depression and PTSD. Transcranial magnetic stimulation (TMS), a non-invasive form of brain stimulation, is another option, and 50–60% of individuals with depression who do not respond to medication have experienced clinically meaningful response with TMS.7 In 2005, the FDA approved Cyberonics, Inc’s Vagus Nerve Stimulation (VNS) Therapy System, an implantable generator connected to electrodes that deliver electrical signals to the left cervical vagus nerve, for TRD. Despite this long list of treatment options, some patients remain untreatable and are candidates for benefiting from a novel approach.

DBS has been shown through positron emission tomography (PET) imaging studies to reverse pre-treatment blood flow changes in depressed patients, similar to how antidepressants work.

In 2013, the FDA approved a premarket approval application (PMA) for the NeuroPace RNS System to treat certain patients with epilepsy. The University of California, San Francisco, is recruiting approximately 12 participants to evaluate the use of the RNS System from NeuroPace, Inc, for treatment-resistant MDD in a randomised, crossover-assignment, two-phase study (PReSiDio). Participants are randomised to an experimental arm or sham comparator arm and receive treatment in three stages.

The primary outcome measure of the study, which is estimated to complete in June 2035, is the change in Montgomery-Asberg Depression Rating Scale score.

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Watch Pages Emory University, in collaboration with Hope for Depression Research Foundation and the Dana Foundation, is conducting an open-label study to evaluate the use of a new type of DBS device to treat approximately 10 participants aged 18–70 years with TRD. The study is exploring local field potentials (LFPs) with the Medtronic Activa Primary Cell + Sensing (PC+S) “Brain Radio” System, which is not approved by the FDA. This device can record the electrical activity in the brain. Investigators are studying LFP in the brains of individuals with TRD before and during active stimulation and recording the readings for up to three years. The estimated study completion date is September 2023.

Ongoing Research for DBS to Treat Schizophrenia and PTSD Individuals with schizophrenia and PTSD could also potentially benefit from DBS treatment. JHU is recruiting 3 participants aged ≥22 years for an open-label pilot study to evaluate the use of DBS of the substantia nigra pars reticulata (SNr) in patients with treatmentresistant schizophrenia. Participants are implanted with a DBS therapy system from Medtronic and receive treatment using a method similar to that used in subthalamic nucleus stimulation in patients with Parkinson’s disease. The primary outcome measures – change from baseline in the Scale for the Assessment of Negative Symptoms (SANS) and the Brief Psychiatric Rating Scale (BPRS), as well as incidence of adverse device effects (ADEs) – are evaluated one year after implantation.

The VA Greater Los Angeles Healthcare System is studying the use of DBS in a difficult-to-treat population – Iraq and Afghanistan war veterans. Approximately 6 veterans aged 25–70 years with PTSD are being recruited for this study based on recent findings that PTSD patients experience abnormal activity in a specific brain region that is likely responsible for core PTSD symptoms. Participants are randomised to two arms to receive DBS through a Medtronic Activa DBS device. The primary outcome measure is the frequency and severity of all adverse events at one year. The estimated study completion date is December 2025.

A Potential Path to Decrease Suicide Attempts and Deaths Worldwide, the estimated risk of suicidal ideation and suicide attempts in individuals with MDD is 15%.8 Approximately 18–55% of individuals diagnosed with schizophrenia will attempt suicide in their lifetime,9 and PTSD is also a risk factor for suicide.10 As suicide rates continue to increase each year in some locations, the need for an innovative solution for individuals who struggle with suicidal ideation is paramount. The availability of more treatment options each year could show a decreasing trend in suicide attempts and deaths – but these staggering statistics suggest that the time for something new is now.

REFERENCES 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

Key Substance Use and Mental Health Indicators in the United States: Results from the 2019 National Survey on Drug Use and Health. (2020). Substance Abuse and Mental Health Services Administration. https://www.samhsa.gov/ data/sites/default/files/reports/rpt29393/2019NSDUHFFRPDFWHTML/ 2019NSDUHFFR1PDFW090120.pdf Deep Brain Stimulation for Movement Disorders Information Page. National Institute of Neurological Disorders and Stroke Website. https://www.ninds. nih.gov/Disorders/All-Disorders/Deep-Brain-Stimulation-MovementDisorders-Information-Page#:~:text=Deep%20brain%20stimulation%20 (DBS)%20is,slowed%20movement%2C%20and%20walking%20problems Deep Brain Stimulation (DBS). The Johns Hopkins University Website. https://www.hopkinsmedicine.org/psychiatry/specialty_areas/brain_ stimulation/deep_brain.html Major Depressive Disorder and Treatment-Resistant Depression: Targeting Suicidal Ideation. Psychiatry Advisor Website. https://www. psychiatryadvisor.com/howtotreat/major-depressive-disorder-andtreatment-resistant-depression-targeting-suicidal-ideation/ Zhdanava M, Pilon D, Ghelerter I, et al. The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United States. J Clin Psychiatry. 2021;82(2).

Polychrones J. Psychedelics make a comeback to treat mental health conditions. J for Clin Studies. 2020;12(6):6–7.

Stern AP. Transcranial magnetic stimulation (TMS): Hope for stubborn depression. Harvard Health Blog. 2018. https://www.health.harvard.edu/ blog/transcranial-magnetic-stimulation-for-depression-2018022313335 Orsolini L, Latini R, Pompili M, et al. Understanding the complex of suicide in depression: From research to clinics. Psychiatry Investig. 2020;17(3):207– 221. https://doi.org/10.30773/pi.2019.0171 Sher L, Kahn RS. Suicide in schizophrenia: An educational overview.

Medicina (Kaunas). 2019;55(7):361. https://doi.org/10.3390/medicina55070361 Fox V, Dalman C, Dal H, et al. Suicide risk in people with post-traumatic stress disorder: A cohort study of 3.1 million people in Sweden. J Affect Disord. 2021;279:609–616. https://doi.org/10.1016/j.jad.2020.10.009

Jaime Polychrones Jaime Polychrones is a Senior Content Writer for the Cortellis suite of life science intelligence solutions at Clarivate. Her previous roles include writing and editing for books, online magazines, educational coursework, and government regulatory publications. Her primary assignments at Clarivate include reporting on FDA drug/device advisory committee meetings and drug approvals.

Email: jaime.polychrones@clarivate.com

www.journalforclinicalstudies.com

Journal for Clinical Studies 13

Regulatory

Clinical Trials – Somewhere Between Tradition and Digital Modernity – A Wakeup Call It is undisputed that clinical trials are complex and pose challenges for companies. This is especially true for emerging biotech and medtech start-ups with products growing out of the preclinical stage. But how can clinical trials be run more effectively and efficiently for the benefit of all, stakeholders, and shareholders?

Dr. Jonson's equation obviously did not work out. Clinical registration studies are not pharmacological phase I or phase II a studies in a 100 % controlled environment, but an organisational, highly complex and decentralised project with a large number of actors. Small mistakes in the set-up can quickly scale up to massive problems. Such a project is teamwork, regardless of the degree of organisational and technical optimisation, today and in the future.

Phantom – Patent Pain In the minds of young companies from the pharmaceutical or medical device sector, clinical trials lie somewhere in the future and are at best perceived as a necessary evil. Even the fact that clinical trials are part of the largest cost block of product development and take up a considerable part of the remaining patent term is acknowledged by the companies and their investors with a maximum shrug of the shoulders.

It seems to be a mantra, even a belief, that clinical trials are expensive, take a long time and regulatory requirements are the main culprit. This mantra, nourished by constant repetition, turns out to be a self-fulfilling prophecy, injected into the young companies by consultants, often former employees of the large research companies, who never had to worry about the size of their budgets.

Perhaps it is worth looking at the different models of data collection.

Seventy percent of all studies are, with an increasing tendency, accesses to already existing data, so-called retrospective data collection. Medical device manufacturers in particular are making increasing use of this instrument to support the clinical evaluation. This is where the most comprehensive time and cost advantages should be gained through direct data access.

But prospective studies also offer considerable potential for optimisation, especially when one considers that the designs of the studies, but also the products, are changing.

The current products promise more cure of the disease instead of only alleviation of the symptoms. This usually means shorter treatment times per patient (for example, the classic treatment of chronic wounds vs. healing with cold plasma technologies), or the current approaches in personalised medicine (for example, the use of mRNA technologies).

Especially with personalised treatments, it is no longer primarily about the clinical validation of a drug (that would be difficult to do with

Figure 1 14 Journal for Clinical Studies

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Regulatory

Figure 2

the small number of patients) but about the validation of processes, quasi the GCP-compliant validation of a manufacturing process. The regulators certainly still have some homework to do here.

These treatment approaches also offer the possibility of optimising studies through strategic standardisation.

For some time now, the study designs of classic product developments have been depicting several questions, which, however, increases their complexity and thus places higher demands on the operational implementation. Here, properly implemented digital processes can reduce the interfaces in data transmission, thereby reducing the complexity of operational implementation and achieving qualitatively better and significantly faster results.

While in the case of classic product lines with long patient stays, time-saving potential, which can be considerable, is mainly possible at the beginning and end of a project, in the case of the first projects mentioned above, considerable potential can also be realised during the operational implementation.

In general, the use of modern technologies integrated into a modern organisation and modern data collection is crucial to optimise patent utilisation times and achieve maximum sales targets.

Suspicion – Regulatory Density Current technologies obviously do not meet the requirements of modern clinical research, otherwise the studies would not be permanently more expensive! Well, there seems to be some truth hidden in this provocative statement. After all, digital systems for administration and data collection have been increasingly used in clinical trials for more than 15 years, and yet the costs of the projects increase significantly by more than 10 % annually.

By default, the culprit is quickly identified – the high density of regulation. But is that the case? Compared to the 90s and 2000s, the density of regulation has rather decreased than increased. The www.journalforclinicalstudies.com

legalities of individual countries no longer must be considered. Who in the industry does not remember the "Nordic Requirements “? Of course, the qualitative requirements have increased. But is that really such a bad thing? And does this argument justify making studies more expensive?

Is it not rather the case that the traditional process flows are reflected in the technologies and that the systems are also purchased and used according to an outdated organisational model?

Logically, in such a system, the interfaces are doubled following the "head of issues" and thus also the difficulties in obtaining valid data (see Figure 1).

Approach – Integrated Technologies Current technological developments enable us to integrate new business models, which open new opportunities for some market participants, but also make some business models obsolete.

In Figure 2, you can easily see where your company currently is and whether the next technological development step should be taken, considering your current and planned projects. Keep in mind that the step towards a comprehensive digital enterprise can only have its full effect in combination with organisational adaptations.

Goal – Integrated Organisational and Process Flows Intelligent algorithms may not be the sole panacea, but in the future, they may represent the ultimate interface of all repetitive activities in medical product development. Due to an increasing demand and shortage of specialists, an urgent approach to optimise the allocation of resources.

Summary – Proof of Concept In a concerted orchestration of all stakeholders, amazingly collaborative achievements were made in the current pandemic: from idea to licensed vaccine in just one year. But these concerted actions were absolute exceptions – and they will remain so.

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Regulatory

The radical optimisation of clinical research and disruption of established ways of working must now be the ultimate goal in order to permanently shorten processes, accelerated by digital trends and artificial intelligence. For example, direct access to anonymised data from patients enables retrospective projects to be shortened to days, prospective studies to be reduced in complexity and risks to be minimised.

for patients and healthcare systems. Consequently, there is increasing pressure on business models that neither develop their own products nor collect their own data. Funds and resources are being reallocated, clinical monitoring, data management and administration are hardly in demand. Flexibility and digital competence are becoming important characteristics of future employees in clinical research.

The value chain changes drastically through the monetisation of data points. As a result, there is a considerable time gain in organisation and monitoring. In the future, generally applicable digital business models in clinical development and the elimination of analogue business processes will thus become an advantage

Shortening development cycles significantly and improving data quality to quickly bring the new generation of products, which not only alleviate symptoms but hold out the prospect of a cure, to patients requires a powerful joint effort to transform analogue processes into digital business models. The course for this must be set now so that the momentum is not lost. Consistent digitalisation leads to more security by reducing dependencies and a considerable gain in time. This time, entrepreneurs must be the masterminds and drivers so that the pressure on regulators increases to accompany this development forcefully.

Sven Engel After several years in molecular biology – biotechnology research at a global pharmaceutical company, Sven was drawn to clinical development and international marketing at the same company, and he was able to round off his knowledge of pharmaceutical value creation. In 1999 Sven founded a very successful and internationally active CRO and in the same year started the development of one of the first classical CTM systems, as it is standard in many clinical research projects today. Today, he is CEO of an IT company and consults for biotechnology and medical technology companies with the planning and implementation of clinical research projects.

Metalevel: Core elements of a modern "digital" corporate structure 16 Journal for Clinical Studies

Volume 13 Issue 6

Corporate Profile

Ramus Corporate Group is a union between Ramus Medical, Medical Diagnostic Laboratory Ramus and Medical Centre Ramus. All the companies are situated in the Ramus building in Sofia, Bulgaria. They are certified in compliance with the requirements of ISO 9001:2015.

Ramus Medical is full service CRO, working CTs in a variety of therapeutic areas and medical device.

• •

• • • • • •

Medical Centre Ramus with Phase I Unit

Medical writing for drugs and devices Scientific review of documentation Clinical trial management Monitoring Data management Regulatory advising and services during clinical trial

• • • •

Total laboratory automation with Abbott GLP-System Bioanalytical laboratory – ISO/IEC 17025:2017 accredited

PK/PD studies Medical devices investigations Phase I–IV Non-interventional studies

Medical Diagnostic Laboratory Ramus (SMDL-Ramus)

Others:

• • •

• • •

• •

30 clinical laboratories in Bulgaria and North Macedonia 325 affiliates for sampling in Bulgaria and North Macedonia More than 20 years’ experience in the CT field as central and safety laboratory; Largest PCR laboratory in Bulgaria Laboratory System integrates cluster generation, sequencing, and data analysis

, fast, correc t!

Safe

Readability user testing Bridging report Carriage and storage of dangerous goods in compliance with ADR principles

Medical Diagnostic Laboratory Ramus Ltd

26 Kapitan Dimitar Spisarevski Street, 1592 Sofia, Bulgaria Tel/Fax: +359 2 944 82 06 www.ramuslab.com email: info@ramuslab.com

Ramus Medical Ltd Tu

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www.journalforclinicalstudies.com www.journalforclinicalstudies.com

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26 Kapitan Dimitar Spisarevski Street, 1592 Sofia, Bulgaria Tel./Fax: +359 2 841 23 69 www.ramusmedical.com email: office@ramusmedical.com

Dimitar Mihaylov Marketing Director

Journal for Clinical Studies 17 17

Regulatory

The Future of Healthcare Ecosystems: The Real-World Impact of IDMP A lot of lip service has been paid by the IDMP software industry to the potential of data-driven processes beyond regulatory compliance. But the opportunities are very real – and wideranging – and pharma companies and their software providers have an important role to play in enabling these advances, through their ambitions for and approach to data-driven information management and transparency. Biotechs, without legacy systems and processes to hold them back, might even lead the way. Here, Frits Stulp of Iperion – a Deloitte business, sets out the enhanced role that could be played by a standardised data-driven ecosystem that’s actively promoted by the pharma industry.

For pharma process decision-makers, deep within regulatory functions, it’s easy to lose sight of the evolving needs of the people who use their products – from patients themselves, to the clinicians prescribing them, the pharmacies dispensing them, and the payers and insurers approving and settling the bills. Yet these changing needs will and do have a bearing on the choice and use of treatments, their safe application, and their efficacy. And as ambitions grow, to empower patients to have a greater say in and understanding of their own health, pharma companies need to rethink the way that they engage and provide information to the different stakeholders across the healthcare ecosystem, right down to the individuals who need treatment.

Dr. Google Will See You Now Consider students who wake up with a sore throat or fever, and a mobile device in their hands. Especially after the extended waiting times during the pandemic, their first port of call is more likely to be Google or Amazon than a health line or doctor’s surgery. Unless something needs to be professionally prescribed, their choice of medicine will be dictated by search listings, customer reviews and price. A drone might drop it to their door the same day, so that they never need to get out of bed.

