Advisor 465

ISSN 2041-3661

2 0 J U LY 2 0 2 0

FDA revokes emergency authorisation for coronavirus antibody test Since the beginning of the COVID-19 pandemic, the FDA has been obliged to balance the urgent need for access to diagnostic and antibody tests with a level of oversight that helps to ensure accurate tests are being deployed. The FDA is permitted to provide Emergency Use Authorization for products to prevent or treat conditions caused by emerging infectious threats. The agency must also continue to review emerging data and act if the known and potential benefits of the product no longer outweigh its known and potential risks. Approval for an antibody test was revoked on 14 June due to the high number of false test results. See page 5 u ICMRA stresses the value of safe and effective COVID-19 vaccines For several months, the International Coalition of Medicines Regulatory Authorities (ICMRA) has been helping to coordinate the eforts of regulatory agencies around the globe as they tackle the continuing COVID-19 pandemic. In addition to bi-weekly meetings where key topics are discussed and policies aligned, on 17 June 2020 ICMRA issued statements for patients and healthcare professionals to highlight the benefits and safety of vaccines, and their importance in preventing and controlling infectious diseases. The statements explain the robust scientific and independent processes that medicines regulators follow, and emphasise the importance of vaccinations for individuals and communities. More on page 6 u EMA publishes ‘Points to Consider’ on methodological aspects of ongoing trials On 26 June 2020, the European Medicines Agency (EMA) published an adopted guidance document entitled ‘Points to consider on implications of Coronavirus disease (COVID-19) on methodological aspects of ongoing clinical trials’. The document was drafted by the Biostatistics Working Party and looks at the implications for data management, as well as statistical considerations for ongoing clinical trials affected by the pandemic. The document will be reviewed in a future issue of Advisor . Source:

UK’s MHRA publishes latest GCP inspections metrics The UK’s Medicines and Healthcare inspections during the 12 months to 31 March 2018, and in May 2020 issued its annual metrics report for the period. The majority of MHRA GCP inspections are carried out under the risk-based compliance programme and are either systems- based or trial-specific. The number of inspections in the most recent reporting period was lower across all inspection types except those of non- commercial organisations, where there was a 50% increase compared with the previous 12-month period. Learn more on page 3 u products Regulatory Agency (MHRA) performed 88 GCP FDA provides guidance on statistical considerations for COVID-19 trial modifications The FDA has released new guidance on statistical considerations for clinical trials afected by the COVID-19 pandemic, in an efort to ensure data integrity. The short guidance document was issued on 16 June. It focuses on statistical issues arising from the need to modify the conduct of trials during the COVID-19 pandemic. A short summary of the guidance can be found on page 7 u

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STOP PRESS – global news

Free scientific advice to academia developing medicines for rare diseases On 23 June 2020, the European Medicines Agency announced a waiver of fees for scientific advice for academia developing orphan medicines. The academic sector plays an important role in the development of innovative medicines and scientific methods, with the potential to benefit patients with rare diseases. Early interaction with EU regulators is important for academia, to help them navigate the regulatory process and to ensure robust evidence is generated to establish a medicine’s benefits and risks. Ultimately, it helps the academic sector to translate its discoveries into authorised patient-focused medicines. However, the fees for protocol assistance can be prohibitive. Source: Global regulators discuss data requirements for Phase 3 trials of COVID-19 vaccines On 22 June 2020, international regulators from 28 regulatory authorities and the World Health Organization discussed COVID-19 vaccine development and the evidence needed for regulatory decision making, at the second regulatory workshop on COVID-19 vaccines. The rapid authorisation of COVID-19 vaccines requires robust and sound scientific evidence on quality, safety and efficacy. It was agreed that international regulatory convergence, where possible, on certain key aspects of Phase 3 trial design will help developers to generate robust evidence on the quality, safety and efficacy of potential COVID-19 vaccines that meets the needs of regulators around the globe. Topics discussed included eligibility criteria for the inclusion of diverse populations, primary endpoints and other methodological considerations related to Phase 3 trial design. Source:

