September 2024

Core Reference Webinar

Keep a placeholder for Wednesday 04 December 2024, 12:30 - 13.45 CEST (11.30 - 12.45 UK time)

Title: EMA Policy 0070 Real Life Experience – Voydeya

Presenters: Raquel Billiones, PhD and Alison McIntosh, PhD for the CORE Reference Team 

Register by clicking here.

The next CORE Reference webinar will focus on preparing an EMA Policy 0070 Anonymisation Report (AnR), using examples from the Voydeya submission completed in Spring 2024 and with clinical data published on 26 June 2024. Members of the CORE Reference team will discuss specific challenges presented by rare diseases, including selection of appropriate anonymisation methods and will outline some of the problems challenges this poses with maintaining data utility. The webinar will also cover interactions with the EMA and present some  lessons learned from the Voydeya anonymisation process.

This webinar will:

  • Provide a brief overview of the Policy 0070 AnR and associated anonymisation methodology
  • Outline challenges presented by rare diseases as illustrated by the Voydeya submission
  • Outline challenges posed in maintaining data utility 
  • Review interactions with EMA including the pre-submission meeting
  • Discuss challenges and learnings from the Voydeya anonymisation process. 

Previous related presentation: The CORE Reference webinar on 7 June 2024 included a general introduction to the Policy 0070 Anonymisation Report (AnR) Template. For details, see https://www.core-reference.org/media/1088/core-reference-seminar-emwa-valencia-may-2024-and-webinar-07-june-2024-slides.pdf (refer to webinar slides 21 – 37 or presentation video at 30 – 58 minutes).

Medicines and Vaccines

ICH

1. Following the adoption of the E11A Guideline, a Step 4 Introductory Training Presentation has been developed by the E11A Expert Working Group. The ICH E11A Introductory Training on Pediatric Extrapolation can be downloaded here.

CTR and CTIS

1. CTIS newsflash 10 Sep 2024 is available; all issues are here. Latest updates:

  • Guidance on how to ensure tasks and RFIs are not missed
  • Guidance on the CTIS timetable which should be considered a guide only
  • Public Portal new features (see note below)
  • Dates for upcoming events and webinars
  • Known issues with ASR submissions 
  • List of latest system improvements/fixes
  • Submission numbers for July and August 2024
  • Where to find additional information and guidance.

The Public Website is up and running and Advanced Criteria Search allows searches for ‘submitted circumstantial events’ i.e., Serious Breaches, Unexpected Events, Urgent Safety Measures. Search these events to help with process improvement and improved quality management.

2. CTIS Public Portal new features that will be available from 20 Sep 2024 mean that users can perform advanced searches, subscribe to an RSS feed, and download their search results and clinical trial information.

3. A new EU CTIS walk-in clinic will be organised for 20 November 2024, 16:00 to 17:00 Amsterdam time. This walk-in clinic on CTIS functionalities provides an opportunity for sponsors to receive practical information about the Clinical Trials Information System by asking questions to CTIS experts in real time.

4. A reminder about the CTIS Information Day on 17 October 2024. This virtual event aims to support sponsors of clinical trials in proceeding with the transition to meet the deadline of 31 January 2025. 

5. CTIS Evaluation Timelines V2.1, September 2024, are out now.

6. Expectations around posting CSR for publication on CTIS were recently shared by Sponsors at DIA and are summarised below [credit: Julie Holtzople]:

  • The scope for CSRs under CTIS is clear now, and is the same as Policy 0070. This includes CSR Sections 1 through 15 and Appendixes 16.1.1, 16.1.2, and 16.1.9. Module 2 is not in scope for CTIS publication.
  • CSRs are going to be due for upload on CTIS before Policy 0070 based on regulatory timelines which will be challenging for sponsors
  • CSRs are not expected to be reviewed on CTIS
  • There are more CSRs in scope for publication on CTIS than EMA Policy 0070. Reminder: Policy 0070 covers central procedures whereas CTIS includes any submission to any countries individually.
  • There was a brief discussion around posting technical results on CTIS. It was suggested that for now, the EUDRACT form could be used to upload results to CTIS.
  • If you transition a study as part of a substantial modification to a new sponsor, updating the org ID number triggers the system to publish documents.
  • Brief note on Policy 0070: EMA expects to provide an update on plans for Part 2 restart for packages that have been on hold sometime in 2025. Phase 2 implementation details are not currently under any discussion within the EMA.

EU Regulatory

1. The Italian Medicines Agency (AIFA) has released a guideline for the classification and conduct of observational studies. This document is in Italian.