Granted, this example is more applicable to consumer drugs, but a specialist cancer nurse once admitted that she, too, would turn to Google to check the specific oncology-related advice about possible drug interactions when dispensing medicine to patients, if that information wasn’t otherwise readily to hand. These kinds of scenarios are likely to become steadily more common too, as society demands free choice/for patients to have informed influence over their own care.

This, then, is a call to action to the pharma industry to provide that information in a readily and useable format, and to regulatory agencies to become the ‘go-to’ place for approved information.

Linking IDMP Initiatives to 21st Century Healthcare It is in such situations that data standards like ISO IDMP for medicinal products, being implemented currently in the EU but with growing support internationally, offer to make such choices more viable – supported by accessible and reliable information, in an agreed global format, which can be understood by clinicians, pharmacists and the general public (as well as regulators, payers, insurers and so on).

18 Journal for Clinical Studies

In due course, consideration for all stakeholders will be essential for life sciences companies, and their IDMP plans and decisions today will be instrumental in dictating how well they can adapt to this new world of more transparent healthcare that is centred around the patient.

The not-for-profit organisation, CTADHL, has made it a mission to promote a new era of ‘health literacy’ through global collaboration and partnerships. Among its activities, it is working towards harmonisation and adoption of ISO IDMP around the world – between EMA/EU requirements and those of the US FDA, for instance, and by the World Health Organization (WHO). We are also seeing a lot more clinical discussion now about the need for cross-border prescribing, aided by an interoperable data set which describes medicines in a uniform way from country to country so that prescriptions from other territories can be understood and exact equivalents identified.

As biopharma innovation becomes more mainstream, and as more personalised treatments feature more commonly, more tailored information on drug suitability and counter-indications will become important.

In the crowded market for medicinal products, the need for custom, personalised products is growing. The absence of new big blockbuster drugs is helping to drive this development, inviting the industry to better understand their patients. Unless each variant of a product has its own data stamp, clinicians won’t be able to safely prescribe it. At the same time, patients will increasingly expect to more fully understand for themselves the characteristics of products, the available alternatives and how these compare, and how a given product addresses or targets their situation. Standardised data will be essential in enabling all of this.

The Road Ahead So where are pharma companies today in regard to this new global, data-enabled healthcare ecosystem, which places the patient at the centre?

Although some pharma companies are making the right noises about patient centricity today and working hard to provide better resources for their customers, in many cases the gap between the information provided by pharma brands and that patients actually need and receive remains considerable.

Too often, patient information leaflets and equivalent digital resources are treated as marketing material or compliance-oriented activity, rather than something that empowers patients to make informed choices. Currently, it tends to be the market regulators – as labelling/leaflet gatekeepers and public guardians – rather than the pharma companies themselves that are advocating for patientcentricity in published patient information.

To change the emphasis, software needs to embrace and promote use of data standards, enabling better insights, actionable reporting on adverse drug events, product shortages, and more. This rich and actionable data, and reliable data analytics, are crucial to enable improved, safer medicines.

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Keeping a broad perspective when rolling out IDMP projects is an important first step in staying open to optimal external information provision and international data exchange across national, regional and global healthcare ecosystems. Other opportunities include greater integration with patient forums, where allowed, so that pharma companies can meet current and future customers where they are and provide relevant and helpful information to them at the point of need.

Understanding what patients – and other stakeholders across the healthcare environment – need is critical. The European Medicines Agency, which has an active interest in patient advocacy, aims to help here, by facilitating conversations between healthcare providers, pharma companies and patients, towards better outcomes for all.

Trailblazers Required For pharma companies, proactive interventions in the form of better external information which is fit for purpose will help build stronger and more trusted relationships, by demonstrating that their priority and focus is the health and wellbeing of patients.

But it could well be biotechs/biopharma start-ups that show the way. Their relative freedom, unencumbered by legacy products, data and regulatory records, is likely to accelerate their progress. These companies won’t be as dependent on expensive, specialist tools, but will be able to take advantage of a fresh approach to objectwww.journalforclinicalstudies.com

based information, external collaboration and harmonised data exchange, underpinned by IDMP. This is something all companies must embrace anyway, so it makes sense that these more dynamic, younger companies might take data-based process innovation a step further – and provide an example for the wider industry to follow.

Frits Stulp Frits Stulp is Managing Director of Iperion – a Deloitte business – where he leads a team of regulatory/IDMP experts active in various projects to deliver value to both pharmaceutical companies as well as regulators.

In addition to having more than two decades’ industry and consultancy experience, Frits is regarded internationally as a subject matter expert on IDMP and he proactively shares his rich knowledge and experience wherever he can. Iperion, now part of Deloitte, is a globally operating life sciences consultancy firm which is paving the way to digital healthcare, by supporting standardisation and ensuring the right technology, systems and processes are in place to enable insightful business decisionmaking and innovation.

Email: frits.stulp@iperion.com

Journal for Clinical Studies 19

Regulatory

A Guide for Establishing and Governing Data Collection Standards Companies that leverage internal data collection standards can increase efficiency, speed execution, and improve data quality.

But establishing standards is hard and maintaining them is even harder. How should you get started? And how do you ensure compliance with standards across your organisation?

Many data management teams report that their standards initiatives have stalled or failed because executives aren't boughtin, standards are over-proliferated, or they are stuffed with exploratory variables. In this guide, leaders across pharmaceuticals, biotechnology, generics, and medtech will learn best practices to build and maintain an effective clinical data collection standards program while driving team adherence.

The guide also provides recommendations on defining specification and variable tables and when it is appropriate to develop internal standards versus using existing widely accepted standards.

Best practices are drawn from real-world experiences and case studies to provide leaders with actionable insights and advice for defining their approach to data collection standards.

Establishing Standards for Long-term Success Beginning your journey toward data collection standards1 requires two essential resources: a team willing to drive the development and improvement over time of proposed templates or standards; and executive buy-in to get started on the right foot and ensure speedy approvals once completed. In addition, internal alignment is critical to the success of your standards, so involve downstream teams such as programming and statistics to incorporate their needs and requirements early on. Here are some tips to get started.

Involve all stakeholders with a 'horse in the race.' Involve representatives from each group to ensure alignment across biostatistics, clinical, medical, and data management. Each group will have competing interests and therefore should be represented in decision-making meetings, especially when discussing compromises and trade-offs.

Identify the right people. When nominating people across each area, consider their natural tendencies and inner motivations. Look for individuals with an inclination to organise and classify. These projects are usually added on top of the person's day job, so look for the unique team members who think data standards are both cool and crucial to success.

Categorise decisions as you go. If your organisation doesn't have standards in place, the most pragmatic way to get started is to codify decisions as you go and build a library of standards over time. Capture critical choices, the reasons for each decision, and usage guidance within a simple standards manual and FAQ guide. Selecting a few case report forms (CRF), auditable records designed to capture patient information to fulfil the goals of a clinical trial, is a great way to set a baseline.

Tap your partners for learnings. Your data and technology providers can be valuable partners in creating data collection standards. They 20 Journal for Clinical Studies

might have existing standards for you to springboard off, which already include lessons from multiple clients. Vendors may also have visibility across studies in your organisation and can identify commonalities to help formulate your standards.

Defining Data Standards When it comes to data collection, identifying your endpoints and objectives is key. What data is necessary to feed your analysis?

Standards should only collect what's required to support your study objectives. Exploratory data could be helpful but diverts resources from critical areas and places an additional burden on patients and sites. Take these first steps to start defining your data standards.

Don't reinvent the wheel. You should leverage industry standards such as CDISC's Clinical Data Acquisition Standards Harmonization (CDASH) as a foundation. Years of industry collaboration have contributed to their design and using them will help ensure traceability and mapping to end deliverables such as SDTM variable names.

Make area-specific forms as needed. Every therapeutic area often has distinct data collection requirements and will need standardised forms. When possible, make area-specific forms additive to your corporate standards rather than a variation. Introducing variations can be a slippery slope toward version proliferation and a breakdown of control.

Keep fields lean. Placing an item in your standard requires every study going forward to collect that data. Packing CRF standards with exploratory fields will significantly increase costs for data collection, cleaning, and monitoring. Each field also places additional burden on the patient, and patient burden is something we must all seek to reduce.

Provide "suggested templates" as an add-on. Official standards should be infrequently changed and rigorously enforced. To increase your efficiency and consistency and allow some flexibility, offer unofficial templates that function as starting points and can be readily changed.

Keep it real. Define standards that capture reality. Limiting your CRFs to collect only what you want to occur, or excluding options that would capture unwanted outcomes, will result in dirty data and avoidable queries as research sites attempt to document activities accurately.

Align with site's source documents. Investigator sites may already capture some data. Designing CRFs to fit the site's source documents, thus ordering your fields to match the site's natural procedural order, streamlines data entry.

Go beyond CRFs. Standardise the supporting documentation such as the CRF completion guides, test cases, and mappings to transformation programs. When a study reuses collection instruments, programmers can leverage the programs that transform the data to SDTM. The time savings generated by reusing supporting documents and downstream programs are critical to making the financial case for standards and securing executive-level buy-in.

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Figure 1: Sample Specification and Variable Table

Defining CRF Standards in Practice These best practices for establishing and maintaining data management standards are ideal for companies that have run at least five clinical trials. Why? At that point, companies can capitalise on the www.journalforclinicalstudies.com

efficiencies of standardising. If you aren't ready yet, assess whether your company has the necessary level of maturity to begin working on internal standards. Factors such as staff willingness to change and the ability to enforce standards will be vital in making decisions.

Journal for Clinical Studies 21

Regulatory Once you are ready, identify the core forms that are most consistent protocol to protocol. Examples include demographics, vital signs, and medical history. The objective is to standardise common forms where you are collecting the same data. Start small and with basic forms to avoid overwhelming your resources. As you gain experience and success with the common forms, you will be well-positioned to extend into therapeutic specific forms such as oncology and orthopaedics.

As you start defining your CRF standards, track and manage versions at the individual form level and form grouping. For example, version 12.0 of a therapeutic area standard may include version 4.0 of the serious adverse event form for that therapeutic area. The superset of CRF specs can also include standards for default EDC settings, subject numbering guidelines, abbreviations, and other standardised conventions.

Please see Figure 1 as an example of one company's specification and the variable table used to provide instructions, variable names, code list values, and more for each data element and unit on its form.

Setting up Governance, Deviations, and Practices for Updates A practical standards program includes a formal deviation process whereby individuals can ask for permission to vary from the standards for a study. Provide clear guidelines on submission for deviations that do not include email since it lacks the tracking and workflows necessary for effective management. The governance committee must approve any deviation from a standard, and the expected answer to requests should be a "no." Typically, only deviations that are necessary for analysis should be approved. Follow these three steps to create a formal structure.

Build company-wide commitment with executive committee support.

The executive committee provides oversight and approves new standards and changes. Building a strong, cross-functional executive committee is crucial to maintaining corporate buy-in. Without executive-level alignment, you will see unauthorised changes, deviations will become common, and standards will fail to deliver expected benefits.

Manage deviations and change requests through a governance committee(s). A manager-level governance committee should do most of the standards work across three main functions: approving/ denying deviation requests, developing new standards, and reviewing existing standards periodically to evaluate whether updates are needed. The governance committee needs direct access to other teams, such as biostats programming, to ensure they fully understand the impact of the deviation before making a decision.

Committee decisions should be documented and shared with downstream study stakeholders and vendors. When working with a vendor, it's important that your standards are provided upfront so that they understand what to look for. Separate committees or subcommittees may be required for different therapeutic areas to ensure sufficient domain experience, agility, and scale.

Capture standard updates. Making updates to standards is an infrequent but important part of a healthy standards program.

Proactively improve them by including those standards with recurring deviation requests. This is where tracking deviation requests and approved deviations can help drive informed decisions and maintain confidence in the quality and relevance of standards across the organisation.

Cultivating Adoption and Use Many standards initiatives don't deliver efficiencies because deviation 22 Journal for Clinical Studies

requests were too readily approved, or study teams proceeded independently without regard for the process. Fostering adoption of the standards across your organisation is crucial to the initiative's success, so ensure everyone involved in a study understands the value of data collection standards. To do this right, prioritise change management with these three tools.

FAQ docs. Develop an FAQ or similar policy document that outlines what types of changes are acceptable and not allowed. Documenting what is not permitted, along with the supporting rationale, will decrease the burden of redundant requests on governance committees.

Onboarding and training. New employees start jobs with existing perspectives, approaches, and habits. Training on data collection standards should be mandatory for every new employee hired within the data management and biostats organisation to ensure alignment and consistency.

The course should include the standards, the organisation's philosophy on standards, the areas required to use standards, the importance of adhering to standards, and the negative impact on costs and speed that deviations can have on a study. Set expectations that standards have been established for a reason, that pre-approved deviations or variations of a standard need to be documented, and that requests to diverge from standards will be declined except for exceptional circumstances.

Figure 2: The impact of deviations

Consistency and execution. Leverage your data management team to perform spot quality control checks. Have them review and doublecheck the CRFs, data exchange specs, and other documents for new studies to ensure the standards are being followed. Library reports in some electronic data capture (EDC) systems also provide usage and deviation metrics and insights, making it easier to identify what is working and what is not.

Collaborating with Technology Providers Technology partners are a critical part of implementing any successful standards program. Sponsors own the adoption and utilisation of standards by their teams, but vendors often implement standards and use them when configuring systems or case report forms. Maximise partner relationships by adopting these three strategies.

Tap into technology partner expertise. Vendors know their own systems end-to-end and provide valuable insights and advice on the optimal means to accomplish your goals. Don't be afraid to ask for advice.

Enlist vendors to help enforce standards. Equip vendors with your standards to verify approval from the governance committee when they see a deviation. A good partner will collaborate and support this.

Provide a point of contact. Give vendors a point of contact for communicating requests to deviate from standards. Having a single place to go for questions or conflicts prevents delays and helps keep the process moving forward.

Volume 13 Issue 6

Regulatory strong committee also can pick up what needs to be changed to improve standards. Repeated deviation requests provide insights into how a standard may not meet requirements.

Evolve the thinking. Reviewing standards for relevance and impact will ensure alignment with company requirements and longterm value. This process should also include comparing internal standards with evolving industry regulations. During this review, look at your upcoming trials and consider adding new standards that can accelerate CRF development. If there are common deviation requests, this is an excellent time to ask if the standard is too limited and make appropriate changes.

Standards Enable Speed and Effectiveness A standards program can deliver significant improvements for clinical teams if established with solid principles and governance right from the start. Standards enable faster builds in EDC systems and higher quality data entry at sites. With alignment around the data that should be captured for every study, companies get complete reporting, more efficient cleaning, and transformations, and simplified data sharing and analysis across sources and studies.

This can transform clinical data teams, helping them move faster and more efficiently. If they can work with greater speed and precision, patients will get access to life-changing medicines faster.

That is the ultimate goal, after all.

REFERENCES A good time to re-evaluate your standards is when your company explores new strategies and technologies for data management.

Bringing in a new system can introduce innovative capabilities and more efficient ways of working and collaborating across teams.

Don't miss out on efficiency gains because your standards tie you to old systems and outdated processes.

Ensuring Success It is essential to understand where things can go wrong. Recognising shortcomings can prevent issues down the road and drive maximum value out of data collection standards. Here are five tips for driving long-term success.

Experience matters. Start discussing data standards after completing numerous studies. By waiting to gain experience executing trials, you can identify the most common forms and the best starting point.

Recruit a seasoned team of champions. For a successful implementation, leverage both internal and external resources.

Your internal data management resource should have at least five years of experience in the medical field. Partner with a technology provider with proven, purpose-built solutions for clinical studies and first-hand experience working with companies of your size.

Don't try to boil the ocean. Once you secure buy-in’s from key stakeholders throughout your organisation, start small. Pick the forms best suited to building a foundation. While these vary from company to company, consider starting with forms from the CDASH CRF library. CDISC provides a library of CRFs designed as a baseline for companies to take and modify according to their own needs.

Maximise the review board's authority. Deviations should only be approved under unique circumstances and thorough review. A www.journalforclinicalstudies.com

1.

The term "standard" has different meanings in different organisations.

For the purpose of this article we consider it the documents, data, and processes established by the organisation to serve as a model or formal guideline.

