Clinical Research and GCP Update

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Course notes for the webinar held on Tuesday 13 April 2021

Presented Material for the webinar on Tuesday 13 April 2021

“Clinical Research & GCP Update” April 13, 2021 A 90 min virtual course delivered online 2pm BST, 3 pm CEST, 9am EDT

Please log in 10 to 15 mins before the start time to ensure that you have connection and sound. If you are unable to hear the webinar when it starts check that you do not have a pop-up box on your desktop that requires attention. If you still have problems email johu@brookwood-global.com This webinar will present short summaries and key information relating to a number of recent developments and information. It will be a mix of presentations, poll questions and discussion. Our pledge: if necessary, we will extend the session to ensure that all of your questions are answered. Introductions • Overview of the latest inspection findings and key points of focus. • Remote inspections – advice from inspectors. • Are you ready for the period post pandemic? … the inspectors will be! • How ICH E8 (R1) will affect clinical trial conduct. • How will you involve patients in your clinical trial development? – new MHRA requirement • ICH GCP renovation: the process, progress and what we can expect. • Dealing with non-compliance – have you identified the risks and making sure your CAPAs are not ‘wishy washy’. • Update on the EU Clinical Trial Regulation – current status, CTIS progress and associated guidelines Participant question time Bonus session – if you wish and your time allows you may stay on for this extension to the webinar. • Now that UK has left the EU … new requirements and data protection. • Hot news items

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A course designed and undertaken by Brookwood Global © 2021 5 Studley Court Mews, Chobham, Surrey, GU24 8EB, UK Tel: +44-1483-811383; info@brookwood-global.com www.brookwood-global.com Dedicated to training and independent certification in clinical research and GCP

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Brookwood Global (Canary Ltd), 5 Studley Court Mews, Chobham, Surrey, GU24 8EB, UK Tel: +44-1483-811383; info@brookwood-global.com www.brookwood-global.com Dedicated to training and independent certification in clinical research and GCP

PROFESSOR DR DAVID HUTCHINSON Professor Dr David Hutchinson is a well- known and respected teacher of clinical research and GCP with considerable experience of clinical trial management and regulations. He has made a significant contribution to the field of training and the professional development of clinical research and quality assurance professionals and has delivered presentations worldwide. He is Visiting Professor in Clinical Research & GCP in the Faculty of Health & Medical Sciences, University of Surrey and provides clinical research training for undergraduate and postgraduate students. Since 1985 he has designed and delivered training programmes, some with certification, to thousands of clinical researchers (sponsors, investigators) worldwide. He has taught GCP responsibilities to investigator sites, and regulatory authority personnel, throughout Europe and extensively in Eastern Europe. He has trained members of the Saudi FDA and MHRA as well as other EU regulators. He has provided GCP training to hundreds of medical professionals in conjunction with the Dubai Ministry of Health and Al Jalila Foundation, Dubai, UAE. He has developed and delivered numerous clinical research and GCP training programs for both commercial and academic clients. As well as being principal author and editor of Clinical Research and Quality Assurance ‘Advisor’ newsletter, David is author of numerous books and articles on clinical research and QA topics including: • 12 Golden GCP Rules for Investigators (available in English, French, German, Polish, Bulgarian, Russian, Spanish, Japanese, Czech, Turkish and Chinese) • 10 Golden GCP Rules forPharmacists • 12 Golden ISO14155 Rules for Studies on Medical Devices (withJoris Bannenberg) • PV for ALL: a guide to recognizing and reporting product safety information (with Lisbeth Tofte Hemmingsen) He has written, narrated and developed numerous online GCP training programmes with testing and certification, accredited by the Faculty of Pharmaceutical Physicians (Royal Colleges of Physicians of the United Kingdom) – now available in 14 languages. David was founding editor of the British and European Journal of Clinical Research, the British Journal of Medical Economics and Good Clinical Practice Journal. He is a former President and life member of the Association of Clinical Research Professionals. David is a Fellow of Research Quality Assurance (RQA). In the past, David has taught GCP to members of the UK’s national and local ethics committees as well as on the European course in Pharmaceutical Medicine (ECPM, University of Basel) and the Kings College London course on Ethical Principles. David has completed an ISO9000 training course with continuous assessment and examination in Quality Assurance Auditing (Auditor/Lead Auditor). Outside clinical research David is a Certified NLP Master Sports Practitioner (mental performance coaching) and coaches numerous professional golfers. He has RYA Yachtmaster powerboat qualifications, is a Football Association Referee Coach and professional game referee observer. He supports Nottingham Forest, loves curry’s and enjoys a game of golf (but only in the sun!) when time permits! David is founder and owner of Brookwood International Academy. • • Essential Good Clinical Practice Essential Pharmacovigilance (with Lisbeth TofteHemmingsen)

