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Issue 64

The Journal of the Pharmaceutical Information & Pharmacovigilance Association

September 2021

REFERENCE SAFETY INFORMATION IN CLINICAL TRIALS THE IMPACT OF COVID-19 ON HOSPITAL MEDICINES INFORMATION SERVICES WHAT MADE CHLOROQUINE AND HYDROXYCHLOROQUINE SO CONTROVERSIAL DURING THE COVID-19 PANDEMIC? IMPROVING PHARMACOVIGILANCE WITH MODERN TECHNOLOGIES MANAGING UNCERTAINTY RETURNING TO OFFICE WORKING THE ROLE OF ARTIFICIAL INTELLIGENCE IN TRANSFORMING CLINICAL TRIALS

£12.00 or Free for Members 9 771478 327005 64

CONTENTS 1

Letter From The Editors

Benefit-Risk Assessment

The Impact of Covid-19 on Hospital Medicines Information Services

What Made Chloroquine and Hydroxychloroquine So Controversial During the COVID-19 pandemic?

How to Use Pharmaceutical Industry Medical Information Services

Global AND Local: 15 Elements of a Medical Information Conversational AI Strategy

Thoughts and Industry Insights on Returning to Working in the Office Post-Pandemic

Connecting Pharmacovigilance

Reference Safety Information in Clinical Trials

The Role of AI in Transforming Clinical Trials

Improving and Scaling Pharmacovigilance with Modern Technologies

Industry Return to Office Working Policies What our Insights Show

Managing Uncertainty

Global Medical Information and Standard Response Documents

Key Topics on Sustainability

A Beginner’s Guide to Safety Reporting in Clinical Trials

Vice President’s Report

Copyright for any article accepted for publication in PIPELINE is transferred to PIPA once the article is submitted. Copyright covers the exclusive rights to reproduce & distribute the article in any form (such as photocopies or electronic copies) and applies to the complete article and any part within. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form without written permission from PIPA. PIPA will, wherever possible, grant permission to authors to subsequently use their articles, or to others to take limited numbers of copies, provided permission is obtained from the editors in advance. PIPA members are permitted to print a copy of PIPELINE and / or save a single copy of the electronic file for their personal use.While all reasonable efforts are made to ensure the accuracy of the information presented in this journal, the editors do not accept any liability for loss arising from reliance on the information presented.The opinions expressed in the journal are not necessarily those of PIPA, its Committee or companies to which members belong - unless otherwise stated. PIPELINE Editor: Dora Amene Design and Print: Zebrahouse Design and Print Ltd

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LETTER FROM THE EDITORS By Pooja Shah

Welcome to the Autumn edition of PIPELINE! And what a year it has been: from the successful rollout of the COVID-19 vaccines to the easing of restrictions and life returning to as “normal’ as it has felt in over 16 months, to the UEFA Euros 2020 and the Olympics. It is great to see a return to celebrations with family and friends in larger numbers and the option to travel abroad. Have you been away or are you planning a trip abroad? Whether you have taken the plunge to get on a plane or decided the UK is a better option for you right now, we hope you have all managed to get a well-deserved break and had some R&R time. With all the changes that have taken place this year, the uncertainty remains. Cleo Whitehead has written a brilliant article on dealing with uncertainty which we hope some of you will find helpful. September seems to be a pivotal month for companies making provisions for staff returning to the office, ending the 18-month working from home spell. Whilst that’s great news for some of us, there are others who are not in a huge rush to return to the office full time. This edition of PIPELINE has a fantastic article written by Julia Day from CK Group on returning to the office and another article by Lauren Hursthouse on working from home.

As always, we welcome your feedback and encourage you to interact with us and the other PIPA members via our online platforms. On that note, we hope to ‘see’ you all online at one of our events in the near future. We’re sure this busy but eventful year will continue to play out for the remaining 3 months. Make it count and stay safe! If you want to make a contribution to PIPELINE, please feel free to contact us at journaleditor@pipaonline.org.

The PIPA Committee made a conscious decision to keep this year’s annual PIPA conference virtual again. We felt it was better to take the conservative approach once more, as we couldn’t predict the current situation when preparations started, and the safety of our members is always paramount. However, the PIPA 2021 virtual conference was not one to be missed. For the first time, we had two presentations by the MHRA as well as many other topical sessions - plus the usual networking opportunities with our speakers and delegates, as well as the opportunity to ‘meet’ our exhibiters. In this busy edition, we are delighted to present you with a wide range of articles. Our Vice-President has written an insightful article on ‘How to connect Pharmacovigilance with respective teams’. Ka-Mei Au’s piece on artificial intelligence in clinical trials is an informative read as AI is everywhere, and definitely seems to be the way forward for our industry. Another one of our committee members, Anne Lloyd, has written a fantastic article on how reference safety information should be used, tackling common inspection findings from the MHRA. For the last 5 years, reference safety information has been a hot topic with the regulatory authorities and many blogs and papers have been written on this topic: we’re delighted to include PIPA’s contribution to this ongoing discussion.

Pooja Shah PIPELINE Editor

We’ve listed only a few of our many topical articles that we have collated for this edition, and we hope you enjoy reading it as much as we have enjoyed putting it together. 1

BENEFIT-RISK ASSESSMENT A robust yet practical approach for small-to-medium sized companies By Kieran O’Donnell

Summary An organisation must have a Pharmacovigilance (PV) system in place designed to monitor the safety of their products and detect any changes to their benefit-risk (B-R) balance. Activities central to the objectives of that PV system include: • the preparation of Risk Management Plans (RMPs) • signal detection and the ongoing monitoring of B-R • the coordination of these activities with periodic safety reporting • product labelling and information • the management and reporting of Individual Case Safety Reports (ICSRs). Regulators and big pharma in the US and EU are well used to applying elaborate, costly and time-consuming assessment methodologies including BRAT (BenefitRisk Assessment Team) and PrOACT-URL (Problems, Objectives, Alternatives, Consequences, Trade-offs, Uncertainty, Risk attitudes, and Linked decisions). Numerous case studies have shown the benefits of these models as robust B-R assessment models. However, not all companies have the experience, budget, and resources available to adopt these models. Such organisations are more likely to rely on a purely qualitative approach to B-R assessment, or even to dive straight in to writing an RMP and managing signal detection and ongoing monitoring of B-R as need dictates. Whilst clinical expertise and product knowledge are critical inputs to both approaches, the qualitative approach inherently introduces a degree of bias and will arguably be less efficient and effective i.e., be less likely to determine B-R assessment outcomes consistent with the regulator’s outcomes or challenge what the organisation considers to be already known. Furthermore, unless the B-R Assessment is managed within an integrated B-R system it may result in uncoordinated,

but perhaps still compliant, signal detection and B-R monitoring, and be poorly aligned to associated processes such as periodic reporting and individual case management. This article explores the adoption of a proportionate and semi-quantitative approach to B-R Assessment which, through incorporating the value-adding elements of the 2

Mapping objective to ProACT-URL and BRAT methodologies ProACT-URL EU-based, from IMI protect

BRAT (Benefit-Risk Action Team) US-based, from UMBRA framework & PhRMA

Regulatory landscape

Problem

Define decision context

Deﬁne decision context

Objective

Identify benefit and risk outcomes

Identify important relevant information

Alternative

Define the decision context

Deﬁne decision context

Consequence

Extract source data

Identify data

Customise framework

Identify important relevant information

Assess outcome importance

Weigh the information

Trade-off Uncertainty Risk tolerance

Linked decisions

Display & interpret key B-R metrics

Weigh the information

proven frameworks that can feasibly be managed with reasonable expertise and resources akin to Small-to-Medium sized companies, can fully achieve the objectives of the PV system whilst addressing the typical downfalls of a purely qualitative approach. Proposed B-R Assessment When Small-to-Medium sized companies jump straight in to preparing their RMPs and SmPCs without considering them as outputs of a robust B-R Assessment, it is not unusual for those documents to be subject to significant rework and/or challenge by the assessors during the application process. Through a change in approach, resource can be re-focused on the B-R Assessment to achieve the aforementioned advantages. This approach can be used as the baseline source of core B-R information and can be broken down into 6 sequential activities.

Describe methodology, create BRT Charter, coordination with SDM & BRM, operational aspects of routine B-R post MAA

Evaluation context

Nature of the problem and its context Product, indication, pharmacoepi, alternative Rx, population, stakeholders, decision-makers Source data

Link to SmPC. Ongoing-B-R Review

B-R Assessment Data uncertainty, risk mitigation/further characterisation, link back to decision makers, past decisions, tools to address risk, RMP, measures, stakeholder burden, effectiveness

Important relevant information

Benefit-Risk Assessment

Value ranking & weighting

Document all sources, descriptions of each value, creation of source data tables Identify objectives for each value, strengths & weaknesses of the available data, link to EPAR, exposure, incidence, create value tree

Value ranking & weighting, move from qualitative to quantitative, group discussion, B-R effects table, forest plotting, baseball cards

The Evaluation context, Source data, Important relevant information, Value ranking and weighting and the Benefit-Risk Assessment all support the preparation of the (EU-)RMP. Outputs and visualisations can be used to display the data and facilitate objective review. Following the Evaluation context which is closely aligned to (EU-)RMP Parts I and Modules SI – SV, B-R Assessment moves on to the comparative review of the Source data. At this time, it can be useful to display the data using source tables.

Further to the Evaluation context, it is possible to start creating value trees which display and organise the respective risks and benefits, grouping them into logical clusters. The source tables collate and compare data, whilst the value trees provide a visualisation and an initial impression of the respective benefits and risks. At this point the value trees don’t provide any measure of strength/significance of the risk or benefit value, and they don’t imply any priority in their positioning in the tree. Nonetheless, they can support the initial formation of where actions may be necessary to target imbalance in the B-R.

Once all the benefit and risk values have been compiled, the general organisation and value grouping can be transferred to a table and each value ranked and weighted. There are other visualisations that can be generated, but as a minimum those shown here are both simple and insightful.

Ranking & Weighting scores

This exercise involves a team of key experts from various functions e.g., medical, pharmacovigilance and regulatory. They determine two things:

the core company safety information in the SmPC. Following the standard review/assessment of the dossier and subsequent approval, the B-R Assessment can serve as a baseline source of information used to quantitatively determine the impact of any change in the benefit and/ or risk information to better inform decision making consistent with the regulator’s paradigm. As benefit and risk values have been identified in the B-R Assessment, this facilitates a risk-based approach directing the frequency, coordination, and approach to signal detection and the ongoing monitoring of B-R supporting other activities such as ICSR management and periodic reporting. As such, the objectives of the PV system can be maintained and the organisation’s PV leadership better able to demonstrate the effective monitoring of the safety of their products and the detection of any changes to their B-R balance.

1) Ranking- the significance of each benefit and risk value relative to each other, and 2) Weighting- the extent to which each product fulfils each value. The group assigns a score for each product and each value. Whilst there are various approaches based on this MultiChoice Decision Analysis (MCDA) model i.e., individual vs. group or mean of scores vs. weighted scores based on respective expertise, there is significant value in group scoring through moderation and discussion, with the result of understanding why different key experts in the team perceive risk and benefit differently. Ultimately, the sum of each product’s benefit and risk scores together with the difference in scoring between products identify additional Risk Minimisation Measures (aRMMs) or other actions that are both proportionate and practical, and designed to address the benefits or risks and therefore optimise the B-R profile.

Kieran O’Donnell

Mapping between the B-R Assessment and the RMP and electronic common technical document (eCTD) dossier formats, enables information to be ported into the corresponding sections of the RMP, therefore reducing time spent on the RMP whilst informing the contents of

Director Kieran O’Donnell Limited

THE IMPACT OF COVID-19 ON HOSPITAL MEDICINES INFORMATION SERVICES Reflecting on a year of change By Dave Abbott

Over the last year, much has been said about the impact of Covid-19 on the NHS and wider society. There probably isn’t an area that hasn’t been affected in some way by the restrictions that Covid-19 has made necessary, the changes to working practices to accommodate this, and the new and changed work that has developed from the need to respond to it. Medicines Information services in the NHS were not exceptional in this respect, and many teams both inside and outside the NHS will have had similar or greater demands placed on them. However, there were some unique challenges for Medicines Information teams, both working in the NHS at a time of great service pressure, and working within an information service at a time when evidence was limited, but the demand for specific advice high.