Ami Dudzinski Mehr Ami Dudzinski Mehr, vice president, Vault CDMS MedTech, Veeva Systems, has over 20 years of professional services experience and has devoted her career to implementing EDC and IRT/IVRS software for clinical trials. Ami is currently part of the Vault CDMS leadership team, responsible for strategy in the MedTech space. Earlier in her career, Ami was responsible for trial build and enablement delivery at Oracle and Phase Forward.

Email: ami.mehr@veeva.com

Drew Garty Drew Garty, chief technology officer, Vault CDMS, Veeva Systems. Drew's career in pharmaceutical technology spans over 20 years and includes experience in eClinical system architecture, design, and development, as well as process design, solution validation, and international implementation and support. Before Veeva he was at Parexel, where he led the operational institutionalisation of EDC, increasing the utilisation of EDC from 25% to over 95% in less than two years.

Email: drew.garty@veeva.com

Journal for Clinical Studies 23

Market Report

Unlocking the Business Benefits of Text Mining in Regulatory Operations As IDMP implementation advances in Europe, data is becoming a key asset for the life sciences industry. Currently, pharma companies are focusing on the heavy burden of initial data collection, but ultimately it is data maintenance that will become the prevalent challenge. This can only be tackled by paying continuous attention to the quality and integrity of data.

Advanced text mining technologies, applied in the context of end-to-end regulatory information management, can help considerably both with accurate data ingestion and ongoing data maintenance. Amplexor’s Renato Rjavec explains.

The protracted business of collating and cleaning up data, in preparation for the new target operating model for EMA regulatory submissions, in which original product data must be submitted alongside eCTD dossiers, has triggered a whole raft of activity and resource use for European and global life sciences organisations.

The road to full IDMP compliance has not been an easy one; nor does it end with initial registrations. On the one hand, many marketing authorisation holders (MAHs) are still trying to locate source data, vet its quality, and plug any gaps. The information they need may straddle regulatory information management (RIM) systems, Excel spreadsheets and any number of static documents (labelling, CMC documents, and so on). This may be strewn across functions as diverse as Regulatory, Supply Chain, Pharmacovigilance and Commercials – each department frequently employing its own preferred formatting and terminology. Extracting and cleaning up all of these fragments of data to form something meaningful and usable is a massive undertaking.

Yet the work to this point – building a complete and viable data set - is just the tip of the iceberg. The job of maintaining and updating all of this information, and keeping it tightly aligned with anything appearing in document form, will be never-ending.

Under the emerging target operating model (TOM) for regulatory submissions, once IDMP is live and mandatory in the EU, any discrepancies between the product data and the dossiers filed in parallel will immediately spark Agency queries and set back registration timelines.

Ensuring that data and content remain in sync and up to date, and that FHIR messages (conforming to the Fast Healthcare Interoperability Resources standard data formats/API requirements for exchanging electronic health records) are fully aligned with the content of submitted eCTD sequences, will be essential to efficient process management and registration progress.

Assessing the Technology/Process Options To keep on top of Agency expectations, teams responsible will need to harness technology strategically. Processes must be established 24 Journal for Clinical Studies

to ensure that the contents of the dossier match the contents of the IDMP/SPOR dataset for each submission. (Under IDMP, Substances Products Organizations and Referentials – SPOR – data services provide the vehicle for implementation of ISO IDMP standards in the regulatory and e-health worlds.)

Continuous Data Extraction One option is to pull data from documents as an ongoing operational process, but this approach is likely to be very labour intensive and offers companies very little additional benefit beyond compliance.

Structured Authoring The opposite option is to leverage well-structured data to generate content. Structured content authoring technology (in which documents are assembled automatically from pre-approved content fragments/data sets) would appear to be the optimal long-term option, however the technology is not yet mature enough to offer a failsafe and simple-to-use solution, allowing dossiers to be created intelligently using approved source data.

Advanced Text Mining A better approach, at least for the time being, is to establish parallel processes to prepare documents and data, keeping both in tight alignment and ensuring this is the case as a quality control requirement until the final submission.

In this context, companies would do well to harness an already proven technology – advanced text mining. This has strong potential for application both at a data extraction/quality checking level, and for ongoing data and content maintenance.

The accuracy of such tools has reached around 95 per cent in the context of automated data extraction, meaning that teams can place a lot of trust in it – saving human resources for an oversight role or to home in on more complex use cases.

So How Does it Work?

Text mining technology uses machine learning and natural language processing to help teams detect patterns or data points in existing documents, such as content around the composition of a drug, any counter-indications, or manufacturing detail. Once identified, it can extract this information and encode it properly using the correct controlled vocabularies and flow it into the company’s RIM system for onward processing. On top of the technology’s strong track record at doing this accurately, text mining tools are also very good at detecting whether the original data used in the documents was wrong, flagging this as a potential quality or consistency issue.

Double the Potential: Aiding Data Extraction & Ongoing Data Maintenance In initial data collection use cases, where text mining is already gaining traction, the technology is helping greatly to improve Volume 13 Issue 6

Market Report

the efficiency of IDMP data extraction from a range of different documents, automatically populating RIM data records directly from those static files. This provides teams with a good foundation for data enrichment, allowing skilled professionals to focus their time on populating additional fields that are now needed.

At an ongoing data maintenance level, advanced text mining tools support proper data validation and user guidance to ensure that data is and remains complete, consistent, and properly encoded, ready for a final review and approval by a human supervisor. This vital validation step ensures that discrepancies are picking up and gaps identified and flagged to the experts overseeing the data quality.

Tangible ROI The return-on-investment potential of advanced data mining tools in both data extraction and data maintenance use cases is impressive – as long as the technology is harnessed appropriately within the context of end-to-end regulatory information management processes.

In a data extraction context, where a set of documents must be read to populate product records, potentially taking someone four hours per record, a text mining solution can (very conservatively) halve that time. With a potential saving of 100s of euros/dollars per record, companies processing tens of thousands of authorised records per year could see cost savings run into the millions.

For data/content validation – checking the consistency of data and eCTD dossiers, which becomes critical in the IDMP era – the potential to use smart text mining to compare product records with submission document content is enormous too and can generate considerable business value. By at least halving the current error/ discrepancy rate via automated content validation, companies could on average yield a cost saving of 100s of euros per submission.

Multiply that by 10,000 submissions annually, and the math stacks up robustly.

Across the two use cases then, text mining can play a vital and direct role in improving efficiency, reducing costs, improving quality and minimising errors. More than that, advanced text mining has a meaningful role as part of a broader, end-to-end RIM capability www.journalforclinicalstudies.com

– aiding planning, editing and formatting throughout, through its ability to validate data across the entire lifecycle.

Latent Potential If more companies were aware of text mining and how mature the technology is today, its take-up would be considerably higher than it is currently. Once responsible teams are made aware of such solutions, it usually takes only a small proof-of-concept study to showcase the potential and lay to rest any concerns about the technology’s accuracy and efficacy.

Ideally, text mining technology should be deployed seamlessly as part of a broader RIM project – as part of an IDMP data migration initiative, as companies press on with data cleaning, structuring, and importing, ready for the IDMP go-live date. Similarly, for ongoing data validation (maintenance, updates), text mining needs to be integral to RIM too, so that the benefits can be leveraged effectively in everyday regulatory operations.

Whether the teams responsible are exposed to the technology directly or not, it is something that should be on their radar when assessing how they will accomplish their projects and keep within their allotted timeframes and budgets.

Renato Rjavec Renato Rjavec is Director of Products, Life Sciences at Amplexor. Amplexor Life Sciences helps organisations that are developing pharmaceutical drugs, medical devices, and biotechnology to launch products and break into new markets quickly using end-to-end regulatory and quality management solutions. Its solutions and services expedite the management of highly structured data and the creation and delivery of consistent, compliant global content. Amplexor’s services include technology consultancy, implementation, and management services. Its partner in the area of text mining is Averbis.

Email: renato.rjavec@amplexor.com

Journal for Clinical Studies 25

Market Report

Medical Writing – Benefit of Good Medical Writing Knowledge is vital at every stage of a medicine’s lifecycle – from that first glint in the scientist’s eye at their origin, to the delivery of a medicine to patients with detailed instructions on their safe use. And at each stage, this knowledge is passed on in writing. Medical writers are professionals with a broad expertise in communication, who are skilled at presenting complex information in a manner that is clear, logical, and attuned to the needs of a particular audience.

Throughout the lifecycle of a medicine, documents are written to report trials, quality manufacturing, packaging, labelling, safe usage, and performance of drugs once in the market. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines – particularly ICH E6 – provide a unified standard to facilitate the mutual acceptance of clinical data by regulators, laying out the essential documents required to proceed through the clinical lifecycle and meet regulatory requirements.1,2 The global medical writing market size was valued at USD 3.4 billion in 2019 and is expected to expand at a compound annual growth rate (CAGR) of 10.9% from 2020 to 2027.3 Advances to improve a medicine run alongside enhancements in composing the associated knowledge, so that the scientific and clinical communities as well as the public at large fully benefit from it.2 Coherent, logical and appealing documentation aids decision-making, while poor-quality writing can hinder it and run the risk of drawing flawed conclusions.

From the regulator’s perspective, better quality documentation fosters timely evaluation. At the user’s end, well-written information means that the patient receives the right medicine, at the right dose and with the right instructions on how to take the medicine. The diversity of regulations and document types globally continues to expand, while the expectations around document quality and transparency and the downward pressures on cost and speed are immense. As a result, the profession of medical writing has advanced tremendously in the past 20 years.

What Does it Take to be a Medical Writer – Skills and Qualifications?

Although the opportunity is exciting and a privilege, the sheer volume of information to which we are exposed, need to absorb, and operationalise is daunting.4 Thus, the skills required to be a medical communicator are substantial – not only scientific and linguistic, but also interpersonal, with a capacity for prioritising and juggling multiple projects, adapting to change, and adhering to tight deadlines. It is a rare individual who can thrive as a modernday medical communicator. Whether working in regulatory writing, scientific publications, health communication, continuing education, or promotional writing, medical writer professionals face the ongoing challenge of getting the messages to often informationoverwhelmed and time-constrained audiences quickly, clearly, and meaningfully.

Medical writers often have formal training in science, which provides a solid foundation for gathering and evaluating medical information. While medical writers come from all educational and professional backgrounds, they do share some traits. Medical writers 26 Journal for Clinical Studies

have an interest and flair for both science and writing. They have a clear understanding of medical concepts including statistics and are able to present data and its interpretation in a way the target audience will understand.5 Skills in Microsoft office and email communication play a vital role. Although it’s not required, many medical communicators hold an advanced degree – some have a medical or science degree (eg, MSc, PhD, MD) or experience in academic settings or as bench scientists, pharmacists, physicians, or other health care professionals. Certificates and certifications are additional credentials that demonstrate your knowledge and proficiency in the medical communication field.2 Growth of a Medical Writer

GOLDEN RULE: IF YOU AREN’T SURE, ASK. Based on the wide range of companies and organisations that employ medical communicators, the field is generally divided into different writing settings and specialisations, each requiring specific technical writing skills or knowledge of medical terminology and practices (Table 1).6 Medical writers specialise in a variety of fields, such as continuing medical education, patient education, scientific publications, regulatory documents, and research-grant applications. Clear, accessible, and accurate writing underpins the dissemination of precious and cumulative knowledge. It is essential to understand that everything medical writers do, it communicates their value (Table 2).2 The Need for Proficiency in English – The Foundation of Medical Writing At the simplest level, word choice can have a critical effect on how well a message is communicated.2 Words that are inaccurate or unfamiliar to those outside the field can obscure the message and discourage the reader. The rules of grammar govern the construction of sentences and dictate how words, phrases, and clauses are combined; a failure to follow the rules will distract or confuse the reader. More subtly, the location of words and phrases within a sentence can drastically alter the perceived message. At a less granular level, a medical writer weaves sentences together into paragraphs that form the body of a document.

Those with a medical or science background commonly need refreshers in writing and editing mechanics.7 No matter what your training has been, you should take an inventory of what you know and don’t know how to do.

Volume 13 Issue 6

Market Report Table 1. Essentials of Medical Writing Areas of Strength and Experience

Examples

Deliverables

• • • • • • •

Regulatory documents Manuscripts for peer-reviewed journals, abstracts, posters, podium presentations Grants, slide decks, newsletters Promotional materials (eg, white papers, websites, branded presentations, video scripts) Educational materials (eg, continuing medical education [CME] guidelines) Training materials for sales representatives Educational materials for patients or the general public (eg, lay summaries, health news)

Writing Styles

• • • •

Prescriptive (eg, regulatory documents) Scientific (eg, manuscripts, video abstracts, educational materials) Promotional (eg, websites, branded slide decks) Plain language (eg, patient/caregiver materials)

Subject Areas

• • • • • •

Therapeutic areas Rare diseases Pharmaceuticals Devices Pharmacoeconomics Modalities (eg, biologics, gene therapy)

Project Responsibilities

• • • • •

Writing clear concise content Project management Collaboration with scientific graphic designers Incorporating revisions and compiling feedback from multiple stakeholders Annotating references, formatting references and documents, tables and figures

Types of Clients

• • • • • • • • •

Pharmaceutical companies Biotech companies Hospitals Academia Professional societies Medical communication companies Medical education companies Medical advertising agencies Public relations agencies

Table 2. Dos and Don’ts of Medical Writing Do: • • • • • • • • •

Don’t: Let the writer know if you will be unavailable Provide text as requested (by the deadline) Keep the writer informed of any changes to the program that might affect the document Use the agreed upon review system Provide actionable comments Provide specific references and source documents Meet deadlines for review of the document Consolidate comments by functional area (eg statistics, safety, regulatory) Decide upon preferred styles and wording early in the process. This step is particularly important for large submissions so that the full set of submission documents can be consistent in style and presentation

•

Basic grammar and usage: Parts of speech and grammatical principles form the foundation of writing in every discipline.

Can you identify a dangling modifier or notice the lack of a pronoun referent?

•

Sentence structure: Even if you know grammar, you may need a refresher on achieving emphasis and organising your sentences for clarity. Do you know the difference between an independent and a dependent clause? Do you understand parallel structure?

• • • • • •

Ignore questions or forget to respond to the medical writer Send multiple versions of a document to the entire team; this can lead to version control issues Focus on minor wording issues and miss the “big picture” Get distracted by findings that do not pertain to the study objectives and endpoints Skip comment review meetings Wait until the final draft to actually read the document

Although medical writing deals with facts, it is sometimes helps and even necessary for medical writers to identif y figurative language, such as metaphors and metonyms, that don’t express literal truth (Table 3).8 It’s also noteworthy that scientists use metaphor and analogy to make sense of the world and to express their ideas to others. For this reason, scientists often use metaphors in their writing. www.journalforclinicalstudies.com

Journal for Clinical Studies 27

Market Report Table 3. Metaphorically Speaking – Tips to Identify Figurative Language Literal or Figurative Language

The word literal comes from the Latin word literalis, which means “of or belonging to letters and writing.” It came to mean “according to the exact meaning of the word” (eg, the word’s dictionary definition). In contrast, the word figurative refers to figures of speech. A figure of speech is any deviation from literal meanings or common usage. This could mean using some deviation from ordinary grammar or word order, or it could mean using a word to mean something other than its customary meaning.

Metaphor

A metaphor is a figure of speech in which a word or phrase (eg, the sun) is applied to an object or action to which it is not literally applicable (eg, Juliet). The word metaphor comes from the Greek for to transfer.

Metonyms

Metaphors are often confused with metonyms. A metaphor creates a new link between 2 concepts from separate conceptual domains (eg, Juliet belongs to the domain of humanity and the sun belongs to the domain of astronomy).

In contrast, a metonym relies on an existing conceptual link. For example, people in the United Kingdom, Canada, and other Commonwealth realms often use the word crown to refer to the monarch (who occasionally wears a crown) or to the national government in general.

Simile

A metaphor is an implied comparison. In contrast, a simile is an explicit comparison of 2 unlike things, typically by using words such as, as, like, or than. Similes take the grammatical form of a literal comparison but express something that is not a statement of fact: My love is like a red, red rose. – Robert Burns

Clichés

Some metaphors and other figures of speech are so overused that they become clichés. A cliché is an overused phrase or opinion that betrays a lack of original thought.

Mental Models and Content Considerations The ability to use information easily and effectively is essential to medical communication. Usability – the ability to use items easily and effectively – has long been important to medical communication.