DR COLIN WILSHER Colin Wilsher is a well-known GCP expert and is a mainstay of Brookwood’s training courses and regulatory intelligence for the ‘Advisor’ newsletter. Colin also manages the @GCPadvisor Twitter account. Prior to becoming freelance and setting up a GCP consultancy, he worked for ten years in the clinical auditing group of Pfizer Medical as a GCP Auditor and then as Director and Regulatory Intelligence Lead in the Inspection Management group of Medical Quality Assurance at Pfizer. He qualified as a Chartered Psychologist in the late 1970’s and went on to do a PhD in Neuropsychopharmacology at Aston University, UK. Whilst at Aston University he was a Clinical Investigator leading two randomised placebo controlled clinical trials of a Nootropic drug treatment of developmental dyslexia. He also has a teaching degree (PGCE) and completed post-doctoral studies at the Department of Psychiatry, Rutgers Medical School, New Jersey, USA. For four years he worked for a US subsidiary of the Belgium pharmaceutical company (UCB Pharma Inc) in the USA, as a Clinical Development Coordinator running Phase 3 studies across the USA. Following this he went on to work, in the UK, for 16 years for UCB Pharma Ltd. His roles included working in; Regulatory Affairs (a member of BIRA /TOPRA) from 1990 to 2002); CNS Therapeutic Group; and Local Clinical Quality. In 2002 he joined Pfizer clinical quality assurance group as a clinical auditor and GCP Technical Specialist and becoming a Director of Regulatory Intelligence. Colin has served on the UK Regulatory Authority MHRA GCP Consultative Committees from their inception until 2010. He has also served on the MHRA Risk Based Inspection Stakeholder group and the MHRA Risk Adaptation Consultative Group. He joined RQA (Research Quality Association, formally the British Association for Research Quality Assurance, BARQA) as a member in 1994; has been an active member of the GCP Committee for many years; was twice elected Chairman of the GCP Committee; and is a Fellow of Research Quality Assurance (FRQA). In 2013 he was honoured with the prestigious "Research Quality Association Award for 2013" and in 2019 was awarded an Honorary Life Fellowship of RQA. He was an active member of the Audit Working Party of EFGCP (European Forum for Good Clinical Practice) and for 5 years was a member of the EFGCP Ethics Working Party. He was on the editorial board of the Quality Assurance Journal (QAJ) and is a senior correspondent of ‘Advisor’ newsletter. Colin held an honorary faculty position in the School of Psychology at the University of Wales 1998 to 2018.

Clinical Research & GCP Update

Meet your team …

Prof Dr David Hutchinson Founder & Owner Brookwood Global

Dr Colin Wilsher GCP & Regulatory Intelligence Specialist Brookwood Global

Aims of this webinar

To provide an update in the following areas: • Overview of the latest inspection findings report • How ICH E8 (R1) will impact clinical trial conduct. • Involving patients in clinical trials. • ICH GCP renovation: the process, progress and what we can expect. • Readiness for the period post pandemic. • Update on the EU Clinical Trial Regulation – current status, guidelines and EMA’s Q&A document.

• Dealing with non-compliance and CAPAs. • Other news items … as a bonus session.

Overview of the latest inspection findings

Next one due May 2021

In total, 98 GCP inspections were requested by CHMP and carried out by the inspectorates of the EU Member States in 2018.

https://www.ema.europa.eu/en/documents/annual-report/annual-report-good-clinical-practice-inspectors-working-group-2018_en.pdf

MHRA inspection metrics (2018)

• Commercial sponsors = 8 • Contract Research Organisations (CROs) = 11 • Investigator sites = 19 • Phase 1 unit inspections = 7 • Non-commercial organisations = 12 • GCP inspections of UK labs conducting clinical trial sample analysis = 17 (up from 13 previous period)

Findings are summarised into one of 42 categories and graded as critical, major or other

MHRA inspection metrics (2018)

Contract Research Organisations = 11 • 2 at same CRO • 4 (40%) had critical findings • 9 (90%) had major or critical findings

Commercial sponsors = 8 • 6 systems, 2 triggered • 4 (50%) had critical findings • 100% had major or critical finding

Investigator sites = 19 but data based on 21 (2 non-UK inspections)

• 1 (5%) had a critical finding • 13 (62%) has major finding(s) • The emphasis was on how the investigator site had been overseen by the sponsor/CRO

Areas with most major findings!