Global discussion on new priorities to strengthen medicines collaboration Representatives from the European Commission, the European Medicines Agency and the FDA held their 2020 bilateral regulatory dialogue meeting on 18 and 19 June. During the virtual meeting, the authorities reviewed ongoing joint initiatives, discussed strategic priorities for the coming years and identified areas where their current close collaboration can be further strengthened. Topics discussed included • sharing experience and common challenges relating to COVID-19 vaccines • cooperation on bespoke therapies for ultrarare diseases • using real-world evidence to support regulatory decisions • the mutual recognition agreement on Good NIH platform to harness COVID-19 patient data to speed treatments Researchers in many countries are battling to find treatments and vaccines for COVID-19. The US National Institutes of Health (NIH) has launched the National COVID Cohort Collaborative (N3C), a new initiative that aims to build a centralised national data resource – the NCATS N3C Data Enclave – that the research community can use to study COVID-19, and identify potential treatments as the pandemic continues to evolve. N3C will enable the rapid collection and analysis of clinical, laboratory and diagnostic data from organisations nationwide. It will harmonise the aggregated information into a standard format and then make it rapidly available to researchers and healthcare providers to help accelerate COVID-19 research and provide information that may improve clinical care. Source: Manufacturing Practice inspections • orphan and paediatric medicines. Source:

CBER updates list of guidance documents expected in 2020 The FDA’s Center for Biologics Evaluation and Research (CBER) – the division that regulates biological products for human use – has updated the annual list of guidance documents that it expects to deliver in 2020. The list indicates which guidance documents have already been delivered; although not stated explicitly, the various documents related to COVID-19 may be the reason for the update. Source:

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STOP PRESS – global news continued

MHRA publishes latest GCP inspections metrics In May 2020, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) issued its annual GCP inspections metrics report for the 12-month period from 1 April 2017 to 31 March 2018. FDA acknowledges the importance of collaboration Anna Abram and Mark Abdoo – both senior FDA personnel – have co-authored an interesting FDA Voice article published on 25 June 2020. They explain their views on the importance of collaboration between regulatory agencies, and focus on the FDA’s interactions with the European Commission and the European Medicines Agency over the past decade. The article – which highlights how history has paved the way for numerous critical collaborations on many scientific and regulatory fronts as part of the FDA’s response to COVID-19 – is a useful read for anyone interested in how and why international agencies partner together. Source:

In future issues of Advisor we will review the agency’s findings for inspections of sponsors and investigator sites. Below we provide a general overview, and look in more detail at the findings for inspections of contract research organisations (CROs). Overview During the latest 12-month metrics period, the MHRA GCP Inspectorate performed 88 GCP inspections, comprising • investigator sites (17) • UK laboratory facilities conducting clinical trial sample analysis (13) • commercial sponsors (12) • non-commercial organisations (12) • Phase I units (9) • CROs (9) • bioequivalence inspections performed outside the UK (6) • inspections requested by the European Medicines Agency (EMA) (9) • a CRO inspection performed outside the UK (1). The total number of inspections is approximately 10% lower than in the previous 12-month period (99), with only the number of inspections of non- commercial organisations showing an increase. There were 11 triggered inspections compared with 26 in the previous 12 months. Triggered inspections

are usually performed as a result of information received by the GCP Inspectorate (eg. in response to a serious breach report or in relation to a centralised marketing authorisation application). In this period, they were described as follows: • two UK inspections of non-commercial sponsors • six non-UK bioequivalence inspections • three EMA-requested inspections. The latest report (released on 11 May 2020) relates only to inspections performed by the MHRA in the UK, and includes those that were both carried out and completed in the 12-month metrics period. Metrics from inspections requested by the EMA are produced by the EMA, and findings from inspections of GCP laboratories and UK-triggered bioequivalence inspections are reported by the GCP/Good Laboratory Practice Inspectorate. Across all key sectors (sponsor, CRO and investigator), the MHRA classifies inspection findings according to the same 42 categories. For sponsors and CROs, key areas leading to notable findings were pharmacovigilance, data integrity and essential documents/record keeping. There were no critical findings reported from CRO inspections and generally fewer findings overall for CROs compared with the previous 12 months. One sponsor had particular difficulty in meeting the pharmacovigilance requirements (as laid out in