2. The EMA has finalised a reflection paper on establishing efficacy based on single-arm trials (SATs) submitted as pivotal evidence in a marketing authorisation.

3. The EU Commission released the Updated rolling plan (Sep 2024) for the Implementation of the Regulation on Health Technology Assessment (Regulation (EU) 2021/2282). As a reminder, the Health Technology Assessment Regulation (HTAR) entered into force on January 11, 2022 and it will be applicable as of January 12, 2025.

UK and MHRA News

1. In August 2024, the ISRCTN clinical study registry launched a new and improved Transparency Tracker. Registry records will also now display badges to highlight prospective registration, regularly update ongoing records and post protocols, statistical analysis plans, and add results to the record.

2. On 5 September 2024, the UK HRA announced that over the next six weeks they will be getting in touch with sponsors to find out whether studies from before 2018 have been completed. Tell us about your older studies.

3. UK HRA published its latest Clinical Trials Update bulletin on 19 September 2024 highlighting the recent updates to “requirements around the constitution of RECs and research transparency requirements”.

FDA Guidance and News

1. The FDA issued a draft guidance “Incorporating Voluntary Patient Preference Information over the Total Product Life Cycle”. This guidance provides recommendations on when and what methods could be used to collect and submit patient preference information (PPI) across the total product life cycle. This helps sponsors and patient preference study developers adopt updated methodologies and considerations when designing their studies appropriately to inform benefit-risk decision making. Comment submission to the draft guidance is open until 05 December 2024. The FDA will also host a webinar on 15 October 2024 to discuss the draft guidance. Registration is not needed, more information and the link to the webinar is available here.

2. FDA has launched the Guidance Snapshot Pilot Program to support transparent communication and dissemination of FDA guidance documents on topics that will help to modernise trials and accelerate drug development. FDA intends to increase general public awareness and engagement for their guidance documents through the Snapshots which will summarise guidance documents using visuals and plain language. Review the page to see which guidance documents are in the programme, how to read the Snapshots, and appreciate their limitations. 

3. In September 2024, FDA issued draft guidance ‘Considerations for Generating Clinical Evidence from Oncology Multiregional Clinical Development Programs’ that, when final, will provide sponsors with recommendations for conducting multiregional clinical trials (MRCT) in support of applications for drugs intended to treat cancer. An MRCT is a trial that is conducted in more than one region under a single protocol, with ‘region’ defined as a geographical region, country, or regulatory region. Submit comments by 18 Nov 2024.

4. Final September 2024 FDA Guidance ‘Conducting Clinical Trials With Decentralized Elements’ is available. This guidance provides recommendations regarding the implementation of decentralised elements in clinical trials. Decentralised elements allow trial-related activities to occur remotely at locations convenient for trial participants and can include telehealth visits with trial personnel, in-home visits with remote trial personnel, or visits with local health care providers.

5. In September 2024, FDA issued draft guidance, “Integrating Randomized Controlled Trials for Drug and Biological Products into Routine Clinical Practice”. When final it will support the conduct of randomised controlled trials with streamlined protocols and procedures that focus on essential data collection, allowing integration of research into routine clinical practice. Submit comments by 17 Dec 2024.

6. The FDA has released the final guidance on Study Data Technical Conformance Guide - Technical Specifications Document. The guidance provides specifications, recommendations, and general considerations on how to submit standardised study data using FDA-supported data standards. It supplements the guidance for industry Providing Regulatory Submissions in Electronic Format — Standardized Study Data (eStudy Data). 

EMA Guidance and News

1. On 29 August 2024, EMA released Guiding principles on the use of large language models in regulatory science and for medicines regulatory activities. This document provides guiding principles on the use of general-purpose large language models (LLM) in regulatory science and for regulatory activities and provides high-level recommendations to regulatory authorities to facilitate the safe, responsible and effective use of LLMs. In the ‘Conclusion’ section, it states: “In this fast-evolving field, it has never been more important to provide a structured approach to integrating advanced AI tools into regulatory processes to safeguard public health and maintain trust in medicines regulatory authorities”.

2. Join the Scientific Symposium on Advanced Therapy Medicinal Products (ATMPs) on 10 October 2024, at EMA’s Amsterdam headquarters or online. The event will highlight how ATMPs are revolutionising patient care, featuring discussions on regulatory advancements and groundbreaking treatments for unmet medical needs. It will also outline the evolution of EMA’s Committee for Advanced Therapies, the CAT, and its adaptation to the challenges posed by novel classes of ATMPs. Register now - the deadlines for registration are 24 September for in-person attendance and 1 October for remote attendance.