Sponsor

CRO

• Record keeping/Essential Documents • Pharmacovigilance • QA, SOPs • Serious breach reporting • Monitoring • Oversight of trials • Data management • Data integrity • Competent authority • Insurance • Computer systems validation • Archiving

• Data integrity • Record keeping/Essential Documents • Monitoring • Quality systems/QA/SOPs • Computer systems validation • Pharmacovigilance • Serious breach reporting

• Data management • Competent authority • Contracts & agreements

Areas with most major findings!

Investigator Sites

• CRF Data / Source Data • Data integrity control • Protocol compliance • Medical oversight by the PI • Subject confidentiality • Research Ethics Committee • Record keeping/Essential Documents • Informed consent

• IMP management/pharmacy • Clinical sample management • Pharmacovigilance

7 CRITICAL sponsor findings

1. Pharmacovigilance - RSI 2. Record keeping & essential documents 3. Clinical Trial Authorisation 4. Protocol compliance 5. Data integrity control processes

CRITICAL sponsor findings - RSI

Solutions

Problem • The version of the Reference Safety Information (RSI) used to assess expectedness of SARs was not documented (nor was there any procedural requirement to do so). Impact • Potential for the incorrect RSI to be used to evaluate expectedness.

The RSI is trial-specific. Make sure that you identify the RSI and ensure that the version to be used in the trial is documented.

Make sure that your SOP requires this.

CRITICAL sponsor findings - RSI

Solution

Problem • There was no process in place to ensure the Reference Safety Information (RSI) had been approved by the MHRA prior to implementation. Impact • The incorrect version of the RSI was used for expectedness assessments during case evaluation with subsequent under reporting of SUSARs and the subsequent impact on DSURs.

Use only the RSI approved by the regulatory authority for all evaluations of expectedness. Do not use unauthorised updates. Effectively communicate to all concerned which RSI is to be used.

CRITICAL sponsor findings - RSI

Solution

Problem • Issues with the accuracy of a tracker developed to track Investigator Brochure (IB) approval dates were identified and did not include the RSI approval dates for comparator products. Impact • Potential for the incorrect IBs and hence RSI to be used leading to under-reporting of SUSARs.

The tracker should be validated and tested. There should be documented quality checks that the tracker is accurate. The tracker should include RSI approval dates for comparators as well as IMP.

Critical inspection findings - RSI

• The company’s procedures did not require that the RSI used at the onset of an event should be used to evaluate the case throughout the follow up period. ̶ This led to the incorrect version of the RSI being used for expectedness assessments during case evaluation with subsequent underreporting of SUSARs.

MHRA inspection findings - critical

The RSI is a hot topic for inspections and care must be taken to ensure that you get this right as it has a potential impact on under reporting of SUSARs, the accuracy of the DSUR and the safety of patients .

MHRA Blog on RSI (Part III) & CTFG guidance

• Reference Safety Information (RSI) for Clinical Trials- Part III • Posted by Mandy Budwal-Jagait, Gail Francis and Dr Maria Beatrice Panico 5 February 2021 • https://mhrainspectorate.blog.gov.uk /2021/02/05/reference-safety- information-rsi-for-clinical-trials-part- iii/ • Remember applicable law in the UK is SI 2004/1031 • Also relevant: CT-1, CT-3, national legislation in Member States, CTFG Q&A on RSI

CRITICAL sponsor findings – Essential Documents

• The TMFs presented to inspectors were incomplete or inaccurate, which resulted in an inability to reconstruct the trial or procedural conduct to enable the verification of GCP compliance. • Several documents were filed outside the core electronic TMF (eTMF). Whilst the TMF master list did state that these were filed across various locations, it did not index exact locations and direct access could not be provided to inspectors.

CRITICAL sponsor findings – Essential Documents

• Inspectors had to request a large number of documents in order to conduct the inspection as well as an additional office-based inspection. • The TMFs reviewed were incomplete to such an extent that they impeded/obstructed inspectors carrying out their duties. • There was a failure to define the TMF within the quality system.

CRITICAL sponsor findings - TMF

• A number of “Data” files were classified as non-essential and filed outside the eTMF, this included SAE data listings. ̶ Such data files, however, were essential for demonstrating key safety processes and sponsor oversight and thus should have been held in the eTMF. • Documents could not readily be located due to file naming conventions that had been applied. • There were several examples of documents/data not being uploaded in a timely manner alongside evidence of the eTMF having been updated substantially just prior to the inspection.

