September 2023

Medicines and Vaccines

CTR and CTIS

1. Before submitting a ticket with the CTIS User Support Service, users are advised to consult the latest lists of known issues for sponsors or Member States published on Website outages and system releases. These documents outline the issues that sponsor and authority users may encounter when using the CTIS secure workspaces, with possible workarounds.

2. Transitioning trials to CTIS. As a reminder, the following guidance is available:
   1. Guidance for the transition of clinical trials, as published by the European Commission under EudraLex volume 10.
   2. Best Practice Guide, as adopted by the Clinical Trial Coordination Group. UPDATE: v2.0 was released 12-Sep-23, including the update “Consolidated Investigator’s brochure (IB) and/or Investigational Medicinal Product Dossier (IMPD) not previously harmonised under CTD acceptable when submitting a transition application.” The cover letter template was also updated.
   3. Module 23 of the CTIS online training programme.

3. Reminder: EMA is hosting a CTIS Walk-in Clinic at 16:00-17:00 CEST (Amsterdam Time) on 20 September 2023. Participants will be able to submit their questions in advance starting 6 September or during the event via Slido with the code #clinic239.

4. On 18 August 2023, EMA released minutes from the Clinical Trial Advisory Group meeting held in June 2023. The main points discussed included implementation of the EU CTR and transition trials.

5. The presentation from the CTIS bitesize talk on Part 1-only applications and Part II requirements in CTIS from 30 August 2023, is now available.

6. The European Commission published a new version of the CTR Quick Guide for Sponsors on 28 August 2023. This revised guide includes clarifications on how to submit the IMPD-Q (Investigational Medicinal Product Dossier – Quality) on the manufacturing of the Investigational Medicinal Product at a decentral point of care, at one of the clinical trial sites in the additional Member State.

7. The September 2023 edition of ‘Clinical Trials Highlights’ is in a new and easily navigable format and updates the community on the ACT EU initiative (including a summary report on the June 2023 Multi-stakeholder Workshop on ICH E6 R3), CTIS (including recent improvements and transparency rules, with stakeholder feedback on the latter reflecting diverse views on the use of deferrals and redaction functionalities, with agreement on the need for simplification) and the clinical trials landscape in the EU. A section on ‘Recent and upcoming CTIS events’ is also useful.

8. At the EMA CTIS Forum Stakeholders Meeting held on 14 September 2023, EMA advised that it is expected that updated CTIS transparency rules will be implemented in H1 2024. An update on the revision of the CTIS transparency rules (currently defined in the Appendix on disclosure, dated 2 October 2015) was provided, following a consultation that took place from 3 May to 28 June 2023. Formal endorsement of those updates should take place at EMA Management Board on 03 October 2023 for implementation in CTIS in Q4 2023-Q1 2024, and this is to be confirmed in further communications to address new features and the impact on legacy trials once Management Board endorsement occurs. The main goals of this update are simplification of the process (reduce the burden and complexity for users), improved user experience in CTIS and purposeful transparency (relevant information available for patient and researcher communities). This should lead to significant changes to current ways of working, including decreased numbers of documents required to be published, change in timing of publication (based on trial category), and removal of deferral functionalities.

FDA Guidance and News

1. On 12 and 13 September 2023, FDA hosted a two-day, virtual public meeting to explore GCP considerations for clinical trials with pragmatic or decentralised features. Speaker bios, full recordings, slide decks and transcripts are posted at the link above.

2. An NIH Pragmatic Trials Collaboratory Grand Rounds webinar explored  “Opportunities to Improve Clinical Trials: Draft Revision of the ICH Good Clinical Practice Guideline (E6[R3]).”  The presentations and related discussions on the draft ICH E6(R3) guidelines by Prof. Sir Martin Landray, University of Oxford,  Khair ElZarrad, CDER USFDA, and Adrian Hernandez, Duke Clinical Research Institute from the 18 August 2023 can now be viewed online.

3. DIA will host a live-virtual training on 9, 14 and 16 November 2023, Moving Forward with Decentralized Clinical Trials, to share key takeaways from the recently issued FDA Draft Guidance on Decentralized Clinical Trials.