Meeting usability expectations involves understanding both the cognitive model’s writers use to create content and those that readers rely on when using content to achieve a health care objective.

Such mental models, however, vary from audience to audience on the basis of experiences. As a result, medical writers need to understand what mental models entail to create materials that meet an audience’s usability expectations:9 • Step 1: identify the audience • Step 2: select a method for collecting data: to do so, medical writers can use the following tools: • Individual interviews: asking individual members of an audience questions about their expectations, assumptions, and associations for where and how certain

28 Journal for Clinical Studies

care is provided Focus groups: assembling 5–10 members of an audience and asking them to answer questions as a group, as such situations might help individuals remember details or provide clarification Step 3: craft questions for collecting information Step 4: apply information to create initial materials Step 5: test, revise, and finalise materials •

• • •

Time Management – Tricks and Tips Imagine that you are promised $86,400 per day for the rest of your life. You must use the money each day, or you will lose it; none of it carries over to the next day. Each day contains 86,400 seconds, which is stewarding this non-renewable resource. Everything requires time, and the better one uses time, the greater will be the rewards. Time management is essential for maximum effectiveness (Table 4).10

Volume 13 Issue 6

Market Report Table 4. Strategies for Meeting Time-management Challenges Challenge

Strategy

Increase Efficiency

• •

Start Quickly and Effectively

For starting your day…

For starting a project…

•

• • •

Keep track of project details and maintain an accurate schedule (eg, Excel, OneNote).

Use organisational templates.

•

Before leaving work, plan a specific task for the beginning of the next day.

Work during the most productive working hours.

Jumpstart the day with an easy task or get a difficult task out of the way early.

Maintain big-, medium-, and small-picture plans of goals.

Fight Procrastination

• • • • • •

Work in small time chunks (<3 hours).

Enforce breaks to foster and enhance creativity.

Use mindless tasks as a break between projects.

Commit to working on an undesirable task for 5 minutes; this tricks you into working longer.

Monitor time realistically to find time sinks.

Avoid procrastination pitfalls (eg, Facebook, perfecting PowerPoint slides)

Manage Distractions

• • • • • •

Do one thing at a time.

Use a “to-do” checklist.

Only check emails at specific times of day.

Schedule known interruptions.

Postpone your response to nonurgent emails.

Use “do not disturb” digital functions when necessary.

Control Your Meetings

• • • • • •

Schedule meetings with enough notice to allow for participants’ preparation.

Provide a clear agenda.

Keep and disseminate accurate and detailed notes.

Schedule 15 minutes before and after a meeting to allow for final preparation and follow-up.

Follow up immediately after the meeting.

Communicate clearly.

Protect Your Time

• • • •

Keep your calendar up to date, block off work time.

Say “no,” if needed, yet offer a solution or an alternative.

Be clear about expectations (yours and client’s) around a project.

Frontload your day or week.

• •

Mentoring Programs: One Size May Not Fit All As the demand for skilled medical writers increases, companies are seeing the value of mentorships; however, different mentorships fit different situations. When implementing mentoring programs, best practices should be developed first to ensure the programs are beneficial and to clearly define the mentor/mentee responsibilities.

Mentoring programs benefit both companies and employees:11 • • •

Mentees can learn new knowledge-based skills, build confidence, and advance their medical writing career.

Companies can see improved productivity levels and increased employee retention and satisfaction and facilitate a culture of growth.

Mentoring relationships can foster cross-cultural exchange and understanding while improving communication skills

Maximal vs minimal mentoring: Maximal mentoring is a professional relationship between a mentor and a mentee that is mutually beneficial.

It requires mentors and mentees to move away from the mindset of traditional mentoring. In doing this, mentors and mentees can enjoy a relationship founded on equality, respect, and trust. The mentoring process is not generic, but rather is highly customised to the needs of the mentee. There is an emphasis on the mentee as a whole person; the focus goes beyond career-related needs and goals. Maximal mentoring can be positive, uplifting, appealing, attractive, and fun. Traditional or minimal mentoring, in contrast, is a generic professional relationship.

Collaborative Writing: Ensure Success with an Effective Strategy Collaborative writing projects often stir up a mix of emotions in www.journalforclinicalstudies.com

•

Plan time for getting organised.

Gather all needed materials before beginning.

Begin with easy tasks to familiarise yourself with the project.

Use a spreadsheet to track parts of the project.

the writing professionals tasked with their completion. While these collaborative projects can provide an opportunity to learn new skills, generate new ideas, and gain new perspectives, negative feelings can overwhelm those involved and hinder the writing process. Considering the members of the team, knowing their strengths and weaknesses, and knowing each team member’s professional goals can help identify the most appropriate methods to use throughout all major phases of the collaborative writing process (Table 5).12 Further Resources to Explore As you explore the medical writing profession, the next step is to become aware of the resources available. Table 6 provides books, style guides, publication ethics followed, and professional associations and societies for medical writing.7 Managing or Outsourcing in Medical Writing Drug development is a billion-dollar industry with complex processes of obtaining product approvals.13 A well-documented, well-communicated, and well-developed research is needed to gain product approval, which increases the demand for experienced writers in the field of medicine. Strategic alliances between pharma companies and contract research organisations (CRO) have become an ongoing trend. Around 20 major partnerships have been finalised in the last five years. For instance, in October 2016, Quintiles and IMS Health underwent the biggest merger in the CRO industry and re-established the weightage of both the companies. The merger helped Quintiles to use IMS’ internal database in order to design targeted and complex clinical trials.

Journal for Clinical Studies 29

Market Report Regulatory writing is expected to be the fastest growing segment.

It is used throughout the process of product development for clinical documentation. Top pharmaceutical, medical device, and biotechnology companies are significantly investing in research and development activities to maintain their position in the market by introducing innovative products.

full-service outsourcing, functional service provider models, use of sole proprietors/freelancers, etc) to enable pharmaceutical companies to deliver high-quality document work on time and on budget. Matching the right service provider with the right document plan is a key first step, but no matter what the model, setting clear expectations for the partnership is critical (Table 7).6 In the current global development environment, establishing strong and lasting working relationships with thoughtful investment in cooperative success is a competitive advantage for both sponsors and service providers.

As medical writing has advanced as a functional competency, a variety of business models have been developed (in-house writing,

Table 5. Collaborative Writing – Strategies to Overcome Overwhelming Negative Emotions The Planning Phase

The Writing Phase

The Editing Phase

•

Three different collaborative writing methods are: layering, combining, and stitching • The layering method involves the team meeting to discuss the content and overall direction of the project while one person (usually the team leader) writes the first draft.

• The combining method of writing allows for each team member to contribute written content.

• Finally, the stitching method takes a highly structured and focused approach at a level of each paragraph, including topic sentences. While this method does require more meetings to plan specific content, the time invested up-front can ultimately help save time later.

Establishing an efficient editing process is critical in collaborative writing • In-parallel editing as a process in which the team leader sends the document to each team member to review simultaneously. The leader is then responsible for incorporating revisions into one document.

Incorporating and keeping track of each author’s edits can be challenging for the team leader • In-series editing is a time- and effortsaving alternative.

The team leader sends a draft to Author 1 to make edits.

In turn, Author 1 sends the edited draft to Author 2 for review. The series continues until each author has edited the document, which is then returned to the leader

•

Feasible schedule that takes the project scope, work style of team members, and prior obligations into consideration.

Agree on a file naming convention that works well for everyone

Table 6. Resources to Explore the Medical Writing Profession Books About Medical Writing

Style Guides

Publication Ethics

Professional Associations & Societies

•

• • • •

•

•

•

•

•

The Accidental Medical Writer. Brian G. Bass and Cynthia L. Kryder.

Booklocker.com, Inc, 2008.

Essentials of Writing Biomedical Research Papers. 2nd ed. Mimi Zeiger. McGraw-Hill, 2000.

Health Literacy from A to Z: Practical Waysto Communicate Your Health Message. Helen Osborne. Jones and Bartlett Publishers, 2005.

Targeted Regulatory Writing Techniques: Clinical Documentsfor Drugs and Biologics. Linda Fossati Wood and MaryAnn Foote, eds. Birkhauser, 2009.

•

AMA Manual of Style Associated Press Stylebook Chicago Manual of Style Publication Manual of the American Psychological Association Scientific Style and Format: The CSE Manual for Authors, Editors, and Publishers

• •

•

Code of Conduct and Best Practice Guidelines for Journal Editors (Committee on Publication Ethics) White Paper on Publication Ethics (Council of Science Editors) Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals (International Committee of Medical Journal Editors) Good Publication Practice Guidelines- GPP3 (International Society for Medical Publication Professionals)

• • • • • • • •

Association of Health Care Journalists Board of Editors in the Life Sciences Council of Science Editors Drug Information Association Editorial Freelancers Association International Society for Medical Publication Professionals National Association of Science Writers Regulatory Affairs Professionals Society Society for Technical Communication

Table 7. Client Characteristics and Potential Strategies Writer – Client Relationships to Consider Whether to Avoid

Strategies to Handle Challenging Situations

Strategies to handle challenging situations

• • •

Clarify expectation of scientific depth, goals, audience, and length of deliverable.

Offer a realistic timeline.

Turn down the project.

Chronic project scope creep without compensation

• • •

Write detailed specifications for the project.

For major scope creep, ask for increased compensation.

For repeat clients with this attribute, consider a quote that includes the relevant percentage of scope creep for that client.

Lack of boundaries (e.g., emails/phone calls at night

•

Clarify times when you’ll check emails.

Lack of consideration (e.g., scheduling teleconferences or videoconferences without first asking for your availability)

• • •

If unavailable, then state it. Usually, the client will reschedule the call as needed.

If you know about an upcoming meeting to be scheduled, provide available dates and times proactively.

Provide dates for other commitments (meetings and vacation) ahead of time.

30 Journal for Clinical Studies

Volume 13 Issue 6

Market Report

A look ahead The adoption of clear writing principles is becoming important for another emerging reason: the march towards open and accessible information as pioneered in the European Union region.2 But now, those compiling these documents will see how their work will be accessible to academics, clinicians, and the public. A medical writers’ expertise and professionalism will need to be deployed more than ever to come up with documents of the highest quality, which demonstrate sound science and good practice of the bodies behind these documents. Pharmaceutical companies are developing drugs more quickly, and new medical devices and diagnostic tools are being released every day.13 With this comes the increased need to meet regulatory and insurance requirements and to relay medical and consumer information. All of this results in greater opportunities for medical writers and communicators.

Overall, being a medical writer is a wonderfully rewarding career and always keeps you on your toes. Every team and project are different, not to mention the constant change that goes with writing drug and device documents. Asserting behind-the-scenes leadership is often critical to the successful conclusion of a writing project, which in turn builds your team’s confidence in you as a writer and valued team member. Being able to communicate effectively and diplomatically is essential in developing successful relationships with your teams. Although this profession can be demanding at times, developing strategies that make you more efficient is key. In the end, sometimes the best option is how you personally approach each challenge. Sometimes the best option is you!

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International council for harmonisation of technical requirements for pharmaceuticals for human use (ICH). Available at: https://www.ich.org/ page/efficacy-guidelines. Accessed on 30 October 2021.

Medical writing the backbone of clinical development. Available at: http://www.trilogywriting.com/wp-content/uploads/2017/03/MedicalWriting-Special-Edition-low-resolution-PDF-1.pdf. Accessed on 30 October 2021.

Medical Writing Market Size, Share & Trends Analysis Report By Type (Clinical, Regulatory), By Application (Medical Journalism, Medico Marketing), By End Use, By Region, And Segment Forecasts, 2020–2027.

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EMWA. A career guide to medical writing ever thought about being a medical writer. Available at: https://www.emwa.org/Documents/ Resources/EMWA%20MW%20Career%20Guide%20Oct2016.pdf.

Accessed on 30 October 2021.

Kimber KM, Bass B, Drake T, Cooper N. Three exercises to identify ideal clients you can nurture into long-term relationships. AMWA Journal.

2021;36(2):86-89.

AMWA. Ultimate guide to becoming a medical writer. Available at: https:// info.amwa.org/hubfs/pillar_content/Ultimate-Guide-to-Becoming-aMedical-Writer/Ultimate-Guide-to-Becoming-a-Medical-Writer.pdf.

Accessed on 30 October 2021.

Thomas LA. Metaphorically speaking. AMWA Journal. 2021;36(1).45-47.

Amant KS. A cognitive model approach to creating usable health care content. AMWA Journal. 2021;36(3):101-105.

Christianson M. Tricks and tips for time management. AMWA Journal.

2021;36(1):15.

Burder M. Mentoring programs: one size may not Fit all. AMWA Journal.

2021;36(1):22.

Herron C. Collaborative writing: ensure success with an effective strategy.

AMWA Journal. 20212021;36(1):19-20.

Medical writing market worth $7.7 billion by 2027 | CAGR: 10.9%. Available at: https://www.grandviewresearch.com/press-release/global-medical-writingmarket. Accessed on 30 October 2021.

Tahseen Khan Tahseen Khan is a principal regulatory writer at Labcorp drug development in Mumbai, India. He did M.Sc. in Biotechnology, and has over 10 years' experience in drug development. In his current role, Tahseen acts as a lead writer authoring clinical documents including overview, summaries, study reports, investigator's brochures, protocols, and other documents prepared for drug approval primarily for FDA submission. Tahseen is a professional member of American Medical Writer's Association (AMWA).

Email: tahsinkhan.bt@gmail.com

Journal for Clinical Studies 31

Therapeutics

Anticipating a Renaissance in Neuroscience Drug Development Ten years ago, our team published a commentary on what at the time appeared to be the “Death of CNS Drug Development: Overstatement or Omen” after several large pharmaceutical companies abandoned or severely restricted neuropsychiatric drug development efforts citing costly and long development periods with relatively lower chances of successful drug applications.1 Development of central nervous system (CNS) drugs is fraught with obstacles not typically encountered in other therapeutic areas, in part due to a general bias regarding psychiatric illness and treatment – mental health issues are largely viewed as being less significant than “real” diseases or more “physical” ailments – with an accompanying perceived less favorable risk to benefit ratio.

CNS trials also have intrinsic complexities generally not shared in other therapeutic areas including: • • • • • •

a relative lack of understanding of basic biology and underlying pathophysiology poor predictive validity of preclinical models and uncertain correlation of potential surrogate biomarkers with clinical benefit more frequent use of subjective “soft” endpoints (ultimately resulting in heightened placebo response) more frequent failure to differentiate active treatment from placebo suggesting a lack of assay sensitivity variability in both disease course and response over time, and relatively novel mechanisms of action for many CNS drugs that are by definition associated with a higher risk of failure.

For these reasons, the discovery and development of drugs for a variety of CNS indications has yielded one of the lowest success rates of any therapeutic area. Not only are the number of novel compounds available for clinical development in CNS lower compared with other areas, but regulatory approval times are also consistently longer.2,3 Investment in novel neuroscience drug development is therefore often regarded as “too risky” by drug developers.

The outlook for availability of new treatments for patients with neurological and psychiatric diseases has not been promising for the past decade, and when new treatments are approved they are often not accessible to patients.2 The gaping unmet medical need remains high in neurodegenerative diseases, neurological rare diseases, and psychiatry. Mental and addictive disorders afflicted more than one billion people globally in 2016, causing 7% of all global burden of disease,4 which has only been exacerbated by the COVID-19 pandemic.5 Neurological disorders are one of the leading causes of disability-adjusted life-years and the second leading cause of death globally.6 Notwithstanding these known challenges, there appears to be a renaissance of CNS drug development in which both big 32 Journal for Clinical Studies

pharma and smaller biotech have renewed their focus on CNS drug development and financing in recent months (Acadia, Biogen, Denali, Nuemora, Novartis, Sage, and Voyager Therapeutics to name a few). This resurgence is in part due to a changing funding model. Traditionally, drug companies have relied heavily on profits from their commercialized products to fund not only extensions of their approved products, but also their own bench work on novel molecular entities. Now funding through government agencies and public-private partnerships is becoming more common to facilitate drug development. For example, the National Institutes of Health has increased funding for research by 78% in the last 5 years for Alzheimer’s disease; importantly NIH funding was directly or indirectly associated with every one of the 210 new drugs approved across therapeutic areas by the FDA from 2010 to 2016.7,8 Publicprivate partnerships have also emerged for a number of specific CNS indications, including for example the National Cooperative Drug Discovery/Development Group for psychiatric disorders, the Parkinson’s Progression Markers Initiative, European Autism Interventions, the NIH HEAL Initiative, and the Alzheimer’s Disease Neuroimaging Initiative.9 For Alzheimer’s disease specifically, public-private partnerships have increased 214% in recent years, which allows leveraging of resources, spreading costs, and managing risk of drug development across several sponsors.6 A large increase in venture activity in neuroscience has followed and is now second only to oncology. One example of this is ARCH Ventures which has significantly invested broadly in both psychiatry and neurodegenerative disease with the creation of the biotech company Neumora, who aims to match distinct patient populations to targeted therapeutics.10 Neumora includes BlackThorn Therapeutics, the startup Abelian, Syllable Life Sciences, and a deal with Amgen to license two of their abandoned neuroscience products.