Medicines Information services provide information and advice to healthcare professionals, patients and carers to support patients getting the greatest benefit from their medicines. In early 2020, as the impact of Covid-19 could be seen approaching the UK, it became apparent that the work of hospital pharmacies would need to evolve. What new work needed to be picked up, and how could this be delivered when people were under increased pressure both inside and outside of work?

Background

Logistics - dispersed workforce, dispersed enquirers

NHS Medicines Information services are based in most Trusts in the UK, and coordinate through the UK Medicines Information group (UKMI). Staffed predominantly by pharmacists and pharmacy technicians,

One of the first impacts noticed was the need for social distancing. As staff moved to remote working to support

this, new ways of maintaining connectivity with colleagues and enquirers had to be developed. Face-to-face contact was replaced by Microsoft Teams as the ubiquitous way of communicating.

medicines could be given by bolus or under gravity rather than by pump allowed IV pumps to be moved to support the surge in demand from the expanded ICUs. Advising on potential alternatives to medicines suffering a critical shortage helped to support the ongoing care of patients when the volume of patients was increasing exponentially. Providing ready-to-use information on how to administer medicines and giving advice on medicines use helped to support other NHS colleagues who had been redeployed to other less familiar specialist areas, so helping to maintain patient safety.

For those on site, accessing PPE and enabling social distancing introduced their own challenges. Moving around the NHS estate became more complex, with designated “hot” and “cold” areas, with different PPE requirements. This was particularly relevant to Medicines Information staff redeployed to “hot” areas for the clinical component of their work, with all the complexities this might cause.

Then, as the acute pressures of Covid-19 patients in hospitals lessened, a new wave of questions developed with the roll-out of the vaccine programme. How do you manage products that need to be stored at extremes of temperature? Can people with particular medical histories have the vaccine? A particular recurring question was whether we could find out the excipients of vaccines that patients had had a reaction to in the past.

This all made the logistics of answering medicines questions more demanding, as enquirers worked in unfamiliar areas remote from their normal support networks, and Medicines Information teams also learned to work in a very different setting. Information rich, answers poor

For all these questions, the support provided by Medical Information teams in the pharmaceutical industry was invaluable.

Covid-19 also affected the types of queries that Medicines Information services were asked. Some services noticed an increase in calls about care after patients had been discharged, as people tried to navigate new pathways of care without the normal routes for asking questions being open. However, almost all centres also began fielding calls about medicines to prevent or treat Covid-19 and later on questions about vaccines.

What do we want to keep from our experiences? So, as we approach what may potentially be an end to the acute pressures of Covid-19, what have we learned? Pleasingly, the skillset of Medicines Information professionals, of finding information and turning this into advice to support the care of individual patients has been recognised and appreciated. Remote working, once seen as an impossibility in the NHS, has become established practice. And for me most significantly, collaboration within and between NHS Trusts and between the NHS and the pharmaceutical industry has become much more common place.

The unique challenge with these calls was the lack of definitive answers and the rapidly evolving evidence base. As with all areas of medicine there is evolution of the evidence base and degrees of uncertainty around any advice provided, however the pace and scale of changes through Covid-19 was unprecedented. As the evidence base evolved and developed, more and more specialist areas published advice, and then updated their positions as more information became available. One of the roles of Medicines Information, through the national UKMI network and particularly the Specialist Pharmacy Service, was to corral and structure the waves of information coming out from a plethora of sources. This index of resources and summaries of advice was kept up to date through the “Do Once” SPS group via pages hosted on the SPS website (www.sps.nhs.uk).

Whilst it will be nice to go back to a world of not wearing masks, goggles and edging down the side of hospital corridors to give everyone space, we must be careful not to slip back into our previous working silos, and realise that more is possible than we might think if we look for the opportunities rather than the barriers.

More locally, Medicines Information services were seen as ports of call for finding and assessing information on medicines, to turn it into advice for the care of patients the primary skill set for professionals working in this area.

Dave Abbott Highly Advanced Pharmacist - Medicines Advice Leeds Medicines Advice Service, Leeds Teaching Hospitals NHS Trust

This supported patient care in a variety of ways. For example, putting together information on which IV 7

WHAT MADE CHLOROQUINE AND HYDROXYCHLOROQUINE SO CONTROVERSIAL DURING THE COVID-19 PANDEMIC? By Sarah Paterson

Towards the end of 2019, a new coronavirus (COVID-19 or SARS-CoV-2) emerged in Wuhan, China. Little did we know the virus would spread worldwide, causing a major pandemic and putting our healthcare services under pressure. In 2020, the seriousness of COVID-19 became clear and the search for an effective drug therapy was on. Chloroquine and hydroxychloroquine were among those which were highly considered. With both drugs classed as ‘safe’ and ‘reliable’ (Touret and Lamballerie, 2020), in addition to their positive in vitro antiviral activity, their potential use in the treatment of SARS-CoV-2 was credible. However, shortly after clinical trials were initiated, both drugs’ benefits did not outweigh their known and potential risks and were revoked for emergency use. Although this was disappointing, clinical trials give pharmaceutical companies the opportunities to identify gaps in drug safety data, potentially leading to new and improved product labels/ leaflets, patient care and general knowledge surrounding active ingredients. Talk in the media Early in the pandemic, hydroxychloroquine and chloroquine received the strong focus of public attention of all potential therapies against SARS-CoV-2. As already licensed drugs, with well-established safety profiles, in vitro antiviral activity, and existing manufacturing processes, the potential for rapid distribution and at scale seemed promising. Therefore, interest for their clinical use in the treatment of COVID-19 escalated very quickly. While numerous clinical trials were initiated including the Solidarity Trial (an international clinical trial launched by the World Health Organisation and partners), discussions in the media had already surged. In the US, President Donald Trump gave multiple press briefings and made several comments on social media regarding the use of hydroxychloroquine and chloroquine. He referred to the drugs as ‘great malaria and powerful drugs’ and confirmed his own use of unapproved hydroxychloroquine to prevent coronavirus infection https://www.

cnbc.com/2020/05/18/trump-says-he-takeshydroxychloroquine-to-prevent-coronavirus-infection. html. Trump unethically promoted the safety of the drugs stating ‘they have been around a long time, so they know the side effects’, ‘What do you have to lose. Take it’ thereby falsely advertising the products before clinical 8

trials were completed or considered safe for use causing an influx of sales and adverse events. Coronavirus and hydroxychloroquine: What do we know? - BBC News

important warnings given by authorities such as the FDA, European Medicines Association (EMA) and Medicine and Healthcare products Regulatory Agency (MHRA) advising against the use of these medications outside a hospital setting or clinical trial. https://www.fda.gov/drugs/ drug-safety-and-availability/fda-cautions-against-usehydroxychloroquine-or-chloroquine-covid-19-outsidehospital-setting-or

In addition, attention spurred on by the political leaders, such as Trump, French president Emmanuel Macron and Brazilian President Jair Bolsonaro - who expressed ‘there is no scientific evidence, but it has worked with me’ Coronavirus and hydroxychloroquine: What do we know? BBC News - caused not only indiscriminate unsupervised use by members of the public but also created drug shortages and affected enrolment in clinical trials for other potential treatments.

The silver lining Pharmacovigilance is the science relating to the collection, detection, assessment, monitoring and prevention of adverse effects with all pharmaceutical products. Pharmacovigilance plays a critical role throughout a drug’s lifecycle - starting from clinical trials through to post-marketing. It is inappropriate to assume that a product is deemed ‘safe’ due to the number of years a product has been on the market. If a product is used outside of its approved indication(s), for example in an emergency like the COVID-19 pandemic, then it is highly likely that new safety data will be reported. In this case, both hydroxychloroquine and chloroquine were revoked for emergency use in COVID-19 patients due to new emerging clinical trial data. The process was fundamental in identifying necessary safety label updates, including undesirable effects such as anxiety and other psychiatric disorders and further information on the QTc prolongation, thus benefiting healthcare professionals and consumers. https://www.ema.europa.eu/en/news/ meeting-highlights-pharmacovigilance-risk-assessmentcommittee-prac-23-26-november-2020

The concerns Both hydroxychloroquine and chloroquine have been used for more than 50 years for the treatment and prophylaxis of malaria, and more recently for autoimmune diseases such as Lupus and Rheumatoid Arthritis (Touret and Lamballerie, 2020). They are considered safe drugs with generally mild side-effects including: • Nausea • Vomiting • Diarrhoea • Abdominal discomfort. However, the boundary between the approved therapeutic dose and toxic dose is very slim, therefore, if taken incorrectly, can be life-threatening. Chloroquine poisoning has been associated with severe cardiovascular disorders. More recently, COVID-19 clinical trial data, including a study published in the Lancet medical journal, has led to further concerns regarding cardiotoxicity and myopathy. The study presented an investigation into 96, 032 hospitalised COVID-19 patients from 671 hospitals worldwide. The authors established that patients treated with chloroquine or hydroxychloroquine were more likely to experience an abnormal heart rhythm and die in hospital than those who weren’t. As a result, in July 2020, the WHO suspended the hydroxychloroquine arm in the Solidarity Trial and the US Food and Drug Administration (FDA) revoked the products for emergency use (FDA Letter). https://www.who.int/emergencies/diseases/novelcoronavirus-2019/global-research-on-novel-coronavirus2019-ncov/solidarity-clinical-trial-for-covid-19-treatments

Conclusion It is unquestionable that the COVID-19 pandemic has been catastrophic in so many ways. It has been devastating for families, countries, economies and more. While the race to develop an effective vaccine seems to have been successful, the search for an effective drug treatment for COVID-19 and its complications remains an ongoing challenge. The healthcare industry will continue to collate and communicate safety information worldwide during its search for the next potential treatment, essentially keeping pharmacovigilance practices as a number one priority.

The approval of a new product, or approval of a new indication of a product, needs constant pharmacovigilance monitoring to maintain and assess its overall benefitrisk profile. It is essential that new medicines should only be used as part of a clinical trial or in line with nationally agreed protocols. The encouragement given by the media and politicians was careless and led to

Sarah Patterson Pharmacovigilance Associate Alliance Pharmaceuticals Limited

HOW TO USE PHARMACEUTICAL INDUSTRY MEDICAL INFORMATION SERVICES As many of you will be aware, PIPA has a strong relationship with UK Medicines Information (UKMi). Members of the PIPA committee liaise regularly with representatives from the UKMi Executive to further facilitate an effective working relationship between Pharmaceutical Medical Information (MI) departments and NHS UK Medicines Information pharmacists, who are one of Medical Information’s largest customer groups. One of the initiatives undertaken by the UKMi / PIPA working group has been to develop a guidance document for UKMi pharmacists to assist them with their interactions with pharmaceutical MI departments. In preparing this document, feedback from both UKMi and pharmaceutical MI teams was used to develop a pragmatic guide to ensuring a successful enquiry resolution. This document has recently been updated, and shared throughout the UKMi network, and we are delighted to publish the latest version for your information.

Medical Information Services in the Pharmaceutical Industry are a valuable resource for information about their products that is not otherwise freely available; e.g. unpublished data on stability, excipient details for licensed products, and information on usage and availability of unlicensed products.

The UKMi Quality and Risk Management group in conjunction with the Pharmaceutical Information and Pharmacovigilance Association (PIPA) have prepared a list of things to consider when MI services contact a pharmaceutical company Medical Information Department based on feedback from professionals working in the area.

The staff providing the service will have access to extensive information about their products. Companies are able to provide information to help with clinical decisions on how patients are going to be treated, but the Association of the British Pharmaceutical Industry (ABPI) Code of Practice does not permit them to provide medical advice or clinical interpretation of the information.

Who to Contact • In most cases, Medical Information is the appropriate department for technical medication enquiries, and Customer Services for supply and availability enquiries. • Ensure that you are contacting the correct company for the product that you are requesting information for. This is important for example, when a company has taken over another company’s livery, or mergers have taken place.

In addition some medical information departments may not have access to extended stability data and are only able to release ‘off-label’ information in response to specific enquiries. 10

Information About You

the information not being held in the UK with some requests escalated to global headquarters.

• Introduce yourself and state where you are calling from (e.g. hospital site). Include your job title and/or that you are ringing from Medicines Information.

• Requests for unpublished data on file may take longer to respond to as it will need internal review and approval.

