November 2023

CORE Reference 2023 Utility Survey

CORE Reference 2023 Utility Survey

Please complete the 2023 CORE Reference Utility Survey - which is due to close on 05 December 2023 - if you have yet to do so. We need a decent ‘n’ to improve the robustness of the result. Please support us by clicking here to complete the survey. Thank you.

Medicines and Vaccines

 CTR and CTIS

  1. EMA has released the following updates to CTIS training modules #10 and #13:
  2. The EU Clinical Trial Information System (CTIS) Sponsor Handbook, v3.03 is now available. Included as new links (see page 3) are:  CTCG cover letter template for transitional trials; Guidance for transition of trials from CTD to CTR; and the ACT EU site. A later version of the “CTCG Best Practice Guide for sponsors of multinational clinical trials with different Part I document versions approved in different Member States under the Directive 2001/20/EC that will transition to the Regulation (EU) No. 536/2014” (v3.0) has been released, succeeding v2.0 provided in Section 5.1 of the Sponsor Handbook v3.03 above.
  1. EMA is organising a href="https://www.ema.europa.eu/en/events/clinical-trials-information-system-ctis-bitesize-talk-training-materials-ctis-pre-requisites-updates">CTIS bitesize talk on training materials, CTIS pre-requisites, and updates on transparency rules planned for 29 November at 15.30 Amsterdam time. This will be the last one of the year. Participants can submit their questions in advance until 21 November via Slido with the code #bt29nov.
  2. The next CTIS: Walk-in clinic is scheduled for 13 December 2023.
  3. CTIS Newsflash 10 November 2023: Winter clock stop: All timers within the evaluation of a clinical trial application will stop on 22 December 2023 at 23:59:59 CET and resume on 8 January 2024 at 00:00:01 CET. Due to this winter clock stop, the timelines for the applications may be affected. More information is available in the CTIS evaluation timelines document. All issues of the CTIS Newsflash are available on the EMA website.
  4. Expedited procedure for transitioning trials to CTIS: the Clinical Trial Coordination Group (CTCG) has agreed on an expedited, harmonised Member State (MS) evaluation procedure open until 16 October 2024 - where validation of minimum application dossiers will be restricted to documents already authorised under the CTD. After this date and depending on the MS workload, this expedited procedure may not be available.

    As a reminder, the following guidance is available:  

    a. Guidance for the transition of clinical trials, as published by the European Commission under EudraLex volume 10.

    b. Best Practice Guide (V3.0, updated November 2023) and cover letter template (V3.0, updated November 2023), as adopted by the CTCG. 

    c. Module 23 of the CTIS online training programme.

  5. For information only: CTIS Training Environment downtime (no data wipe out) on 01 December 2023.

  6. ACT EU Clinical Trials Analytics Workshop will be held on 25+26 January 2024. Stakeholders can present/discuss how they are using or planning to use clinical trial registry data e.g. to find trials on certain medical conditions, track healthcare innovation, or to apply Artificial Intelligence for novel insights. These discussions will help guide EU decision-makers on improving access and usability of clinical trials data. 

  7. An updated version of the ACT Q&A on the protection of commercially confidential information and personal data while using CTIS has been published. Version 1.3 (dated 29 November 2023) includes updates pertaining to the new transparency rules released earlier this year and their implementation in CTIS.

EU Regulatory

  1. An ACT EU work plan for 2023-2026 has been published. This Accelerating Clinical Trials in the European Union work plan reflects the priorities for the initiative, including implementation of the EU CTR. Note: the timeline for the ‘Implementation of new CTIS transparency rules’ are for this to be completed by Q4 2024 (see slide 10).

  2. European Health Data Space (EHDS) will set up strict rules for the use of individual’s non-identifiable health data for research, innovation, policy-making and regulatory activities. This will have implications for protecting personal data and commercially confidential information. A policy briefing, published in October 2023 by Dr Elizabeth Redrup Hill, outlines and discusses the challenges associated with cross-border data sharing with EU Member States and is available to download here.

UK and MHRA News

  1. MHRA to launch the AI-Airlock, a new regulatory sandbox for AI developers. See AI/ML subsection for details.
  1. UK MHRA has published a set of resources:  Updates to Common Issues Identified During Clinical Trial Applications. 
  1. UK Government Policy Paper: Full government response to the Lord O'Shaughnessy review into commercial clinical trials, detailing progress made in the last 6 months.