Not only have government-backed funding and public-private partnerships increased significantly, but regulatory agencies have taken deliberate albeit sometimes provocative steps to encourage innovative neuropsychiatric drug development. Four regulatory approaches to making CNS drugs available as rapidly as possible are available within the US Food and Drug Administration’s Accelerated Approval program: Fast Track status, Accelerated Approval, Priority Review, and more recently Breakthrough Therapy designation introduced in 2012 as part of the Safety and Innovation Act.11 Similarly, the European Medicines Agency (EMA) developed programs beginning in 2005 that include accelerated assessment, conditional marketing authorization, and a priority medicines scheme (PRIME) added in 2016. Utilization of these programs has remained fairly stable over the past decade until 2020 when they increased sharply.

An estimated 34% of approvals were expediated in 2000 compared to 60% of new drugs approved through at least one expedited program in 2019.12 Historically, the majority of applications taking advantage of these programs have been in oncology,13 with the exception of limited rare CNS diseases (e.g., Duchenne muscular dystrophy). The only CNS exceptions are the recent approval of aducanumab in 2021, Volume 13 Issue 6

Therapeutics

FDA Accelerated Approvals since Program Inception15

droxidopa for orthostatic hypotension in 2014, and natalizumab and Betaseron for multiple sclerosis. The FDA has also awarded more than $15 million to academia and industry to enhance the development of products for patients with rare diseases across therapeutic areas through the Orphan Products Clinical Trials Grants Program.14

Given this increased scientific knowledge across CNS diseases and the advancement of biomarkers intended to predict clinical improvement, companies can in turn be more vigilant with licensing compounds, evaluating risk, and identifying potential failures earlier in development.15

Regulators have also attempted to make robust and distinct efforts to facilitate the pathways to treatment solutions. In fact, the FDA published five separate guidance documents for industry in 2018 and 2019 alone for neurological conditions including Duchenne Muscular Dystrophy, migraine, early Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), and partial onset seizures.16 Similarly, EMA has issued or revised guidance for autism, pain, ALS, Duchenne and Becker Muscular Dystrophy, multiple sclerosis, and Alzheimer’s disease since 2015.

Following are some recent examples of drug development successes in neurology, rare disease, and psychiatry that have borne out the fruit of these advances.

In addition to increased funding, accelerated approval pathways, and regulatory collaboration with sponsoring companies, other reasons for the renewed interest in neuroscience drug development have also been postulated: •

•

•

Rapidly growing scientific knowledge about the nervous system and how CNS diseases are diagnosed and characterized, which for many years has been poorly understood.14 Some authors note we may be simply observing a new wave of medical breakthroughs, not just in CNS indications such as Huntington’s disease and ALS, but across therapeutic areas.17,18 Biomarkers and genetic targets are increasingly being considered as surrogate endpoints, which allows for less reliance on predictive preclinical models and enables targeting patients who are more likely to produce a positive response.15,19 Given the FDA and EMA’s accelerated approval pathways, those surrogate endpoints may be used to speed commercialization and patient access.

Although the program is not without criticism and is intended to strike a balance in bringing products to market more quickly while allowing for “reasonably likely” surrogate endpoints, these programs encourage innovation and development. Biomarkers and genetic targets are also increasingly used not just as surrogate endpoints, but in determining the optimal patients to enroll in a trial which is useful for heterogeneous disease populations like Alzheimer’s disease.

Emergence of novel therapeutic modalities such as RNA interference (RNAi) and regenerative medicine with gene therapy based on adeno-associated virus (AAV) vectors, particularly for neurodegenerative diseases, has fueled many recent licensing deals and investments.20

www.journalforclinicalstudies.com

Neurology (specifically Alzheimer’s Disease) Earlier this year, Biogen’s aducanumab became the first newly approved treatment for Alzheimer’s disease since 2003, and importantly is the first that targets the underlying pathophysiology of the disease with reduction of amyloid beta plaque, a hallmark of the disease. Biogen accomplished this partially by seamlessly blending components of early and late phase trials which accelerated the pathway to approval and took advantage of more recent regulatory opportunities. Aducanumab was conditionally approved by the FDA using an accelerated pathway (fast track designation) where a drug’s effect is based on a surrogate endpoint that is “reasonably likely” to predict clinical benefit to patients. The FDA considered the reduction of amyloid load, as measured with amyloid positron emission tomography (PET), to be a valid surrogate endpoint of clinical benefit in AD; essentially the approval was based on an endpoint that “is thought to predict clinical benefit but is not itself a measure of clinical benefit.”21 This position was unprecedented in CNS and raised numerous questions regarding whether amyloid plaque reduction is a reliable surrogate endpoint (others like Roche’s crenezumab and Eli Lilly’s solanezumab targeted amyloid plaques with no evidence of clinical benefit and development was subsequently discontinued).22 Many are hopeful this approval will invigorate the formerly stagnant field, increase investments in new treatments, and encourage greater innovation.23 Eli Lilly is now pursuing donanemab’s effect on beta amyloid plaques much like Biogen, also hoping to demonstrate a clinical effect on the slowing of cognitive decline. Roche has resurrected the previously shelved gantenerumab. Both have been newly granted breakthrough therapy designation by the FDA. Eiasi and Biogen have also recently submitted a rolling submission to the FDA for lecanemab, a follow on to aducanumab under the accelerated approval also granted breakthrough therapy designation. The rolling submission allows completed portions of the application to be submitted to the FDA for review on an ongoing basis.24 Rare Diseases The use of the accelerated approval pathway is especially pertinent Journal for Clinical Studies 33

Therapeutics to patients with rare diseases. Recruiting patients for participation in traditional confirmatory rare disease clinical trials is often very difficult, which delays potentially beneficial products in entering the market. Reliance on surrogate endpoints can allow for trials with smaller sample sizes with less cost and potentially earlier access.x One example of the renewed investment in the rare disease space is Novartis’s 2018 acquisition of the gene therapy company, AveXis, reportedly for $8.7 billion. The acquisition was in part meant to accelerate Novartis’s strategy to pursue high-efficacy, first-in-class therapies, and broaden their leadership in neuroscience.26

promising initial safety and efficacy data in small proof-ofconcept studies that lend encouragement to initiate larger studies, some of which have launched. While there are still regulatory hurdles that differ from country to country as well as licensing obstacles for psychedelics, there appears to be a ground swell of acceptance of not only this class of drugs but also of the disorders they are treating.

Ironically the stigma associated with many psychiatric disorders has recently lifted partially due to the resurgence and newfound acceptance of one of the most highly stigmatized class of drugs of the past.

The following year the FDA approved Zolgensma (onasemnogene abeparovec-xioi), the first gene therapy approved to treat children under age two with spinal muscular atrophy. Later in 2020, the FDA granted accelerated approval to Viltepso (viltolarsen) injection for the treatment for Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. Further approvals followed with Amondys 45 (casimersen) injection for patients with DMD who have a confirmed mutation of the DMD gene that is amenable to exon 45 skipping.27 Additionally, the FDA approved Epidyolex (a cannabidiol oral solution also approved for Lennox-Gastaut and Dravet syndromes) from Greenwich Biosciences for the treatment of seizures associated with tuberous sclerosis complex based on Priority Review, along with Fintepla (fenfluramine; Zogenix) for seizures associated with Dravet syndrome. The FDA cited 2020 as a strong year for innovation and advances in neurological rare disease despite challenges from COVID-19 pandemic.28

Summary The advances in our knowledge of pathophysiology of neuropsychiatric diseases including development of potentially more predictive biomarkers and new treatment modalities, permissive regulatory guidance and rulings, increased sources of funding and a general de-stigmatization of CNS disorders have created the perfect storm to help drive the recent renewed interest in CNS drug development that will likely be sustained well into the future. While continued refinement of the pathways to accelerated approval and the resolution of payer/pricing issues to help ensure patient accessibility are needed, some have opined that the next five years will be known as another “golden era” of neuroscience drug development much like 25 years ago when Prozac, Zoloft, and Paxil were all introduced to the market followed by a new wave of antipsychotic medications. This anticipated renaissance of CNS drug development is encouraging for greatly improving both the quality and extent of life for those afflicted with various CNS disorders.33

The FDA very recently accepted the submission of Amylyx’s amyotrophic lateral sclerosis (ALS) drug based on phase 2 evidence only without requiring a phase 3 trial, purportedly because they recognize the urgency and unmet need for patients.29 The ALS Association and patient advocacy efforts pushed for the expedited approval – an example of a public awareness campaign that led to increased funding and regulatory flexibility.

REFERENCES

As with neurology, associated critiques of the accelerated pathway have also been raised in the rare disease space. For example, accelerated approval of eteplirsen for DMD in 2016 was questioned on the reasonable likelihood of clinical benefit. Payers balked at making it accessible to patients, and Sarepta didn’t launch required post-marketing studies until 2019. Complete data on the drug’s safety and efficacy are still not publicly available, but despite this the FDA granted approvals to their second and third DMD drugs in 2019 and 2021.30 Psychedelics The recent resurgence in psychiatry is exemplified by the incredible growing interest and revitalization in psychedelics. Hallucinogenic drugs have been lauded as potential treatments for anxiety and depressive disorders as well as addiction, each of which have exhibited a recent rise in prevalence and high rates of relapse. Decades old treatments for these and other conditions are associated with side effects and only modest improvement in symptoms. Regulatory agencies have demonstrated their willingness to consider the approval of psychedelic treatments as noted by FDA’s recent breakthrough designation for 3,4-methylenedioxymethamphetamine (MDMA), two psilocybin-based compounds, and the recent approval of esketamine for treatment-resistant depression – perhaps one of the biggest breakthroughs in depression treatment since SSRIs and now one of the world’s most commonly used antidepressants.31 The psychedelic market is expected to grow from an estimated $2 billion in 2019 up to $10 billion by 2027,32 with over 30 organizations with psychedelic drug development programs underway. Several companies already have 34 Journal for Clinical Studies

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Batta A, Kalra BS, Khirasaria R. Trends in FDA drug approvals over last 2 decades: An observational study. J Family Med Prim Care. 2020;9(1):105-114.

Rehm J, Shield KD. Global Burden of Disease and the Impact of Mental and Addictive Disorders. Curr Psychiatry Rep. 2019;21(2):10.

Ettman CK, Cohen GH, Abdalla SM, Sampson L, Trinquart L, Castrucci BC, Bork RH, Clark MA, Wilson I, Vivier PM, Galea S. Persistent depressive symptoms during COVID-19: a national, population-representative, longitudinal study of U.S. adults. Lancet Reg Health Am. 2021; Oct 4:100091.

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GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(5):459-480.

Cummings, J, Bauzon, J, Lee, G. Who funds Alzheimer's disease drug development? Alzheimer's Dement. 2021; 7:e12185.

Galinka Cleary E, Meierlein JM, Surjit Khanuja N, McNamee LM, Ledley FD. Contribution of NIH funding to new drug approvals. PNAS. 2018; 115 (10): 2329-2334.

Brady LS, Potter W. Public–private partnerships to revitalize psychiatric drug discovery. Expert Opinion on Drug Discovery. 2014; 9: 1-8.

Mast J. ARCH unveils its Really Big Neuroscience Company with $500M, an Amgen deal and eyes on depression, Alzheimer's and a lot more. October 7, 2021. Accessed October 7, 2021. https://endpts.com/arch-unveils-itsreally-big-neuroscience-company-with-500m-an-amgen-deal-and-eyeson-depression-alzheimers-and-a-lot-more/ Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review.

Updated February 23, 2018. Accessed October 7, 2021. https://www. fda.gov/patients/learn-about-drug-and-device-approvals/fast-trackbreakthrough-therapy-accelerated-approval-priority-review Hwang TJ, Ross JS, Vokinger KN, Kesselheim AS. Association between FDA and EMA expedited approval programs and therapeutic value of new medicines: retrospective cohort study. BMJ 2020; 371.

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FDA News Release: FDA awards 12 grants to fund new clinical trials to advance the development of medical products for the treatment of rare diseases. Updated October 8, 2019. Accessed October 7, 2021. https://www. fda.gov/news-events/press-announcements/fda-awards-12-grants-fundnew-clinical-trials-advance-development-medical-products-treatmentrare-0 CDER Drug and Biologic Accelerated Approvals Based on a Surrogate Endpoint as of June 30, 2021. Accessed October 7, 2021. https://www.fda. gov/media/151146/download CDER Conversations: Advancing the development of treatments for neurological disorders. Updated April 30, 2018. Accessed October 7, 2021. https://www.fda.gov/drugs/news-events-human-drugs/advancingdevelopment-treatments-neurological-disorders Wong CH, Siah KW, Lo AW. Estimation of clinical trial success rates and related parameters, Biostatistics. 2019;20(2):273–286.

Armstrong K. Better days ahead? The emerging state of CNS drug development. Updated March 8, 2018. Accessed October 7, 2021. https:// premier-research.com/perspectives-better-days-ahead-emerging-statecns-drug-development/ Rosenberg A. Are we poised for a neuroscience research renaissance?

Maybe. Updated February 9, 2016. Accessed October 7, 2021. https:// lifescivc.com/2016/02/are-we-poised-for-a-neuroscience-researchrenaissance-maybe/ Sheridan C. Platform progress opens the door for CNS dealmaking.

Biopharmadealmakers.nature.com. Updated July 1, 2019. Accessed October 7, 2021. https://www.nature.com/articles/d43747-020-00710-3 Cavazzoni P. FDA’s decision to approve new treatment for Alzheimer’s disease. Updated June 7, 2021. Accessed October 7, 2021. https://www. fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-newtreatment-alzheimers-disease Planche V, Villain N. US Food and Drug Administration approval of aducanumab – is amyloid load a valid surrogate end point for Alzheimer disease clinical trials? JAMA Neurology. 2021:E1-E2 Mullard A. Landmark Alzheimer’s drug approval confounds research community. Nature. 2021;594:309-310.

Eisai initiated rolling submission to the US FDA for biologics license application of lecanemab (BAN2401) for early Alzheimer’s disease under the accelerated approval pathway. September 27, 2021. Available at: https://eisai.mediaroom.com/2021-09-27-Eisai-Initiates-RollingSubmission-To-The-U-S-FDA-For-Biologics-License-Application-OfLecanemab-BAN2401-For-Early-Alzheimers-Disease-Under-TheAccelerated-Approval-Pathway. Accessed October 7, 2021.

National Organization for Rare Disorders (NORD). FDA’s Accelerated Approval Pathway: a rare disease perspective. June 11, 2021. Available at: https://rarediseases.org/wp-content/uploads/2021/06/NRD-2182-PolicyReport_Accelerated-Approval_FNL.pdf. Accessed October 7, 2021.

Novartis enters agreement to acquire AveXis Inc. for USD 8.7 bn to transform care in SMA and expand position as a gene therapy and Neuroscience leader. April 9, 2018. Available at: https://www.novartis.com/news/media-releases/novartisenters-agreement-acquire-avexis-inc-usd-87-bn-transform-care-smaand-expand-position-gene-therapy-and-neuroscience-leader. Accessed October 7, 2021.

FDA News Release: FDA approved targeted treatment for rare Duchenne Muscular Dystrophy mutation. Updated August 12, 2020. Accessed October 7, 2021. https://www.fda.gov/news-events/press-announcements/ fda-approves-targeted-treatment-rare-duchenne-muscular-dystrophymutation US Food and Drug Administration. New drug therapy approvals 2020.