• Provide your contact details, so they can be recorded, with details of when you will be available to be contacted. If you will not be available at certain times, provide alternative contact details such as generic email and telephone details, or contact details of a colleague.

The Response • If you need a written response, state this when you first make your enquiry to allow them to plan and provide this within the required timeframe. If you need an urgent response this is likely to be by phone.

Information About Your Enquiry

• If you think it would help to clarify the answer provided, consider asking what resources have been used to compile the response.

• Be clear what your question is and provide all background information that will help the company provide the best answer possible. Having a specific and clear question will help the person you are contacting give you a useful answer to your question.

Follow-up and Feedback • Obtain a reference number and ask who you are speaking to and their job title in case follow-up is required. However, some companies do not permit their employees to share their personal details.

• Let the Medical Information Department know the urgency of the enquiry and if the enquiry is for a specific patient to help them prioritise work.

• If you have constructive feedback following a good or poor interaction, contact the company and ask to speak to the Medical Information Manager. Feedback is always useful.

• Provide details such as indication, strength and formulation where appropriate. • For enquiries associated with adverse events (AEs), product complaints and other safety information, enquiry handlers will request additional information. They need minimum information such as patient initials, age and gender, so have this information ready where possible. The Pharmacovigilance department may need to contact you for additional information, since this forms part of product surveillance.

UKMi/PIPA liaison group June 2021

• Advise where you have already looked (e.g. the SmPC) to avoid duplication of work. • If you want the Medical Information Department to look in specific places, e.g. their own unpublished data on file, let them know when you make your enquiry. Urgency and Deadlines • Be clear about when you need the answer. However, the company may need some time to get the information together so be prepared to compromise. • Medical Information Departments will always prioritise enquiries for a specific patient, but some companies can take up to 10 working days to respond to complex enquiries. This may be due to 11

GLOBAL AND LOCAL: 15 Elements of a Medical Information Conversational AI Strategy By Richard Marcil and Jessica Naman

The pandemic has significantly accelerated Healthcare Professional (HCP) digital behaviours as well as increased Medical Information engagement. Across the world, Medical Information teams have been developing robust, self-service capabilities to grow capacity, accessibility, and customer satisfaction, while delivering compliant real-time engagement.

Consistent with other industries, conversational Artificial Intelligence (AI) is gaining a strong foothold in life sciences, and particularly in Medical Information. It’s a powerful technology and one that requires global and local planning, as manufacturers seek to deliver consistency, compliance and cost effectiveness across markets, and market-level teams adapt the technology and conversation sets to local stakeholders’ requirements - externally and internally.

teams. Global teams require conversational consistency and compliance across markets, and an easy integration into global content and safety systems. Local teams will require ready adaptation of content into local customerfacing assets - digital and analog - as well as customer validation and Customer Relationship Management (CRM) systems.

In this article, we look at 15 elements of conversational AI strategy that are key to successful scaling global AND local implementations:

Branding should be simple and consistent. Globally, many companies have moved to an AskManufacturer. com model, for simplicity and straightforwardness. Traffic driving will also be essential to growing utilisation, engagement and - ultimately - customer and clinical insights. Local teams will be key to driving visibility and access to these assets, using commercial-like tactics.

2. Promotion and Awareness

1. Customer Experience While seemingly obvious, choose a platform that truly meets the needs & requirements of global and local 12

3. Data and Insights Leverage

7. Languages

Data and insights responsibilities will be shared amongst global and local teams. Global will often provide the technical infrastructure for data uptake and safety reporting integration, while local teams action data in near real-time - again, at customer and therapeutic level.

Most Life Science companies use English for the “core” set of conversations - the “master” so to speak. This master is adapted to other languages, typically by the local teams. The image below is an example of a conversation builder showing the English master, which is then replicated to Italian, Spanish and Japanese. This ensures consistency and compliance from a Global perspective, and easy adaptation by Local teams.

4. Consistency and Accuracy of Responses Global teams will want to see a consistency of responses across markets whether it is the UK, Japan or America, and Local teams will ultimately adapt AI conversation flows and responses for their own country or region as per market and regulatory requirements. In time, consistency will lead to simplicity and universality.

8. Workflow and Process Definition Good workflow and process definitions are essential for global and local teams working together. Like a product monograph or label, Global will define and develop the core conversation sets and inform appropriate “on” label and “off” conversations. Local teams will build off of this and adapt these conversations for local markets, augment or add missing ones, and optimise customer onboarding and offboarding, including escalations and handoffs to humans.

5. Content, Information and Label Differences This builds on the point above, it’s important to remember that conversation sets become business assets, from conversation flows, responses, and their respective data sets. Here, local teams will likely also consider marketspecific functionality, from service support to self-service automation to human escalation.

9. Development Costs

6. Accessibility & Access

Global most often takes the lead in the initial set-up and stand-up of the technology, including the configuration of the conversational AI platform, its validation, its integration in the tech stack, and even development of a core set of English conversations - again the “master”. When this is done, conversational AI becomes an organisational capability that any and every local team can, and should, take advantage of.

Short of broadscale enterprise governance policies, accessibility and access are owned by local teams. This is especially key to driving traffic, utilisation, and cost deflection (from other more expensive channels) and generating powerful customer and clinical insights. This is an area where local teams will want to work closely with internal stakeholders to support broad visibility and access.

10. Data and Privacy

funding efforts, which local teams will require short of the largest markets.

Data and privacy are equally shared across global and local teams. For both Global and Local, there is tremendous value in aggregate and customer-level data for clinical insights and medical-to-medical innovation. There is also great accountability around the data and privacy, so it’s important that conversational AI be integrated into the privacy, security, and information risk management frameworks of the organization.

15. Safety Reporting Standardisation Safety reporting standardisation is globally led as one would expect with Life Science companies, but the accountability is very much local. Ultimately, it’s important that the chosen conversational AI platform be able to identify, manage and report adverse events and product quality complaints with the same accuracy as humans - if not better - across multiple markets. This is key to meeting safety and pharmacovigilance requirements, delivering better customer service and experience on and off hours, and driving business efficiency.

11. Integration into Medical Information Databases Integration into Medical Information databases varies tremendously from company to company, and sometimes region to region based specifically on the company’s needs for case management, compliance, content efficiencies and human-escalation. These are all the more important as conversational AI agents take on voice and Interactive Voice Response (IVR) channels, i.e. first point of contact.

In summary, customers now expect real-time, personalised and helpful engagement with Life Science companies - after all, they are getting this in every other aspect of their lives, e.g. financial, retail, travel, telecommunications, etc. Life Science companies are broadly scaling conversational AI capabilities to meet these needs as well as to drive operational effectiveness and efficiency. Best practices suggest that it’s the interplay of Global and Local - a coordinated investment approach to business value - that leads to the strongest, fastest, and most impactful business transformations and implementation of this AI technology.

12. Ongoing Optimisation and Maintenance “Conversational maintenance” i.e. optimisation is a local responsibility first and foremost, given the unique nature of each market and the local conversation set. Local markets perform conversational maintenance and tuning based on their local interactions. However, Global will also uptake these optimisations across markets to the benefit of all markets (at least with the right conversational AI platform). Lastly, Global will most often assume the technology maintenance, e.g. new features, functions and configurations of the global conversational AI platform.

Curious to learn more about what is involved in deploying conversational agents? Get in touch with Richard Marcil with any questions at richard@conversationhealth.com

13. Technology and Vendor Assessments Technology and vendor assessments are very important and a shared responsibility from the outset, with global teams leading the charge but with affiliates deeply inputting on needs and requirements i.e. integrations, languages, and resource load. In time, you will likely have a distinction of responsibilities and partners too global partners for the technology platform that Global continuously optimises, and local partners that help with conversation development and maintenance i.e. consultants, agencies, etc.

Richard Marci Chief Customer Officer conversationHEALTH

14. Speed to Scale Speed to scale is a material consideration as Med Info teams race to add capacity, accessibility, and responsiveness to operations. Global is typically the lead due to technology, vendor assessments and platform validation as per above - and it’s certainly something we’ve seen with recent COVID-vaccine scale ups. Practically speaking, global leadership is also tied to initial

Jessica Naman Director of Marketing conversationHEATLH

THOUGHTS AND INDUSTRY INSIGHTS ON RETURNING TO WORKING IN THE OFFICE POST-PANDEMIC By Lauren Hursthouse

“Are we returning to working in the office after the pandemic?” A question on most employers and employees lips as the country is slowly but surely opening up again and we move towards the lifting of lockdown restrictions. Have employees had their vaccinations? Is the office COVID-safe? What are employees attitudes to returning to working in the office? How well have we adjusted to working from home (WFH) for over a year? Will employers adopt new ways of working permanently? A survey by the Chartered Institute of Personnel and Development (CIPD), the professional body for Human Resources (HR) and professional development, found that 40% of employers said they expect more than 50% of their workforce to continue WFH post-pandemic. Data from the Office of National Statistics (ONS) estimated that <5% of the workforce were WFH pre-pandemic. In the biotech and pharmaceutical sector, working from home is not a novelty and many roles were already fully homebased pre-pandemic. When it comes down to whether people would prefer to WFH full time or return to the office full time, the responses are a bit of a mixed bag and it is not as straightforward an answer. There are several contributing factors such as length of commute, office environment, home office space (or lack thereof), home commitments, personality type (introvert/extrovert) and whether the individual thrives around others or in solitude. The pandemic situation has thrown different working models into the spotlight and demonstrated how quickly people can adapt to a sudden change in circumstances to maintain business fluidity and productivity.

the office. Some are even missing their commutes, as they had built in exercise or listening to podcasts and do not get time to do these things elsewhere in the day. • Having a separate home and office environment sets a clear boundary between work and home life and a chance to totally switch off from work.

PROS for returning to the office: • Some polls suggest that people are missing the office environment and the corridor side conversations, coffee chats and face to face interaction that we used to have when working in

• Human interaction: we are social beings and are not meant to be living solitary lives. The office provides a great environment for interaction and 15

collaboration. No matter how many Zoom or Teams meetings you have, you can’t beat a face to face interaction. A new phrase known as “Zoom fatigue” has been coined since having to be at our computer screens for extended periods of time.

time in bed or use the time to fit in a run or gym session before starting their working day. Others like having a separate space totally away from their home, especially if they do not have a dedicated home office. There are even some who would like a combination of the two, a sort of hybrid model, working partly from home and in the office. I do not think there is a right answer and the importance is flexibility as we transition into this new mode of working post-pandemic.

PROS for continuing to WFH: • A lot of people have adjusted really well and are finding that they can have more flexibility and do not have to pack their work hours into the traditional 9-5 model (if your company allows for this). This helps to promote a healthier work/life balance and supports employees with families. That said, I did not envy those parents trying to do home schooling and WFH at the same time: they deserve a big round of applause!

If only we had a crystal ball! It is hard to say what the future of flexible working will look like, but it is definitely on the UK Government’s agenda: the Guardian newspaper recently reported that they are looking into legislating to make WFH the “default” option by giving employees the right to request it. Please note that any views expressed are my own and not PIPA’s.

• Increased productivity and profitability for employers, not to mention a reduction in operating costs.

