December 2023

Medicines and Vaccines

ICH

 CTR and CTIS

1. CTIS transparency rules: a quick guide for users was published on 1 Dec 2023 on the ACT EU website entitled “Revised CTIS transparency rules, Interim period & Historical trials: quick guide for users.”  This guide provides a summary of what will be published under the revised rules, the relevant timings of publications per revised rules, and on the new section of the updated Q&A document on protection of CCI and PD (info re Q&A document v1.3 were in November monthly update, downloaded document here).

EU Regulatory

1. The ACT EU initiative hosted a multi-stakeholder workshop on clinical trial methodology guidance on 23 November 2023. According to the organisers “Stakeholders and regulators exchanged views on key methodology topics, with a focus on patients' needs. Over 110 participants from key stakeholder groups and the European Medicines Regulatory Network (EMRN) had the opportunity to work together in breakout sessions to identify the main challenges for key topics on clinical trial methodology and to propose the best way forward.” Recordings of the live broadcast sessions are available here.
2. On 21-Dec-23 two  updates were made to the EU Clinical Trial Regulation
   • EU Commission Q&A relating to EU CTR - v6.7 
   • Guidance on Transition of Trials 
   Overall the updates are relatively minor, with the Q&A including additional clarifications relating to safety reporting and other changes reflecting much of the evolution of guidance occurring in other areas.

UK and MHRA News

1. MHRA rolled out a New Notification Scheme to streamline initial clinical trial authorisation (CTA) applications. The scheme only applies to CTA applications for Phase 4 and certain low-risk Phase 3 clinical trials and excludes first in human, Phase 1 or Phase 2, or amendments at this time. CTA applications submitted under this scheme will be processed by the MHRA within 14 days, instead of the statutory 30 days, provided the sponsor can demonstrate the trial meets the MHRA’s criteria. Also read the previous press release.

2. UK Clinical Trials Performance Metrics: Dec 2022 – Nov2023: Assessment Clinical Trial Authorisation Applications, Clinical Investigations and Substantial Amendments.

FDA Guidance and News

1. FDA makes a statement about the importance of clinical trials transparency and reiterates the legal and ethical responsibilities of the entire clinical research community to register and submit their clinical trial results information.

2. As part of Project Equity, FDA issued a draft guidance in April 2022 recommending that sponsors of certain drugs, biological products, and devices (medical products), submit Diversity Plans (DPs) that describe their plan to enrol racially and ethnically representative populations in clinical trials intended to support the approval or licensing of these medical products. The Oncology Center of Excellence has published a summary of the first year of diversity plans submitted under the draft guidance to the Center for Drug Evaluation and Research’s oncology review divisions.

3. FDA is making public any preliminary notices of noncompliance (pre-notice) it issues to describe potential noncompliance with certain requirements under federal law for submitting registration and/or results information to ClinicalTrials.gov. Pre-notices may be issued for potential violations such as: 
   • Failing to register an applicable clinical trial
   • Failing to submit required clinical trial information for an applicable clinical trial
   • Submitting false or misleading clinical trial information
   Pre-notices request that the responsible party address any noncompliance within 30 days after receiving the letter. If FDA subsequently determines that the responsible party failed to comply with the legal requirements, FDA will issue a notice of noncompliance.

4. FDA Voices article by FDA Commissioner ‘Increasing Options in Clinical Research to Facilitate Medical Product Development’. 

5. The FDA finalised a rule allowing Institutional Review Boards (IRBs) to waive or alter elements of informed consent for certain clinical trials that pose minimal risk to human subjects. The rule finalises the five criteria for IRBs to waive or alter informed consent including:
   • For research involving identifiable private information or identifiable biospecimens, the research could not be practicably carried out without using the information or biospecimens in an identifiable format 
6. FDA issued a draft guidance “Master Protocols for Drug and Biological Product Development,” along with an accompanying guidance snapshot and recap podcast episode. The draft guidance clarifies FDA’s thinking on the design and analysis of trials conducted under a master protocol as well as the submission of documentation to support regulatory review.