4. On 19 September 2023, FDA issued draft guidance titled Demonstrating Substantial Evidence of Effectiveness Based on One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence. This Confirmatory Evidence guidance complements the draft guidance Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products (December 2019) and the final guidance Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products (May 1998). The Confirmatory Evidence guidance supplements and expands the 2019 recommendations by providing further detail on the use of data drawn from one or more sources (e.g., clinical data, mechanistic data, animal data) to support the results of one adequate and well-controlled clinical investigation, and provides examples of types of data that could be considered confirmatory evidence. Click here for more details of the draft guidance. Electronic or written comments on the draft guidance should be submitted by 18 December 2023.

5. On 3 October 2023, the ClinicalTrials.gov team will hold a virtual event to discuss the modernisation of the PRS and provide a mini-tutorial on how to register a trial using the modernised interface, PRS Beta. Team members will also be available to answer your questions. See this NLM Technical Bulletin article for more information and how to register.

6. FDA Final Guidance ‘Considerations for the Conduct of Clinical Trials of Medical Products During Major Disruptions Due to Disasters and Public Health Emergencies’ dated September 2023 recommends approaches that sponsors can consider when there is a major disruption to clinical trial conduct and operations due to disasters or public health emergencies. The Appendix on page 6 of the guidance further explains those approaches by providing answers to 26 questions that the FDA received about conducting clinical trials during major disruptions.

7. The latest release of the modernised ClinicalTrials.gov includes the ability to save study records. To learn more, please read the latest Release Notes.

EMA Guidance and News

1. EMA has released the Day 1 Meeting Report from the multi-stakeholder workshop on ICH E6(R3) - Public Consultation - held in July. The aim of the workshop was to engage all stakeholders of ICH E6(R3), including but not limited to, patient, healthcare professionals, assessors, inspectors, industry and academia: Day 1 report plus video recording. Day 2, focussed on discussions in a number of breakout sessions and was not publicly broadcast. 

2. EMA has announced that from 20 October 2023 they will publish Risk Management Plans (RMPs) for all centrally authorised products. This will include the main body and Annexes 4 and 6 for initial evaluations and RMP updates.
   In addition, from 20 October 2023, RMP summaries will not be published.
   EMA already has published guidance on the Anonymisation of Protected Personal Data and assessment of Commercially Confidential Information during the preparation of RMPs from October 2022 and has published a template to provide a declaration for the RMP publication (that it does not contain any personal protected data nor commercial confidential information).

3. EMA is looking for new data partners to collaborate with DARWINEU, to generate real-world evidence that will support scientific evaluations and regulatory decision making on medicines in the EU. See ‘Real World Data’ subsection below for more details.

4. On 21 September 2023, the European Parliamentary Research Service (EPRS) released a 12-page Briefing on the Revision of the EU Pharmaceutical Legislation. The document is quite technical and compares options considered ahead of the revision.

Real-World Data

1. EMA wants to know if your public or private institution has access to real-world healthcare data. EMA is looking for new data partners to collaborate with DARWIN EU, the Data Analysis and Real-World Interrogation Network. You can submit an expression of interest by 31 October 2023 to become a potential new data partner for DARWIN EU. The data will be used for studies to generate real-world evidence that will support scientific evaluations and regulatory decision making on medicines in the EU. Information on how to do that is available on the DARWIN EU® Coordination Centre website.

Transparency and Disclosure Resources and News

1. Khaled El Emam of Replica Analytics & Electronic Health Information Laboratory publishes a monthly Newsletter on LinkedIn. It is worth subscribing so that you can sift through it based on your interests. We’ve pulled a couple of potentially interesting points out of the August 2023 Newsletter here - if not directly to MWs, then certainly to our statistician, programming and DM colleagues - so do please share: 
   1. The annual Synthetic Data Summit will be on 30 November 2023 in London. Presentations will showcase experiences with how synthetic data has been used in practice within the life sciences industry on real world data and clinical trial data, as well as providing perspectives on regulating synthetic data and emerging research. 
   2. A de-identification training course will be held in NYC on 23 and 24 October 2023. 

2. Following stakeholder comments on an earlier draft version, TransCelerate published the final version of “Clinical data sharing: a proposed methodology to enable data privacy while improving secondary use” in August 2023. The data sharing solutions were developed to promote reuse of clinical trial data while protecting patient privacy.  Transcelerate highlight that the methodology is not a  replacement for current anonymisation approaches used by sponsors, vendors, and other relevant stakeholders and how the methodology will work in connection with current approaches to increase data utility should be considered. A transparency checklist  can also be downloaded and used independently of the methodology.