FDA Guidance and News

    1. FDA will no longer update the What’s New page of the classic ClinicalTrials.gov website. The page will remain available for historic purposes until the classic website is retired. For the most recent information regarding ClinicalTrials.gov, please add the News and Updates page on the modernised website to your favourites.

    1. 06 November 2023 Draft FDA guidance Submitting Clinical Trial Datasets and Documentation for Clinical Outcome Assessments Using Item Response Theory provides technical specifications for the submission of clinical outcome assessment (COA) data that use Item Response Theory (IRT) and supplements the FDA CDER Patient-Focused Drug Development (PFDD) Methodological Guidance Series.  A COA refers to the assessment of a clinical outcome made through a report by a clinician, a patient, a non-clinician observer, or through a performance-based assessment; thus, there are four types of COAs: clinician-reported outcome (ClinRO), patient reported outcome (PRO), observer-reported outcome (ObsRO), and performance outcome (PerfO) measures. Comments can be submitted here.

    2. 06 November 2023 Final FDA guidance was published entitled “Submitting Patient-Reported Outcome Data in Cancer Clinical Trials”.  The guidance provides technical specifications for submitting patient-reported outcome (PRO) data collected in cancer clinical trials to support a marketing application for a medical product in oncology, where a PRO is a type of clinical outcome assessment (COA) used to collect patient experience data. Comments can be submitted here. 

    3. Plain Language Summaries generated by AI are now available for nearly 50,000 clinical trial results on ClinicalTrials.gov. See the AI/ML subsection below for details.  
    4. FDA has published final guidance outlining the eligibility and submission requirements for applicants interested in submitting new drug applications (NDAs) or biologics licence applications (BLAs) for the real-time oncology review pilot (RTOR). To be considered for RTOR, the guidance outlines eligibility requirements including “Easily interpreted clinical trial endpoints (e.g. overall survival, response rates), as determined by the review division and Oncology Center of Excellence (OCE).”
    5. FDA has issued final guidance on developing drugs for  COVID-19: Developing Drugs and Biological Products for Treatment or Prevention. The guidance provides updated recommendations that reflect the evolving scientific knowledge and the current state of the pandemic. This supersedes the final guidance of the same name initially issued on 12 May, 2020 and reissued on 22 Feb, 2021. The guidance provides FDA’s current recommendations on the design of phase 2 and phase 3 trials with a focus on trial population and design, efficacy endpoints, as well as safety and statistical considerations.

    EMA Guidance and News

    1. EMA is relaunching its corporate website on December 05, 2023. The website will feature a new, simple medicines search, clearer navigation, and a revamped ‘What’s new page’. More information can be found here. The website’s main address will stay the same and all the links will be functional post the re-launch.
    2. EMA published a concept paper (dated 12 October 2023) on the development of an addendum to the guideline on clinical development of vaccines. The addendum would provide guidance on appropriate clinical studies to be conducted in immunocompromised individuals before or after initial marketing authorization to evaluate the need for alternative dose regimens and to support inclusion of specific recommendations for use of vaccines in this population or in specific sub-populations in the Product Information. 

      Real-World Data

      1.  FDA has announced Real World-Data Grant Awards on 16 Nov 2023. Recipients were awarded grants for demonstration projects to examine the use of real-world data (RWD) to generate real-world evidence (RWE) in regulatory decision making. The awards and grantees are: 
      • Methods to Improve Efficiency and Robustness of Clinical Trials Using Information from Real-World Data with Hidden Bias – Duke University and North Carolina State University 
      • Generating Reproducible Real-World Evidence with Multi-Source Data to Capture Unstructured Clinical Endpoints for Chronic Diseases – Harvard-MIT Center for Regulatory Science and Harvard Medical School 
      • Real-World Data to Generate Real-World Evidence in Regulatory Decision-Making  – ECOG-ACRIN Medical Research Foundation 
      • Development of Novel Methods to Enable Robust Comparison of Real-World Progression Free Survival (rwPFS) and Clinical Trial PFS in Multiple Myeloma  – Janssen Research & Development, LLC.