CRITICAL sponsor findings - TMF

• The paper TMF was used as a document archive rather than a working TMF and trial team members did not have access to the paper TMF, but instead used an electronic “shadow TMF” during the trial. • Upon review, it was found that there were a large number of documents in the “shadow TMF” which were not filed in the paper TMF. • There were a number of essential documents for a trial retained by vendors which were not defined in the TMF plan or TMF index. • Lack of effective oversight QC of e-TMF by sponsor.

CRITICAL sponsor findings – TMF SOPs

• The Standard Operating Procedures (SOPs) that were supposed to detail the eTMF best practices for quality management did not define the TMF and how it should contain all trial essential documents. It also did not define all the different systems that make up the TMF. • No clear policy and process to ensure the accurate completeness of the TMF contemporaneously.

• Is it possible for a sponsor to issue a protocol waiver in response to an investigator seeking to modify trial entry criteria to make it easier to recruit trial participants?

CRITICAL sponsor findings – Protocol Compliance

• The trial had not been conducted in accordance with the approved protocol as deliberate protocol waivers had been implemented and a process existed where waivers to eligibility criteria could be granted by the sponsor.

• Is it possible for a sponsor to undertake an interim analysis of data mid-way through a clinical trial for business decision purposes?

27 CRITICAL sponsor findings – Data Integrity Control

• The organisation permitted unplanned reviews of unblinded clinical trial data (in double blind trials) for business decision purposes. • Had a significant potential to introduce bias into the trial, impacting data integrity. • There were several examples where management had requested unblinded data to be provided to them for double blind clinical trials. • This request and review was outside of any agreed interim/preliminary analysis described in the protocol, prior to formal completion of the trial.

These unplanned reviews of unblinded data were interim analyses, as in most cases the intention was to compare treatment arms with respect to efficacy and safety prior to formal completion of the trial to make internal decision regarding the future of development programmes, resource and planning.

28 CRITICAL sponsor findings – Data Integrity Control

• For some trials, the unblinded data was reviewed before the Statistical Analysis Plan (SAP) was finalised. • There was a lack of adequate rationale and review of the potential consequences considered and documented for unblinding for unplanned interim analysis. • Senior management within the organisation were able to authorise their own requests to unblinded data.

29 CRITICAL sponsor findings – Data Integrity Control

• There was a lack of contemporaneous documentation of the actions taken following accidental unblinding within the trial to demonstrate how any potential bias was minimised. • There was no process for ensuring that any inadvertent unblinding or unplanned unblinding was transparently documented in the Clinical Study Report (CSR).

Remote or Office-Based Inspections

• We have 5 poll questions for you.

• The start of lockdown this time last year meant a complete change to the way of working for the inspectorates worldwide. • MHRA have shared their experience in a recent blog. • https://mhrainspectorate. blog.gov.uk/2021/03/26/i nspectors-grounded-a- year-of-innovation/

MHRA remote inspections

• Since the start of lockdown MHRA has carried out over 750 inspections conducted remotely across the Good Practice Standards (GxPs). • The MHRA inspectorate has maintained an international perspective on our remote inspections, sharing our experiences through the International Coalition of Medicines Regulatory Authorities (ICMRA) and Pharmaceutical Inspection Co- operation Scheme (PIC/S), including training other regulators in our approaches.

Some changes will continue post-pandemic

• ‘Day 1’ of the inspection involved remote data review and accessing electronic systems - most of our inspections were on site̶ This happened beforehand. • The changing ways of working will continue post-pandemic, including ̶ desk-top assessments for low risk organisations̶ amending the way MHRA operate their Inspection Action Group for critical findings to ensure that inspectors are not in a cycle of re-inspecting sites that are not yet in compliance.

Methods

• Within the first month of lockdown, remote inspections were taking place in all areas. • A variety of file-share platforms have been used, including those already established in the companies inspected, as well as FileShare and, more recently, Teams Channels. • Teams channels can now be set up for every inspection and allows sharing of large data files, as well as providing a space for inspectors to discuss inspections with the companies, replicating the inspection team being ‘in the room’ together as far as possible.

The future

• One of the unexpected outcomes of remote inspections, is that they actually take longer to perform than the on-site model due to the limitations (even with technology) of not having that real time presence of questions raised and answered or being able to ‘dig around’ to see what the compliance level of a facility is really like. • The consensus view across global regulators is that working remotely is a great ‘tool’ in our inspection toolkit, but will never replace what can be achieved in person – and there are many areas that are just not suitable for remote approaches. • MHRA inspectors will continue to innovate, incorporating ‘visual technologies’ into their toolbox̶

“which will enable us to have some level of ‘eyes on site’ for those areas where it is critical to see the facility or clinic where the work takes place”.

