REGULATORY PUBLIC DISCLOSURE (RPD) - April 2023

Medicines and Vaccines

ICH

Clinical Trials Transformation Initiative (CTTI) have published their report on the ICH M11 webinar from back in Jan 2023. If you missed the webinar, then this is a useful 4-page summary.

CTR and CTIS

1. On 19 April 2023, EMA is hosting a CTIS Walk-in Clinic at 16:00-17:00 CEST, which is an opportunity to ask real-time questions to CTIS experts. Upcoming CTIS Webinars: 17 May 2023 and 14 June 2023.

2. The PHUSE Data Transparency Working Group has published a blog post on EU CTR implementation. Check it out for a summary of Year 1 of the regulation from a sponsor perspective, with a focus on transparency aspects.

3. On 12 April 2023, EMA released an updated version (3.02) of the CTIS - Sponsor Handbook. This version includes newly added information about multi-factor authorisation in CTIS, as well as links to CTIS bitesize talks.

4. EMA has published a document with all official EU/EEA Member State public holidays for 2023 as recorded in CTIS.

5. Starting 24 April 2023, the regular maintenance windows in CTIS will be amended with the aim to limit downtime due to planned system interruptions. Users are advised to avoid using CTIS during the following times:

• Tuesday and Thursdays, from 18:00 to 21:00 Amsterdam time
• Each first Saturday of the month, from 10:00 to 14:00 Amsterdam time.

6. During the upcoming May holidays, the CTIS User Support Service will be providing service limited to critical or blocking issues: 9 May, 18 May, 19 May, 29 May.

7. A public consultation on the CTIS transparency rules is foreseen to be launched in May 2023 on the EMA website. The review of existing rules aims at simplification to improve user experience while also reducing the risk of data breaches and maintaining high levels of transparency.

8. The 14th issue of the Clinical Trial Highlights has been published, including recent improvements in CTIS and the launch date for the multi-factor authentication (MFA) in CTIS.
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EU Regulatory

On 26 April 2023, the European Commission proposed a reform of the EU pharmaceutical legislation (Background Document; EC Proposal) to modernise the pharmaceutical sector with a patient-centred approach whilst fully supporting innovation and competitiveness. It adopted a proposal for a new Directive and a new Regulation, which revise and replace the existing general pharmaceutical legislation (Regulation 726/2004 and Directive 2001/83/EC) and the legislation on medicines for children (Regulation 1901/2006) and for rare diseases (Regulation 141/2000/EC). Also read the introductory article here. Besides putting patients at the heart of the legislation, there will be a concerted effort to tackle antimicrobial resistance. Of note, and per Article 6(6) of the Proposal, the Agency shall ensure the opinion of the Committee for Medicinal Products for Human Use (CHMP) is given within 180 days after receipt of a valid application. This could shorten procedural timetables for the CHMP.

UK and MHRA News

The plain language glossary co-created by MRCT Center-CDISC is being expanded and will be available both on the MRCT Center and CDISC websites by early 2024. The current pilot Clinical Research Glossary contains 53 commonly used clinical research terms. Read DIA Global Forum’s short article for more background information.

Health Canada

The Regulator, Health Canada, has distributed ‘Draft Guidance Document Registration of Clinical Trials and Public Disclosure of Results: Transparency of Health Canada-authorized clinical trials’ dated 23 Feb 2023 for comment purposes.

FDA Guidance and News

1. In fiscal year 2022, 41% of trial results were submitted to the ClinicalTrials.gov database, compared with 34% in the previous year and just 29% in fiscal year 2020. In fact, the vast majority of results - 96%, on average - were eventually submitted to the database. But results for most of the trials were late, with just over one-third submitted by the obligatory due dates - NIH Clinical Trials Reporting Compliance: A Shared Commitment.

2. In April 2023, FDA opened a draft guidance for comments by 05 July 2023: Patient-Focused Drug Development: Incorporating Clinical Outcome Assessments Into Endpoints for Regulatory Decision-Making. This guidance (Guidance 4) is the fourth in a series of four methodological patient-focused drug development (PFDD) guidance documents that describe how stakeholders (patients, caregivers, researchers, medical product developers, and others) can collect and submit patient experience data and other relevant information from patients and caregivers to be used for medical product development and regulatory decision-making.