7. FDA issued the final guidance “Rare Diseases: Considerations for the Development of Drugs and Biological Products". This guidance clarifies the FDA’s thinking on important considerations in developing drugs and biologic products for rare disease. Comments can be submitted at Rare Diseases: Considerations for the Development of Drugs and Biological Products; Guidanceor Industry; Request for Comments.

8. FDA issued the final guidance “Development of Monoclonal Antibody Products Targeting SARS-CoV-2 for Emergency Use Authorization”, which replaces the guidance issued in February 2021 titled “Development of Monoclonal Antibody Products Targeting SARS-CoV-2, Including Addressing the Impact of Emerging Variants, During the COVID-19 Public Health Emergency”. The guidance provides updated recommendations that reflect the evolving scientific knowledge and the current state of COVID-19.

EMA Guidance and News

1. EMA and HMA released a joint report that reviews the EU regulator’s responses to the COVID-19 crisis, highlighting the key learnings for future health crises. In the aspect of transparency and communication, EMA increased its proactive communication in providing factual information on COVID-19 vaccines, strengthened its engagement with stakeholders and the social media on disseminating factual scientific information, reactivated the policy on publishing the clinical data that support marketing authorisations for COVID-19 medicines and expedited publication of assessment reports.

2. EMA has released a Q&As document (dated 6 Dec 2023) on medicinal products development and assessment involving companion diagnostic (CDx) - more details under the medical devices section.

3. EMA published the updated General Guidance on Anonymization of Protected Personal Data and assessment of Commercially Confidential Information during the preparation of Risk Management Plans (main body and annexes 4 and 6) on 29 November 2023. This document provides guidance on what PPD information to delete, retain, or generalise in an RMP and also a non-exhaustive list of items that may be considered CCI if not in public domain.

4. A new version of the EudraCT Training Environment is now live and can be accessed by users who already have access to EudraCT. Full instructions on how to access it can be found here.

5. EMA released an overview of general and specific comments on ICH E6 (R3) Guideline for Good Clinical Practice, which will be sent to the ICH E6 (R3) EWG for consideration in the context of Step 3 of the ICH process.

Real World Data

1. Formal protocolized Real World Data (RWD) studies can provide robust evidence for safety signal assessment of drugs. The Rapid Signal Assessment Using Real World Data (RSA RWD) Initiative has launched its first set of solutions — the RSA RWD Framework and RWD Analysis for Signal Assessment Template, which offers a potential alternative to a full study protocol for use in the RSA process.

2. FDA released two final guidances that detail the use of RWE in regulatory decision-making (1) Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological; and (2) Data Standards for Drug and Biological Product Submissions Containing Real-World Data. US FDA blog article can be accessed here.

Transparency and Disclosure Resources and News

1. In a blog post, the software and services company Certara answered questions that were asked during a webinar on the reinstated Policy 0070 requirements to publish clinical studies submitted for marketing authorisation. The on-demand webinar entitled “How to Plan for a Successful EMA Policy 0070 Submission”, presented in September 2023, covered updates and changes to the policy and their impact on sponsors, discussed lessons learned and how past experience can be leveraged to the newly reinstated process of submitting clinical data to Policy 0070.

2. Sharma et al have published an article entitled “The emerging transparency paradigm for clinical trials in Europe.” Their article details how to “practically navigate the EU transparency rules within the global context and achieve a balanced, holistic approach.”

3. TransCelerate have released the Individual Participant Data Return (iPDR) Package, developed in collaboration with patients, sites, and clinical research organisations. It consists of a template, considerations guide, and socialisation presentation and is designed to provide general considerations to enable data return to clinical study participants.