      Further information is available here.

      2.  A new blogpost by the PHUSE Real World Evidence (RWE) Working Group entitled “Submitting RWD: Challenges Faced by Industry While Working on Real-World Evidence Studies” examines the challenges of submitting real-world data to regulatory bodies.

      Transparency and Disclosure Resources and News

      1. EMA has published a letter (dated 29 September 2023) responding to three questions asked by the European Ombudsman about their plan and timelines (including the next steps) for extending the scope and addressing the backlog of procedures under Policy 0070.
      2. Sharma et al explain how to practically navigate the emerging transparency paradigm for clinical trials in Europe in this Regulatory Focus Feature. Table 7 provides useful comparisons of transparency requirements in the EU and US by trial phase. NOTE: Be aware of reference in the article to the EU deferral process, which is now obsolete per the 05 October 2023 revised transparency rules for the publication of information on clinical trials submitted through CTIS.
      3. Pfizer has launched a Clinical Trial Participant Data Return Initiative which provides trial participants with their own personal clinical trial data when a trial ends. This is a first of its kind program which allows participants to share their trial data with their healthcare provider after their study participation concludes.
      4. Chen et al. published their study in preprints, entitled “Clinical Trial Registration and Reporting in China and the United States: Legal and Regulatory Frameworks, Compliance and Enforcement”, which analysed and contrasted the laws and regulations governing clinical trial registration and reporting in China and the US. The US regulation mandates disclosure of trial results to both the national regulator and the public, while the Chinese law does not mandate disclosure to the public. The paper is available open access.
      1. Krystelis Whitepapers: The most recent addition available for download is titled ‘Riding the CTIS rollercoaster: What is the impact of the new transparency rules?’ This paper sheds light on the 05 Oct 2023 revised EU CTR transparency rules. 
      1. Gamertsfelder et al. published their research “Towards transparency: adoption of WHO best practices in clinical trial registration and reporting among top medical research funders in the USA” (abstract only) in which they reported that the largest public and philanthropic funders of clinical research in the US only implemented 4.1/11 (37%) of WHO best practices in clinical trial transparency.

      1. A report on “Evaluating Clinical Trials Transparency Policies at UK Public Research Institutions” presented by DeVito and Lewis concluded on 3 key findings:
        1) Transparency Requirements should be concrete, universal, and come directlyfrom the institution; 2) The processes for transparency practice should be described in detail; 3) The monitoring/auditing of transparency practices should be documented with specific and well-described escalation pathways, responsible parties, and potential penalties for noncompliance.

      1. This article by Avis Favaro based on new research by Mohsen Alayche from UAEM, Kelly Cobey, David Moher et al describes how nearly a third of all clinical trials run in Canada have ended up as research waste. 
      1. For information only: Health Canada will not be shutting down over the Christmas period, rather they will honour the Canadian bank holidays: 25+26 December 2023 and 1 January 2024.​

