May 2024

Medicines and Vaccines

ICH

Recordings are now available of a Joint US FDA – Health Canada ICH Public Meeting held in Feb 2024 which included presentations by FDA, Health Canada, PhRMA, and BIO experts on ICH guidelines reaching significant ICH milestones.

CTR and CTIS

1. Clinical Trials Highlights Issue 19 - Apr 2024 is out now. Topics include transparency in CTIS, ACT-EU, CTIS development, training, and events. ‘Clinical Trials Highlights’ Newsletter archive.

2. The 03 May and 17 May 2024 CTIS Newsflashes are available on the EMA website. There is detailed information regarding addition of a new CTIS feature on plans to share individual participant data (IPD). A new field collects information on if and how the data will be made available to other researchers to allow sponsors to record in a structured way how IPD will be shared; it is recommended that sponsor users select “Yes” or “No”, to meet the requirements of the International Committee of Medical Journals Editors (ICJME). See the full Newsflash documents for other information.

3. EMA has published a revised version of Quick guide: Transition of trials from EudraCT to CTIS (sponsor users), version 1.4, May 2024. Minor changes have been applied: minor update to the introduction and overview of transitional trials; CTIS: how to get started and how to transition a trial reference link added.

4. EMA has released version 2.0 of CTCG Best Practice Guide to sponsors on requirements for updating the application dossier Part 1 after CTR transition. Requirements are summarised in a table and depend on i) if one or several additional MSC is/are planned to be added to the trial, ii) if recruitment and/or treatment is ongoing in at least one MSC and iii) if remaining procedures are restricted to trial-specific follow-up interventions without subject recruitment and/or treatment. Part I documents in line with the requirements in the table should be updated when there is a need for changing the content of the Part I dossier in a substantial modification application.

5. On 30 April 2024, EMA released the following sponsor support material: updated CTIS Structured data form instructions - initial application, additional MSC, substantial and non-substantial modifications. This document provides guidance on the data fields sponsors will be required to fill in when creating an initial application, an additional MSC application, a substantial modification and a non-substantial modification and can be downloaded here.

6. A  Regulatory Focus article from RAPS by Chris Bamford and  Carolina Arias entitled “The EU Clinical Trials Regulation – Experiences from the first 18 months” published November 2023 is now open access and available to download.

7. CTIS 17 May 2024 newsflash confirms that for all clinical trial applications submitted on or after 18 June 2024:

  • it will no longer be possible to defer the publication of data and documents;
  • data and documents will be published according to the established timelines for the trial category, population age and trial phase;
  • publication of documents will be focused on key documents of interest.

Data on all clinical trial applications submitted before 18 June 2024 will be made publicly available in line with the principles and timelines defined in the revised transparency rules.

8. The next CTIS Walk-in Clinic will take place on 10 July 2024 at 16:00 – 17:00 CEST. Participants are able to submit their questions via Slido from 20 June to 3 July 2024, with the code #clinic246. Details of the event here. The CTIS experts will address all the questions related to system functionalities. Questions about the interpretation of the CTR and /or national processes are out of the scope of this event.

9. The EMA has released Version 4 of Guidance for the Transition of clinical trials from the Clinical Trials Directive to the Clinical Trials Regulation, dated May 2024. What has changed compared to Version 3, dated March 2024:

  • Clarification of consequences of non-compliance with transition requirements
  • Addition of Annex II (Decision tree administrative transition clinical trial)
  • Clarification on the interface with medical devices and in vitro diagnostic 
  • Clarification on active sites
  • Minor amendments to elements related to the CTIS transparency rules
  • Addition of information on EE and EL in Annex I.

EU Regulatory

1. In Q2 2024, ACT EU is launching two consolidated advice pilots offering: a) harmonised scientific advice to support the submission of marketing authorisation and clinical trial applications (CTAs) in the EU, and b) consolidated technical/regulatory advice on CTA dossiers prior to their submission in CTIS. More information on the pilots will be available in due course on the ACT EU website.