3. EMA is organising the following free scientific events:

Real-World Data

  1. The report of the CIOMS Working Group XIII on Real-world data and real-world evidence in regulatory decision making is now available as pdf for free download here.

Transparency and Disclosure Resources and News

1. The MRCT Center is organising 3 webinars in October 2024 which will discuss and provide practical tools in incorporating health literacy and accessibility best practices into communicating participant-facing clinical research information. Register free below. Recording links and any webinar materials will be provided to registrants who are unable to attend live. In this article, iPDR is defined as a study participant’s individual data that is distinct from a return of layperson summary of aggregate results.

2. An online paper by Paula Boyles examines individual participant data return (iPDR) where iPDR is defined as a study participant’s individual data that is distinct from a return of layperson summary of aggregate results. 

3. This blog post Engaging Gen Z in future healthcare: the role of pharma, Open Science and the Third Sector, by Daya Deb, a clinical medical student at the University of Oxford, describes the importance of engaging with Generation Z, “a demographic characterised by its digital ease, social consciousness, and demand for transparency and authenticity”..., “a generation that values transparency and expects open access to information.”

4. The EFPIA blog on Data anonymisation: balancing privacy and progress aims to contextualise data sharing. It provides a visual aid of the so-called “anonymisation gradient” to “help individuals outside of clinical trial disclosure better understand the balance of retaining data utility and protecting patient privacy.”

EMA Policy 0070 in Practice

1. Real Life Sciences will hold a free webinar on 16 Oct 2024 at 3pm UK time. Entitled “Qualitative Anonymization Best Practices for Policy 0070 and PRCI Disclosure Submissions” it will consider the differences between qualitative and quantitative methodologies as well as several best practices to projects are completed on-time and approved by the Health Authority. Registration details here.

Development Strategy News

1. Patient-Focused Medicines Development (PFMD) is seeking public input on the Patient Engagement (PE) & Patient Experience Data (PED) project through this survey. The initiative aims to create a PE & PED Integrated Navigator to guide stakeholders in implementing meaningful PE in their studies. 

2. Following the July webinar, TransCelerate is organising a webinar “Vulcan UDP (Utilizing the Digital Protocol): Spotlight on Connectathon Results and Plans” on 15 October 2024, 9-10.30am ET. 

Vulcan’s UDP is an umbrella project accelerating ICH M11 and end-user value. The webinar will provide a brief background of the UDP project, insight into the UDP Connectathons (technical events that test development work within business processes) focusing on study-level elements of the title page, eligibility criteria, objectives/endpoints/estimands, and discuss the practical steps to prepare for implementation.

3. On Thursday, 25 September 2024 the WHO released a final guidance document aimed at improving the design, conduct and oversight of clinical trials in countries of all income levels and it is available to download here. A news release with further information is available here. A recording of the launch webinar presentation is available here. Developed over two years the guidance aims to enhance the integrity and effectiveness of clinical research globally.

Artificial Intelligence/Machine Learning

1. On 29 August 2024, EMA released Guiding principles on the use of large language models in regulatory science and for medicines regulatory activities. See 'EMA Guidance and News’ section above for further details.

2. FAIR (findable, accessible, interoperable and reusable) data principles add value to organisations by reducing time needed to find valuable information, facilitating interoperability, reusability and enabling AI initiatives. A webinar on Maturity Frameworks Supporting the Implementation of FAIR Data Principles was held on 4 Sep 2024. The recording is available here.

3. The UK Research Integration Office is organising a webinar on AI in Research: Supporting Research Integrity through Governance and Ethics on 9 Oct 2024.

4. The European Commission has published the FAQs on Data Act (Regulation (EU) 2023/2854) to support its implementation.

5. The US, EU and the UK have signed the first international treaty on the use of AI. Other countries are joining to sign the pact which “requires signatories to be accountable for any harmful and discriminatory outcomes of AI systems. It also requires that outputs of such systems respect equality and privacy rights.”

6. The comment paper by El Fassi et al Not all AI health tools with regulatory authorization are clinically validated calls for new validation standard to evaluate FDA authorisation as an indication of clinical effectiveness in medical AI.

7. Quer and Topol have published The potential for large language models to transform cardiovascular medicine. This is the 4th in a series of four papers about artificial intelligence and digital innovations in cardiovascular care.

8. A recent RAP article reviews a selection of free AI tools and how they can be applied to support the creation of quality regulatory deliverables. The authors reviewed a selection of AI tools for supporting regulatory functions including writing. Their article focuses primarily on the review of free AI tools that were known to the authors at the time of the publication. 