3. The latest ClinicalTrials.gov Beta Update release includes the addition of features to the Record History, notably, an accessible view of a single version of a study record for interventional studies. Look for improvements to the home page search feature and the table view as well.

4. Comparison of Availability of Trial Results in ClinicalTrials.gov and PubMed by Data Source and Funder Type - this study examines the dissemination and timing of trial results by data source (i.e., ClinicalTrials.gov and PubMed) and funder type (i.e., NIH, non-NIH U.S. federal agency, industry, and other).

5. FDA published final guidance for industry, “A Risk-Based Approach to Monitoring of Clinical Investigations Questions and Answers” to provide industry with recommendations on implementing a risk-based approach to monitor investigational studies on human drugs, biologics, medical devices, and combinations of these products. It expands on FDA’s 2013 guidance for industry “Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring” with additional recommendations to facilitate and encourage sponsors to implement risk-based monitoring. This guidance complements and does not supersede the 2013 guidance.  

6. In its April 2022 Draft Guidance, the FDA recommends that sponsors develop and submit a Diversity Plan to help ensure the adequate participation of relevant and underrepresented populations and analyses of data collected from clinically relevant populations. As the FDA Draft Guidance is finalised, sponsor companies and other industry stakeholders seek added clarity on this critical issue. In response TransCelerate BioPharma have released the Diversity of Participants in Clinical Trials Initiative - FDA Diversity Plan Early Insights and Considerations.

7. FDA issued a notice that the COVID-19-related guidance documents which were issued since the start of the pandemic public health emergency (PHE) will either be discontinued or be revised after 11 May 2023. Among them, 22 guidances will be discontinued after the end date, 22 guidances will be discontinued after a wind-down period for transition, and 24 guidances will be revised and retained. Of note, the ‘FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency’ and ‘COVID-19: Master Protocols Evaluating Drugs and Biological Products for Treatment or Prevention’ both fall under guidance documents that FDA is revising to continue as is for 180 days after the PHE declaration expires, during which time FDA plan to further revise them. ‘Statistical Considerations for Clinical Trials During the COVID-19 Public Health Emergency’ will no longer be in effect after PHE expires.

8. The FDA has issued draft guidance on “Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics.” The guidance recommends randomised controlled trials (RCTs)  as the “preferred approach” to support accelerated approval. The draft guidance provides recommendations relating to “Randomized Controlled Clinical Trials to Support Accelerated Approval”, “Single-Arm Trials to Support Accelerated Approval” and “Confirmatory Trial Following Accelerated Approval.” Comments on the draft guidance should be submitted by 27 May 2023.

EMA Guidance and News

1. EMA has issued the new “Guideline on computerised systems and electronic data in clinical trials”, replacing the previous “Reflection paper on expectations for electronic source data and data transcribed to electronic data collection tools in clinical trials”. The guideline describes the generally applicable principles and definition of key concepts, the requirements and expectations for computerised systems, including validation, user management, security, and electronic data for the data life cycle. For such trials, study protocols will need to specify the data capture methods. 

2. EMA has opened a public consultation on a reflection paper that discusses key concepts for single-arm clinical trials that are submitted as pivotal evidence in support of marketing authorisation applications for medicines in the EU. Stakeholders are invited to send their comments via an online form by midnight (CET) on 30 September 2023. 

3. EMA will host a webinar on 16 May 2023, 15:30-17:00 CEST to prepare to re-start publishing clinical data from September 2023, in line with related Policy 0070. The webinar will focus on the background and scope of the re-start, and provide guidance for applicants and industry stakeholders, including SMEs intending to submit clinical data for publication. Visit the EMA page here for more info and to register.

Real-World Data

1. PHUSE has created a new Real World Evidence Working Group which aims to support, address and answer questions around real world evidence. Current projects are “Quality and Reusability of Real-world Data,”  “Real World Evidence Guidance,” and “Submitting Real-world Data”. 