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separate regulations) for a product that combined a drug and a device. Investigator inspections resulted in relatively few findings overall, but an increasing focus on non-commercial sponsors is evident both from the number of inspections performed and the fact that the MHRA runs a dedicated GCP symposium day for non-commercial sponsors. CRO inspection findings Although only nine CROs (including vendors of electronic systems and niche providers of services used in clinical trials) in the UK were inspected by the MHRA in the 2017–2018 period, the metrics report includes data for 10 inspected CROs. The anomaly is the inclusion of one of the 16 non-UK inspections. This inspection was of a provider of eSystems for clinical trials, where the organisation opted to host the inspection outside the UK even though it was part of the UK risk-based domestic inspection programme. Although counted as a non- UK inspection, within the inspection report it is included in the CRO metrics. All 10 were systems

inspections and none were triggered inspections. Across the 10 inspections there were no critical findings; eight (80%) inspections had at least one major finding. Although again based on a relatively low number of inspections, these findings are favourable compared with the previous 12-month period, where there were two (25%) critical and seven (87.5%) major findings in eight CRO inspections. The total number of findings and the number of findings per inspection are shown in Table 1. Overall, inspection findings for CROs covered 22 of the 42 possible categories of inspection finding. The distribution of major inspection findings from CRO inspections is summarised in Table 2. The 28 major inspection findings fell into just 11 diferent categories. However, more than 60% were in just four categories: record keeping/ essential documents, data integrity control processes, computer systems validation and monitoring. The improvement in CRO inspection findings may indicate better sponsor–CRO trial oversight and supervision. Source:

Table 1 . CRO inspection findings (1 April 2017 to 31 March 2018).

Number of inspection findings

Mean number of findings/ inspection

Maximum number of inspection findings

Critical Major Other

0 28 58

0 2.8 5.8

0 6 9

Not applicable

Total

86

8.6

Table 2 . Categorisation of major CRO inspection findings (1 April 2017 to 31 March 2018).

Major findings as a percentage of all major inspection findings a

Category

Record keeping/essential document s Data integrity control processes Computer systems validation Monitoring Project/trial management Quality assurance Quality systems Contracts and agreements Pharmacovigilance Organisation’s oversight of a clinical trial Data integrity

21.5 14.5 14.5 10.5

7 7 7 7 4 4 4

a Percentages are approximate and reflect the bar charts in the metrics report.

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FDA revokes emergency authorisation for coronavirus antibody test

On 14 June 2020 the FDA revoked the Emergency Use Authorization (EUA) for one of the first antibody tests for coronavirus, due to performance concerns with the test’s accuracy.

In the USA, legislation permits the FDA to use EUA for medical countermeasures needed during public health emergencies. The FDA Commissioner may thus allow the use of unapproved medical products or unapproved uses of approved medical products in an emergency, to diagnose, treat or prevent serious or life- threatening diseases or conditions caused by chemical, biological, radiological nuclear or emerging infectious disease threats when there are no adequate approved and available alternatives. Chembio test Antibody tests (types of serological tests) can help to provide information on a person’s and population’s exposure to COVID-19. On 14 April 2020, Chembio Diagnostic Systems’ (Chembio’s) DPP COVID-19 IgM/IgG System – a SARS-CoV-2 antibody test – became one of the first antibody tests authorised by the FDA in response to the pandemic. At the time of the authorisation, based on the information that Chembio submitted to the FDA, the agency concluded that the test met the statute’s “may be efective” standard for EUA, and that the test’s known and potential benefits outweighed its known and potential risks. However, as the FDA learned more about the capability for performance of SARS-CoV-2 serology tests, and about the level of performance needed to allow users to make well-informed decisions – through both the continued review and authorisation of serology tests as well as through a research partnership with the National Institutes of Health’s National Cancer Institute (NCI) – the FDA developed general performance expectations for these tests.

Data submitted by Chembio, as well as an independent evaluation of the Chembio test at the NCI, showed that the test generates a higher than expected rate of false results, which is also higher than the rate reflected in the authorised labelling for the device. In the context of the current pandemic, the FDA considers that it is not reasonable to believe that the test may be efective in detecting antibodies against SARS-CoV-2, or that the known and potential benefits of the test still outweigh its known and potential risks, including the high rate of false results. In view of these considerations and the risk to public health from false test results, the FDA concluded that it was appropriate to revoke the EUA, and as a result the test may no longer be distributed. Speaking as the revocation was announced, Jef Shuren (Director of the FDA’s Center for Devices and Radiological Health) said, “By continuing to monitor authorized tests and emerging scientific evidence, we are able to make changes when appropriate – including taking action when a test’s benefits no longer outweigh its risks. Through these eforts, we are able to help assure that FDA-authorized tests meet the needs of the American public.” Source: ; a copy of the revocation letter issued on 14 June 2020, which reviews the performance data in more detail, is available at . Don’t miss out on the latest news and bulletins between issues. Follow us on Twitter @gcpadvisor