Updated January 8, 2021. Accessed October 7, 2021. https://www.fda. gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-newtherapeutic-biological-products/new-drug-therapy-approvals-2020 Armstrong A. Amylyx can proceed with ALS submission to FDA afterall, marking a win for patients’ advocacy efforts. Updated September 15, 2021. Accessed October 7, 2021. https://www.fiercebiotech.com/biotech/ amylyx-als-drug-submission-to-fda-after-reversed-decision Kaltenboeck A, Mehlman A, Pearson SD, Institute for Clinical and Economic Review. Strengthening the accelerated approval pathway: an analysis of potential policy reforms and their impact on uncertainty, access, innovation, and costs. Updated April 26, 2021. Accessed October 7, 2021. https://icer.org/wp-content/uploads/2021/04/Strengthening-the-

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Bell J. Big pharma backed away from brain drugs. Is a return in sight?

Updated January 29, 2020. Accessed October 7, 2021. https://www. biopharmadive.com/news/pharma-neuroscience-retreat-return-braindrugs/570250/

Christine K. Moore Christine K. Moore, Ph.D. is Vice President, Scientific Solutions: Neuroscience at Worldwide Clinical Trials. Dr. Moore has been involved in industry drug development and commercialization of treatments for CNS indications for the past 20 years, with nearly 50 publications. She has been part of numerous CNS programs in psychiatry, analgesia, and neurology, designing protocols and contributing to clinical development plans as well as commercialization efforts for CNS compounds.

Email: christine.moore@worldwide.com

Natalia E. Drosopoulou Dr. Drosopoulou is the Vice President of the Neuroscience Project Management Team. She received her Ph.D. in Biochemistry, specialized in Developmental Neurobiology from King’s College of London. With over 18 years in the clinical research industry, her experience spans from small intricate Phase I studies to large global Phase III programs.

Email: natalia.drosopoulou@worldwide.com

Henry J. Riordan Dr. Riordan is the Chief Development Officer and cofounder of Worldwide Clinical Trials. He has been involved in the assessment, treatment and investigation of various neuroscience drugs and disorders in both industry and academia for the past 25 years.

He has over 125 publications, including co-authoring two books focusing on innovative CNS clinical trials methodology.

Email: henry.riordan@worldwide.com

Journal for Clinical Studies 35

Therapeutics

Patient Engagement and Real-World Data Drive Innovation in Orphan Disease Drug Development An estimated one in 10 people are affected by a rare disease, and the cumulative economic burden of rare diseases surpasses that of common conditions like cancer or diabetes.

Yet of the 7,000 known rare diseases, approximately 95% lack effective treatments. Rare disease research is complicated by small and dispersed patient populations and often limited understanding of disease pathogenesis and progression. These realities create a range of challenges for drug development, including patient identification, endpoint selection, and trial design. However, the orphan disease landscape also offers compelling opportunities to explore innovative patient partnerships and uses of real-world data (RWD) to accelerate medical breakthroughs for individuals with rare disease.

With 350 million people worldwide affected by a rare disease, the collective impact of rare diseases on individuals and society is immense. Innovative technologies including gene therapy and gene editing are bringing effective treatments within reach for many conditions. In 2020, there was a 41% increase in orphan drug designation requests to the FDA from 2019, and 58% of approved drugs were orphan-designated products. While sponsors face many challenges in the orphan drug space, there has never been a better time to partner with the rare disease community to develop novel therapeutics. In particular, real-world data (RWD) is a powerful tool to assist drug developers in bringing better treatments to rare disease patients and families.

Challenges in Orphan Drug Development Small, dispersed patient populations and a lack of adequate data often go hand-in-hand in orphan drug development. Small patient numbers can make recruiting for site-based natural history studies and clinical trials challenging, limiting the amount of information gathered about disease progression. Even when site-based studies do move forward, the time and travel involved may be prohibitive for some patients, potentially skewing study populations toward participants who have the time and resources necessary to seek care at tertiary care centres and away from those who primarily receive care in the community setting. For example, we analysed health-care facilities visited by 151 participants in our RWD platform with a self-reported diagnosis of one of nine lysosomal storage disorders (LSDs). Fifty-eight percent of these participants did not receive care from a health-care facility we scored as a top-tier centre for LSD care (unpublished results, AllStripes Research). For many of these patients and their families, participating in a site-based study may not be feasible.

Furthermore, in a type of chicken-or-the-egg problem, lack of understanding about rare conditions hinders efforts to identify additional patients. Limited disease characterisation results in a shortage of care hubs and health-care professionals (HCPs) specialising in a given indication. As a result, every patient is following a unique care journey, including how they are diagnosed, what treatment they receive, and the outcomes they experience.

These factors make it challenging to predict where patients are being managed and create knowledge gaps in the health care and research communities that ultimately delay diagnosis of new patients. Indeed, 36 Journal for Clinical Studies

a 2020 study from the National Organization for Rare Disorders (NORD) found 28% of patients waited seven or more years for an accurate diagnosis, more than a third were misdiagnosed, and some remain undiagnosed.1 Half of patients and caregivers surveyed by NORD attribute these delays to a lack of disease awareness among HCPs. These challenges can also impede clinical trial planning and seeking regulatory approval. Before sponsors can test the efficacy of an experimental therapeutic, they need to understand the condition they are trying to treat and identify meaningful endpoints that will indicate whether their drug is effective. Identifying these endpoints can be challenging in many rare conditions, where no one biomarker, statistic, or measurement may adequately describe a disease’s progression or improvement. The nature of rare conditions can further complicate clinical trials since traditional randomised, multiarm designs may not be feasible for such small, sometimes critically ill populations. Finally, limited understanding of the pathogenesis and progression of rare diseases can make conversations with regulators challenging, as neither sponsors nor regulatory agencies may have a concrete playbook of requirements a drug must meet in order to be approved.

Patients as Partners For sponsors seeking to tackle the myriad obstacles to orphan drug development, one priority should take precedence over all others: developing a deep partnership with the patient community. In rare diseases, where there may be few or no clinical experts in a condition, patients and caregivers are essential key opinion leaders (KOLs).

Successful sponsors will seek to engage with the patient community as the experts they are, soliciting their input in drug programs as early as possible.

The FDA has provided resources to guide sponsors in incorporating the patient community into research planning and decision-making via their Patient-Focused Drug Development (PFDD) initiatives.2 Given the limited data available in rare disease, PFDD represents an essential part of orphan drug development. Patients, caregivers, and patient advocacy groups each have intimate knowledge of the patient journey, from the path to diagnosis through progression and management. These lived experiences help sponsors understand the true burden of a disease and what a drug must accomplish in order to be considered beneficial by patients and families. Forging community partnerships early on can also benefit both patients and sponsors in the long run by facilitating trial recruitment, retention, and long-term engagement – all of which are essential given the small sample sizes in rare disease. In short, the patient community is a critical research partner for sponsors, and the importance of relationship building and incorporating community feedback into orphan drug programs early and often cannot be overstated.

The Power of RWD for Rare Diseases With community partnership as the foundation for orphan drug programs, sponsors should also invest in RWD to address the challenges in rare disease research. The power of RWD, or data generated outside a clinical trial, has been discussed extensively in common indications like cancer and cardiovascular disease, Volume 13 Issue 6

Therapeutics and the paucity of data in orphan diseases creates an even more compelling opportunity for sponsors to invest in robust RWD solutions. The richest source of RWD in rare disease is patient medical records. Embedded in each patient’s chart is an in-depth history of their condition, from initial symptoms to diagnosis to current management. Integration of medical record data with other RWD sources can also enhance sponsor understanding of rare disease. Insurance claims can be used to analyse patterns of patient care, including which specialists and facilities patients visit and the costs of diagnosis and treatment. Wearable devices can capture biometric data like heart rate or sleep patterns, providing real-time information on patients’ symptoms and progression.

Patient surveys or patient-reported outcome measures can interrogate topics like quality of life that would be nearly impossible to measure without directly engaging the rare disease community.

Each of these sources of RWD illuminates a unique aspect of the rare disease patient journey and can help build a comprehensive understanding of a condition, even in spite of the obstacles to orphan drug development described above.

Robust RWD can help sponsors overcome challenges inherent in each stage of the orphan drug development process. When coupled with patient surveys, medical record data about symptoms and progression can provide in-depth insights into a condition’s natural history, filling gaps in the existing literature. These disease insights can power the development of real-world endpoints for future clinical trials. Natural history data can also yield a detailed picture of the patient journey through the health-care system, especially when coupled with claims data, enabling HCP identification and outreach.

Post-approval, medical affairs and commercial teams benefit from a comprehensive map of the patient journey as they strive to educate HCPs about the condition to improve diagnosis rates and ensure patients have access to these new treatments. Finally, detailed knowledge of a condition's natural history can also assist sponsors in educating regulatory agencies, who are less likely to have familiarity with rare diseases than more common indications.

RWD also represents an invaluable resource for clinical trial planning and preparing for regulatory discussions. One of the most frequently cited challenges in orphan drug development is clinical trial recruitment. Successful recruitment starts with site selection, a challenging task when the geographic distribution of patients is unknown, and no centres of excellence exist. Claims and medical record data can help identify where patients receive care and which sites may be most convenient for prospective trial participants. RWD can also assist sponsors in designing clinical trials to meet the unique needs of the rare disease community. As noted previously, traditional placebo-controlled studies may not be feasible or ethical in orphan indications. The FDA has provided a framework for the use of RWD and RWE in non-traditional study designs that help address these challenges. For example, in an “adequate and well-controlled study,” historical RWD may be used as an external control arm in place of a traditional placebo cohort.3 While acknowledging the limitations to using RWD in such single-arm trials, the FDA has also shown willingness to consider these types of trials in regulatory decisions, for example, in the approval of Novartis’s SMA gene therapy, Zolgensma.

Such flexible trial designs can help not only mitigate the challenges of small populations but also allow more patients to access potential treatments earlier. Finally, RWD can be used for post-approval monitoring. The FDA has indicated that approved gene therapies will likely require long-term follow-up periods given the possibility of delayed adverse events.4 Investing in RWD solutions early on can help sponsors build toward long-term success of their programs and ensure they can follow gene therapy recipients over time without overburdening patients and families. www.journalforclinicalstudies.com

Incorporating RWD into orphan drug development efforts offers compelling benefits to patients as well. One of the most widespread uses of RWD is health economics and outcomes research to support payer conversations and ensure patients can access treatments. RWD can also be used to generate evidence that early intervention improves outcomes, providing support for adding appropriate conditions to newborn screening (NBS) panels. NBS in turn can shorten families’ pathways to diagnosis, support, resources, and intervention.

Additionally, RWD can facilitate patient stratification by disease course or other factors, which can be used to provide anticipatory guidance to patients and families. Finally, use of RWD reduces the burden of patient participation in research. While prospective, sitebased studies require substantial travel or time commitments, many sources of RWD already exist or can be collected remotely. With small patient populations, every data point counts, and effective incorporation of high-quality, reusable RWD can help prevent patients and families from becoming overburdened by requests.

These examples illustrate ways in which RWD can help sponsors provide tangible benefits to patients beyond the development of an effective therapeutic.

Developing a RWD Ecosystem The tremendous promise of RWD for use in orphan drug development does not come without challenges. Like all types of data, each RWD source is best suited for specific applications and has specific limitations. In order to maximise the value of data from medical records in particular, sponsors should prioritise RWD solutions that capture high-quality data across the complete patient journey.

The reality of medical record data is that a patient’s clinical story is captured across multiple care facilities and electronic health records, and interoperability of clinical information remains a challenge globally but particularly in countries like the United States that lack a national health-care system. In rare diseases, this fragmentation is all the more disruptive as patients are often seen at multiple academic and community institutions. To ensure datasets derived from medical records are as complete as possible, sponsors and research organisations should consider several data-quality parameters: 1.

2.

3.

4.

Time period: Are data available across the patient's journey (from pre-diagnosis to present day), without any significant time gaps?

Comprehensive care map: Are data from all of the patient's known care facilities available, across tertiary care and community centres?

Diagnostic data: Are deep data from the diagnostic period available? These notes are likely to contain a wealth of information related to disease onset and progression.

Specialty data: Are data from critical specialty types available (for example, neurology notes for an epilepsy condition)?

In addition to evaluating the completeness of the medical record dataset, sponsors and researchers should also consider how best to structure clinical information from medical records, to enable comparisons across patients and rare diseases. As noted, one of the reasons medical records are such a rich source of data in rare disease is that clinical notes contain details about the patient’s journey and progression that cannot be found elsewhere. However, these notes are unstructured and not recorded in a standard manner across institutions. Furthermore, as so little is known about many rare diseases, it is not always clear what clinical information should be structured for analysis. While data collection standards do exist in clinical research – CDISC and NINDS standards are excellent starting points – the reality is that no gold standard currently exists for how to structure complex clinical data from medical records in rare diseases.

Journal for Clinical Studies 37

Therapeutics Rare Disease as the Future of Drug Development Recent advances in clinical care and therapeutic development are creating a future where all diseases will one day be considered rare. The increasing use of technologies like genomic profiling and artificial intelligence allow for patient stratification at a level of granularity never before possible. Likewise, advances in gene therapy and gene editing technologies are helping sponsors develop targeted therapeutics for specific subpopulations. With the drug development landscape moving away from one-size-fitsall therapies for large indications and toward bespoke therapies for smaller and smaller subsets of indications, investing in rare disease makes clear practical sense for sponsors. Some may be intimidated by the many challenges facing drug developers in the orphan disease space. Yet today holds tremendous opportunity to set new standards for involving the rare disease patient community and using RWD to fill critical knowledge gaps. By embracing this unique moment, sponsors can take part not only in developing more effective treatments for critically underserved populations but also in defining a new playbook for the drug development industry as a whole.

REFERENCES 1.

2.

3.

4.

How can we best overcome the challenges inherent in using RWD and achieve their full promise for orphan drug development? The clearest path to achieving this goal in the coming years is through development of a robust RWD ecosystem that incorporates input from all rare disease stakeholders and integrates across RWD types.

For example, sponsors will find that patients are the best partners in helping ensure completeness of medical record datasets over time, because they know best where and by whom they have been treated.

As such, sponsors should invest in RWD platforms that bring the patient to the table; help build strong, ongoing relationships; and facilitate longitudinal patient follow-up. Additionally, sponsors will see the greatest success in their RWD efforts when they invest early in a RWD strategy that marries disparate data types, complementing weaknesses or gaps in one dataset with information from another.

For instance, while claims data can be useful in analysing patterns of patient care, not all rare conditions have ICD-10 codes. Linking claims data with clinical data from medical records can help mitigate this limitation, enhancing overall understanding of care patterns.

Likewise, quality-of-life data are critical for understanding disease progression but are rarely captured in medical records; it is therefore essential that patient survey data be integrated with the clinical story.

Finally, given the breadth of endpoints and data elements of interest in rare disease, establishing standards for RWD capture will require collaboration among all stakeholders in the rare disease community.

Robust data standards, in combination with flexible, iterative approaches to data capture and study design, will allow investigators to compare findings within and across rare diseases. Successful sponsors will invest in infrastructure and solutions that incorporate patient input and facilitate the collection, standardisation, and analysis of the full suite of RWD to generate evidence that advances their clinical programs.

38 Journal for Clinical Studies

National Organization for Rare Disorders. Barriers to Rare Disease Diagnosis, Care and Treatment in the US: A 30-Year Comparative Analysis. 2020, https://rarediseases.org/wp-content/uploads/2020/11/ NRD-2088-Barriers-30-Yr-Survey-Report_FNL-2.pdf, accessed on 20 Oct 2021. https://www.fda.gov/drugs/development-approval-process-drugs/cderpatient-focused-drug-development, accessed on 20 Oct 2021.

US Food and Drug Administration. Framework for the FDA’s Real-World Evidence Program. 2018, https://www.fda.gov/media/120060/download, accessed on 20 Oct 2021.

US Food and Drug Administration Center for Biologics Evaluation and Research. Long Term Follow-Up After Administration of Human Gene Therapy Products: Guidance for Industry. 2020, https://www.fda.gov/ media/113768/download, accessed on 20 Oct 2021.

Caitlin Nichols Caitlin Nichols, PhD is Research Director at AllStripes Research, oversees scientific communications and the design and execution of real-world data research partnerships with industry, academic, and patient advocacy group stakeholders. She received a PhD in Biological and Biomedical Sciences from Harvard University. Dr. Nichols was formerly a scientific curator on the Product Science team at 23andMe, where she helped develop and improve consumer genetic test reports.