References: https://www.bbc.co.uk/news/business-52567567

• Some people have really flourished being able to WFH. This may be because they have more energy and are not feeling drained by their two hour commute each day - perhaps they have built in an exercise routine into their day instead. Or it could be because they are better able to focus without the usual office distractions and interruptions. Or perhaps it is because they have had a chance to really be “seen” by their teams.

https://www.cipd.co.uk/knowledge/fundamentals/emp-law/ employees/workplace-guide-returning-after-coronavirus#gref https://www.cipd.co.uk/knowledge/fundamentals/relations/flexibleworking/planning-hybrid-working https://www.mbaskool.com/business-concepts/human-resources-hrterms/16870-work-from-home.html https://www.agilitypr.com/pr-news/public-relations/employees-putthe-brakes-on-returning-to-offices-nearly-half-now-want-to-wfhpermanently/ https://www.peoplematters.in/blog/life-at-work/the-phenomenon-ofwfh-and-beyond-26608

• Quite an obvious positive impact WFH has had is on the environment as less cars, trains, planes and buses have been operating throughout the pandemic and, as a result, air pollution levels have improved. This is a huge benefit not only to the environment but also to public health, especially in urban areas.

https://employmenthero.com/blog/remote-working/ statistics/?gclsrc=aw.ds&gclid=EAIaIQobChMI6-Ouope_8QIVgvtCh0BdQjiEAAYAiAAEgKlbvD_BwE https://www2.deloitte.com/global/en/pages/human-capital/articles/ adapt-the-workplace.html?id=us:2ps:3gl:con:awa:062421:fowork 21B:place:ad3:kwd-909456383658:returning%20to%20the%20 office&gclid=EAIaIQobChMIhr-cuoW_8QIVS7TtCh0fOwCREAAYASAAEgL_kvD_BwE

From a Pharma Industry-specific viewpoint, the pandemic has forced us into the world of digitalisation and headway has been gained for the future, and implementation, of de-centralised clinical trials. We have shown that we can work remotely and still interact, build relationships with colleagues and key stakeholders, innovate under pressure, meet deadlines and manage projects despite not being able to meet face to face. This was driven out of the necessity to survive in an unprecedented situation. Now, as we move out of lockdown, we need to carefully consider the future of our working models.

https://www.theguardian.com/business/2021/jun/17/labourdemands-clarity-on-plans-to-make-working-from-home-a-defaultright

Lauren Hursthouse Clinical Trial Scientist ICON plc

What will the future look like? It is important to remember that no one size fits all: some people prefer having no commute and getting the extra 16

CONNECTING PHARMACOVIGILANCE a company-wide responsibility By Janine Gavin-Poulter

Pharmacovigilance should be a company-wide global concept. However, this is sadly not always the case. As Pharmacovigilance professionals, it is not always known how Pharmacovigilance connects with different departments across the wider business. But whether you are new to the Pharma/CRO industry or an experienced PV professional, there will inevitably come a time when you will become aware of the need to connect with a different department, usually as the result of a new or updated regulation.

It is pivotal to PV compliance that other departments in a company are actively involved with pharmacovigilance requirements to ensure that the complexities of PV regulations are adhered to. The truth is, PV cannot go it alone to ensure all such requirements are met. Here, I have provided some useful information on how to make PV a company-wide responsibility.

All the involved parts of the organisation need to remain in collaboration in order to minimise any risks to the company. Unfortunately, it’s not until the findings of an audit or inspection have been revealed that you learn the hard way that there was something that was not considered. This could be anything from the lack of sufficient oversight of a market research programme to the lack of communication regarding a company sponsored website; from not being involved in the due diligence process of reviewing safety-related data as part of product acquisitions to reviewing the product labelling for advertising to the public and healthcare professionals (HCPs). All of the involved parts of the organisation need to have a strong communicative and collaborative approach if the risks to the company are to be minimised.

So what considerations are needed to help combat risks and drive efficiencies? • Examine the knowledge around pharmacovigilance across departments: are personnel aware they may need input from safety and are they themselves in possession of safety-related data? Do you know who the main stakeholders are in each department? 17

• Identify ways to improve and teach personnel. For example, utilise PV education programmes, not just provide an industry standard PV SOP. The need to keep on proactively training is a must!

Put it this way, if someone was to ask you what activities come under your company’s marketing function, could you answer it? Could you also answer who your main point of contact is? Are there any market research programmes, consumer research questionnaires or company sponsored websites that are either progressing, active or completed? Are you aware of all of your social media channels? Are there tools and processes in place to actively screen, collate and review product safetyrelated information? Who is responsible for this activity and are they trained? How is this communicated to PV and in what timeline? How is the data reconciled? If you have no idea…..then connect!

• Create a robust system where changes can be implemented: this is where collaboration comes into play with your stakeholders. PV connects to many departments, from Regulatory Affairs to Medical Information, from Marketing/ Digital Marketing to Artworks, from Quality to Product Acquisitions and Sales. One question needs to be answered here: are the roles and responsibilities of the personnel in these functions clearly defined? Connecting to multiple departments is where to make a start, and it is always good practice to get to know your colleagues across the different business functions to have a clear overview of roles, where contributions are needed and ways of working together.

The table below includes some examples where PV needs to be involved (please note that this list is not exhaustive, these are purely examples). Remember that Regulatory Authorities closely look at these types of activities during an inspection, so be sure to be ready to understand your PV infrastructure and who should be involved.

Function

Where PV needs to be involved

Legal

Any possible safety data involving a claim should be provided to PV as per the company’s timeline

Sales

Any databases, for example Salesforce, should be screened on a weekly basis to identify any potential safety data not previously sent to PV

Quality

If there is an associated AE to the PQC, this should be shared. Any risks associated with the use of a product needs to be shared with the PV team and vice-versa

Medical Affairs

PV need to be included in the review of Abbreviated Prescribing Information (API) to ensure all important safety information is included as per the relevant Code(s) of Practice

Product Mergers & Acquisitions

Involvement from PV is needed to review the safety profile of the product during the due diligence phase

Janine Gavin-Poulter Vice President PIPA

REFERENCE SAFETY INFORMATION IN CLINICAL TRIALS By Anne Lloyd

In March 2016, the Medicines and Healthcare products Regulatory Agency (MHRA) published a blog entitled ‘Reference Safety Information (RSI) for Clinical Trials’ having observed that this theme often led to inspection findings. A further blog was published in January 2017 to address some of the queries raised in response to the first blog. Despite these, and discussing the current issues seen in relation to the use and control of RSI at various meetings, the MHRA continued to see non-compliance, including unreported suspected unexpected serious adverse reactions (SUSARs) and an absence of adequate risk mitigation measures due to incorrect use of the RSI. They therefore published a further blog in February 2021. Even though the Brexit transition period ended on 31-Dec-2020, the MHRA still accept the provisions of the CT-11 and CT-32 and the Clinical Trial Facilitation Group (CTFG) Q&A on RSI3. Therefore, they expect that they are followed, along with The Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1013 as amended)4, as that is their interpretation of how the legislative requirements can be met and will help in terms of harmonisation and running global trials.

In a similar way, SARs due to lack of efficacy or disease progression, should not be expected unless they have been approved as part of the trial protocol or included in the RSI. The RSI is used by the sponsor for identifying SUSARs and by the NCA to determine the continuing risk-benefit of the trial. The expectedness assessment is not a medical decision, and the RSI should include MedDRA preferred terms (PTs), which can be compared with the PTs the SAR has been coded to. However, the decision to include a SAR in the RSI section is based on medical assessment. There must be a good rational why a SAR is expected (e.g. biological plausibility, temporal association) and appropriate risk mitigation measures must be in place.

Organisations had until 01-Jan-2019 to ensure that their procedures and RSIs followed the CTFG Q&A on RSI by performing an impact assessment against the approved RSIs. It was expected that a retrospective review be performed and any unreported SUSARs identified be submitted and serious breaches be reported.

The frequency of the expected SARs should be indicated using the Council for International Organisations of Medical Sciences (CIOMS) categories (very common; common; uncommon; rare and very rare). A frequency of not known is not acceptable because it does not allow assessment of whether the new SAR report represents an increased frequency and therefore is unexpected. If the frequency cannot be calculated, the number of SARs should be provided.

What is the RSI? For clinical trials, the RSI should be the list of medical events that defines which reactions are expected for an Investigational Medicinal Product (IMP), whether it is the drug under investigation or a comparator. If a serious adverse reaction (SAR) is considered related to an IMP (suspected) and the SAR is not included in the RSI (unexpected), then this becomes a SUSAR and requires expedited reporting to the relevant National Competent Authorities (NCAs) and, for cases originating in the UK, to the Research Ethics Committees (ECs).

The RSI can be a clearly defined section within the Investigators Brochure (IB) or section 4.8 of the Summary of Product Characteristics (SmPC), but they are not one and the same. This must be clearly defined and communicated to the people conducting the expectedness assessments to ensure that they are using the correct one.

It is important to remember that fatal and life-threatening SARs should not be considered expected, unless explicitly stated in the RSI and approved by the NCA. This includes all SARs with a fatal outcome. 19

If you have different RSIs for different regions, you need to make sure that all SARs are assessed against the RSI approved in the region where you are submitting the SUSARs, not the RSI from the region in which the event occurred.

• Assess new information that may impact on the risk benefit ratio of the trial. • Determine if, as a result of the information, your IMP and its dosing regime are still appropriate for the trial population.

Maintaining the RSI

• Make an informed decision about the clinical trial authorisation.

The RSI and the process for managing and maintaining (including tracking the updates and monitoring compliance metrics) should be clearly defined within the sponsor’s quality system to enable the staff who are using and maintaining it are able to do so in a compliant manner.

If an RSI is applicable to more than one trial, and if an update is approved for one trial, it does not mean that the RSI can be used in the other trials before it has been approved by the NCA. However, you can submit the RSI update as a substantial amendment for all of the trials in the UK that it applies to, with a list of the trials in the cover letter, and the assessor will review the impact and issue an approval for them all in one go. You can also submit more than one amendment at a time, so you do not need to wait for a protocol/Investigational Medicinal Product Dossier (IMPD) update to be finalised before submitting the RSI update, as long as you make it clear in the covering letter what other submissions have been made and how they are linked.

The RSI needs to be part of the initial clinical trial application and once it has been approved it has to be used unless the regulator (e.g. the Clinical Trial Unit at the MHRA) agrees otherwise, which would require the sponsor to submit a substantial amendment to change it. if a trial is being conducted in both the UK and European countries, the RSI must be approved by all the NCAs where it is being performed. If you implement RSI without regulatory approval, then the regulator has not had the opportunity to:

The RSI used must be the one approved on the onset 20

For the Development Safety Update Report, the RSI in place at the start of the reporting period must be used for all the DSUR line listings.

1. Communication from the Commission — Detailed guidance on the request to the competent authorities for authorisation of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial (CT-1); https://eur-lex.europa.eu/legal-content/ EN/TXT/?uri=CELEX:52010XC0330(01).

If the IB or SmPC are updated, then a risk assessment should be performed of the new version against the current version. If there are no changes to the RSI or the changes are minimal or not relevant to the study or patient population, then you can choose to continue with the current RSI.

2. Communication from the Commission — Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human use ( ‘CT-3’ ); https://eur-lex.europa.eu/legalcontent/EN/TXT/?uri=CELEX:52011XC0611(01).

If you are using a clearly defined section of the IB as your RSI and have important new safety information that you want to communicate to your investigators, this can be done without sending them an unapproved IB. For example, sending out updated line listings or a dear doctor/investigator letter.

3. Clinical Trial Facilitation Group (CTFG) Q&A document – Reference Safety Information, Nov-2017; https://www.hma.eu/fileadmin/dateien/Human_ Medicines/01-About_HMA/Working_Groups/ CTFG/2017_11_CTFG_Question_and_Answer_on_ Reference_Safety_Information_2017.pdf.

If a new version of the SmPC is approved, this can be made available to those conducting the trial if those conducting the expectedness assessment clearly understand which version should be used as the RSI.

4. The Medicines for Human Use (Clinical Trials) Regulations 2004, Statutory Instrument 2004 No. 1031 (as amended); https://www.legislation.gov.uk/ uksi/2004/1031/contents/made.

date of the SAR and this does not change if follow-up information is received. An update to the RSI does not allow you to downgrade all the old SUSARs.

If there are new events listed as expected, then the substantial amendment must be sent, together with a covering letter explaining the rationale for the additional events, and the new RSI must not be implemented until approval is obtained. If the amendment is submitted mid DSUR period, the amendment should state that the new RSI will not be implemented until the end of the current DSUR period.

Anne Lloyd, FPIPA PIPA Committee Member

THE ROLE OF AI IN TRANSFORMING CLINICAL TRIALS By Ka-Mei Au

Emerging technology and patient centricity are currently some of the biggest topics surrounding clinical research. Here we discuss some of the ways in which artificial intelligence (AI) can be utilised to transform key steps in clinical trials to increase clinical trial efficiency, improve patient safety and the patient experience. Enrolment:

matched against the eligibility criteria of ongoing trials. This level of precise automation allows eligible candidates to be identified within minutes rather than months and relies less on the patient to find suitable trials for themselves. With such high processing rates, more potential candidates can be identified and contacted, increasing clinical trial awareness and recruitment outreach to more diverse populations.

