July 2024

Medicines and Vaccines

CTR and CTIS

1. To reflect the changes introduced by the revised CTIS transparency rules and the new version of the public portal, several modules of the CTIS online training programme have been updated: Modules 02, 07, 10 and 11.

2. The CTIS Newsflash, dated 28 Jun 2024, provides key updates on CTIS and links to useful reference materials including resources for Sponsors on the revised transparency rules:

In addition, the recording of the CTIS Bitesize Talk: Revised transparency rules and the new Public Portal which took place on 20 Jun 2024 is now available.which took place on 20 Jun 2024 is now available.

3. 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 has been updated to V5, dated 19 Jun 2024. The updated guide clarifies that “expedited transition procedure focuses on validation, not assessment, of the minimum dossier of CTD approved documents in line with Guidance published at EudraLex Volume 10. Realising that only a few months remain for transition, sponsors are recommended to withdraw any CTD substantial amendment application not decided upon yet and instead submit consolidated Part I documents directly.”

4. A new CTCG document on safety is available which clarifies topics in addition to Section 7 of the Q&A in EudraLex Volume 10 in relation to CTIS (annual safety report, safety-relevant notifications, reference safety information and requests for information sent within the ‘adhoc’ workflow).

5. EMA published the presentation on Revised CTIS transparency rules and new version of the public portal from the Joint PCWP - HCPWP meeting held on 2 Jul 2024.

6. The EMA has launched a survey to get user feedback on their Clinical Data  Portal. This survey aims to collect your views on the user satisfaction and usability of the Clinical Data Portal (CDP) of the European Medicines Agency (EMA), where the clinical data is published. We expect this survey to take less than 5 minutes. We value your feedback and your responses will help EMA to identify and address potential shortcomings of the current portal and make the clinical data more easily available to all. All answers will be kept confidential and only aggregated responses will be reported. Access the survey here.

7. EU CTR Q&A Update Version 6.9 (09 July 2024) of EU CTR Q&A published on EudraLex Volume 10. Version 6.9, dated July 2024. Changes compared to the superseded version include new question 6.6 on intermediate data analysis along with updates to Annex II, III, IV and V. Summary of updates:

  • Alignment of Q&A responses with revised CTIS transparency rules 
  • Guidance for authorisation strategy replacing PI at existing trial site in exceptional cases resulting from unforeseen urgent circumstances
  • For paediatric clinical trials not falling within the scope of Article 46(1) of the Paediatric Regulation (EU no 1901/2006), where it is for scientific reasons not possible to submit the summary of results within six months, the summary of results shall be submitted at the latest within twelve months after the trial has ended
  • New question providing guidance on what are considered intermediate data analysis in light of the CTR, format and procedure for their submission, and exceptions thereof, in cases
    • Where the blind of the sponsor and/or investigators should be maintained resulting from an intermediate data analysis by an IDMC
    • Where the protocol provides clear criteria on the decision on how to continue the clinical trial (e.g. on dosing regime in an early phase trial)
    • Where for justified reasons described within the protocol it is not possible to submit a summary of the intermediate results within one year.

8. A general introduction and overview to CTIS is presented in the online article by Singh and Shaik entitled “Understanding The Basics Of EU Clinical Trials With CTIS.”

9. EMA published yet another update (V1.7, dated 19 July 2024) of Revised CTIS transparency rules and historical trials: quick guide for users, to include slide 17 on substantial modification for change of sponsor.

10. CTIS Release Notes – Release v1.0.42.0 date 8 Jul 2024 outlines the latest updates to the CTIS system.

11. CTCG has released new templates:

Cover letters are essential documents providing relevant background information on the application, and a clear overview of what has been submitted in CTIS. A high-quality cover letter will facilitate validation and assessment. This also applies to the ‘List of Changes’ to be submitted as a response to the RFI.

European Health Data Space (EHDS) News

1. The European Commission has released the 2024 Digital Decade eHealth Indicator Study Annex – Country Factsheets. The report summarises the eHealth indicators  of each of the 27 member states, including eHealth maturity scores based on access to eHealth data.

UK and MHRA News

1. The UK HRA held a workshop in March 2024 ‘to explore the barriers and potential solutions for registering clinical trials. A summary from that workshop has been published: Make it Public workshop summary. Four key themes were identified: resources needed for registration; cost of registering; difficulty in finding a suitable registration platform for all study types; and restrictions or complexities with the registration platform.