9. On 29 Sep 2024 FDA published “Digital Health and Artificial Intelligence Glossary – Educational Resource.” The glossary is a compilation of commonly used terms in the digital health, artificial intelligence, and machine learning space and their definitions.

10. The Technical University of Dresden, Germany, is organising a hybrid symposium on Large Language Models in Medicine on 10 October. This event will an overview of the capabilities of LLMs in healthcare, with a focus on their usefulness in oncology care. The event will also cover LLM’s “role in supporting healthcare, shed light on legislation surrounding real-world data usage, and present various implementation projects showcasing the practical applications of LLMs in medicine from research and company perspective.”

11. On 09 September 2024, EMA published a FINAL revised reflection paper on the use of artificial intelligence in the life cycle of medicines. The aim is to ensure that trust in medicines regulatory decision making and patient safety are not undermined. The paper highlights principles for applying AI and machine learning safely and effectively across various stages of medicine’s development, from initial discovery to post-authorisation. Public consultation on the draft paper has helped - in this final version - to clarify scope; harmonise and explain technical terms; reword terminology on risks; further consider the EU AI Act and the fast-changing landscape; support the future drafting of formal EMA scientific guidelines on AI.

News from Asia Regulators

The Health Sciences Authority of Singapore released the eCTD Specification package version 1.0 for implementation effective 25 September 2024. The package comprises the following documents:

  • SG-HSA eCTD Specification and Validation criteria
  • Technical files (defined lists, validation matrices, stylesheets, schema)
  • Sample eCTD submissions

The target launch date of eCTD portal is March 2025. More info here.

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. Devices information or regulations that impact the reporting of device studies are also covered. Contextualisation is provided, where possible, to help readers understand how the information could be used. 

General Updates and News

1.EMA is initiating a new pilot programme for the expert panels to support manufacturers manufacturing and notified bodies certifying orphan medical devices with the challenges linked to generating clinical evidence for these devices in the premarket phase. This supports the implementation of MDCG 2024-10 Guidance on Clinical Evaluation of Orphan Medical Devices. The European Commission and the EMA are organising a joint webinar on 23 Sep on this new pilot programme. 

2. Taher et al have published the paper Developing a process for assessing the safety of a digital mental health intervention and gaining regulatory approval: a case study and academic’s guide that describes getting regulatory approval for a novel digital mental health tool considered as Software as a Medical Device.

3. The Notified Body BSI is organising a webinar on 17 Sep 2024 on the Notified Body’s role in patient safety in recognition of the WHO Patient Safety Day.

4. Melvin et al. have published the paper Orphan and paediatric medical devices in Europe: recommendations to support their availability for on-label and off-label clinical indications. The article examines “the use of medical devices in orphan and pediatric conditions, the relevant aspects of regulations and associated guidance…” It also suggests possible policy and practice interventions to ensure the continued availability of essential devices for children and people with rare diseases.

5. The FDA has released the draft guidance on Chemical Analysis for Biocompatibility Assessment of Medical Devices which is open for comments till 18 Nov 2024.

6. A new version (Rev.1) of MDCG 2021-4 guidance Application of transitional provisions for certification of class D in IVD medical devices according to IVDR has been released. The updated provisions are important in ensuring continued availability of essential IVDs in the EU.

7. The International Medical Device Regulators Forum (IMDRF) is a voluntary group of medical device regulators from around the world with the aim to strategically accelerate international medical device regulatory convergence and harmonisation. IMDRF has recently released the Document Implementation Report which provides a status update on developing harmonised technical documentation for Medical Devices by participating countries.

8. Team NB has updated the Code of Conduct for Notified Bodies (NB) under the EU MDR and IVDR with the aim to improve “implementation of the European CE certification of medical devices through the harmonisation of NBs". NBs are designated in the EU to assess the conformity of medical devices before they are placed on the market.

9. UK MHRA has updated its Guidance on Clinical Investigations (Clinical Trials for Medical Devices). The September updates impact the sections on IVDs and Amendments. 

EU Transparency

1. EFPIA engaged Lygature (a specialist research organisation) to assess the impact of current disclosure activities. The outcome report “provides an overview of the major mandatory and voluntary disclosure types that the pharma industry supports and reveals gaps in our collective understanding of the broader public health impact of disclosure activities.” The report suggests the need for a comprehensive approach to measuring the value of data disclosure.

EUDAMED News

1. A webinar exploring the differences between the EU and US regulatory landscapes, entitled “Developing an Effective Regulatory Strategy for the Evolving 2024 Medtech Landscape” will be held on 22 Oct 2024 (10 AM EDT; 4 PM CEST). Register for the free webinar here.

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