      Development Strategy News

      1. The PHUSE Data Transparency Winter Event will take place from 6-8 February 2024. Relevant 150-word abstracts should be submitted for consideration by Thursday 7 December 2023.
      2. TransCelerate BioPharma plans to address the gap between data privacy and data utility with a new methodology titled Clinical Data Sharing: A Proposed Methodology to Enable Data Privacy while Improving Secondary Use. This 18 Oct 2023 guest column in Clinical Leader summarises the methodology and approaches for modifying 12 common clinical data set variables. 
      3. Messenbrink et al‘s paper Developing Generic Templates to Shape the Future for Conducting Integrated Research Platform Trials summarises EU-PEARL's efforts to develop a platform study protocol template. Note that the final release was based on an older TransCelerate CPT (the most current at the time). Although the template falls short of being able to accommodate all master protocol designs, it does provide standards for one of the most challenging (platform studies), and represents a good starting point on which structural configuration can be based.
      1. Save the date for the next ACTEU multi-stakeholder workshop on methodology guidance - tune in on 23 November 2023 to listen to the discussions.
        Click here for live broadcast and agenda. The European Medicines Regulatory Network provides guidance on #ClinicalTrial methodology, supporting the implementation of new and innovative approaches to the conduct and design of clinical trials. It is essential that patients, industry, academia, health technology assessment bodies and payers contribute to the development of this guidance to ensure that the needs of all actors are taken into account.
      1. Free FDA Webinar on 29 and 30 Nov 2023 ‘'Discussing Approaches to Enhance Clinical Study Diversity Public Workshop' - The workshop will include presentations and panel discussions with representatives from sponsors, CROs, academia, patients, and other interested parties, who will share their experiences and approaches for increasing enrollment and encouraging participation of historically underrepresented populations in clinical studies. Learn more and register here. Expect the recording to appear on the webpage sometime after the Webinar. 
      1. Free Webinar by Khaled El Emam on 13 Dec 2023 at 16.00-17.00 UK time, providing an overview of key learnings in 2023 about synthetic data generation research and applications - a reflection on the last 12 months in this space, and expectation on how the market will evolve over time. Register here.
      1. In March 2022 US FDA, published draft recommendations to sponsors developing human gene therapy products incorporating genome editing (GE) of human somatic cells which includes considerations for clinical studies. CRISPR Medicine News (CMN) produces news and information related to genetic medicine, gene therapy and genome editing for the treatment of human diseases. You can sign up for free weekly CMN Newsletters by email. CMN has also compiled a comprehensive list of CRISPR gene editing clinical studies which they keep updated. 
      1. This Parexel Whitepaper - Advancing clinical development through innovative trial design - highlights some widely-used clinical trial designs, including master protocol, enrichment, and adaptive designs. As the use of these designs has become more mainstream, it is imperative that design definitions and understanding penetrate the clinical research space. If these topics are unfamiliar, this resource is a good place to start as it provides well-referenced summaries. 
      2. EMA’s 4th annual Big Data Multi-stakeholder forum will be held on 4 December 2023 to discuss data-enabled opportunities with stakeholders to improve medicines development in the EU and inform and strengthen collaboration with stakeholders and partners on the delivery of the data activities included in the Network Strategy to 2025. Live broadcast, agenda are here; expect a recording of the event to be posted in due course.
      3. El Kababji et al’s paper Evaluating the Utility and Privacy of Synthetic Breast Cancer Clinical Trial Data Sets published in the Journal of Clinical Oncology describes a recent study evaluating synthetic data generation on eight breast cancer clinical trial datasets to help with a dearth of evidence on oncology clinical trial synthetic data sets, and on the utility of privacy-preserving synthetic data.

      Artificial Intelligence/Machine Learning

      1. Khaled El Emam and team have published Consolidated Reporting Guidelines for Prognostic and Diagnostic Machine Learning Modeling Studies: Development and Validation in JIMR.org. In El Emam’s words: “There are many reporting guidelines for machine learning modeling studies. While they overlap in their reporting items and checklists, they do not all say the same things. This makes it confusing for data scientists and peer reviewers in journals to know which ones to follow. For this reason we consolidated the current guidelines into a single set of reporting items and a checklist. Arguably this consolidated list provides the most comprehensive coverage to date on this topic, and there is no compelling reason to develop yet another set of guidelines, unless they extend the scope to other data modalities, such as NLP and image studies, for example”.
      1. MHRA to launch the AI-Airlock, a new regulatory sandbox for AI developers. According to the MHRA “The AI-Airlock will assist in the development and deployment of software and AI medical devices.” Further information on how the sandbox will enable NHS patients to benefit earlier from emerging technologies without implications for safety and post market surveillance will be confirmed when the Airlock opens in 2024.
      2. Plain Language Summaries generated by AI are now available for nearly 50,000 clinical trial results on ClinicalTrials.gov. The company who generated the summaries cautions that while the use of AI to produce the initial summary can save time, “the use of AI is not a complete replacement of a skilled human writer”. The company plans to add more trial summaries in the future, and to automatically generate a plain language summary whenever a new record is made available on ClinicalTrials.gov, on a daily basis. Access all summaries for free here. Read the full story here.
      1. Anderson et al, 2023 have published an interesting article entitled “Generative AI as a Tool for Environmental Health Research Translation.” The authors submitted five previously published open access articles to ChatGPT for summarising (at the level of eighth grade readability) and contacted an article author to have them rate the generated summaries without their knowledge that ChatGPT had been used. The average rating of summaries across the five studies by authors (where a score of 1 was poor) was 3.9 (range 3 to 5). doi: 10.1029/2023GH000875
      1. To understand the development pipeline and worldwide geographic distribution of clinical trials for AI/ML-enabled medical devices that may enter the market in the upcoming years, the authors of a new Policy Corner article analysed the trends in clinical trials for AI/ML-enabled medical devices registered between 2010 and 2023. Read the results in “Development Pipeline and Geographic Representation of Trials for Artificial Intelligence/Machine Learning-Enabled Medical Devices (2010 to 2023)” by Serra-Burrieet al.
      1. BioRxiv, the preprint server for biology, announced in early November a pilot to use large language models to generate outlines of all new preprints posted on the site. Summaries are generated at 3 different reading levels, from general to expert. The pilot does not apply to medRxiv, a sister preprint server for health sciences, which typically publishes studies that have clinical relevance. Also read a Nature news article on this.
      1. A roundtable discussion on real-world applications for AI across the drug development cycle entitled “Can’t ChatGPT Do That? Practical Applications for AI in Drug Development” is to be held on Thursday Dec 7 2023. Registration is required. 
      1. In this “AI Uncovered” podcast, Tim Martin interviewed Sarah Tilly (President-elect of EMWA) to discuss the impact of AI on medical and regulatory writing. Listen here.
      1. In an experiment, ChatGPT was used to generate 102 distinct blog articles that contained more than 17,000 worlds of disinformation related to vaccines and vaping. These observations were published in the article Health Disinformation Use Case Highlighting the Urgent Need for Artificial Intelligence Vigilance.