MHRA GCP Inspections: Expectations and the dos and don’ts for hosting 10Mar2020

MHRA: Electronic System Access by Inspectors 10March2020 • Direct access will be required to all systems that make up your TMF and potentially any key clinical trial support systems for example if your SOPs, procedural documents and training records are held in a QMS eSystem, access will be required. • Inspectors should be provided with the means to access and review all of the relevant systems , • Computerised System Validation (CSV) we'll also need access to systems that manage that system, for example, helpdesk systems . • Access to electronic systems should be read-only, but should not be otherwise limited, • Access to audit trails which we will want to see. Audit trails may also be requested to be extracted.

MHRA: Electronic System, Inspection access - Do’s 10March2020 • DO : Ensure this is all set-up well in advance, • DO : Ensure as a company you know all the systems that make up your TMF and ensure you can give Inspectors direct access . Discuss this with your Lead Inspector up front to ensure access is provided as expected. • DO : Aid electronic system access:- links on desktop; short crib sheet; ensure lock-out times are reasonable; minimise need for numerous passwords where possible; etc.. • DO : Inspectors are happy to have training in electronic systems new to them, however, do make sure the training is efficient and useful in ensuring competence in using the system, for example a system demonstration is much more useful than presenting slides

Hosting Remote Inspections?

• Need for extensive input from IT & support services for prolonged periods of time both pre, during and post inspection. • Need for several virtual “Inspection Management Rooms” for Sponsor/CRO/Vendor with multiple work parties, (preferably 24/7 availability if Global reach). • Arrange remote training (if requested) for Inspectors on all systems they will access. • Do your SOPs allow for this training? – do the SOPs need amending?

Hosting Remote Inspections?

• Access arrangements for multiple Inspectors, at multiple times. • Read Only access for Inspectors ̶ they may test this! • Arrange for Audit Trails (of all systems) to be available for Inspection remotely. • Rescind access after Inspection ̶ Again they may test this! ̶

Beware that Inspectors may require access after inspection …̶ discuss with Lead Inspector & how to control.

• Consider if various systems Audit Trails can adequately track Inspectors access to various systems/files.

Potential Issues for Inspection Hosts:- Direct Access to all Sponsor systems during Remote Inspections

• Ensuring reliable access & support from IT at all times. • Increase personnel resources compared to on-site inspection • Possibility of Inspectors having wide access to systems across all Sponsor/Vendor platforms, including SOP system holding SOP exceptions (waivers) & deviations. ̶ Consider what access your systems allocate & control. • Consider possible Inspection Scope Expansion̶ Inspection of certain (pre-defined) clinical trials may have been requested in the Inspection Plan, but if total access (to all systems) is available, there could be inspection of other trials or other development programs.̶ This may involve more Host resources/support to manage this expansion!

Potential Issues for Inspection Hosts:- Direct Access to all Sponsor systems during Remote Inspections

• Difficult to be adequately forewarned of current areas of interest of the Inspectors – everything is in play at all times. ̶ A live systems audit trail tracking of inspectors’ access, might be helpful. • Challenge of assisting Inspectors with timely & appropriate information & resource̶

compared to an on-site inspection, where Host will know what is being reviewed by Inspectors and questions they are asking (i.e. their areas of interest).

• Consider risk of possible Regulatory Spread – other sections of the Inspectorate (GXPs) or other related Agencies (e.g. data protection) could possibly become informed.

Some Features of a recent UK Remote GCP Inspection, during COVID-19 emergency

• Inspection lasted about one month, rather than about 1 week. • Inspectee had 5 days notice to provide pre-inspection requested e-Documents. • 4 GCP Inspectors, each inspector separately inspects remotely for 5 days, sequentially. • Trial specific & safety (e.g. RSI) focus ̶ Not traditional full systems inspection. • CAPAs from previous systems inspections in-scope.

Some Features of a recent UK Remote GCP Inspection, during COVID-19 pandemic

• Either remote access to e-SOP system or (if remote access is not a feature), electronic copies of SOPs supplied. • Using e-Repositories for document provision. • Inspectors review e-TMF on their own ̶ and only contact Host if any questions. • Use of WebEx or MS Teams to interview. • Be prepared to provide information on COVID -19 mitigation measures.

Are you ready for the period post-pandemic?

What were the challenges?

• Protecting trial participants and site staff • Quarantines, travel limitations • Site closures • Those involved become infected • IMP supply chain limitations and interruptions • Difficulties meeting protocol requirements − Protocol violations/deviations • Lab testing difficulties • Ability to monitor and oversee study conduct

• Missing data, data integrity • Safety reporting deficiencies • Postponed audits • Remote inspections

• What impact has the pandemic had on your clinical trials?