FDA Guidance and News

1. On 27 June 2024, FDA Reports Information on Real-World Evidence Submissions in a public report on submissions to CBER (which include 4 protocols) and CDER (which include 10 protocols and 4 NDAs/BLAs) that contain real-world evidence (RWE). The use of real-world data (RWD) to improve the efficiency of drug and biologic development programs that rely on traditional clinical trials is well established and encouraged by FDA. This is the first annual report describing submissions to CBER and CDER that contain analyses of RWD to generate RWE intended to support regulatory decision-making about a drug or biological product’s effectiveness or safety.

2. FDA published draft guidance entitled “Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies.” This guidance is intended to assist sponsors conducting certain clinical studies involving drugs, biological products, and devices to meet requirements for the submission of Diversity Action Plans. The guidance is open for comment until 26 Sep 2024.

3. The latest ClinicalTrials.gov updates are available: 

4. The FDA has released a guidance snapshot on Digital Health Technologies for Remote Data  Acquisition in Clinical Investigations. A guidance recap podcast is available here.

5. The FDA announced the upcoming launch of the FDA Rare Disease Innovation Hub, an initiative aimed to enhance patient outcomes by accelerating the development and approval of treatments for rare diseases.

6. The FDA has released for comment the draft guidance Purpose and Content of Use-Related Risk Analyses (URRA) for Drugs, Biological Products, and Combination Products. A URRA plays a vital role in identifying potential risks associated with user interaction with a combination product. The guidance informs manufacturers of drug- and biologic-led combination products about the purpose and content of a URRA used to support a marketing application.

7. July 2024 FDA released finalised guidance on evaluating real-world data (RWD) from electronic health records (EHR). See ‘Real World Data’ subsection below for details. 

EMA Guidance and News

1. EMA is hosting a webinar on the newly launched consolidated advice pilots on 17 July 2024, outlining their scope and benefits. The pilots aim to improve the quality of applications for clinical trials and/or marketing authorisation. Participants can submit questions between 24 Jun to 10 Jul 2024 via Slido, using the code #pilotsCA.

2. EMA has issued a concept paper on the revision of the COVID-19 vaccines guidance documents. The paper is open for public consultation until 30 Sep 2024. The proposed guideline will replace the EMA considerations on COVID-19  vaccine approval (EMA/592928/2020) and the reflection paper on the regulatory requirements for vaccines intended to provide protection against variant strain(s) of SARS-CoV-2 (EMA/117973/2021).

Real-World Data

1. Prilla et al have published a review presenting the EMA experience of pilot activities to explore suitable pathways and approaches for generation and use of RWE for regulatory decision making (conducted from Sep 2021 to Feb 2023).

2. EMA released an ICH reflection paper on pursuing opportunities for harmonisation in using real-world data to generate real world evidence, with a focus on effectiveness of medicines. The paper outlines a strategic approach to address challenges and discusses how to enable the integration of RWE into regulatory submissions and timely regulatory decision-making. The authors state that the reflection paper represents the initial step of an incremental approach towards harmonisation of regulatory RWE guidance.

3. July 2024 FDA released finalised guidance on evaluating real-world data (RWD) from electronic health records (EHR). The final guidance entitled: “Real-World Data: Assessing Electronic Health Records and Medical Claims Data to Support Regulatory Decision-Making for Drug and Biological Products” offers clarification of study design elements including on selecting study variables and validation.

4.PHUSE blog post titled "RWD: The FDA’s Guidance on Assessing Registry Data to Support Regulatory Decision-Making". Read now; Project Information.

Transparency and Disclosure Resources and News

1. The newly released Public Library of Science (PLOS) Open Science Indicators (OSI) includes a new and very important indicator - study registration or preregistration. For the purposes of the OSI, study registration is defined as “the plan for a research study, including research questions/ hypotheses, details about the research design, and/ or plans for data analysis, which has been made available for public sharing in order to ensure unbiased reporting and support the differentiation of planned and unplanned research directions.” The latest OSI results indicate that while overall pre-registration rates remain low, the proportion of pre-registered studies has increased, with clinicaltrials.gov as the most commonly used registry. PLOS also shares the complete dataset that dates back from 2018.

2. The PHUSE data transparency autumn 2024 event will take place 17–19 September 2024 from 15:00-17:30(BST)/10:00-12:30(EDT). This is a virtual event and free to attend. Registration opens on 5 Aug 2024.

3. RAPS is holding a free Webcast entitled “Author Clinical Study Reports with Data Privacy & Disclosure in Mind” on 7 Aug 2024. Register for the event here. The aim is to discuss the effect that medical writing has on clinical data disclosure and to show how lean authoring with disclosure in mind can increase the efficiency of the public disclosure process. 