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ICMRA stresses the value of safe and effective COVID-19 vaccines Efforts are being made by the International Coalition of Medicines Regulatory Authorities (ICMRA) to improve the public understanding of and confidence in vaccines. ICMRA held its fifth virtual meeting of regulators

of COVID-19 clinical trials that might produce conclusive evidence on the efects of potential treatments and vaccines against COVID-19 – provided that the safety of trial participants is ensured – was stressed. Members reiterated that the research community should pool resources into large, well-designed, randomised clinical trials to determine which investigational or repurposed medicines would be safe and efective for the treatment or prevention of COVID-19. Master protocols Participants discussed the use of COVID-19 clinical trial master protocols around the world to accelerate the development and approval of potential treatments and vaccines. ICMRA members are currently working on a list of ongoing and planned COVID-19 clinical trials with master protocols in diferent countries and regions, in order to compare the protocols and identify possible overlaps (eg. objectives and types of investigational agents studied). Regulators aim to update this list on a regular basis. ICMRA Working Group The ICMRA Working Group on COVID-19 provided meeting participants with an update on its activities related to clinical trials, potential

from around the world on 12 June 2020 and discussed high-level policy issues and regulatory approaches to ensuring a coordinated response to the ongoing COVID-19 pandemic. ICMRA is a voluntary grouping of 29 medicines regulatory authorities from around the world, set up to provide strategic coordination, advocacy and leadership. It acts as a forum to support international cooperation among medicines regulatory authorities. On 28 April 2020, ICMRA members committed to strengthening global collaborative eforts in order to facilitate the rapid development, approval and global roll-out of safe and efective medicines to prevent and treat COVID-19. In this role, ICMRA is holding bi-weekly meetings to allow medicines regulatory authorities worldwide to discuss COVID- 19-related policy approaches and regulatory flexibility, aiming not only to expedite COVID-19 medicines and vaccines development and approval but also to prevent medicines shortages. Their virtual bi-weekly meetings commenced in April 2020 and the most recent took place on 12 June 2020. Clinical trials Meeting participants discussed the progress made on the development of ICMRA guiding principles for COVID-19 clinical trials and the prioritisation of compounds. They agreed that a clear distinction between exploratory clinical trials and confirmatory studies with investigational or repurposed medicines for the treatment of COVID-19 is critical for clinical trial prioritisation. Regulators shared concerns about the discontinuation of clinical trials globally and the growing number of underpowered studies that might not generate the robust data required for regulatory decision making. The need for the continuation

therapeutics and vaccines. Topics under discussion include ethical questions around human challenge trials and post-approval requirements for COVID-19 vaccines.

Improving vaccine confidence On 17 June, ICMRA issued two statements about the importance, safety and efectiveness of vaccines. International regulators from around the world have come together and jointly developed these page 7 u

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u page 6 statements – one for healthcare professionals and one for the general public – to give assurance that the regulatory processes for the authorisation and safety monitoring of vaccines are robust, independent and focus firmly on public health. In recent years, vaccination coverage has dropped to sometimes dangerously low levels in some countries, which increases the risk of the disease spreading and afecting the unvaccinated. The ICMRA statements reiterate that it is everyone’s responsibility to get vaccinated in order to protect not only themselves but also their friends, communities, vulnerable populations who cannot get immunised and generations to come. The statement aimed at the general public highlights the value of vaccines in the context of the current pandemic and addresses a range of topics,

including the following: • vaccines save lives • getting vaccinated is an act of responsibility • vaccines undergo rigorous scientific evaluation by regulatory authorities • vaccines have continuously proven pharmaceutical quality • assuring vaccine safety is an extremely important part of their regulation • each vaccine lot is individually tested by the national control laboratory • regulators and health authorities continue to rigorously monitor the safety, efectiveness and quality of vaccines that have been approved and released for use. Source: , ,

FDA provides guidance on statistical considerations for COVID-19 trial modifications As part of its ongoing efforts to limit the impact of the COVID-19 pandemic on clinical trial conduct, the FDA has issued new guidance entitled ‘Statistical Considerations for Clinical Trials During the COVID-19 Public Health Emergency’.