• Have you done a risk (impact) assessment for each of your trials?

You should have done a risk assessment for each trial • Consider the impact on each of your trials̶ prioritise critical tasks for each trial • Look at the existing risk assessments and build in relevant changes • Focus on:̶ human subject protection̶ data integrity • When the two conflict human subject protection comes first • Regularly review and re-assess the risks • Document everything ̶ because this will be needed post-pandemic!

Specific risk considerations may include …

Data integrity • Oversight maintenance • Remote data capture • Move to centralized monitoring • Missing data • Source data verification • Monitoring plan for now and later • Amendment of data management plans • Statistical analysis plans • What is and is not related to COVID-19?

Human subject protection • Continuation or discontinuation of IMP or trial • Visits to investigator site • Contact with ‘people’ • Safety of IMP if not monitored • Self medication • Procedures to obtain and deal with safety data • Additional safety monitoring if IMP is withdrawn • Engage with IRB/IEC as soon as possible (if possible)

Did you need to make SOP changes?

Did you make SOP changes?

• Changes to working practices – home based, virtual meetings. • Impact on study conduct̶ the informed consent process̶ study visits and procedures, study monitoring̶ adverse event reporting̶ changes in investigator(s), site staff, and/or monitor(s) secondary to travel restrictions, quarantine measures, or COVID-19 illness itself. • Maintaining oversight. • Data collection and maintaining data integrity. • Lack of audit/inspection – more responsibility to get it right and have a quality culture. • Procedures for getting SOPs changes and other documents signed off.

How did you reduce risks to trial participants?

Risks to trial participants

• Stopping visits to trial site may affect participant safety • Concomitant medications that may be needed to combat illness • Trial patients taking immuno-suppressants, ‘at risk patients’ • Distribution of IMP/treatments to patients at home • Oversight and supervision of trial participants • Help and advice provision

Did you revise and keep to your monitoring plan?

• The sponsor should consider the extent and nature of monitoring necessary for each trial.̶ What must be done now, what can be done later?̶ Cancelling of on-site monitoring visits and extending of the period between monitoring visit̶

Implementing phone and video visits (without unnecessarily increased burden to the investigator site and taking into account trial participant integrity) ̶ Increased centralised monitoring and central review of data if possible and meaningful̶ Remote SDV is exceptional cases.

Do you have a post-pandemic plan?

Post-pandemic measures planning

• It is essential that robust follow-up measures are planned and ready to be implemented when the situation is normalised. • This should include increased on-site monitoring for a period that is sufficient to ensure that the impact of the reduced monitoring can be rectified, and problems resolved or properly documented. • Data subject to remote source data verification are likely to require re-monitoring̶ in particular if it was based on pseudonymised documents, which cannot be considered as source documents, ̶ remote monitoring is expected to only have focused on the most critical information

Documented post-pandemic plan

• Some countries and regions will return to normality before others. • A plan is therefore required for each centre within a country, together with an overall plan. • This should be based on a risk assessment and critical to quality factors identified.

What does being ready for the post-pandemic period mean? • Know what options are available to you now ̶ Take into account regulatory guidance • Know what you have done in every trial̶ And be able to justify it • Document every decision̶ You will need to be able to show inspectors maybe years down the line • Know what you have been unable to do during the pandemic̶ Make sure it is documented

What does being ready for the post-pandemic period mean? • Know what is pandemic related and what is not!̶ Inspectors will not like using the pandemic as an excuse for poor practice

How E8(R1) will affect trial conduct and influence changes to E6

E8 key aspects linking to E6

• Principles • Quality • Quality by design • Designing quality into clinical trials • Critical to Quality Factors • Risk proportionate approach • Involvement of wide range of stakeholders in clinical trial design • Examples of critical to quality factors

Note terminology difference E8 – clinical “studies” - was “trials” in previous 1997 version. E6 – always clinical “trials”

E8 (R1) Draft Step 2b - General Principles

• Protection of Clinical Trial Subjects • Scientific Approach in Clinical Study Design, Conduct, and Analysis • Patient Input into Study Design

How do you think patients could be involved in clinical trial design? • Input on what really matters to patients • The length of a study • Selection of the study population • Selection of meaningful assessment criteria

ICH E8 R2 Draft and influence on ICH E6(R3): Expect to require Patient Input into Trial Design

Consulting with patients and/or patient organisations in the design, planning and conduct of clinical trials to help ensure that all perspectives are captured. Patients’ views could be requested on all phases of drug development.