Among the many reasons why clinical trials are terminated, the single biggest contributor is insufficient patient intake, accounting for 55% of trial terminations [1]. This is followed by lack of efficacy which only accounts for 15% of terminated trials [1]. Doctors can recommend clinical trials they are aware of to their patients, but otherwise the onus is often on the patients to find clinical trials themselves. This could be by looking through government websites, medical research charities and seeking out patient recruiters for clinical studies. However, this can be overwhelming and time-consuming, especially for those who are unfamiliar with these resources and the complicated medical jargon. Finding suitable candidates with comparable confounders and underlying conditions from the very start of a trial is also important to identify safety issues as soon as possible. There is also a need to increase focus on recruiting more diverse patient populations in clinical studies in order to reduce the disparity in health outcomes between different patient ethnicities. Several barriers that prevent ethnic minorities from participating in clinical trials have been identified – one of them being a lack of clinical trial awareness [2]. AI tools can improve the enrolment process for both the patient and clinical researchers, and to help mitigate these current issues in healthcare.

Monitoring: A requirement for patients participating in clinical trials is having to regularly visit the research site for check-ins. These visits have traditionally been considered essential to enable investigators to assess

For example, natural language processing (NLP) is being used to extract and analyse patient health records in the US to find suitable study candidates for clinical trials [3]. The software can analyse structured and unstructured data, including doctor’s notes, pathology reports and other medical data in free-text form. All extracted data is used to form a unified patient graph which can then be 22

the effects from the investigational medicinal product (IMP) and to monitor the patient’s health. However, the frequent travelling can put a strain on the patient’s time and potentially finances, depending on the methods of travel reimbursement. This has also been highlighted as a barrier for ethnic minorities participating in clinical trials [2]. The disparity in socioeconomic factors between different ethnicities means that the burdens associated with clinical trial participation are more significant for minority groups. These burdens not only deter people from entering clinical trials, but also increases the risk of patient drop-out during the study.

then analysed by AI-enhanced software. Implementing this technology helps in a number of ways: patient participation in a clinical trial becomes more convenient, more data can be collected which allows more conclusions to be drawn from a study, time and resources are saved for the investigators from analysing such large volumes of data, and patient safety is improved through continuous tracking. Wearable devices may be used to track physiological changes in the user [4]. The technology can detect and flag key physiological changes which may be indicative of disease progression and predictive insights on the user’s health can be made so that pre-symptomatic medical attention can be given. As an example of industry and service provider collaboration, Chugai have made use of the Biovitals platform to develop a digital solution for objectively assessing the pain associated with endometriosis [5]. By using biosensors and AI-based algorithms, the severity of pain can be quantified, thus reducing the variability that is commonly seen with traditional methods of pain assessments. Although the validity of this solution is still being investigated in a study, this development demonstrates the novel ways in which AI can be utilised to improve the way clinicians can remotely conduct difficult and subjective assessments.

To lessen the burden on the patient, patient monitoring may be done at regular, but less frequent, check-in appointments. This then poses a different issue of patient safety. Any asymptomatic changes in a patient’s health will likely be undetected until the patient attends their next check-in appointment and the clinician performs their routine tests, thus delaying the detection of potentially harmful developments and any necessary medical intervention.

The use of technology is not just limited to the monitoring of routine physiological changes. Speech signals can be processed using an app to detect changes in neurological health using auditory phenotyping [6]. Samples can be analysed at any time, providing real-time updates of neurological disease progression. These RPM methods, aided by the use of AI, can also be applied to clinical trials to not only improve the patient experience, but to also vastly improve patient safety by minimising the risk of adverse events and reactions, and investigators would be able to collect more valuable patient data. Adherence: Good adherence rates in clinical trials are essential in obtaining reliable data which valid conclusions can be drawn from. For many studies, once patients are enrolled, they will receive the study drug or placebo to take home. They will often be asked to maintain a patient diary to document when the study drug has been taken. This process is heavily dependent on the patients and is susceptible to human error.

With AI, remote patient monitoring (RPM) is now becoming more common in clinical trials. This means that physiological measurements can be taken continuously in real time from patients through the use of wearables and biosensors. The information can be collected without any patient input and

A reason for non-adherence in a clinical trial may be as simple as the patient forgetting to take the medication. 23

Even in instances where the patient has remembered to take the medication, and has done so correctly, they may forget to document this in their diary. When the patient re-visits the research site for check-ins, this diary will be checked and if there are blanks, the investigator will have to rely on the patient’s memory of events. AI can be used in different ways to maintain patient adherence remotely in clinical trials.

• Improved efficiency overall: With more processes becoming automated, this will give employees more time to focus on other more urgent tasks. Cons of AI in clinical trials: • AI technology can be expensive to begin implementing. • AI technology could have a steep learning curve for employees.

One way in which this has been done is by using visual phenotyping to assess adherence, acting as an interactive medical assistant which patients can use through their smartphones [7]. Patients will be able to take a video of themselves taking the medication and from the video, the software will be able to confirm that the correct person has taken the correct medication.

• Patient-centric processes involving AI require patients to have access to smart technology which they can competently use. This may be an issue for older populations and those from lower socioeconomic backgrounds. • Data protection and security concerns surrounding third party organisations which have access to patient information.

Non-adherence driven by fear and misunderstandings about the drug is also an issue in clinical trials. AI-based conversational chatbots can be used to address this. They can be used to perform daily check-ins to take the medication and can also use NLP to respond to any queries and concerns a patient might have about the drug. The software could then pull up the relevant information for the patient. By making the educational information so easily accessible and personalised, patient non-adherence driven by fear of the treatment can be tracked and resolved.

• AI is not perfect, so processes should not be built on the assumption that the technology will be error free. • AI interventions in clinical trials may inflate efficacy through optimal study populations and dosing, thus widening the gap between drug efficacy and realworld effectiveness. Although there are many positives to come from implementing AI technology in clinical trials, there are important issues that need to be overcome as outlined above. AI interventions would undoubtedly increase the speed and efficiency of clinical research which could help bring new life-changing treatments to the market sooner, but the biggest problem would be whether the observed outcomes from such clinical trials will be reflective of real-world situations.

AI and machine learning can also be used to predict which patients are at risk of non-adherence, thus allowing the trial coordinators to proactively intervene in such cases to maintain high adherence rates. Pros of AI in clinical trials: • Improves enrolment: automated processes can increase clinical trial enrolment rates, find optimal candidates and increase outreach to minority groups.

Points to consider:

• Efficient patient safety monitoring: any issues a patient may have during a trial can be predicted or immediately detected through real-time RPM and, therefore, can be resolved sooner.

• The observed efficacy in clinical trials will likely be inflated with such strong technology interference. This may require increased numbers of postauthorisation studies to ensure safety and efficacy remain as expected.

• Improved compliance: automated reminders can be given to patients, adherence can be tracked and those at risk of drop-out can be detected, prompting intervention.

• Observed clinical outcomes could be reflective of drug effectiveness if the same AI interventions are also used by real-world patients. • However, accessibility to such technology in the real-world will need to be considered, especially for those from lower socioeconomic backgrounds.

• Patient-centric solutions: making the clinical trial processes more convenient, personalised and informative for the patient. 24

• If pre-symptomatic changes in patient health in a clinical trial are always detected early enough for medical intervention, the number of adverse events may be reduced and gaps in the drug safety profile may be formed. This may need to be reflected in post-market risk management plans. • If non-adherence always prompts AI interference and reminders, genuine reasons for non-adherence may go undetected (e.g. IMP formulation is unpleasant or difficult to swallow). • Additional regulation and understanding around the technology used in clinical trials will be essential. In this rapidly evolving digital era, the pharmaceutical industry is constantly looking for new and innovative ways to make clinical trials more efficient, accurate and streamlined for patients. It seems that AI technology will be fundamental in transforming clinical trial processes however, from the points raised above, it is clear that there are complexities in the discussions surrounding science and ethics that arise from using AI in clinical trials. For it to be used successfully to improve the clinical trial processes, patient safety and healthcare for the general population, it is paramount that careful considerations are made on the way AI technology is regulated, there is a clear understanding of what contexts it can be used in and when it is best to use human judgement instead.

1. Enrollment issues are the top factor in clinical trial terminations https://www.pharmaceutical-technology.com/comment/reasonsfor-clinical-trial-termination/ 2. Increasing Diversity in Clinical Trials: Overcoming Critical Barriers https://www.sciencedir ect.com/science/article/pii/ S0146280618301889 3. Deep 6 AI https://deep6.ai/ 4. Biovitals by Biofourmis https://www.biofourmis.com/biovitals/ 5. Chugai and Biofourmis Partner to Develop an Objective Assessment of Pain Using Digital Technology https://www.chugai-pharm.co.jp/english/news/ detail/20200722113000_744.html 6. Aural Analytics https://auralanalytics.com/ 7. AiCure https://aicure.com/

By Ka-Mei Au Drive Phase PV

IMPROVING AND SCALING PHARMACOVIGILANCE WITH MODERN TECHNOLOGIES By Jennifer Markey

Pharmacovigilance organisations are struggling to meet greater demand with increasing adverse events from multiple sources and greater patient and regulatory scrutiny. New approaches to safety combined with modern technologies can scale pharmacovigilance processes to handle larger volumes of adverse events, make compliance easier, and improve decision-making. Innovation in artificial intelligence, cloud technologies, and unified safety solutions are making a big impact on pharmacovigilance by driving greater efficiencies and better leveraging of safety data. Between 2009 and 2019, the number of adverse events (AEs) recorded by the FDA Adverse Event Reporting System (FAERS) increased more than 300%, from 409,040 to 1.66 million cases.[1] Given the growth in case volume, the expanding number of sources for potential adverse events, and the complexity of new therapies – there is a significant opportunity to use innovative technology to improve efficiency in pharmacovigilance. Untapped Potential of Artificial Intelligence and Automation In a recent survey, 90% of life sciences’ executives recognised that artificial intelligence (AI) is important in driving innovation and achieving new levels of efficiency. [2] Safety surveillance needs to go beyond data mining of spontaneous reporting systems (SRSs) and medical literature. Internal data sources can be supplemented with real world data from electronic health records (EHRs), insurance claims, social media, and online communities. However, with traditional pharmacovigilance approaches, it is challenging – if not impossible – to incorporate, review, and analyse all these data in a timely manner.

AI can have a huge impact on pharmacovigilance and ultimately provide valuable information to protect patients by improving data quality, providing real time data insights during processing, and enabling faster and more proactive signal detection. As drug safety shifts focus from operational tasks to more proactive risk management and greater data transparency among pharma, patient, and providers – AI will become more essential.

Automating many manual and repetitive processes, AI can enable greater consistency as well as provide valuable insights for data scientists, medical reviewers, and physicians. They can understand their data in a much more comprehensive and extensive way that has not been possible before.

Simpler and More Efficient Unified Safety Solution Many pharmacovigilance systems are fragmented with multiple tools and technologies from different vendors that often do not work well together. Significant resources 26

are spent developing and maintaining integrations, assuring compliance, and carrying out manual activities, such as moving or copying data and content between the siloed systems. With complex processes, there are many opportunities for errors, tasks not being completed in a timely manner, and other compliance risks.

features – minimising impact and providing some control to each company. Designed to bring together stakeholders while keeping administration simple, cloud solutions enable greater collaboration. Biotech / pharma companies and their CROs or service providers can securely access and use the same safety system for better alignment, real-time data visibility, and oversight.[4] Granular security and flexible workflows control what each party can see and tasks they can perform in the system. For example, some service providers can process and review cases, while others can only view them without changing the record. Companies can also streamline cross-functional safety processes by adopting regulatory, quality, and clinical applications built on the same cloud platform.

Modern pharmacovigilance applications are built on a single cloud platform, operating as a unified solution to enable seamless processes, reduce or eliminate manual activities, and provide a single source of safety data and content. With case intake, case processing, operational reporting and analytics, aggregate reporting, coding, content management, and submissions in one solution, it is much easier to track and complete activities, process adverse events from intake to submissions, and analyse data for potential signals.

Improving and Scaling Pharmacovigilance with Modern Technologies

Unifying pharmacovigilance data with relevant information from intake to post-market surveillance allows for better risk mitigation and improves safety decision-making. It also provides more opportunities for the AI engine to learn from decisions. Making it easier to connect data points that, when considered together, can enable earlier identification of safety signals – improves determination of a drug’s benefit-risk profile and shifts companies to more proactive and predictive pharmacovigilance.