Development Strategy News

1. Whitehead et al published The Renovation of Good Clinical Practice: A Framework for Key Components of ICH E8 that details TransCelerate's thinking on how to implement quality by design (QbD). Looking at the original outline, as well as operational feasibility, are key fundamentals that should be started at the point of study conception, and continue long past the end of protocol development. Open dialogue, critical thinking and stakeholder engagement are needed for culture and engagement.

2. A consensus-based extension to the SPIRIT 2013 Statement and extension to the CONSORT 2010 Statement for factorial trials (trials where 2 or more interventions are assessed in the same set of participants) was developed. The SPIRIT extension modified 9 of the 33 items in the SPIRIT 2013 checklist, which should be addressed in all protocols of factorial trials to increase the trial’s utility and transparency; the CONSORT extension modified 16 of the 37 items in the CONSORT 2010 checklist and adds 1 new item, which facilitate transparent reporting of factorial trials.

3. The final Data Quality Framework for EU Medicines Regulation has been released by EMA. It defines principles and procedures that apply across EMA’s regulatory mandate and ‘...provides general considerations on data quality that are relevant for regulatory decision making, definitions for data quality dimensions and sub-dimensions, as well as their characterisation and related metrics. It provides an analysis of what data quality actions and metrics should be considered in different use cases and introduces a maturity model to guide the evolution of automation to support data-driven regulatory decision making.’

4. A Joint US-FDA | MHRA-UK | Health Canada Good Clinical Practice & Pharmacovigilance Compliance Workshop will be held on 13, 14 and 15 February 2024. Register for no fee here. Agenda here. This workshop will focus on Global Clinical Trials in Good Clinical Practice, Bioequivalence, and Pharmacovigilance in the post pandemic world. Presentations and panel discussions will provide information on the recent updates made to ICH E6(R3) and regulatory perspectives on implementation of proportionate and risk-based approaches to the design and conduct of the trial to help ensure that the quality of the trial data generated is of sufficient quality to support good decision making.

5. Lawrance et al published Reflections on estimands for patient-reported outcomes in cancer clinical trials that addresses estimands. In the article, the authors look at how to address estimands for PROs; by doing so, familiar questions already arise, such as 'what happens with PRO data post-disease progression?' and 'what is an acceptable statistical summary for PRO data?'. The introduction and explanation are thorough; Section 2.6 provides an example PRO estimand that can be used to prompt study teams; Section 2.7 highlights some challenges. [Credit to Jonathan McKinnon for the text description]. 

6. Health Canada announced in December 2023 the implementation of the ICH E19 guideline: "A Selective Approach to Safety Data Collection in Specific Late Stage Pre-approval or Post-approval Clinical Trials". Eligible clinical trials must meet certain criteria including Phase 4 trials, late-stage trials involving a drug used outside the conditions of use for which the drug has received market authorization, does not involve a gene therapy or a rare disease, and the safety profile of the drug is well-understood and documented. Read more highlights here.
7. FDA’s Digital Health Technologies for Remote Data Acquisition in Clinical Investigations Guidance for Industry provides recommendations on the use of digital health technologies (DHTs) to acquire data remotely from participants in clinical investigations that evaluate medical products.  DHTs for remote data acquisition in clinical investigations can include hardware and/or software to perform one or more functions.  Use of DHTs as recommended in this guidance may improve the efficiency of clinical trials for sponsors, investigators, and other stakeholders and may increase the opportunities for individuals to participate in research and make participation more convenient.

Artificial Intelligence/Machine Learning

1. EMA and HMA have adopted a workplan to facilitate the responsible use of AI in medicines regulation, while also addressing the technology’s risks. The workplan is designed to oversee AI activities until 2028. It addresses four areas: (1) guidance, policy and product support; (2) AI tools and technology; (3) collaboration and training; and (4) experimentation. The EMA/HMA announcement is here and provides further details on the four critical areas. The workplan is here and includes a timeline of planned activities for 2023-2028 (slide 5 & 6). From mid-2024 work will be initiated in preparation of the AI Act coming into force. Earlier this year EMA presented a draft reflection paper on the use of AI in the medicinal product lifecycle and the end of the consultation period is 31 Dec 2023.