See Draft E8(R1) 2.3

E8 (R1) Draft: Patient Input into Trial Design

• Involving patients at the early stage of trial design is likely to increase trust in the study, facilitate recruitment, and promote adherence, which should continue throughout the duration of the study. • Patient input also helps to − provide their perspective of living with a condition, which contributes to the determination of endpoints that are meaningful to patients, − select the right population

− consider the duration of the trial − select use of the right comparators. • This ultimately supports the development of medicines that are better tailored to patients’ needs.

See E8(R1) 2.3

ICH Reflection paper : Proposed ICH Guideline to Advance Patient Focused Drug Development

• Proposal endorsed 18 Nov 2020 • Out for consultation 07 Mar 2021 • New ICH guideline addressing what to measure in a clinical trial, including refining the set (list) of important impacts and concepts from patients, to select, modify or develop clinical outcome assessments (COAs) • New ICH guideline addressing methods for elicitation/ collection, analysis, reporting and application of qualitative or quantitative assessments

EU Clinical Trial Regulation 536/2014

“Involvement of patients or patient’s organisations”. Whereas 18; Article 2.2.11; Annex I 17.e

UK MHRA … applicant company will be asked for evidence on the patient involvement. Blog 23Mar2021

• When new applications for selected medicines (new active substances and new indications) are received, the applicant company will be asked for evidence on the patient involvement • Additional information won’t be requested now • MHRA will be documenting in medical assessment reports if there is evidence of patient involvement… • During the pilot, information provided by the applicants will be voluntary and will not alter the outcome of application. • In future, the agency hopes that a successful pilot will lead to patient involvement playing a greater role in the final assessment process, when clinical trials are approved,

ICH E8(R1) Draft: Considerations in Identifying Critical to Quality Factors

• Engagement of all relevant stakeholders • The prerequisite non-clinical studies, and where applicable, clinical studies, are complete and adequate to support the study being designed. • The study objectives address relevant scientific questions • The clinical study design supports a meaningful comparison of the effects of the drug when compared to the chosen internal or external control groups. • Adequate measures are used to protect subjects’ rights, safety, and welfare • A feasibility assessment is conducted to ensure the study is operationally viable. • The number of subjects included, the duration of the study, and the frequency of study visits are sufficient to support the study objective.

See E8(R1) section 7

E8(R1) Draft: Considerations in Identifying Critical to Quality Factors

• The eligibility criteria should be reflective of the study objectives and be well documented in the clinical study protocol. • Information about study subjects that may be important to understanding the benefit/risk of the drug (e.g., age, weight, sex, co-morbidities, concomitant therapies) is specified in the protocol, captured and incorporated in the design, conduct, and analysis, as appropriate.

• The choice of response variables and the methods to assess them are well-defined and support evaluation of the effects of the drug.

See E8(R1) section 7

E8(R1) Draft: Considerations in Identifying Critical to Quality Factors • Clinical study procedures include adequate measures to minimise bias (e.g., randomisation, blinding). • The statistical analysis plan is pre-specified and defines the analysis methods appropriate for the endpoints and the populations of interest. • Systems and processes are in place to ensure the integrity of critical study data. • The extent and nature of study monitoring are tailored to the specific study design and objectives and the need to ensure subject safety. • The need for a data monitoring committee is assessed.

See E8(R1) section 7

Impact on E6(R3): Expect to have to identify Critical to Quality Factors • CQFs are basic set of factors relevant to ensuring study quality identified for each study. • Emphasis on factors that stand out as critical to study quality. • These quality factors are considered to be critical because, if their integrity were to be undermined by errors of design or conduct, the reliability or ethics of decision-making would also be undermined.

What are CQFs? Attributes of a study whose integrity is fundamental to the protection of study subjects, the reliability and interpretability of the study results, and the decisions made based on the study results.

See E8(R1) 3.2

E8(R1): Risk Assessment

• Having identified the factors relevant to ensuring study quality • Determine the risks that threaten their integrity, the probability and impact of those risks and decide if they should be accepted or mitigated • If risks are to be mitigated − Necessary control processes should be put in place and communicated − Necessary action taken to mitigate those risks

3.2

E8(R1): Quality by Design

• Quality should rely on good design and its execution rather than overreliance on retrospective document checking, monitoring, auditing or inspection. • These activities are an important part of a quality assurance process but are not sufficient to ensure quality of a clinical study.

3.1

ICH GCP E6 renovation: the process, progress & what we can expect.