The short guidance document (issued on 16 June 2020) acknowledges the significant impact of the COVID-19 pandemic on the way in which trials have been performed. The need for social distancing, travel restrictions and site closures, etc, have meant that some studies have been halted or discontinued, while others have been able to continue after implementing modifications made possible by recent regulatory changes. The FDA is conscious that there will be an inevitable delay in certain potential new medications reaching the market. The new guidance therefore outlines considerations for the statistical analysis of primary and key secondary endpoints in a trial afected by COVID-19, to help ensure that the trial will provide interpretable findings with correct statistical quantification of uncertainty.

The policy is only intended to remain in efect for the duration of the COVID-19 public health emergency. Trial integrity To ensure trial integrity, the guidance outlines three requirements when considering trial modifications in response to COVID-19. • Plan for participant safety . Sponsors should proactively plan to address the impact of COVID-19 on the ability to meet the trial objectives. Modifications to the primary or key secondary endpoints would usually require a protocol amendment, and any changes should be reflected in an updated statistical analysis plan before the database is locked and before any modifications to unblinded interim analyses. page 9 u

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• Avoid introducing bias . Sponsors should not propose trial modifications based on data that may bias the interpretation of findings. Generally, for a blinded trial, modifications based on information that reveals the magnitude of the treatment efect or information presented by treatment arm have the potential to introduce bias, eg. stopping a trial before its planned duration based on knowledge of a treatment diference between arms from a previous interim analysis. Safeguards, such as a Data Monitoring Committee, may be introduced to safeguard data integrity and the guidance has several scenarios in which these principles are applied in the context of COVID-19. • Select appropriate participant data . When making trial modifications to address the impact of COVID-19, sponsors should focus on summaries of participant-specific data, such as missing data, treatment discontinuation, treatment interruptions, trial withdrawal and endpoints. Non-participant- specific information, such as information on site closures and the disruption of the supply of investigational product, may also be appropriate to use when considering modifications to the trial. Trial mitigation and analysis To address the impact of COVID-19 on evaluating primary and key secondary trial endpoints, the FDA outlines several design and analysis strategies and notes that multiple strategies may be needed to address the impact of COVID-19 adequately. Source: Webinar recording now available Does your Trial Master File meet the key requirements? A series of self-checklist questions about the sponsor’s Trial Master File – both paper and electronic – as based on EMA TMF guidelines and inspection advice. For this and other webinar recordings visit the website and click ‘Webinars’ www.brookwood-global.com

Principal Author & Editor: Prof David Hutchinson Senior Contributor: Jane Baguley Production Editor/Writer: Sharon Jordan Senior Correspondents: Fabio Camarri, Mark Elsley, Hideki Fujiwara, Lisbeth Tofte Hemmingsen, Peter Marks, Stuart McCully, ColinWilsher Aim To provide news and information to allow clinical research and quality assurance professionals, trainers, regulators, academics and members of ethics committees to stay up to date with clinical research and good practice developments. Scope Executive summaries of key laws and guidelines relating to clinical research in the ICH regions. Summaries of relevant articles and information in other publications, press releases and information on the Internet. Information on: • changes in regulations, codes of practice, guidelines and new clinical research procedures • news from important meetings and conferences • ICH developments and progress • news, views and opinions about ICH GCP implementation • solutions to compliance-related problems • inspection findings and lessons to be learnt • clinical research methodology, statistical and legal issues • quality assurance issues and procedures • self- and independent audit practice • training courses, jobs and other opportunities. Sources of information • We gather news from correspondents and other sources around the world. • We gather intelligence from those actively involved in the regulatory process. • We review the major medical, clinical research and QA journals. • We search the web and regularly visit the websites of the major regulatory authorities in Europe, the USA and Japan, pharmaceutical industry and professional associations, major academic organisations and health associations. • Sources of information, current at the time of publication, are usually quoted at the end of each article. Published by: Brookwood Global (Canary Ltd), 5 Studley Court Mews, Chobham, Surrey GU24 8EB, UK Telephone: +44 1483 811383; Fax: +44 1483 812163 Email: info@brookwood-global.com; website © Canary Ltd 2020 All rights reserved. No part of this publication may be copied, transmitted, reproduced in any way without the written permission of the publisher. Disclaimer: Whilst we try to ensure that information published is correct, the Editors, Advisors or publishers accept no liability for losses or damages arising. You should always seek a second opinion before acting on any information provided.

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