News from Asia Regulators

1. Singapore’s Health Sciences Authority (HSA) has provided an interim update on key changes  to the  implementation of the electronic Common Technical Document (eCTD) following feedback during a consultation earlier this year (02 May to 12 June 2023).

Medical Devices

Medical devices information is kindly compiled by Raquel Billiones.

Update on the EUDAMED

The Notified Body BSI recently released a white paper on the EUDAMED, the EU database on medical devices. Excerpts from the white paper:

The EUDAMED is an Information Technology system being built and implemented by the European Commission (EC) to fulfill many of the obligations of the Medical Device Regulation (MDR — EU 2017/745) and the In Vitro Diagnostic Medical Devices Regulation (IVDR – EU 2017/746)... It is a cornerstone of both Regulations and is intended to provide a living picture of the lifecycle of medical devices and in vitro diagnostic medical devices (IVDs) on the Union market. It integrates six separate and distinct electronic systems (“modules”) that collate and process information related to Actor Registration, UDI & Device Registration, Notified Bodies and Certificates, Clinical Investigation/Performance Studies, Vigilance/Post-market Surveillance and Market Surveillance. Certain information will be publicly accessible via the EUDAMED public site, which will enhance transparency of the regulatory system for the public and healthcare professionals.

The main objectives of EUDAMED are as follows:

• Increased transparency and public access to information
• Enhance traceability of medical devices
• Enable actors to comply with the regulations
• Avoid multiple reporting requirements ie, to multiple individual Member States
• Facilitate the flow of information between economic operators, sponsors or notified bodies and Member States, as well as between Member States themselves and with the European Commission

Update from EMA

Frequently asked questions on medicinal products development and assessment that involve use of a companion diagnostic (CDx): EMA has released a Q&As document (dated 6 Dec 2023) aimed at providing an overview of their current line of thinking on specific issues related to predictive biomarker-guided medicinal products development and assessment that include a “companion diagnostic” (CDx) development. The EMA states that the “Q&As document does not address assessment requirements for clinical trial approval by National Competent Authorities (NCA) or conformity assessment of candidate CDx by a notified body but provides guidance for generating adequate data for the marketing authorisation application for medicinal products. The Q&As should be used in conjunction with the relevant regulations, scientific and regulatory guidelines and procedural guidance documents.

Update from US FDA

1. FDA announced eSTAR for voluntary use for the Premarket Approval Applications (PMA) submission of:

• Original PMAs
• PMA Panel Track Supplements (PTS)
• PMA Real-Time (RT) Supplements
• PMA 180-Day Supplements

eSTAR is an interactive PDF form that guides applicants through the process of preparing a comprehensive medical device submission to enhance the incoming quality of submissions for a wide range of medical devices. The updated eSTAR Template includes a guide that follows the recommendations noted in the final guidance: Cybersecurity in Medical Devices: Quality System Considerations and Content of Premarket Submissions.

2. FDA issued draft guidance on 19 Dec 2023, entitled: “Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices.” Comments should be submitted by 20 Feb 2024. FDA is issuing this draft guidance to clarify how FDA evaluates real-world data to determine whether they are of sufficient quality for generating real-world evidence that can be used in FDA regulatory decision-making for medical devices.

3. The FDA withdrew its membership from the Global Harmonization Working Party (GHWP) for medical devices, of which it has been a member since 2021. The FDA will continue its efforts to ensure alignment of medical device international harmonisation by primarily working with the International Medical Device Regulators Forum (IMDRF). In 2024, the FDA, as chair of IMDRF, will continue to work collaboratively to reach consensus on common goals, foster global regulatory convergence, and leverage resources to make safe and effective medical devices available globally. Read the announcement and the letter to the GHWP here.