2. The European Centre for Disease Prevention and Control (ECDC), the European Chemicals Agency (ECHA), the European Environment Agency (EEA), the European Food Safety Authority (EFSA), and the European Medicines Agency (EMA) published a joint framework for action to strengthen cooperation to support the implementation of the One Health agenda in the European Union (EU).

3. CTCG Clinical Trials Coordination Group have released Recommendations related to contraception and pregnancy testing in clinical trials Version 1.2 (dated 07 March 2024). This is a supplement to existing guidelines related to embryofetal risk mitigation and provides practical guidance on contraception use and pregnancy testing in clinical trials. The CTCG is an HMA working group of experts in the classification, assessment and oversight of clinical trials from National Agencies.

UK and MHRA News

1. MHRA has published a policy paper on the Impact of AI on the regulation of medical products, which considers the opportunities and risks of AI and is also the MHRA’s response to the letter from the UK Department of Science, Innovation & Technology and Department of Health & Social Care Secretaries of State to the MHRA

2. The UK has updated the Guidance for Submissions Related to Human Medicines which should be submitted directly to the MHRA.

FDA Guidance and News

1. Check out 2024's first issue of the “What’s New In Regulatory Science" newsletter from the FDA’s Center for Drug Evaluation and Research (CDER). This issue contains updates on CDER research and other regulatory science efforts that help advance medical product development. Click the sign-up link to subscribe (select regulatory science as the topic area). If you have comments or questions, contact OTSCommunications@fda.hhs.gov. 

2. The National Library of Medicine (NLM) is hosting a webinar on 6 June 2024 to provide updates on the overall ClinicalTrials.gov modernisation effort. Staff will be answering questions to help users prepare for the retirement of the classic ClinicalTrials.gov. Please register in advance. A recording will be made available for those unable to attend the live event.

3. Reminder that ClinicalTrials.gov Classic Website will retire on 25 June 2024. The classic site now includes a banner asking users to utilise the modernized ClinicalTrials.gov.

4. Natural History Studies and Registries in the Development of Rare Disease Treatments Workshop was hosted on 13 May 2024 by FDA’s CDER, NIH’s National Center for Advancing Translational Sciences, and the Reagan-Udall Foundation. The workshop focused on the use of natural history study and registry data in rare disease drug development programs.

Agenda: Natural History Studies and Registries in the Development of Rare Disease Treatments. If a summary of this workshop becomes available, we will share this.

5. NIH and FDA Seek Comment on Draft Glossary of Clinical Research Terms Related to Innovative Clinical Trial Design by releasing a request for information including a draft glossary of clinical research terms related to innovative clinical trial design, including studies using real world data to generate real world evidence. The draft glossary is intended to facilitate communication within the clinical research community by helping establish a common vocabulary to more uniformly characterise clinical research. See the draft glossary for more information. NIH and FDA will accept comments on the draft glossary until 24 June, 2024. Questions about this draft glossary can be sent to SciencePolicy@od.nih.gov.

6. The US FDA organised the 13th Regulatory Education for Industry (REdI) Annual Conference 2024: Innovation in Medical Product Development on 29 to 30 May 2024. Check out the conference overview on YouTube.

EMA Guidance and News

1. The EMA has published the revised Guide on access to unpublished documents which removes the maximum of 5 requests to be submitted per requester/affiliation following the business continuity plan linked to Covid-19.

2. The first issue of EMA’s revamped Human Medicines Highlights Newsletter was issued in May. This is the only newsletter published by the EMA specifically for patients, consumers, healthcare professionals and their representative organisations.

3. The EMA has released an update (Rev. 4) to the Q & A for applicants, marketing authorisation holders of medicinal products and notified bodies with respect to the implementation of the MDR and IVDR (Regulations (EU) 2017/745 and (EU) 2017/746). In addition to several revisions, several new questions have been added: 1.3 (advice on classification), 2.4 (scope of Notified Body Opinion), 2.7 and 2.8 (changes to device and medicinal product, respectively), 3.2 (labelling), and 5 (consultation for companion diagnostics).