3. The DIA Global Clinical Trial Disclosure and Data Transparency Conference will be held virtually on 5-7 December 2023. The conference will cover the latest information on the Public consultation of EU CTR/CTIS Transparency Rules, the Transparency Rules under the EU CTR, guidance on transitioning ongoing trials to CTIS, and more.. Early bird registration rate is available until 9 October.

4. Multi-Regional Clinical Trials (MRCT) Center of Brigham and Women's Hospital and Harvard held a series of 3 webinars during Q3 2023 and these are now posted online together with their respective slides. The first is entitled “Digging Deeper into Pfizer’s Patient Data Return Solution,” the second “Digging Deeper into IRB/HRPP Responsibilities”and the third “Returning Individual Research Results and Data: Digging Deeper into Genetic Results and Secondary Findings”. These webinars add to the guidance, recommendations, and tools on the MRCT Return of Individual Results website which provides information and resources to aid researchers when returning individual patient level data to participants of clinical trials.

Development Strategy News

1. This article by Eric Klaver (Applied Clinical Trials-08-01-2023, Volume 32, Issue 7/8) titled ‘Proposed ICH-GCP E6(R3) Guidance: Principles in Action’ details some of the key differences in the GCP renovation. Covering 3 key areas - early planning, roles & responsibilities, and decentralisation, Klaverc covers many points that impact protocols. From stakeholder engagement, to clearly-defined roles, data flow diagrams, and risk mitigation - these need to be included in future protocol development efforts.

2. EFPIA has published a white paper as part of a project to increase awareness of the use of oncology-relevant endpoints in HTA body/payer decision-making. The paper entitled “Improving the understanding, acceptance and use of oncology–relevant endpoints in HTA body/payer decision-making” and an accompanying infographic can be freely downloaded. According to the authors “Oncology-relevant endpoints refer to all endpoints used in oncology clinical trials to measure outcomes relevant to patients…..in addition to overall survival, patient-reported outcomes as well as progression-free survival in some metastatic settings, pathological complete response or event-free survival in early oncology settings.”

3. Register for the 2-day Virtual Public Meeting: Mitigating Clinical Study Disruptions During Disasters and Public Health Emergencies. During the COVID-19 pandemic, FDA provided recommendations to mitigate the disruption of clinical studies. Join FDA’s CDER for a FREE virtual public meeting on  18 and 19 October, 2023, from 10 a.m. to 1:30 p.m. ET on both days. This meeting is in collaboration with the Clinical Trials Transformation Initiative to discuss the recommendations and to discuss advanced planning approaches to mitigate the disruption of clinical studies during disasters and PHEs. Agenda here; submit your question in advance.

4. Song et al (2023) published “Practice and consideration of master protocol in clinical trials.” The authors provide an overview of the master protocol framework, present information on different types of master protocol and specifically examine master protocols in oncology trials in more detail.  A comprehensive summary table lists the critical design elements of several representative master protocol cancer trials. In addition, the authors examine information on master protocol trials in oncology devices and also COVID-19 studies, again providing representative examples of master protocol designs in these areas. Practical considerations (design, ethical, statistics, and funding considerations) for designing master protocol trials are also discussed.

News from Asia Regulators

On 25 August 2023, China NMPA released a revised draft guidance for Conditional Marketing Authorisation Approval of Drugs for public comments which is open until 25 September 2023. The revised draft guidance addressed existing practical issues since its first release in 2020. To speed up new drug innovation with clinical values, China NMPA launched an expedited drug review program, encompassing the following 4 approaches: breakthrough therapy designation, conditional approval, priority review, and special approval. Guidances for breakthrough therapy and priority review were also first released in 2020. (Page in Mandarin)

Artificial Intelligence /Machine Learning

Calling EMWA members: EMWA are hosting the MedComms SIG ‘Meet & Share’ titled ‘AI in Medical Writing’ on 27 September 2023. Contact info@emwa.org to register for this virtual meeting.

Medical Devices

Updates from US FDA

FDA issued the final guidance Cybersecurity in Medical Devices: Quality System Considerations and Content of Premarket Submissions. This guidance provides recommendations regarding cybersecurity device design, labeling, and the documentation that FDA recommends be included in premarket submissions for devices with cybersecurity risk. The guidance supersedes the “Content of Premarket Submissions for Management of Cybersecurity in Medical Devices” guidance issued on October 2, 2014. The FDA will also host a webinar on November 2, 2023 to discuss this final guidance.