4. Masterclass on 4 Sep 2024 – how to unlock the potential of data sharing in collaborative projects. This is an interactive session to introduce practical tools and resources to help share health data. The masterclass will be based on the new Data Sharing Playbook, which was produced by EFPIA. Register for the event here.

5. Daval and Kesselheim published a Viewpoint article in JAMA in July 2024 entitled “The Origins of ‘Confidential Commercial Information’ at the FDA”. The authors review FDA’s authorities and obligations under current law and conclude that FDA can take steps to allow itself more flexibility to share information in the interest of public health.

EMA Policy 0070 in Practice

1. EMA has launched a Clinical Data Publication Survey to collect user satisfaction and usability of  their Clinical Data Portal for EMA Policy 0070.

Development Strategy News

1. In 2017, FDA’s CDER began the modernisation of the New Drugs Regulatory Program (NDRP), a multi-year framework to increase the efficiency and effectiveness of CDER offices. The modernisation is in response to a rapid increase in drug development complexity and volume in the past two decades and the anticipation of future growth, fueled in part by the recent breakthroughs in genetic science, personalised medicine advances, and a greater focus on rare diseases and disease subtypes. To keep pace, CDER began this initiative to continuously improve its regulatory science and review process for drug applications. In this CDER Conversation, Yoni Tyberg, associate director of the Special Program Staff in the Office of New Drugs (OND), discusses the modernization, its accomplishments, and its impact on public health. A comprehensive list of the achievements is available in the NDRP Modernization - Impact Narrative 2023.

2. The EU-X-CT Cross-Border Clinical Trials Initiative, co-led by the European Forum for Good Clinical Practice (EFGCP) and EFPIA, is dedicated to enhancing access to cross-border clinical trials in Europe. The first Public Stakeholders’ Forum was organised in Brussels in Apr 2014. The report can be found here. The initiative is now working on drafting recommendations for cross-border trial access based on feedback from surveys and discussions at the Stakeholder Forum. These recommendations are expected to be shared for public comment by the end of 2024.

3. TransCelerate, CDISC, and Vulcan co hosted this Webinar (recording:  Vulcan UDP (Utilizing the Digital Protocol): Collaborating to Accelerate ICH M11 and End User Value; slides here) that provides an update to the challenge of defining, adapting, and releasing a fully utilisable digital protocol template. The Webinar included representatives from FDA, EMA, CDISC, TransCelerate and Vulcan. Of note, ICH M11 Step 4 is planned for autumn 2025.

4. A TransCelerate webinar entitled “Mastering Master Protocols and Advancing Platform Trial Research: a CC&R and EU-PEARL Collaboration” is to be held on 10 Sep 2024. Register for the webinar here. Background information on the initiative can be found here.

5. Kliegman et al published the paper A roadmap for affordable genetic medicines that presents recommendations of a multi-disciplinary task force assembled to chart a path towards affordable and accessible genomic therapies.

6. The Pistoia Alliance, a non-profit members only organisation, supports the implementation of the Findable, Accessible, Interoperable and Re-usable (FAIR) guiding principles for research data management and stewardship in the biopharmaceutical industry. The Alliance has launched a survey that aims to collect case studies demonstrating the business value of implementing FAIR principles. The survey will remain open until the end of August 2024.

7. Karl-Heinz Loebel published an article in the DIA Global Forum entitled “How Did We Get Here? A History of eCTD and Prospects for eCTD 4.0”, which gives an overview of the evolution of Common Technical Document (CTD) from the pre-CTD time to the implementation of eCTD 4.0. 

Artificial Intelligence / Machine Learning

1. The International Medical Device Regulators Forum (IMDRF) has published guiding principles for artificial intelligence/good machine learning (AI/ML) practices in medical device development that are identical to a 2021 document published by US, UK, and Canadian regulators. The document entitled “Good machine learning practice for medical device development - Guiding Principles” is open for consultation until 30 Aug 2024. It establishes a common set of 10 guiding principles to promote the development of safe, effective, and high-quality medical devices that incorporate AI.

2. FDA and Clinical Trials Transformation Initiative (CTTI) will hold a free hybrid public workshop on AI in drug and biological product development on 6 Aug 2024 (10:00 AM - 5:30 PM EDT). Registration is open and can be completed here. Workshop agenda is available here.

3. The paper Applying generative AI with retrieval augmented generation to summarise and extract key clinical information from electronic health records by Alkhalaf et al. describes the performance and limitations of applying zero-shot learning to generative AI models to automatic generation of structured summarisation of EHRs data and extracting key clinical information. 

4. Kastrup et al. have published Landscape and challenges in economic evaluations of artificial intelligence in healthcare: a systematic review of methodology. The review “seeks to map the evidence on the general methodological quality of health economic evaluations (HEEs) for AI technologies to identify potential areas which can be subject to quality improvements.”