AI, cloud technologies, and unified solutions have made great strides in many other areas of life sciences. For pharmacovigilance, it is increasing operational efficiencies and making it easier for companies to scale with growing data volumes, changing regulations, and expansion into new markets. With effective collaboration and real-time visibility, pharmacovigilance teams can perform more timely benefit-risk evaluation and decision-making and improve compliance. Continuing technology innovation will allow companies to realise even greater value from their safety data and eliminate more and more tedious or duplicate tasks to increase focus on higher-value activities for patients.

Easily Scaling and Collaborating with Cloud Technologies Modern safety solutions are a unified suite of applications that are delivered as a cloud service. They automatically scale with more data or activity and the environment is continually monitored to ensure expected performance. With true cloud solutions, all customers are on the same version while still having the flexibility to customise workflows, field names, etc. Vendors can allocate more resources to innovation instead of managing and maintaining old software releases.

References: [1] https://fis.fda.gov/sense/app/d10be6bb-494e-4cd282e4-0135608ddc13/sheet/7a47a261-d58b-4203-a8aa6d3021737452/state/analysis [2] Kent, Evelyn. Five AI Trends in Life Sciences. Retrieved at https://lucidworks.com/post/ai-trends-life-sciences/

Cloud applications have several small releases a year compared to a major release every few years for legacy systems that can take 12 or more months to upgrade. With more frequent updates, companies can keep up to date with changing regulatory requirements and leverage new capabilities earlier. Modern cloud vendors reduce the validation burden for customers by performing and documenting all elements of infrastructure qualification (IQ) and operational qualification (OQ) for each major version. They also provide sandbox and test environments, and user acceptance testing (UAT) scripts that can be leveraged for performance qualification (PQ).[3] Customers can choose when to enable specific

[3] Veeva White Paper, “9 Key Considerations When Evaluating Safety Solutions,” FDANews, September 2020. [4] J. Kratz and K. Traverso, “Modernizing Pharmacovigilance Outsourcing,” Xtalks, January 11, 2021.

Jennifer Markey VP Vault Safety Strategy, Europe Veeva Systems

INDUSTRY RETURN TO OFFICE WORKING POLICIES What our insights show By Julia Day

The CK Group recently carried out a survey across a range of organisations within the life sciences arena in the UK to enquire about their plans for returning to offices when the pandemic restrictions finally allow. This was carried out with the 21st June target in mind. However, even with the extended restrictions in place, the results have been fascinating. It was a difficult subject to fit into 9 questions as each item seemed to lead to more questions but we’ve done our best to try and capture some of the effects the pandemic has had on the ways we might work in the future; at least in relation to office presence. Of the companies who responded it was surprising, and quite pleasing, to see that 100% are planning to retain an element of home working.

We had a great response from the 1000 human resources professionals and hiring managers we invited to participate, so if you are one of those who took the time to provide the information, thank you!

What was even more surprising was the element of flexibility that appears to be on offer, with 45% of responders stating they are not implementing a minimum number of days per week or month to be on-site. However, it’s safe to say the overall trend or expectation seems to be 2 - 3 days a week in the office or as and when required by the business, but with no minimum requirement. Interestingly, 38% of responders are not planning on reopening offices at all when the easing of restrictions allow. The flexibility being offered appears to be available to the majority of workers, including new starters and people working at all levels, with 94% of responders stating this was the case.

So, now to share some of the data and insights we gained … First of all, I’d like to set the scene. All the companies who took part were based in the UK, although with a varied geographical remit and size. Around 47% were UK centric, 17% working across the EMEA or EU and 36% operating globally. In relation to size, 26% were small / start up (less than 50 employees); 30% small (50-300 employees); 11% medium (300-700 employees); 33% large (700+ employees). The majority were pharmaceutical and biotechnology companies (50% and 17% respectively) and the rest a mix of medical devices, CROs, service providers and healthcare organisations. 28

All in all, our survey offered some really interesting insight into how the pharmaceutical and life sciences industries have adapted to working in the pandemic. Certainly, from a recruitment perspective, we’ve seen many companies offering much more flexibility, with some even downsizing office space to account for the anticipated home working uptake. We’ve also seen the boost this has given to candidate and skill attraction as well as a surge in job seekers being able to consider companies previously unattainable due to location.

virtual world? Do people really have the space to work from home? Does it suit everyone? Virtual working and technology: do we all know how to use it properly? Is it fit for all purposes? I’ve recently hired someone new into my team – all done for the first time through the use of virtual technology. We finally met the other week and it made me realise how much we can miss out on with no in-person contact. Her first comment to me, much to my amusement, was, “You’re a lot taller than I thought”. I guess time will tell what long-term changes there will be to our working habits, ways and effectiveness.

On the other hand, we’ve also seen and heard from people who have really struggled with home working. Some have had to turn down roles due to living in shared houses and, for example, not being able to man a medical information enquiry line because of their home situation. This has been very disappointing for the individuals, hiring companies and for us, all for reasons completely out of anyone’s control. It certainly seems like a situation with two sides, if not more, and as the old adage goes, one size does not fit all.

Julia Day EU Divisional Manager CK Group

The survey also raised more questions than it answered in some respects. Could this be the start of a truly 29

MANAGING UNCERTAINTY Developing resilience and finding the certainty you need from within By Cleo Whitehead

I think it goes without saying that we like to feel in control of our lives and the situations that take place around us. Whilst this is possible to a certain extent there is no way that we can control everything that takes place. Uncertainty is a natural part of the human experience and COVID-19 is proof that unexpected things happen sometimes without much notice. We aren’t always equipped to know how to handle uncertain situations, and this doesn’t feel particularly comfortable to the human nervous system. and concern, our nervous system will respond to this worry and concern with feelings of stress, anxiety and overwhelm. The truth about worry In the midst of COVID-19 and modern-day life, most of us understand how it feels to be uncertain about something. Whether it’s around finances, a relationship, a career, a house move, or just the future in general, we’ve all experienced uncertainty. We also know that feeling uncertain can leave us feeling anxious, stressed and burnt out, and so it is only natural that we look for ways to manage this uncertainty. Subconsciously, most often we lean on the habitual tool that is best known as “worry”.

“Worry does not take away tomorrow’s troubles, it takes away todays peace” (Randy Armstrong) Worry plays its part in that it provides the illusion that we are in control. Subconsciously we believe that if we think about this situation and all the possibilities, if we play out the situation over and over in our minds – the more likely we are going to be able to handle it, and things will turn out just how we want. However, what can actually happen is that this style of rumination increases cortisol (stress hormone) in the body, over stimulates the nervous system, and lowers our overall resilience and our ability to problem solve and self-actualise. Effectively we enter a stage of flight, fright, freeze and fawn (WHO, 2020).

We are hardwired to look for certainty, safety, and security in our lives. Why? Because once upon a time (many years ago) we would have spent our time fighting for our lives in the wilderness. Whilst life can feel extremely difficult at times, most of us today aren’t physically fighting to stay alive under these conditions. However, our nervous system isn’t designed to understand the difference between REAL danger and perceived danger, so whilst our living conditions have changed for the better, we still operate from this wiring system. Our nervous system is simply picking up on our thoughts about the world around us and responding accordingly. So, if our thoughts are centred around feeling safe and secure our nervous system will respond with feelings of safety and security. However, if our thoughts are centred on worry

So, with this in mind, how can we learn to manage the uncertainty of the human experience and negative situations that take place in a healthy and helpful way? 30

Unfortunately, there are no shortcuts. However, we can learn to bring conscious awareness to these subconscious and often unhelpful patterns of thinking. When something feels stressful it is impossible to just change how we feel about it overnight. However, with mindset work and practical tools we can change how we feel about uncertainty and develop our resilience over time.

resilience and manage stress and uncertainty. In recent years, research emphasises the positive effects of gratitude and savouring on our overall wellbeing (Bryant & Veroff, 2007; Emmons, 2013). When we focus on appreciation and savour the good things in our life, we take our attention away from our negativity bias, our positive emotions increase and our nervous system relaxes. Research around Mindfulness Based Stress Reduction Programmes also shows positive effects on our emotions and ability to regulate mood. Which again has a ripple effect on our resilience and ability to manage adversity (Kabat Zinn, 1982).

Although we can’t control everything that happens around us, we do have control of the way in which we perceive the obstacles, difficult situations and the uncomfortable feelings we experience in our lives. We can control how we manage our mindset when things aren’t going the way we’d hoped. The more acceptance we develop around this uncertainty, the more resilient we can become.

Mindset work through Coaching Coaching is an invaluable tool for personal development, resilience building, and for managing stress and uncertainty. A coach has many roles but one that is vital with any client is to develop their awareness around what they can and can’t control and to support them in placing their focus and energy on the areas that allow them to thrive and flourish in their lives, even in times of stress.

Mindset work & managing uncertainty A term that is now routinely discussed in the field of positive psychology and personal development is growth mindset. This term refers to the idea that our mindset, personality and the way we handle life circumstances is flexible and can grow, develop and change with practice. Current research in neuroscience and neuroplasticity reiterates this claim and it has been linked to resilience and grit in several different populations (Nestler et al, 2012; Teicher et al, 2016). Traits of a growth mindset include: • Reframing failures into positive experience and seeing them as feedback. • Accepting both the positive and negative experiences of life and placing our attention on improving situations and then moving on in a healthy way. • Accepting that uncertainty is a part of life and cannot be avoided. • The belief that we can’t all be good at everything and focusing on our strengths is the most effective way to use our energy.

Talking and sharing

• A high level of worthiness and self-esteem that isn’t dependant on output or action and the ability to offer ourselves self-compassion under any circumstance.

The use of coaching as a resilience tool also leads us nicely to the discussion on the importance of talking about how we feel. When we feel out of control or uncertain, we are often inclined to keep it to ourselves and avoid discussing it with others. Longitudinal studies now show that connection with others drastically reduces our levels of stress. In her evidence-based research, Barbara Frederickson defines this as “micro moments of positivity resonance”. What she means by this is when we share our stress with others, we experience

Positive Psychology Interventions Now this may seem like a lot of traits to develop, but the good news is these traits are built naturally and in combination with each other through positive psychological interventions. There are many interventions that are encouraged when trying to increase our 31

micro moments of resonance. This causes our oxytocin (love hormone) to increase and we feel supported, seen and connected. Which then improves our wellbeing and reduces stress and feelings of being overwhelmed. Dr Rumani Duvasula is a psychologist and therapist from the US who also suggests that many of her clients have expressed guilt around discussing their own worries and concerns during the pandemic – suggesting that the COVID pandemic and what others may be experiencing, like the death of loved ones, somehow invalidates their daily stresses and fears. She suggests this is an important notion to eradicate because our normal everyday experiences - like marriage issues, parenting issues and financial issues - do not go away just because of the pandemic: keeping our feelings buried is one of the biggest causes of mental health crisis in the UK today. Important points to consider The term resilience has been used here on a number of occasions and I think it is important to highlight that being resilient doesn’t mean that we don’t experience discomfort or distress. Discomfort and distress are a natural part of the human experience, and our resilience levels are based on how we manage the inevitable discomfort and distress that comes our way. We have a choice over whether we ruminate, catastrophise, adopt a victim mentality and think that the worst will happen OR we loosen the grip on what we expect should happen in every situation, learn from our experience, and place our attention on what is working and what we can control in our inner and outer environment.

For further information, please contact Cleo at cleo@coachingwithcleo.co.uk References Bryant, F. B., & Veroff, J. (2007). Savoring: A new model of positive experience. Lawrence Erlbaum Associates Publishers. Emmons, R. A. (2016). The Little Book of Gratitude: Create a Life of Happiness and Wellbeing by Giving Thanks. London. Gaia. Fredrickson, Barbara. (2014). Love 2.0 : Creating Happiness and Health in Moments of Connection. New York: Plume. Frankl, Viktor E. (1984). Man’s Search for Meaning: An Introduction to Logotherapy. New York: Simon & Schuster. Russo, S. J., Murrough, J. W., Han, M. H., Charney, D. S., & Nestler, E. J. (2012). Neurobiology of resilience. Nature neuroscience, 15(11), 1475–1484. https://doi.org/10.1038/nn.3234

Using the tools mentioned in this article we can find the certainty in uncertainty and find a place of safety and security within ourselves when our external world feels difficult to manage.