4. The EMA's SME office has launched a survey to gather feedback from small and medium-sized enterprises (SMEs) and industry stakeholders. The deadline is on 12 July 2024. The SME Survey 2024 is available here.

Real-World Data

1. EMA have published a Reflection Paper on use of real-world data non-interventional studies to generate real-world evidence. Public consultation is open until 31 Aug 2024. The paper discusses methodological aspects of non-interventional studies using real-world data in order to generate real-world evidence for regulatory purposes. Comments can be submitted here.

2. A TransCelerate white paper issued Dec 2023 entitled “Assuring Audit and Inspection Readiness – Considerations for the Use of RWD and RWE in Regulatory Decision-Making” is available to download. The white paper is designed to provide greater clarity as to the type of information and documentation regulators may request about the sources and process by which RWD/RWE is compiled to inform a regulatory decision.

3. The Reagan-Udall Foundation for the FDA will Host a public webinar on Real-World Evidence on Thursday, 30 May 2024 at 2 p.m. ET. The webinar will discuss the draft guidance, Real-World Evidence: Considerations Regarding Non-Interventional Studies for Drug and Biological Products. Registration is  here and agenda details here.

4. The newly published Council for International Organizations of Medical Sciences (CIOMS) consensus report describes the potential use of RWE for decision making; RWD and data sources; key scientific considerations in the generation of RWE; and ethical and governance issues in using RWD. It reflects the opinions of the CIOMS Working Group XIII on RWD and RWE  in regulatory decision making, and was finalised after considering comments received during a public consultation. The free PDF report can be downloaded here.

Transparency and Disclosure Resources and News

1. Researchers and study teams need tools and resources for clear, effective communication with patients and participants. The Multi-Regional Clinical Trials Center of Brigham and Women's Hospital and Harvard (MRCT Center) Center’s enhanced Clinical Research Glossary has over 165 plain-language terms, definitions, images, and related content – freely available for download under a Creative Commons license, and a CDISC global standard. 

2. Cochrane Germany has released a position paper on missing clinical trial results. This is a follow on to a panel discussion involving patient groups, ethics committees, and clinical trial units. Check out the video and transcript of the heated debate in German.

3. PHUSE Data Transparency Autumn event 17-19 Sept 2024 - call for speakers is now open. You should submit your 150 word abstract for consideration by 14 June 2024. Guidance and details are here.

EMWA Policy 0070 in Practice

EMA has released the new anonymisation report form template together with the anonymisation report form instructions. The new template was developed jointly by EMA and the Health Canada Public Release of Clinical Information (PRCI) team. The guidance document contains instructions and a set of definitions to guide applicants on how to complete the anonymisation report form for the clinical document package.

Development Strategy News

1. Advances in cellular and gene therapies (CGTs) also known as advanced therapy medicinal products (ATMPs) in the EU are discussed in the article “Emerging technologies and regulatory agency guidance for CGTs”. In her RAPS article Catarina Carrão summarises current guidance on ATMPs and CGTs from the EMA and US FDA perspectives.

2. Singh et al published Simultaneous Global Drug Development and Multiregional Clinical Trials (MRCT): 5 Years After Implementation of ICH E17 Guidelines that touches on an important topic for many protocol authors and reviewers - ICH E17 - a guideline that details principles for planning and designing multi-regional studies that can lead to near simultaneous regulatory submission (see figure above). The authors detail the current level of adoption and discuss the changes in drug development (since the release of the guideline) that impact the utility of the guidelines.

3. LinkedIn article on the prospects for digitisation of protocol development - after ICH M11 is made substantive, towards the end of 2025.

4. This OpenPharma guest blog from Pistoia Alliance President Becky Upton highlights lack of method reproducibility in scientific and medical research. Suggested critical ways to improve reproducibility include clear protocol development and publication, method standardisation initiatives, encouraging replication studies, and training and education. The Pistoia Alliance is a global not-for-profit alliance that advocates for greater collaboration in life sciences and healthcare R&D to overcome common challenges shared by the sector.