      News from Asia Regulators

      1. Due to a lack of financial support, the Thai Clinical Trials Registry (TCTR) will gradually stop its operation, starting on 13 November 2023. 

      From 13 to 19 November 2023:

      • Users will not be able to create a new account or a new record.
      • Draft records can be edited, submitted, and deleted.
      • Submitted records can be edited and deleted.

      From 20 November 2023 until further notice:

      • Draft records can no longer be edited, submitted, and deleted.
      • Submitted records can no longer be edited and deleted.

      Released records, i.e. those with TCTR identification number, can still be edited and updated until further notice. For new registration, please visit WHO website for more information. 

      Medical Devices

      Medical devices information is kindly compiled by Raquel Billiones.

      1. The FDA issued a final guidance “Assessing the Credibility of Computational Modeling and Simulation in Medical Device Submissions” which provides recommendations on a risk-informed framework for credibility assessment of computational modeling and simulation (CM&S) used in medical device regulatory submissions.
      1. Lübbeke et al. published a systematic review, entitled “Clinical investigations to evaluate high-risk orthopaedic devices: a systematic review of the peer-reviewed medical literature” to provide an overview of clinical investigations regarding hip and knee arthroplasty implants published in peer-reviewed scientific medical journals before the EU Medical Device Regulation entered into force in May 2021. They noted that no clinical studies were published before CE-marking for any selected device, and in one-quarter of devices, no studies were published even up to 20 years after CE-marking.
      1. Member State competent authorities for clinical trials and medical devices and the European Commission have published information on the "COMBINE" project. The project was launched in June 2023 to address challenges at the interface between the regulations on clinical trials of medicinal products, medical devices and in vitro diagnostics. The project consists of two phases: (1) analysis of the challenges at the interface of MDR/IVDR/CTR; (2) possible development of solutions that aim to address some of the challenges. Notably, combined studies are studies that involve:
      • A clinical trial of a medicinal product in parallel with a performance study of an in vitro diagnostic
      • A clinical trial of a medicinal product in parallel with a clinical investigation of a medical device.
      1. The US FDA has made a decision to officially withdraw as a member of the Global Harmonization Working Party (GHWP). In the letter Jeffrey Shuren, Director Center for Devices and Radiological Health expresses becoming “increasingly concerned with the divergent harmonization efforts for medical devices and how some of these efforts do not align with FDA’s priorities or international best practices.” The full text of his letter can be found here.
      2. Shakha Malik, a senior regulatory affairs specialist at Medtronic Inc, has written a detailed overview of the EU MDR and the CE marking process (published online by Regulatory Focus on 23 September 2023).

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