ICH website as a source of products and updates

Changes to ICH GCP E6: information sources https://www.ema.europa.eu/en/events/ich ‐ e6r3 ‐ good ‐ clinical ‐ practice ‐ workshop ‐ patients ‐ consumers ‐ pcwp ‐ healthcare ‐ professionals ‐ hcpwp

Changes to ICH GCP E6: information sources

https://www.ema.europa.eu/en/documents/presentatio n/presentation ‐ 12 ‐ introduction ‐ ich ‐ e6r3 ‐ stakeholder ‐ engagement ‐ plan ‐ l ‐ bregnhoj ‐ f ‐ sweeney_en.pdf

June 2020

Changes to ICH GCP E6: information sources

Stakeholders unhappy!

• External Stakeholders’ Letter to EMA and ICH 31 Jan/26 Feb 2016 − Academic stakeholders in 22 countries − 5 organizations, 119 academic researches • Concerns − Need to improve focus on issues most critical for trial quality − One size fits all approach is not suitable for different types of trials − Academic stakeholders are not involved in the ICH processes • Outcome Academic stakeholder representatives invited to meet with Management Committee and ICH E6(R2) EWG representatives to discuss issues raised in their letter

Why change ICH GCP E6 guideline again?

• ICH E6(R2) was finalized in November 2016.

Already at that time it was recognised that the guideline was due for a larger revision.

• This led to the 2017 reflection paper describing the renovation of the efficacy (E) guidelines − ICH E8 (on the general consideration for clinical trials; focusing on the clinical trial design principles) − ICH E6 (on good clinical practice, focusing on the clinical trial conduct principles).

Why change ICH GCP E6 guideline again?

• Since then clinical trials have continued to evolve with new designs and technological innovations. • There is a desire that E6(R3) should be developed to provide guidance − that is applicable to different clinical trial designs − to focus on key principles and objectives. • E6(R2) included a focus on a proportionate, risk-based approach to the design and conduct of clinical trials. • E6(R3) will be designed to further advance this concept and to encourage relevant parties to utilize this approach. One size fits all approach is not suitable for different types of trials

E6(R3) Concept Paper …

• “The action proposed is a full rewrite and reorganization of the ICH E6(R2) Guideline Good Clinical Practice (GCP)”. • “E6(R2) is not fully designed to address emerging technologies, innovations in trial design, the diversity of data sources, testing facilities, and service providers, or to address other emerging complexities of the current clinical trial climate.” • The application of the current standard to new technology is clearly challenging.

• Stakeholders may fail to take full advantage of technological innovations and the full potential of the risk-based considerations related to participant protection, data integrity or other public health considerations.

Overview of E6(R3) Revision - Approach

• A rewrite and reorganization of ICH-E6(R2) − Principles document and Annexes − Align with ICH-E8 as appropriate − Bridge identified gaps within E6 and between E6 and relevant ICH guidances • Clear and concise scope − Expectations should be fit for purpose • Focus on key concepts − Quality by design and Risk-based approach − Proportionality − Critical to quality factors − Other…

Overarching Principles and Annex 1 to replace E6(R2), followed by a second Annex

Overarching principles and objectives applicable to all trials

Annex 2 Non-traditional Interventional Clinical Trials

Annex 1 Interventional Clinical Trials

Will be developed after other two parts

Being developed in parallel

Developments in trial design

• Pragmatic trials − e.g. testing efficacy in a broad routine clinical practice in everyday settings • Adaptive designs − e.g. multiple, pre-specified, investigational therapies can be compared to identify subgroups who respond best to them • Real world studies − e.g. observational data

• Refining the sample size • Abandoning treatments or doses • Changing the allocation ratio of patients to trial arms • Identifying patients most likely to benefit and focusing recruitment efforts on them • Stopping the whole trial at an early stage for success or lack of efficacy.

Developments in technology

• Computerized systems • Remote consent • Telemedical monitoring - #stayathome

COVID-19 has been a further catalyst for change

Latest news from MHRA STEM 15 March 2021

• ICH E6 currently undergoing extensive review (R3) • Estimated ready for endorsement/public consultation by Dec 2021 and full adoption November 2022. • Will include major revisions to − data governance, − monitoring − more on proportionality, − emphasis on reliability of trial results, rather than the accuracy of every single data point, − involvement of subjects in trial design and electronic systems. • (2 Members of MHRA are on ICH EWG as representatives of PIC/S Pharmaceutical Inspection Co ‐ operation Scheme)

When might E8 R1 & E6 R3 be completed (Step 4)?

• E8 R1 - ICH Workplan (23 Sep 2020) - Step 4 planned for Feb 2021 (?) - Sometime 2021? • E6 R3 - ICH Workplan (09 Sep 2020) – R3 Core and Annex I - Nov 2022. MHRA STEM (March 2021):- E6 R3 Consultation Dec 2021, Step 4 by Nov 2022

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