5. A useful FDA PDF Checklist to help ensure the technical compliance of your PDF documents against FDA requirements is available to download from here.

Artificial Intelligence / Machine Learning

1. The US National Institute of Standards and Technology (NIST) has published the initial public draft of NIST AI 600-1 "Artificial Intelligence Risk Management Framework: Generative Artificial Intelligence Profile". The document is under public consultation until 2 June 24.

2. The WHO has published “Ethics and governance of artificial intelligence for health - Guidance on large multi-modal models” WHO has issued this guidance "to assist Member States in mapping the benefits and challenges associated with use of LMMs for health and in developing policies and practices for appropriate development, provision and use."

3. The Notified Body TÜV SÜD is organising the webinar Understanding AI Act Interactions with MDR and IVDR on 11 Jun 2024 from 11:00 to 12:00 CET.

4. MHRA has updated the Guidance on software and artificial intelligence (AI) as a medical device.

5. The MHRA has launched AI Airlock, a new regulatory sandbox designed to help understand risks related to AI as a Medical Device (AIaMD). MHRA will be holding a webinar on 5 June 2024 entitled “AI Airlock - the Regulatory Sandbox for AIaMD in healthcare webinar.” The webinar will provide further information and answer questions relating to the project. Register for the webinar here .

6. Pfizer have published an article titled ‘Three Principles of Responsibility for Artificial Intelligence (AI) in Healthcare.’

7. Anderson et al have published Collective Action for Responsible AI in Health as part of the Organisation for Economic Co-operation and Development (OECD) Artificial Intelligence Papers series. In addition, OECD has also released the white paper AI in Health: Huge Potential, Huge Risks.

Medical Devices

This subsection covers transparency in relation to medical devices, and the emerging intersection of the regulatory medical devices and the regulatory drugs spaces.

General Updates and News

1. A RAPS article entitled “Drug-device combination products: Device regulatory submission content and considerations”is available to view  here. The authors, Soo & Heckman summarise  submission content and best practices of the FDA and notified body (in accordance with EU MDR Article 117) for drug-led combination products and medicinal products that incorporate a nonreusable medical device, respectively.

2. The International Medical Device Regulators Forum  (IMDRF) continues the foundational work of the Global Harmonization Task Force on Medical Devices (GHTF), aiming to accelerate international medical device regulatory harmonisation and convergence. The International Medical Device Regulators Forum (IMDRF) has released several updates:

  • IMDRF/GRRP WG/N52 FINAL:2024 (Edition 2) Principles of Labeling for Medical Devices and IVD Medical Devices: This document applies to all medical devices, including IVD medical devices, and is intended to specify the general content and format of medical device and IVD medical device labeling in paper or electronic format.
  • IMDRF/GRRP WG/N47 FINAL:2024 (Edition 2) Technical Document on Essential Principles of Safety and Performance of Medical Devices and IVD Medical Devices: The guidance provides harmonised Essential Principles to be fulfilled in the design and manufacturing of medical devices and IVD medical devices to ensure safety and performance.
  • IMDRF/GRRP WG/N71 Medical Device Regulatory Review Report: Guidance Regarding Information to be Included: This document provides guidance on the creation of a medical device regulatory review report by Conformity Assessment Bodies.
  • IMDRF White Paper summarising the IMDRF 25th Session Workshop on Reliance held in Washington D.C. in March

3. FDA has drafted proposed updates to the FDA guidance document "Cybersecurity in Medical Devices: Quality System Considerations and Content of Premarket Submissions.” The Draft guidance was issued by FDA 13 Mar 2024. FDA is proposing to add a Section VII to the Premarket Cybersecurity Guidance to address new considerations for cyber devices. The new section identifies the cybersecurity information FDA considers to generally be necessary to support obligations under section 524B of the FD&C Act. 

Also read Lisa M. Baumhardt’s blog reviewing FDA draft guidance on cybersecurity in medical devices (dated 7 May 2024): Can a Device Be Found Not Substantially Equivalent Because of Cybersecurity Risks? A Review of FDA’s Draft Guidance on Cybersecurity in Medical Devices.