Updates on Clinical Investigations from the MDCG and Impact on Combination Products

Clinical investigation is the term used for device clinical studies under the MDR. The EU Medical Device Coordinating group (MDCG) issued new guidances and updated existing ones in 2023. The most recent one on clinical investigations are summarised below:

1. MDCG 2021-6 Rev.1 Q & A regarding Clinical Investigation was updated in Dec 2023. With 19 new entries, 11 revised answers and one new Annex, this update brings important clarifications for those needing to generate clinical data for medical devices and drug-device combination (DDC) products. Key updates:

• Questions 14, 15, and 16 provide clarifications on clinical studies for DDCs. 
• The newly added Annex III provides a useful flowchart to help determine which regulations apply to different types of DDCs.

2. MDCG 2023-7 Guidance on Exemptions from the Requirement to Perform Clinical Investigations is related to the previous one and clarifies the term ‘sufficient levels of access’ to data needed to justify claims of equivalence. Under certain conditions, a manufacturer of a device demonstrated to be equivalent to an already marketed device from another manufacturer need not perform a clinical investigation but use existing data of the equivalent device.

In addition, the MDCG also issued additional guidances on devices without intended medical purposes but still used in healthcare. Check here for a complete list of MDCG guidance documents.

Updates on In Vitro Diagnostics (IVDs)

In the field of IVDs, progress is being made on the designation of EU Reference Laboratories (EURL) for IVDs associated with certain hazards. The first batch of EURLs for Class D IVDs has been named in Commission Implementing Regulation (EU) 2023/2713. These EURLs are involved in the following IVD categories:

• Devices intended for detection or quantification of markers of hepatitis or retrovirus infection
• Devices intended for detection or quantification of markers of herpes virus infection
• Devices intended for detection or quantification of markers of infection with bacterial agents
• Devices intended for detection or quantification of markers of respiratory virus infection.

How the EURLs should be integrated into the conformity assessment process of IVDs is described in MDCG 2021-4.

Updates from CORE-MD: Clinical Evaluation Updates with Impact on Clinical Development and Real World Evidence for Medical Devices

A recent article entitled “Clinical Evidence under the EU MDR: A Notified Body Perspective” examines the process of clinical evaluation of devices under the EU MDR from the perspective of clinical experts from three notified bodies. The article builds on the findings of the EU-funded Coordinating Research and Evidence for Medical Devices (CORE-MD) consortium that reviewed the methodologies for the clinical evaluation and regulatory science of high-risk medical devices and suggested new designs to ensure patient safety and clinical effectiveness of these devices. The use of Real World Evidence in this landscape is also addressed. The findings of the projects within CORE-MD are expected to raise awareness of the limitations of past methodologies and advise on how the limitations can be addressed by establishing best practices in collecting pre- and postmarket evidence. A new guidance on clinical evaluation, with an update of MEDDEV 2.7/1, rev. 4 (2016), and a definition of orphan devices and clarification on their use in the EU is anticipated.

CORE MD Systematic Review of High-Risk Medical Devices in Children

A scoping review on evidence from clinical trials investigating high-risk paediatric medical devices used in paediatric cardiology, diabetology, orthopaedics and surgery was performed in the framework of CORE-MD. The authors noted that one of the limitations of the review was that selection of devices of interest was based on the US FDA sources as there is no central European database of (paediatric) medical devices. 

Update from China

NMPA released the “Clinical Evaluation Guideline on Artificial Intelligence-assisted Detection Medical Devices (Software)” in November 2023. Read the third-party’s review of the guideline here. The guideline refers to the FDA guidance of “Computer-Assisted Detection Devices Applied to Radiology Images and Radiology Device Data” and “Clinical Performance Assessment: Considerations for Computer-Assisted Detection Devices Applied to Radiology Images and Radiology Device Data”.