Kristina Cotter Kristina Cotter, MS, PhD, CGC is Vice President of Research at AllStripes, oversees the design of research studies and partnerships that use real-world data to advance rare disease research. Dr. Cotter is a board-certified genetic counsellor and received her MS in Genetic Counselling from Stanford University and PhD in Molecular Biology from Tufts University. Dr. Cotter was formerly a strategy consultant at Trinity Partners and currently sits on the Scientific Advisory Board of the International Foundation for CDKL5 Research.

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Technology

Querying the Queries – An AI Approach to Manage Clinical Data Quality High quality clinical trial data is essential for a successful clinical trial. This data is the foundation for the analysis, submission, approval, labelling and marketing of a compound.

A focus on data cleaning, an essential process in the collection and management of clinical data, ensures that the data collected is consistent and accurate.

However, it is not unusual for data errors to occur during data entry. Some of the most common are spelling or transcription errors, range errors and text errors, which impact coding. While automated edit checks exist to prevent the entry of inaccurate information, they are not able to detect all potential data entry issues. As data quality is at the crux of clinical trial success, clinical data management teams also use a manual approach to data cleaning by raising queries to the clinical trial sites to resolve any potential safety issues or inconsistencies in the data collected.

Often, on some studies, there can be numerous manually generated queries, which are time consuming and costly. By applying AI (artificial intelligence) techniques to understand the context of these queries, it may help improve automated edit checks or even offer opportunities to put additional checks or processes in place to help identify issues earlier in the studies. By applying machine learning to historic manual queries across different studies to understand common issues across and within studies, it could enable a more targeted approach to process optimisation for clinical trial data cleaning.

The Process of Data Collection Clinical data management teams at each trial site work collaboratively to ensure that the data collected is managed in a conscientious way and then is reported clearly, accurately, and delivered securely to the data repository for access by a CRO or sponsor. An essential part of this process is data cleaning to ensure the data is consistent and accurate.

Taking a closer look at the specifics of the manual queries, the data included the form and variable the query was raised on, the row the query was raised on and the query message.

That information provided the basis for further study with the aim of reducing the number of manual queries. However, there were questions to be researched, including whether or not we could identify themes in the manual queries without subjecting them to human bias.

LDA offered an opportunity to identify these themes. As a type of topic modeling algorithm, LDA is used as a pre-processing step in ML and applications of pattern classification. Its purpose is to reduce the number of data features to a more manageable number before the process of classification. And, secondly to learn the topic distribution of each document in a collection of documents.

Looking across a set of documents, for example, there may be commonalities in words which appear in each document, but these documents may have different numbers of these common words, which makes it difficult to identify and define the appropriate category for each document.

Via LDA, the mission was to determine if the number of manual inquiries could be reduced through the understanding of problematic forms. Could this technology result in more focused edit checks and could queries be auto-generated?

First, each query was tokenized or split into words with common data management words removed, i.e., confirm, verify, check, please, thank you, etc. and LDA applied to the queries to create a number of common topics for further review. The results of the LDA were visualised in the context of the forms used to collect the data and study experts consulted to bring deeper understanding of the context.

Steps to Reducing Manual Queries via AI In looking to determine how AI approaches could be utilized, it was necessary to review several clinical trial situations.

Study Results Provide Efficacy of AI Approach The visualisations provided the study experts with insights into the different topics, identifying the most common words in each topic together with a summary of the context, such as the form and variable that the queries within a topic were raised against. This enabled the team to really understand what was driving queries within a topic.

This understanding provided the basis to explore how these queries may be reduced going forward, for example through enhanced edit checks or, as described below, through a rules-based approach to speed up the discovery of the potential data issue.

For example, in Study 1, a higher than expected number of queries were identified. In this case out of 21,103 queries, 7,560 or 36% were manual. Considering that the average cost of a manual query from start to close is about €150, the high percentage of manual queries added significant cost to the study.

Rules Approach to Further Study Research Based on the efficacy of the AI approach and interpretation of the different topics, next steps included investigating whether the generation of rules could identify some of the queries in the ‘top’ topics identified. This would be a critical foundation for progressing

Generally, to ensure quality, data is checked for inconsistencies such as missing data. This step in the process can be automated as data is entered (edit checks). It can also be done manually after data has been entered through a query to the trial site.

40 Journal for Clinical Studies

Volume 13 Issue 6

Technology

onward, to applying this approach to more studies, and would uncover comparative overlap and differences in each study.

significantly reduce the number of manual queries during a trail and thus increase efficiencies while reducing costs.

To implement a rules-based scenario, however, a dataset would have to be created to assess the impact of the implemented rules using a historical snapshot from Study 1. For example, work with a topic result and an expert to generate rules around the AE and sick day medications (as described above). And finally apply these rules to the data snapshot and come to an understanding of how many manual queries are aligned with the results.

Although automation and AI techniques play a key role, managing and distributing clinical trial data will, for the foreseeable future be a human-machine endeavour. While machines may data-driven and more accurate than manual approaches, it will always require human attributes to provide the critical interpretation for better understanding of this data.

Study 2 was an extension study building on the results of Study 1, plus results from an earlier study in the same clinical indication that would help understand overlap and differences. As expected, there was a large amount of overlap. Interesting to note, however, that the differences in Study 1 that had been addressed were different in Study 2. For example, issues arose in central labs were in Study 1 but not Study 2.

Study 3 proved even more interesting. It was a completely different phase, study, sponsor, indication, and population and yet it also revealed some differences and some overlap.

Potential of the AI Approach as Part of the General Data Management Process.

A final step would be – if the investigation proved successful – exploring the potential of this approach as part of the general data management process.

Via LDA, the mission determined that the number of manual inquiries could be reduced through the understanding of problematic forms. Additionally, this technology would result in more focused edit checks and would allow queries to be auto-generated.

The exercise very definitely demonstrated the benefits of applying AI to the manual data queries generated during the data cleaning process. It proved that this technology provides the opportunity to www.journalforclinicalstudies.com

Jennifer Bradford Jennifer Bradford, PhD is Head of Data Science for the CRO PHASTAR. She previously worked for the Advanced Analytics Group at AstraZeneca, leading the development of the REACT clinical trial monitoring tool, which she later customised and delivered to other sponsors as part of Cancer Research UK (CRUK). Within CRUK and in close collaboration with the Christie hospital she worked on EDC, app development and wearables data analytics in the context of clinical trials. She has a degree in Biomedical Sciences from Keele University and a bioinformatics Masters and PhD from Leeds University.

Sheelagh Aird Sheelagh Aird, PhD is Senior Director, Data Operations for the CRO PHASTAR (www. phastar.com). She has more than 30 years of experience in clinical data management, Sheelagh has directed and delivered projects in all phases of clinical trials across numerous therapeutic areas and data collection platforms. Sheelagh holds a BSc in pharmacology and doctorate in pharmacokinetics from the University of Bath. She has led PHASTAR’s Data Operations group since 2016.

Journal for Clinical Studies 41

Logistics & Supply Chain

The Role of The Falsified Medicines Directive and Delegated Regulation in The Supply Chain of Clinical Trials Companies providing clinical trial supply services to sponsors and contract research organisations (CROs) need to comply with a complex framework of regulatory requirements and industry standards. These include the obligations prescribed in the Falsified Medicines Directive (2011/62/EU) and Delegated Regulation (EU/2016/161) with regards to the verification and decommissioning of safety features on products provided for clinical trial purposes. But whose responsibility is it to perform such obligations among the various stakeholders in the clinical supply chain? What implications does FMDawareness have in terms of compliantly administering clinical trials? And what benefits do FMD related processes offer to clinical trials?

be a complicated process with many unforeseen challenges and an unexpectedly high level of non-compliance on behalf of stakeholders.

The development of several national data-repository systems was not completed by the implementation date hence their integration to the central European database has been delayed. Manufacturers were substantially lagging behind with regards to some of their obligations, such as the timely uploading of unique identifiers to the appropriate data repositories or the appointment of their delegated wholesalers in the verification system. Pharmacies across Europe failed to acquire the IT tools, software systems and procedural know-how to fully comply with their responsibilities. These systemic failures led to a transitional stabilisation or grace period of the implementation that was characterised by an immense number of alerts in the system and a constant breach of the prescribed protocols with non-compliant stakeholders.

Introduction of the FMD To ensure that the integrity of the supply chain of pharmaceutical products remain intact in the European Union (EU), a series of regulatory measures have been adopted by the European institutions and the European Medicines Agency (EMA) in the last decade. The implementation of the Falsified Medicines Directive (2011/62/EU) and Delegated Regulation (EU/2016/161) were among the leading initiatives to prevent the entry of falsified medicinal products into the legal supply chain. These regulatory instruments led to the creation of the European Medicines Verification System (EMVS), an overarching, EU-wide IT infrastructure linking a series of national data depositories to a central EU hub. The directive and delegated regulation also introduced the mandatory placement of safety features – a unique identifier (UD) and an anti-tempering device (ATD) – on each box of prescription medicine produced after the implementation date.

During the implementation process, a plethora of questions have been raised by all the different stakeholders. In many cases, even the regulatory authorities could not provide definitive answers in terms of how the regulatory rules and regulations are to be interpreted in real-life, operative scenarios. Early in the implementation process, the European Commission has started to compile a document with all the relevant questions submitted by the stakeholders and the answers provided by the Member State expert group on safety features. Nothing demonstrates more the uncertainty around the implementation than the fact that, as of November 2021, such document has undergone over more than 20 extensions and modifications and currently include approximately 120 questions.2 To further exacerbate the situation, shortly after the implementation date of the system, the United Kingdom – a previous adaptor of the FMD regulatory framework and infrastructure – has withdrawn from the European Union.

In addition, the new regulatory framework obliges manufacturers, wholesalers, and persons authorised or entitled to supply medicinal products to the public (e.g., pharmacies) to perform certain tasks related to the safety features. Along the different phases of the pharmaceutical supply chain, the authenticity of the unique identifiers and the integrity of the anti-tampering devices are to be verified by the different stakeholders. Also, at certain stages of the distribution process and for specifically designed purposes, the unique identifiers are to be decommissioned and hence removed from commercial circulation. The Delegated Regulation unambiguously defines the responsibilities of each stakeholder with regards to when, how and why they must verify and decommission safety features. Instructions in the Delegated Regulation cover various contexts of distribution, such as when products are supplied to the public, exported outside of the EU, provided to the authorities as samples or subjected to further manufacturing processes for clinical trial purposes.

Benefits, Tasks, and Risks for the Clinical Research Sector The implementation of the FMD offers various benefits within the field of clinical research. An enhanced level of security with regards to the integrity of the supply chain of products used in clinical trials is certainly a benefit for the sector. In the past, several clinical trials have been negatively impacted when falsified products were identified in their supply chain hence a more transparent and rigorous verification system concerning the authenticity of the involved products is highly advantageous. In addition, combined with a thorough documentary check, the verification of the products used in clinical trials via the European Medicines Verification System also allows for more transparency relating to the distribution history of the involved products.

Implementation of the FMD The implementation of the FMD upon its introduction proved to 42 Journal for Clinical Studies

The implementation of the FMD also poses additional operative tasks and responsibilities during the organisational process of clinical trials. The classic clinical trial supply chain – primarily concerning the manufacturing and distribution of previously non-marketed investigational medicinal products (IMPs) – is outside the scope of Volume 13 Issue 6

Logistics & Supply Chain the FMD and the Delegated Regulation. However, when previously marketed, non-investigational medicinal products (NIMPs) are introduced in the clinical supply chain as comparators, rescue medicine or concomitant medications, the obligations of stakeholders prescribed by the FMD regulations do apply. FMD rules are also relevant when commercially marketed products with safety features are considered as IMPs in case they are being examined in different indication(s) than those included in their marketing authorisations.

The types of tasks and the identity of the stakeholders who should carry them out depend on various factors, such as the extent of the manufacturing process (e.g., labelling) the products need to undergo before being introduced to the clinical supply chain.

Apart from the extra operational tasks of verifying and decommissioning unique identifiers as described above, the FMD implementation also introduced several additional administrative and compliance-related tasks with regards to the appropriate supervision of clinical trials. Sponsors or contract research organisations cannot afford to have non-compliant service providers in their supply chains let those be negligent wholesalers ignoring their verifications responsibilities, neglectful manufacturers omitting the step of decommissioning products before labelling them or irresponsible investigational sites where products are not decommissioned before they are administered to patients taking part in the clinical trials.

The price to pay in case of not properly executed FMD tasks is way too high. Products that are not duly verified can turn out to be recalled, withdrawn, indicated as stolen or flat out falsified with a false representation of their identity, composition, source, or history as defined in the guidelines on Good Distribution Practice of medicinal products for human use. Such scenarios can lead to the temporary suspension or ultimate cancelling of an entire clinical trial and might bring about additional legal consequences to the sponsor or the contract research organisation in charge of ensuring compliance with all regulatory requirements. The lack of proper verification protocols can also generate system alerts sent directly to the regulatory authorities, such as the alert for example that is raised when a clinical investigatory site intends to duly decommission the unique identifier of a product that is already marked as ‘supplied to the public’ in the medicines verification system. Such alert would automatically warrant unsolicited attention and a formal investigation on behalf of the regulatory authorities.

FMD Obligations of Manufacturers in the Clinical Supply Chain The verification and decommissioning of the unique identifiers on products supplied for clinical trial purposes can be carried out in numerous stages of the distribution process and by different stakeholders. Manufacturers – as described in Article 16 of the Delegated Regulation1 – must verify the unique identifiers before decommissioning them on packs to be repackaged or re-labelled for further use as authorised investigational or auxiliary medicinal products. When wholesalers provide commercial products to providers of clinical trial manufacturing services for labelling or repackaging, it is such manufacturing service providers’ responsibility to decommission the unique identifiers of the products. When and how such decommissioning takes place depends on multiple factors since once a product is decommissioned for manufacturing processes (e.g., labelling) it cannot be returned to the supplying wholesaler and needs to be destroyed should it end up not being used in the trial for any reason.

Once the unique identifiers of commercial products are decommissioned and the manufacturing processes have been concluded, manufacturers are not bound to apply new safety features to the repackaged or labelled products to be used exclusively in www.journalforclinicalstudies.com

clinical trials. As mentioned earlier, this is because the scope of FMD does not cover the clinical trial supply chain including products not used in commercial circulation. The situation is different in other supply chain scenarios, such as parallel distribution, where the repackaged or labelled products re-enter commercial circulation.

These repackaged or labelled products need to comply with all FMD requirements including the replacement of the old unique identifiers and anti-tampering devices with new ones.

Products manufactured for known use in a clinical trial – as described in Question 1.6 of the previously mentioned document maintained by the European Commission2 – are excluded from the requirement of the FMD. These are products defined as investigational medicinal products (IMPs), manufactured in accordance with the original marketing authorisation but are specifically packaged for a clinical trial in a way that substantially differs from their commercial presentation. The manufacturer of such products would be required to hold a manufacturing and importation authorisation covering IMPs and the manufacturer should be named and authorised in the specific clinical trial application approved by the appropriate regulatory authority. Since these products are not required to carry any safety features; manufacturers have no verification or decommissioning tasks associated with them. Naturally, manufacturers could still opt for placing unique identifiers on these boxes for better transparency and traceability purposes but those are not to be included in and checked against the data repositories of the European Medicine Verification System.

FMD Obligations of Wholesalers in the Clinical Supply Chain Wholesalers – as described in Article 20 of the Delegated Regulation1 – are bound to verify unique identifiers of packs not sourced directly from manufacturers, marketing authorisation holders or their designated wholesalers to be later supplied for clinical trial purposes. Wholesalers are also obliged to verify products returned by pharmacies or other wholesalers. Such returned products are however preferred to be excluded from the clinical supply chain owing to the additional risk they represent. Since the verification of unique identifiers can be carried out voluntarily and at any times, prudent sponsors and contract research organisations are advised to request their wholesaling partners to verify every pack before being supplied. Verification by wholesalers should take place before goods are delivered to the investigatory sites where they are dispensed to patients or before they are delivered to the manufacturing entities responsible for further repackaging or labelling. Wholesalers providing commercially available non-investigatory medicinal products to clinical trials hold the key to ensuring that no falsified medicinal products are provided in the clinical supply chain and no alerts are raised in the medicines verification system that could jeopardise the continuity of the clinical trial.