2. At the 11th Global Summit on Regulatory Science annual conference, regulators from Brazil, Canada, India, Italy, Japan, Germany, Switzerland, Singapore, UK and US presented ways they are integrating AI and RWD into their regulatory authority processes. They discussed how AI and RWD could be applied to drug safety assessments. According to the full published report by Thakkar et al (May 2023) “Several key topics were highlighted and discussed during the conference, such as the capabilities of AI and RWD to assist regulatory science policies for drug and food safety, the readiness of AI and data science to provide solutions for regulatory science.” Unfortunately the full published report is behind a paywall, however a summary of the report is presented here. 

3. DARWIN EU® has completed its first 4 studies using RWD from across Europe, the protocols and results of these studies are publicly available in the EU PAS Register. The DARWIN network also intends to onboard 10 more data partners and initiate around 16 studies in 2023. DARWIN EU® will be fully operational by 2025 with the vision to deliver around 150 RWE studies per year.

4. A study by Wang et al. published in JAMA on 25 Apr 2023 emulated 32 randomised clinical trials (RCTs) of medications with database studies using observational analogues of the RCT design parameters and quantified agreement in RCT-database study pairs. The emulation results revealed a good correlation in the overall observed agreement between the RCT and the database, suggesting that RWE studies can reach similar conclusions as RCTs when design and measurements can be closely emulated, but not without challenges.

Transparency and Disclosure Resources and News

1. A recent article in JAMA by Nelson et al. compared the availability of trial results in ClinicalTrials.gov and PubMed. They reported that 39% of trials did not post results on ClinicalTrials.gov or PubMed after a minimum follow-up of 36 months following primary completion date; of the trials with results, about 24.5% were posted only on ClinicalTrials.gov and 52.2% only on PubMed.

2. Save the date: The PHUSE Data Transparency Summer Event will take place 20-22 June 2023. Registration is scheduled to open on 2 May.

3. The European Data Protection Board (EDPB) adopted version 2.0 of Guidelines 01/2022 on data subject rights - Right of access on 28 March 2023. The overall aim of the right of access is to provide individuals with sufficient, transparent and easily accessible information about the processing of their personal data so that they can be aware of and verify the lawfulness of the processing and the accuracy of the processed data.

Development Strategy News

An article on achieving enhanced diversity in clinical trial populations has been published entitled “Enhancing diversity in Clinical Trials- An Agency Industry Perspective.”  The summary article (Fienkeng M, et al. Regulatory Focus. Published online 31 December 2022) was written by representatives from the US FDA, Health Canada, and Pfizer who attended the September 2022 RAPS Convergence in Phoenix, Arizona and summarises the meeting content and discussions.

Medical Devices

Medical devices information is kindly compiled by Raquel Billiones.

Updates from IMDRF

The 23rd session of the International Medical Device Regulators Forum (IMDRF) took place in Brussels on 27-28 March 2023. Presentations are available for download. 

The IMDRF also released several guidance documents in April:

• Principles and Practices for Software Bill of Materials (SBOM) for Medical Device Cybersecurity. The SBOM is a “list of one or more identified components, their relationships, and other associated information.” It is a resource which can be leveraged to improve cybersecurity risk management processes in both pre-market and post-market activities of medical devices.

• Principles and Practices for the Cybersecurity of Legacy Medical Devices, also known as IMDRF N60 guidance, sets forth foundational security principles and best practices that span the total product life cycle of medical devices. 

• Personalized Medical Devices – Production Verification and Validation. This guidance provides harmonised recommendations for verification and validation aspects of a patient-matched (“personalised”) medical device and a medical device production system.

• (Updated) Medical Devices: Post-Market Surveillance: National Competent Authority Report (NCAR) Exchange Criteria and Report Form. This updated Edition 4 describes procedures and forms for exchange of reports between IMDRF members, including a two-way communication system involving confidential information for serious public health issues.

Updates from Notified Bodies

Team-NB released the results of the 2022 Sector Survey. The 2022 survey has compiled data from 33 notified bodies, the total number of Team-NB members at the end of 2022.

Updates from the UK

In April, MHRA released the guidance on Software and Artificial Intelligence (AI) as a Medical Device (SaMD and AIaMD, respectively). This guidance provides access to important Software Group outputs that might be of assistance. Software Group are responsible for taking all reasonable steps to assure the safety of SaMD and ensure the UK public have access to technology that meets a clinical need. They work across the MHRA to achieve this aim for SaMD and AIaMD.