Teicher, M., Samson, J., Anderson, C. et al. The effects of childhood maltreatment on brain structure, function and connectivity. Nat Rev Neurosci 17, 652–666 (2016). https://doi.org/10.1038/nrn.2016.111

Quick tips to manage & reframe uncertainty.

Websites

• Focus on the present moment through savouring, gratitude and positive distraction and place your attention on what you can control in the now.

Savoring in Psychology: 21 Exercises and Interventions to Appreciate Life (positivepsychology.com) Doctor Ramani – Take your life back. (doctor-ramani.com)

• Find meaning through your experience and ask yourself “what can I learn from this situation”.

The World Health Organisation - https://www.who.int/ The Science of Mindfulness - Mindful

• Talk to people about how you feel, seek support where you can and relieve stress through micro moments of positivity resonance. Remember, you are not an island.

Cleo Whitehead Growth Mindset Coach/Facilitator Coaching with Cleo

• Think about all the things you have managed and overcome in your life until now, and remind yourself that you are strong enough to manage anything that comes your way. 32

GLOBAL MEDICAL INFORMATION AND STANDARD RESPONSE DOCUMENTS By Charlotte Mason

Earlier this year, as part of PIPA’s first Global Forum in March, I had the opportunity to co-chair a discussion session on Global Medical Information, with Bev Lilley from Novo Nordisk. The session was designed to be interactive and to foster discussion with peers in a friendly and secure environment. We ran polls throughout to keep attendees actively involved and I certainly felt there was lots of excellent discussion both in the breakout rooms and in the wider group. I gained a lot from this session, and it definitely proved that even virtually we can engage with, and learn from, each other.

A team/function within a company that cascades up-todate, evidence-based information about products and therapy areas. A team responsible for creating standard response documents/letters for use by other medical information teams within the company for regional or local adaptation.

One of our discussion topics was around global standard response documents (SRDs), and I have summarised the key takeaways from this session below.

Then we explored why having global standard responses documents is beneficial:

What is Global Medical Information? First of all, we broadly defined what Global Medical Information is.

Localisation of Standard Response Documents We set up break out rooms for smaller group discussions on the following: • What do you need to keep in mind when using a Global SRD to create a local version? • How are you notified if there are revisions to the Global SRD? Then we returned to the whole group and discussed ‘Hints and Tips’ for localisation of Global SRDs:

Some key areas to consider are the differences in country-specific pharmaceutical regulations and variations of product labelling between countries e.g. licensed indications and contraindications.

When the material relates to a medicine which is subject to additional monitoring, an inverted black equilateral triangle must be included on it together with the statement below or a similar one:

A pertinent example of differences between regulations is the UK ABPI Code of Practice for the Pharmaceutical Industry (2021) requirement to include the inverted black triangle symbol and adverse event reporting statement in responses to/ information intended for members of the public:

‘This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See [a website address which links directly to the MHRA Yellow Card site] for how to report side effects.’ This inclusion of the inverted black triangle symbol is not a specific requirement in most other European countries or the US.

Clause 26.4 of The ABPI Code of Practice (2021) [1] Any material which relates to a medicine and which is intended for patients taking that medicine must include the statement below or a similar one:

Use of infographics The use of infographics within response documents generated a lot of healthy debate and engagement. Overall, it was the consensus that as long as the infographics are used in a compliant way, they can really enhance response letters. Complex clinical trial designs and results can be easier to understand when displayed visually as diagrams. Points to consider are whether the infographics appear promotional and not to use brand imagery or colours.

‘Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in the package leaflet. You can also report side effects directly via the Yellow Card Scheme at [a website address which links directly to the MHRA Yellow Card site]. By reporting side effects, you can help provide more information on the safety of this medicine.’ 34

Content Management of Global SRDs

The poll results showed that there were only a small number of the attendees who had processes in place. This led us on nicely to present a process flow Bev and myself had put together for the session:

We moved the conversation onto processes and asked the following poll question: • Do you have Standard Operating Procedures (SOPs) or Process Flows for localisation of Global SRDs?

References

Something else to contemplate here is how to communicate any updates or new versions of the Global SRDs to the other affiliate countries - will you send a monthly email report? Will there be an expectation that the affiliate countries check regularly within the content management system for updates (provided they have access to view the global SRDs)?

1. ABPI CODE OF PRACTICE FOR THE PHARMACEUTICAL INDUSTRY 2021: https://www.pmcpa.org.uk/media/3406/2021-abpi-codeof-practice.pdf

Contact email address: charlotte.mason@jazzpharma.com

However you approach this process - once you have it in place - the advantages are: • more efficient ways of working • a reduction in duplication of work • consistency of responses across the business. The concept of the global medical information function varies greatly between companies and is dependent on several factors. Even if you already have a process in place it is always useful to learn how others approach a particular task and this session was a perfect platform for that. I hope this article helps to encourage best practice in relation to the localisation of global SRDs within your organisation.

Charlotte Mason Associate Director Medical Information Jazz Pharmaceuticals

KEY TOPICS ON SUSTAINABILITY By Lauren Hursthouse

The definition of sustainability from the Oxford Dictionary is: “avoidance of the depletion of natural resources in order to maintain an ecological balance”. Sustainability is not just a social responsibility, but a corporate responsibility also. With more and more evidence emerging about climate change and what we are doing to our planet and ecosystems, this article looks at three key topics on sustainability and how we, as consumers, can make a difference. 1 - Shop Local:

6. Buying local is better for the planet

Shopping locally might not be the first thought that you have when it comes to buying your weekly shop but it definitely has its benefits when thinking of more ways to be sustainable and environmentally friendly. Not only does it reduce waste from packaging but also from the fossil fuels used in transportation and so is healthier too!

8. You get to meet your farmers when shopping at local markets 9. It can help you save money Additional resources: https://brightonjournal.co.uk/top-5-benefits-of-shoppingsmall-and-local/

Depending on where you live, the following ways to shop locally may be available to you:

www.onegreenplanet.org/lifestyle/reasons-to-buy-local

• Local farmer’s market

https://www.gov.uk/government/news/eight-reasons-toshop-local-this-week-to-help-the-high-street-bounceback

• Local greengrocers (for vegetables and fruit) • Local eco shop with refillable/reusable container options for foods such as nuts, grains, pasta, shampoo, bodywash, laundry detergent.

https://www.ecowithem.com/ 2 - Palm Oil:

Top reasons to shop local and become a “Locavore”:

What’s in your peanut butter? Have you looked at the ingredients of one of our favourite breakfast/snack/sandwich fillers? Well, it may shock you to realise that a lot of peanut butter jars can contain unsustainable palm oil. Actually, palm oil is in nearly everything – it is in close to 50% of the packaged products we find in supermarkets: everything from pizza, doughnuts and chocolate, to deodorant, shampoo,

1. Locally sourced food will be fresher due to less transport time 2. There is usually much less packaging involved 3. Buying local helps the local economy 5. You know where your food has come from

toothpaste and lipstick. It is also used in animal feed and as a biofuel in many parts of the world.

sustainable palm oil or alternative oil in their products before making a purchase. The WWF have produced a palm oil scorecard and their website allows you to check which manufacturers are committed to a responsible palm oil future, free from deforestation and destruction of nature.

What is palm oil? It is an edible vegetable oil that comes from the fruit of oil palm trees. There are two types of oil that can be produced: crude palm oil comes from squeezing the fleshy fruit and palm kernel oil which comes from crushing the kernel or the stone of the fruit. Palm oil is mainly produced in the Democratic Republic of the Congo, Indonesia (Borneo) and Malaysia.

Additional resources: https://www.independent.co.uk/environment/palm-oilenvironment-orangutans-indonesia-rainforests-icelandchristmas-advert-a8631896.html

What’s the problem with palm oil?

https://www.nationalgeographic.com/magazine/2018/12/ palm-oil-products-borneo-africa-environment-impact/

Palm oil is a major driver of deforestation of some of the world’s most biodiverse forests, destroying the habitat of already endangered species like the Orangutan, Pygmy Elephant and Sumatran Rhino. This forest degradation, along with conversion of carbon rich peat soils, are spewing out millions of tonnes of greenhouse gases into the atmosphere and contributing to climate change. There also remains some exploitation of workers and child labour. These are important issues that the entire palm oil sector needs to take accountability for because there are alternative eco-friendly solutions.

https://greenpalm.org/about-palm-oil/social-andenvironmental-impact-of-palm-oil https://www.worldwildlife.org/industries/palm-oil 3 – Air pollution What are the main contributors to air pollution? Air pollution can be classified into two categories: invisible and visible air pollution. Visible air pollution, as the name suggests, can be visible. The smog that is present in urban areas and cities is an example of visible air pollution. Invisible air pollutants are less noticeable, and thought to be more deadly. Examples are sulphur dioxide, carbon monoxide and nitrogen oxides. Sources of air pollution can be split into Natural sources and Man-made sources.

What solutions are out there? The good news is that palm oil can be produced more sustainably. The Roundtable of Sustainable Palm Oil (RSPO) was formed in 2004 in response to increasing concerns about the impact that palm oil was having on the environment and society. The RSPO sets a production standard and best practices for producing and sourcing palm oil. This has buy-in from most of the global industry and there is encouragement for companies to be totally transparent in their use and sourcing of palm oil and contributing to sustainable palm oil. There is still a long way to go before it becomes 100% sustainable.

Natural sources of pollution include dust carried by the wind from locations with very little or no green cover and gases released from bodily processes of living beings (humans, cattle). Man-made sources can be split into indoor pollution sources and outdoor pollution sources. The major outdoor pollution sources include power generation, vehicles, agriculture/waste incineration, industry and building heating systems. In low- and middle-income

What can you do as a consumer? You can check which brands/manufacturers use a

Instead you should consider what chemicals you’re using in the home and switch to non-toxic alternatives. Here are some other ways you can reduce air pollution in your home: • Service gas appliances regularly • Open windows regularly

What are the main issues with air quality?

• Banish damp and mould

When air quality is poor, pollutants in the air may be hazardous to people, particularly those with lung or heart conditions. Poor air quality affects our health, has a cost to our society, our economy and the environment. It causes acid rain, eutrophication, child health problems, global warming, adverse effects on wildlife and depletion of the ozone layer. Although air quality has improved in recent decades, there are some parts of the world where there are unacceptable levels of air pollution.

• Buy an air purifier Bigger picture - wider solutions to air pollution: • Use public modes of transportation • Better household practices • Conserve energy by putting on extra layers of clothing at home instead of putting the gas central heating on • Practice the concept of reduce, reuse and recycle

How is Air Quality measured?

• Use clean energy resources where possible

Air quality is measured by government agencies by using the Air Quality Index and it tells you about levels of air pollution and provides recommended actions and health advice. The scale is based on particulate matter in the air and ranges from GOOD to HAZARDOUS. Why don’t you check the air quality in your area?

• Use energy-efficient devices Additional resources: https://www.gov.uk/government/publications/clean-airstrategy-2019 https://www.nationalgeographic.com/science/2019/11/ houseplants-dont-purify-indoor-air/

Air Quality Index - Particulate Matter 301-500

Hazardous

201-300

Very Unhealthy

151-200

Unhealthy

101-150

Unhealthy for Sensitive Groups

51-100

Moderate

0-50

Good

https://www.goodhousekeeping.com/uk/house-andhome/household-advice/a30072188/air-pollution/ https://www.thegoodtrade.com/features/natural-ecofriendly-cleaning-products-for-the-conscious-home https://strives-uploads-prod.s3.us-gov-west-1. amazonaws.com/19930073077/19930073077. pdf?AWSAccessKeyId=AKIASEVSKC45ZTTM42XZ&Expires=1600254390&Signature=7ZzhkGNXe8i1sFnHYxn6VwmtLtQ%3D https://www.conserve-energy-future.com/causes-effectssolutions-of-air-pollution.php

What solutions are out there?

Please note that any views expressed are my own and not PIPA’s.

You can purify your air at home by buying/growing specific plants that can purify air. Sounds great right? Unfortunately, it hasn’t been scientifically proven that indoor plants can purify air enough to be beneficial. One study concluded that for a one-bedroom apartment to have “clean” air you would need over 5000 plants. On the other hand, NASA released a study in 1989 indicating that specific plants can potentially improve indoor pollution. It is a nice idea and plants do add something to the home: but it is not a quick fix to the problem.