Wholesalers in possession of a sole Wholesale Distribution Authorization (WDA) have limited options to decommission unique identifiers. The full range of decommissioning options available for wholesalers are described in Article 22 of the Delegated Regulation1 and they do not involve the possibility of decommissioning for repacking or relabelling activities within the context of clinical trial supply. To acquire such decommissioning capabilities, a service provider must hold a manufacturing authorisation and operate according to the Guidelines on Good Manufacturing Practices (GMP).

Also, as frequently misunderstood within the context of the clinical trial supply chain, wholesalers are not authorised to decommission the unique identifiers of commercial products delivered to clinical investigatory sites either. When supplying products to specific institutions that dispense them to the public (e.g., prisons, nursing homes, etc.) wholesalers might be able to decommission unique Journal for Clinical Studies 43

Logistics & Supply Chain

identifiers as required by national authorities. Article 23 of the Delegated Regulation1 lists all the different types of such specific institutions and reasons among which however clinical trial purposes are not included.

FMD Obligations of Pharmacies in the Clinical Supply Chain Within the context of clinical trials, persons authorised or entitled to supply medicinal products to the public typically constitute of pharmacies located at the clinical investigatory sites where the clinical trials are conducted, and patients involved in the clinical trial receive treatment. The implementation of FMD has introduced an additional layer of complexity to dispensing products to patients under the purview of a clinical trial specifically when those products are commercially marketed and hence carry safety features. Article 25 of the Delegated Regulation1 places a clear obligation on pharmacies to verify the safety features and decommission the unique identifier of medicinal products which they supply for subsequent use as authorised investigational medicinal products or authorised auxiliary medicinal products. It is very important to emphasise that omitting to decommission commercially marketed products used in clinical trials is an evident case of non-compliance with the applying regulatory rules and regulations and hence should be avoided by all means.

of the Delegated Regulation, the tasks and responsibilities of manufacturers, wholesalers and persons authorised or entitled to supply medicinal products to the public within the context of clinical trials have been distilled. Providers of clinical trials supply services now navigate the waters of FMD requirements with substantially more confidence. Compliance with FMD regulations must become a norm for sponsors and contract research organisations as the initially granted stabilisation or grace periods have ended and regulatory agencies are announcing focused FMD audits to come for all participants in the clinical supply chain.

REFERENCES 1.

2.

3.

Conclusion The regulatory framework and infrastructure implemented in the last couple of years in the EU have undoubtedly improved the safety of the supply chain for pharmaceutical products. A more transparent, more verifiable, and securer network of distribution for clinical trials supplies certainly benefits the sector of clinical research as well.

The implementation of the regulatory framework has had its fair share of challenges owing to delays in infrastructure development, a lack of clarity about tasks in certain contexts (e.g., clinical trials, parallel distribution, etc.) as well as non-compliance of stakeholders with their transactional tasks and responsibilities. Ambiguity about FMD processes still prevail as certain political developments (e.g., Brexit) and the lack of enforcement of the rules on behalf of certain Member States still stand in the way of a fully harmonised European compliance.

Within the context of clinical trials, not all processes pertaining to the verification and decommissioning of unique identifiers have initially been fully understood. This was particularly the case with commercially marketed products carrying safety features that are supplied to patients involved in clinical trials as non-investigational medicinal products. However, three years after the implementation 44 Journal for Clinical Studies

Commission Delegated Regulation (EU) 2016/161 of 2 October 2015 supplementing Directive 2001/83/EC of the European Parliament and of the Council by laying down detailed rules for the safety features appearing on the packaging of medicinal products for human use https:// eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32016R0161 &from=HU Safety features for medicinal products for human use – Questions and answers – Version 18B https://ec.europa.eu/health/sites/default/files/files/falsified_medicines/ qa_safetyfeature_en.pdf Guidelines on Good Distribution Practice of medicinal products for human use (2013/C 343/01) https://eur-lex.europa.eu/LexUriServ/LexUriServ. do?uri=OJ:C:2013:343:0001:0014:EN:PDF

Tibor Kovács As Commercial Director at PHARMAROAD KFT, Tibor coordinates the activities of the Clinical Trial Supply Division. He oversees business relations with sponsors, clinical research organisations and clinical trial supply specialists. Tibor’s work entails commercial, logistic, and quality assurance related aspects of clinical trial supply services.

He acts as the lead representative of the company during vendor qualification audits. He is a qualified International Clinical Research Auditor accredited by the International Accrediting Organization for Clinical Research. Tibor holds an undergraduate degree from the University of Lincoln in Lincoln, the United Kingdom, a graduate degree from the Asia-Europe Institute in Kuala Lumpur, Malaysia and a postgraduate degree from the Universidad Autónoma de Madrid in Madrid, Spain.

Volume 13 Issue 6

Logistics & Supply Chain

Intricacies and Future Considerations for the Cell and Gene Therapy Cold Chain The rapidly growing field of cell and gene therapy is both exciting and confusing to many, including those who work in the medical community and on the periphery. Advancements of therapies happen at a feverish pace. The number of clinical trials increases exponentially in a short time. And bringing therapies to commercialisation remains a hurdle.

As biotech companies navigate bringing cell and gene therapies from clinical trials to commercialisation, companies within the supply chain also work to understand and support this evolving field of medicine. In the case of cold chain, this means navigating variable temperature requirements and offering solutions that accommodate people unfamiliar with temperature-controlled packaging, as well as innovating ways to track and monitor irreplaceable raw material and completed therapies as they travel from and to the patient. As therapies reach commercialisation and advance beyond one-to-one treatments, adaptability and standardisation become increasingly important.

The Market Cell and gene therapy are overlapping fields of biomedical research and treatment. Both serve to treat, prevent and cure genetic and acquired diseases. But they work differently.

According to the American Association of Blood Banks, cell therapy replaces or repairs damaged tissues or cells with transplanted human cells.1 The cells either originate from the patient (autologous) or a donor (allogeneic). The applications are expansive, as there are hundreds of cells that make up the human body. Most cell-based therapies are currently experimental, with few exceptions. For example, hematopoietic blood stem cell transplantation was first explored in humans in the 1950s and is currently a well-established treatment for blood diseases.

Gene therapies, by contrast, replace genes to help the body fight or treat disease, turn off genes that cause problems or replace genes that cause problems with ones that work correctly. Once a new gene is created, a vector is used to deliver new genes directly into cells – either inside or outside the body.2 Gene therapy was first introduced in the late 1970s, and the first gene therapy trial in humans began in 1990.3 Arguably, the introduction of successful Chimeric Antigen Receptor T-cell therapy (CAR-T) in the early 2000s was a pivotal tipping point in the evolution of the cell and gene therapy market.

Market growth is exponential. In 2012, there were 12 CAR-T clinical trials. By 2019, the number surged to 514. And between 2017 and 2020, three CAR-T products reached commercialisation, with the number estimated to reach double digits by 2024. In 2019, CAR-T therapy earned more than $700 million, and with more products expected to reach commercialisation, this rapid-growth industry is poised to produce over $10.8 billion by 2027.

Since Kymriah and Yescarta received historic approvals of CAR-T therapies in 2017, their products have been infused into an www.journalforclinicalstudies.com

estimated 450,000 patients worldwide. With growing numbers of approvals anticipated, the patient population for CAR-T therapy alone will reach approximately 2 million within the next 10 years.4 Currently, most of the therapies use products derived from blood samples. But with growing momentum to develop treatments for solid tumours and other tissues, more products with different requirements are likely to emerge.

The Supply Chain The supply chain required for cell and gene therapy is simple, but variables not seen in a traditional pharmaceutical supply chain make it especially challenging. Unlike most pharmaceutical products, the raw materials used to develop potentially life-saving cell and gene therapies are most often a patient’s own cells. A trained medical professional collects the cells, ships them to another facility to create the therapy and the therapy is shipped back to the patient’s medical facility for infusion.

However, medical facilities vary in infrastructure, available equipment, and technologies. This poses a challenge when temperature-sensitive cells require temperature control and specialised packaging to transport them safely to a biotech company. Facilities may not have equipment to refrigerate or freeze cells, space to store bulky temperature-controlled packaging or appropriate freezers to condition packaging components. Staff familiarity with and training on temperature-controlled packaging could also introduce risk in the form of temperature excursions.

Since cell and gene therapies are generally a treatment of last resort, patients are often very sick. Many would not be able to donate a second blood sample if the first sample or therapy experienced damaging temperature excursions. Fool-proof temperature control is necessary, especially when shipping a patient’s cells to a biotech company.

Companies specialising in temperature-controlled packaging now make single-use and reusable refrigerated shippers that are easier to use at these sites. These new refrigerated shipping systems require no conditioning, and they weigh significantly less than shippers that use traditional coolants like ice. Just one touch of a button activates the cooling process for refrigerated samples, bringing a room temperature product slowly to 2–8 degrees Celsius.

These systems use evaporative, reactive cooling technology that responds and adjusts to varying ambient temperatures. This ensures the payload is protected from external temperature fluctuations throughout the duration of the shipping process.

Therapies shipped back to a patient’s medical facility are most often shipped frozen using vaporised liquid nitrogen (LN2). This requires special training since LN2 can cause frostbite or skin burn if touched, and its gases can damage delicate eye tissue. This shipping method also proves costly because of the specialised training needed to use LN2 shippers. When moving from one-to-one therapies to commercialised, mass-produced therapies, LN2 costs become too much to sustain.

Journal for Clinical Studies 45

Logistics & Supply Chain

Temperature and Location Monitoring Temperature excursions that cause a patient’s cells or therapy to deviate outside of the allowed temperature range could damage the container’s payload, resulting in a devastating impact on the patient’s health. Maintaining supply chain integrity is critical to mitigating risks and ensuring the safe and secure transportation of health-giving and life-saving cells and therapies.

Stakeholders in pharmaceutical shipments demand increasing levels of transparency regarding the status of shipments, including location tracking and temperature history.

Cold chain and courier companies are increasingly using advanced asset management software systems to monitor temperatures and ensure packages are shipped to the right place, at the right time and arrive in the right condition. A key development includes real time monitoring of payloads via smart loggers and devices that are interconnected to the Internet of Things (IoT), making it possible to access and assess the condition of the payload in transit. Being alerted about a temperature excursion by 46 Journal for Clinical Studies

the shipper before it reaches its destination allows preventive or corrective supply chain actions earlier than would have otherwise been possible, especially if hand-couriered to a final destination.

These new, advanced software systems and the integration of information technologies (IT) within the pharma supply chain, play an increasingly vital role in protecting pharmaceutical shipments from excursions during transport to their destinations. Issues can arise if the shipper is opened during a customs inspection or tampered with during transit. The IoT device can track or warn when a shipper is opened, for how long and if there is a risk to the payload’s temperature requirements.

GPS is currently the only technology that provides real time tracking. While there is growing interest in using GPS-enabled/IoT sensors for temperature tracking, they are not widely used. This is because GPS technology tends to be heavy, expensive and takes up a fair amount of payload space. Additionally, when loaded on an airplane, the tracking signals must be turned off, so they do not interfere with airplane navigation. This technology is most often Volume 13 Issue 6

Logistics & Supply Chain used with individualised CAR-T therapies, where the loss of a product could mean life or death for the patient.

When exact location and condition is not needed, another class of smart devices can be used. These are just in time (JIT) devices, and they often use other methods of communication when passing through a physical IoT gate or provide a download of data via Bluetooth, QR code, bar code, USB connection or other method. This data includes logged temperature information or the number of times the payload was opened, which can be assessed at the end of the journey.

Depending on the location, condition and temperature data needed, real time or JIT devices can be an ideal solution when weighing urgency of data need versus cost and reduction in payload size. Data retrieved and shared can help biotech companies make more informed choices on the most appropriate cold chain solutions to deploy depending on specific shipping lanes.

The latest global tracking technologies to ensure the protection of pharmaceutical payloads offer a wide range of capabilities. These include options to set up automatic maintenance, next shipment alerts and produce customisable reports. Related to advances in tracking technologies is increased interest in developing better, more effective solutions to enable use and sharing of data between packaging providers, logistics providers and biotech companies.

Future Considerations Biotech companies face several complex challenges, including protecting the integrity of temperature-sensitive, high-value payloads during transportation. This must be done while mitigating costs, managing and tracking assets within a complex supply chain, meeting stringent global regulatory standards, navigating complex global shipping lanes and circumventing unforeseen challenges.

Current cell and gene therapies are primarily autologous – using a patient’s own cells - and result in a high treatment price per patient. High treatment costs are not sustainable. As the industry evolves, it is anticipated that more companies will work on allogeneic-based therapies that are more cost effective and more aligned with treatment reimbursement. These therapies could also offer an opportunity to move beyond one-to-one therapies into mass-produced therapies.

Reimbursement constraints for patient therapies will play a role when biotech companies look at mass-produced therapies.

When mass produced therapies become a reality, it would be costly and impractical to continue using expensive and more complex LN2 systems for these therapies. Biotech companies will need to standardise temperature requirements for their therapies and move toward temperature ranges that offer economy and scalability - like dry ice. Cold chain companies and biotech companies need to work together to standardise shipping solutions.

With biotech companies developing ever more complex and temperature-sensitive therapies, there’s growing demand to integrate IT solutions within the supply chain balanced alongside the established requirements of providing improved packaging performance and efficiency within cold chain logistics.

Innovation, IT integration and new technologies to enhance supply chain monitoring and remote tracking will become increasingly important with bulk shipments. These technologies are crucial in addition to the continuous evolution of smart temperature-controlled packaging protecting cell and gene therapy payloads globally. www.journalforclinicalstudies.com

The industry trend to deploy reusable systems coupled with asset management SaaS (software as a service) may catch on for cell and gene therapies. These systems can automatically collect and analyse data from company smart data logger outputs. These monitoring devices are increasingly used in cold chain as they become more affordable and accessible to biotech and pharmaceutical companies. These stakeholders are excited about the prospect of offsetting the costs of these new technologies with savings, based on reduction of lost products, and using data from smart devices to add efficiencies and fine tune distribution models.

Alternatively, IoT devices can be attached to a specialised container to ship a pallet of products providing an isolated monitoring option to pick up data, which can be saved to the Cloud via Bluetooth or Radio-Frequency Identification (RFID).

It’s predicted that advancements in GPS tracking options via an online SaaS system will soon become standard within the industry.

Benefits to biotech companies include knowing where their shipment is throughout its complex logistics journey.

If payloads are intercepted, lost, or get delayed en route, the biotech company can take steps to intervene and recharge or replace coolants, so the package or the bulk system gets delivered before expected temperature duration is exhausted. This presents a strong case for using IoT devices and supporting software and technology to mitigate a temperature excursion caused by a delay.

The cell and gene therapy industry continues to grow and expand as new, life-saving, and health-giving treatments, technologies and distribution strategies evolve. Biotech companies, cold chain companies and other stakeholders will need to work together to standardise product requirements, maximise efficiencies and optimise benefits for patients who depend on their products and services.

REFERENCES 1.

2.

3.

4.

https://www.aabb.org/news-resources/resources/cellular-therapies/ facts-about-cellular-therapies https://www.fda.gov/consumers/consumer-updates/what-gene-therapyhow-does-it-work https://asgct.org/about/history BIOINFORMANT, Global CAR-T Cell Therapy Market – Market Size, Forecasts, Trials & Trends

Vince Paolizzi Vince Paolizzi has over 15 years of experience in various sales leadership roles within the Pharmaceutical packaging industry. He is responsible for the global sales growth of the NanoCool line of products. Paolizzi’s experience includes key account management to maintain strong relationships with customers as well managing multidisciplined project teams to secure new accounts. Prior to joining Peli BioThermal, Paolizzi held various sales positions within the packaging, tooling and food industries. He received his degree in Business Management from West Chester University of Pennsylvania.

Email: vince.paolizzi@pelican.com

Journal for Clinical Studies 47

Ad Index

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Clinerion

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MLM Medical Labs

Page 39

Outsourcing in Clinical Trials

Page 17

Ramus Medical Ltd.

IFC SGS

IBC

Temperature Controlled Logistics in Biopharmaceuticals EU

BC Topa Thermal

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