4. Kim et al published Regulatory Framework for Drug-Device Combination Products in the United States, Europe, and Korea that details an increasingly frequent theme in protocol development - combination products (CPs; also known as drug-device combinations). CPs are challenging as regulatory review may not be limited to a specific regulatory centre - in the US: Inter-Center Consult Request mechanism, in the EU: EC or the Medical Device Coordination group, and in the Republic of Korea: MFDS has established a program to streamline approval of CPs. 

5. The European Commission continues to monitor availability of medical devices and IVDs in the EU. Results from the latest survey (May 2024) are available here.

6. EMA has released an updated question-and-answer document clarifying regulatory requirements for devices used in combination with medicines entitled “Medical devices: new guidance for industry and notified bodies.” This updated Q&A document provides practical considerations on the implementation of the medical devices and in vitro diagnostic regulations for combinations of medicinal products and medical devices (3 May 2024 Rev.4 EMA/37991/2019).

In Vitro Diagnostics

1. The European Commission has issued a press release regarding the adoption by the European Parliament of measures to improve the availability of in vitro diagnostics (IVDs) and increase transparency. The measures include:

  • longer transition times to the IVDR (Regulation (EU) 2017/746)
  • gradual roll-out of the European Database on Medical Devices (EUDAMED)

2. The MDCG has released MDCG 2024-4 which is a guidance on safety reporting in performance studies of IVDs under the IVDR. An appendix provides the Performance Study Summary Safety Reporting Form in Excel format. Studies within scope include combined studies of medicinal products and IVDs.

3. The MDCG has released 4 new templates for Notified Body assessment reviews of medical devices and IVDs. See MDCG site under Notified Bodies.

EU Transparency

The European Database for Medical Devices (EUDAMED)  is  a single database for medical devices and IVDs in the EU, designed to improve transparency and coordinate information.

1. The MDCG has updated the MDCG 2022-9 / Rev.1 which is the template for the Summary of Safety and Performance (SSP) for high risk (class C and D) IVDs under the IVDR. The SSP will be made public via the EUDAMED.

2. A new version of the EUDAMED (3.8.0) has been deployed. Check out the EUDAMED Information Centre for full documentation.

EU COMBINE

1. The COMBINE project aims to analyse the root causes of the challenges encountered by sponsors in conducting combined studies and identify possible solutions to these challenges. In a recently published Analysis Phase Report the Commission, the national authorities, ethics committees, the European Medicines Agency and stakeholders analyse the current challenges faced when conducting combined studies and possible ways forward to streamline the regulatory landscape. The analysis document details the activities undertaken during the analysis phase, culminating in a proposed direction for future work on this topic aimed at improving the EU landscape for combined studies going forward. A press release is available here.

2. In a recently published report by the COMBINE project, the European Commission, national authorities, ethics committees, EMA and stakeholders analyse the current challenges faced when conducting combined studies and possible ways forward to streamline the regulatory landscape. The COMBINE project aims to address the issues linked to the interface between three EU regulations: the Clinical Trials Regulation (CTR), the Medical Devices Regulation, and the In vitro Diagnostic Medical Devices Regulation. The next steps of this project will investigate developing some of the solutions proposed in the report.

UK MHRA

1. On 21 May 2024, the MHRA announced a four-week consultation on improved safety for high risk in vitro diagnostic devices. Members of the public, including patients, medical device researchers, developers, manufacturers and suppliers, clinicians, and other healthcare professionals are invited to provide feedback on the introduction of common specification requirements to the regulatory framework before IVD devices can be placed on the GB market. The consultation closes on 14 June 2024 and responses are provided via a questionnaire in the form of a consultation survey.

2. On 21 May 2024, MHRA announced a proposed framework for international recognition of medical devices. The MHRA’s statement of policy intent describes how the UK Government intends to recognise regulatory approvals from Australia, Canada, the European Union and the United States of America depending on device type, class, and prior approval.

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