5. The European Union’s Artificial Intelligence Act (EU AI Act) was published on 12 July 2024. “The purpose of this Regulation is to improve the functioning of the internal market by laying down a uniform legal framework...for the development, the placing on the market, the putting into service and the use of artificial intelligence systems (AI systems) in the Union....to promote the uptake of human centric and trustworthy artificial intelligence (AI)...” The act governs use of AI for medical devices, in vitro diagnostic devices and other products. A recent blogpost by Hines et al, provides information regarding the potential effects for healthcare. In her LinkedIn post Julia Appelskog presents some key points with respect to the guidance.

6. This Whitepaper published by InteliNotion LLC is titled The Convergence of Generative AI and Structured Content and outlines an approach that combines structured content management with Generative AI (GenAI). In what the authors term "GenAI assisted contextual authoring". The authors provide an approach that leverages GenAI to support document authors. This approach overcomes a significant limitation when looking at AI-driven content generation, marrying the use of AI with study-specific requirements. 

7. Generative artificial intelligence, patient safety and healthcare quality: a review, written by Dr Michael Howell of Google, “serves as a primer on foundation models’ underpinnings, upsides, risks and unknowns—and how these new capabilities may help improve healthcare quality and patient safety.”

8. Haltaufderheide & Ranisch have published The ethics of ChatGPT in medicine and healthcare: a systematic review on Large Language Models (LLMs). The study identified “recurrent ethical concerns connected to fairness, bias, non-maleficence, transparency, and privacy” and calls for critical inquiry “to evaluate the necessity and justification of LLMs’ current experimental use.”

News from Asia Regulators

1. In May 2024, China adopted the ICH guidelines Q2(R2) on Validation of Analytical Procedures and Q14 on Analytical Method Development (page in Mandarin). All relevant studies are required to adhere to the principles outlined in Q2(R2)/Q14 guidelines effective from 24 Nov 2024. China NMPA released the translated versions of both guidelines (page in Mandarin) in Feb 2024.

2. In May 2024, China NMPA released the Technical Guidelines on Decentralized Clinical Trials in Clinical Research of Rare Disease Drugs (page in Mandarin). The guideline provides suggestions on applying Digital Health Technologies in the clinical development of rare disease drugs, and provides references for scientific and standardised implementation of DCT in rare disease drug development.

3. In Jan 2024, China NMPA released the Technical Guidelines on Writing Safety Information in Medication Package Inserts of Anti-tumour Drugs (page in Mandarin). The guideline provides the principles and guidance on the content standardisation of the safety information of anti-tumour drugs in package inserts. 

4. With Singapore's Agency of Science, Technology and Research (A STAR), the Personal Data Protection Commission in the country released the Proposed Guide on Synthetic Data Generation. The guide proposes good practices and risk assessments/considerations when generating synthetic data to minimise risks of re-identification of personal data. The guide also proposes the use of synthetic data as training datasets for AI models.

Synthetic data generation is one of the techniques within Privacy Enhancing Technologies (PETs) that generates artificial data from real data using a purpose-built mathematical model/algorithm. Good quality synthetic data retain the statistical properties and patterns of the source data and analyses on these data can produce results similar to those analysed on the source data.

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

The WHO has introduced an online platform called MeDevIS (Medical Devices Information System), the first global open access clearing house for information on medical devices. A webinar was held on 8 July entitled “Nomenclature of medical devices: EMDN & GMDN” and a recording and slides are available from here. The WHO announcement is here.

 EU COMBINE Initiative: In Vitro Diagnostics (IVDs)

1. The intersection of drugs and diagnostics in clinical trials is one of the key focuses of COMBINE. The MDCG 2020-16 Guidance on Classification Rules for IVD Medical Devices under Regulation (EU) 2017/746 has been revised (revision 3). Two key additions are the definition of “kit” and clarification on “devices for self-testing.”

2. With the extension of the EU IVD Regulations Transitional Periods, the European Commission released a Q&A document on the practical aspects related to this extended transition. In addition, the Q&A on the extension of the MDR transitional period has been updated to keep both Q&As aligned.

3. The International Medical Device Regulators Forum (IMDRF) is a voluntary group of medical device regulators from around the world whose mission is to strategically accelerate international regulatory convergence and harmonisation for medical devices. IMDRF has recently published key guidance on the Table of Contents of technical documentation for IVD and nonIVD medical devices. The Technical Documentation is the marketing authorisation dossier for medical devices, equivalent to the eCTD for drugs.

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