Lauren Hursthouse Clinical Trial Scientist ICON plc

Photo by Marc Wieland on Unsplash

countries, mostly burning fuels such as dung, coal and wood in inefficient stoves or open hearths produces a variety of health-damaging pollutants. These include carbon monoxide, methane, particulate matter (PM), polyaromatic hydrocarbons (PAH) and volatile organic compounds (VOC).

A BEGINNER’S GUIDE TO SAFETY REPORTING IN CLINICAL TRIALS By William Ray - Drug Safety Expert

So, you’ve managed to work your way into a role in drug safety and you’ve started with your case processing - you’ve even created a Council for International Organizations of Medical Sciences (CIOMS) form. But do you know what happens next with the distribution of the case? I’ve come across quite a few people who know a great deal about pharmacovigilance (PV) but have less of an idea of what happens when it comes to the distribution of cases and beyond. It’s useful to know and is an important step. “What is the process then?”, I hear you ask. “You just send an email, right?” Well, I’m getting to that!

can differ from territory to territory, so robust regulatory intelligence is a must, along with internal processes that ensure all ICSRs are suitably assessed, and periodic reports scheduled. Even within European Medicines Agency members, there are differences in reporting requirements for SUSARs: some RAs wanting all SUSARs from within the trial and others only wanting to be made aware of ones occurring in their country. This also highlights not just the need for external regulatory intelligence, but also for PV to be fully integrated into the sponsor clinical trial team, so PV is fully aware of all the countries that a study is operating in.

I am going to describe the process for clinical trials as this is what I am most familiar with, but there are similar processes for post marketing too. Classification of reports There are a few things we need to know about the classification of case reports before we go any further. There are many types of report that are received and generated throughout clinical trials, with their own associated reporting requirements and formats. In general, report types in clinical trials can be split into two categories: expedited and periodic.

Along with being able to accurately identify what reports are required for submission, companies should also be aware of timelines and where they may differ from industry ‘norms’ (i.e. a 15 day SUSAR to be reported to the US FDA requires submission within 14 days to Argentina).

Expedited Reports The bread-and-butter of clinical trial PV is the receipt and processing of serious adverse events (SAEs). Certain SAEs will require expedited reporting to regulatory authorities (RAs), ethics committees (ECs) and investigators involved in the study. For example, Suspected Unexpected Serious Adverse Reactions (SUSARs), would routinely require reporting. Some non-SUSAR ICSRs which, nonetheless, are considered to affect the benefit-risk balance of a study may also require reporting in an expedited manner.

Finally, at this stage, sponsors will need to identify if there are any additions needed to the report to meet local reporting requirements. For example, SUSARs reported to the US FDA will also need an accompanying analysis of similar events (AOSE) and those occurring in Spain require the case narrative to be translated into Spanish for the submission to the Spanish RA. Where studies are blinded, there will usually be the need to unblind ICSRs before reporting, so there not only needs to be a level of regulatory intelligence to identify which parties may be the exception to this rule, but also internal processes to ensure no inadvertent unblinding of other study team members or investigators.

Periodic Reports Periodic reports can also be termed aggregate reports and contain grouped information to be submitted at defined intervals, rather than triggered by specific events. Periodic reports include annual Development Safety Update Reports (DSURs) or more simple line listings of SAEs or serious adverse reactions (SARs).

Submission methods for reports

For both expedited and periodic reporting, requirements

Once a report has been identified for submission, along 39

with the required recipients, the next step is to know HOW to send the report. Distribution can be via gateway, email, fax, courier and/or hand delivered by a company representative. So, we can see this is already getting a bit more complicated than just sending an email. Quite often there are also supporting forms. Web portals can add their own layer of complexity, ranging from the ‘simple’ and accessible UK eSUSAR tool to the Spanish portal, which can only be accessed by someone resident in Spain, or even the EMA EudraVigilance portal, which requires a two-day training course to become a certified user. Again, this highlights the need for PV to be properly integrated and informed of study decisions, so any set-up of portals can be coordinated in advance of reports requiring submission.

inspected you can expect your compliance documentation to be checked.

Safety Information flow

This leads me on to the subject of under- and overreporting. Under-reporting is serious. If a report to an RA is missed this can result in action from the RA. Over-reporting is also a problem. If an RA is flooded with unwanted reports, they will not be happy about it. Under-

An interesting scenario often encountered when working with a suite of trials is cross reporting. This is when reports about the same medicinal product, but different manufacturer, need reporting. In this instance, an agreement between the Marketing Authorisation Holders (MAHs) is required to say who will report such cases. Unfortunately, it is too simple to say that all reports should be reported to RAs or ECs in each trial. This will be dependent on the regulatory intelligence for each party to the level of whether they would like to receive reports from a specific trial, or all reports available across a development programme.

Below is a diagram outlining the process followed by each report as it is distributed and followed up for compliance purposes.

Report unblinded, if necessary, and finalised

Report distributed based on regulatory intelligence with supporting information and webforms

Report triaged using regulatory intelligence

Acknowledgements collected for compliance of submission

Figure 1: safety reporting submission flow

reporting is often linked with subsequent inspections and - if you are a service provider - probably an audit from your client.

As you can see, assimilating all the regulatory intelligence for a given clinical trial and then for a given report can be very complex, especially when there are a lot of countries involved, as is often the case for large clinical trials. Though that being said, rule-based computer systems are being developed that take a lot of the heavy lifting out of the decision making, distribution and compliance metrics. Unfortunately, with these come other issues, such as balancing general rules that will function across a development programme vs study-specific requirements. I have seen both complex and simple systems used – some companies may simply opt for a spreadsheet and use of an email program like MS Outlook for the majority of their submissions. It depends on company preference.

This is just a brief outline of how safety reporting in clinical trials works and has not even considered maintaining safety data exchange agreements with partner companies. I’m sure you can understand that in the day-to-day activities of a safety associate that works in this area, there are many things to consider. There are often complex problems to solve and tight deadlines to meet.

As described in the flow diagram, compliance also needs to be tracked after submission. With EudraVigilance, this will be with receipt of acknowledgement files. With distribution to other recipients, there are a range of methods that can be used to detect if a submission has been received and this depends on the systems being used. Compliance is important and if you are audited or

William Ray Drug Safety Expert

VICE PRESIDENT’S REPORT Autumn 2021

Welcome to our fourth digital-only, edition of PIPELINE. I want this report to reflect only positivity and not the uncertainties the last year brought us. I want to take this opportunity to highlight the great work the PIPA team have done in that time starting with the Operations Team. Both Anne Turnbull and Sharon Braithwaite oversaw and implemented PIPA’s new website to continue to fulfil its mission by delivering useful tools and resources in line with current and future needs of the membership. Our PIPA Committee has never been busier, from publishing new guidance documents to running our free monthly PV and MI webinars, offering advice and guidance to our membership via the discussion forums and being handson to respond to the needs of PIPA and its members.

up as a way to assist those new to the role of the UKQPPV to provide clarity and to assist with navigating the requirements of the role. But we did not just stop there: two days later, we published two new guidance documents on EU and UK Medical Device Vigilance to keep up with the legislative changes in medical devices. You may access these guidance documents via the Pharmacovigilance section of the PIPA website: https:// pipaonline.org/pharmacovigilance/ We hope you find these new publications useful tools, whether in your everyday working or for expanding your own knowledge.

As you will be aware, PIPA hosted its very first twoday digital Global Pharmacovigilance and Medical Information Forum in March, where we had a range of fantastic speakers present PV and MI topics from a global perspective. I had the pleasure of taking part in a panel discussion and open forum on QPPV Hot Topics with Jackie Roberts, PIPA President, Tom Nichols and PIPA Committee Member, Anne Lloyd. The first day of the forum was purely focused on pharmacovigilance and included topics on the impact of Brexit, the globalisation and harmonisation of pharmacovigilance regulations and a comparison discussion on RMP and REMS risk management systems.

So let’s look to a more positive future as we go further into 2021.

The second day was dedicated to medical information where we opened with the laws and regulations that impact global MI provision in the EU & Asia Pacific followed by a discussion about a global chatbot solution. Further on in the day, we explored a topic many MI professionals can relate to: the challenges of delivering a truly global MI database. After this, PIPA’s own Charlotte Mason hosted a discussion session on compliance and the global MI function. We ended the MI day and global forum with an exploration of the laws and regulations that impact global MI provision in the USA.

Janine Gavin-Poulter

In April, PIPA published its latest guidance document: “UK Guidelines for the Pharmaceutical Industry Qualified Person for Pharmacovigilance” which was written by PIPA’s new QPPV Workstream. The guidelines were drawn

Vice President PIPA

PIPA COMMITTEE 2020 Who are we? The PIPA committee is the backbone of the association; and this page features all the current contact details. The Committee is supported by 3 part-time contractors, whose details are also included on this page.

Tom Nichols

Janine Gavin-Poulter Vice President; Code Compliance JGP Consulting

President Drive Phase PV

Email: vicepresident@pipaonline.org; code@pipaonline.org

president@pipaonline.org; Role: Leadership – strategy & committee / KOL liaison / PIPA representation

Role: Correspondence / Membership matters / Constitution compliance / AGM leadership / Consultation responses / Assisting with organisation of PIPA Code & Compliance Forums

Tracy Crooks

Anne Lloyd

Treasurer Reckitt Benckiser

PV Compliance; Conference Co-organiser; CPD lead Ethypharm UK & Martindale Pharma

treasurer@pipaonline.org

pv-liaison@pipaonline.org; conference@pipaonline.org

Role: Financial lead / Audit & compliance / Invoice payment

Assisting the PIPA membership with ensuring their PV compliance. Assisting with PIPA Conference preparation and delivery. Updating and maintaining a CPD programme relevant to the membership.

Pooja Shah

Dora Amene PV Compliance; PIPELINE Co-Editor TMC Pharma

PIPELINE Co-Editor; Conference Co-organiser Richmond Pharmacology

pv-liaison@pipaonline.org journaleditor@pipaonline.org

journaleditor@pipaonline.org conference@pipaonline.org

Role: Assisting the PIPA membership with ensuring their PV compliance. Preparation and proof-reading of PIPA’s journal, PIPELINE.

Role: Preparation and proof-reading of PIPA’s journal, PIPELINE. Assisting with PIPA Conference preparation and delivery.

Charlotte Mason

Martin Baker Medical Information Workstream Alliance Pharma

Medical Information Workstream Jazz Pharmaceuticals

medinfo@pipaonline.org

Role: Assisting the PIPA membership with ensuring excellence in MI.

Nick Venaglia

Emma Boulton

Medical Information Workstream Novartis

PV Compliance; CPD; Training Workstream Co-Chair Napp Pharmaceuticals Ltd

E-mail: medinfo@pipaonline.org

pv-liaison@pipaonline.org

Role: Assisting the PIPA membership with ensuring excellence in MI.

Role: Assisting the PIPA membership with ensuring their PV compliance. Updating and maintaining a CPD programme relevant to the membership.

Harpreet Sandu

Stephanie Bettesworth Communications & Profile; PV Compliance Novo Nordisk

Medical Information Workstream

E-mail: medinfo@pipaonline.org

internet@pipaonline.org pv-liaison@pipaonline.org

Role: Assisting the PIPA membership with ensuring excellence in MI.

Role: Raising awareness and engagement within & beyond PIPA. Assisting the PIPA membership with ensuring their PV compliance.

Sanjay Motivaras

Mehrnoosh Ensan

Training Workstream Co-Chair Audit PV Ltd

E-mail: training@pipaonline.org

Medical Information Workstream; Training Workstream Co-Chair Biogen

Role: Co-ordinating training courses for the PIPA membership.

medinfo@pipaonline.org training@pipaonline.org Role: Assisting the PIPA membership with ensuring excellence in MI. Co-ordinating training courses for the PIPA membership.

Sharon Braithwaite

Anne Turnbull

Membership and Events Co-ordinator Contractor PO Box 254, Haslemere, Surrey, GU27 9AF Tel: 07340 519234

Operations Manager Contractor PO Box 254, Haslemere, Surrey, GU27 9AF Tel: 07904 164812

sharon.braithwaite@pipaonline.o

anne.turnbull@pipaonline.org

Sarah Anthony Administrative and Treasurer’s Support Contractor PO Box 254, Haslemere, Surrey, GU27 9AF

sarah.anthony@pipaonline.org

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