March 2023

Medicines and Vaccines

CTR and CTIS

The EMA have issued a document to help users to easily identify which are the latest updated materials on the EMA website and which materials have been developed since the last time users have consulted them. See CTIS Training Materials - Latest updates, version 1.2, dated February 2023.

The CTR Q&A document has been revised: version 6.4, dated February 2023.

The latest key updates on CTIS are released in the Newsflash dated 10 March 2023, 17 March 2023, 24 March 2023, and 31 March 2023 (which include the latest system improvement updates of March, also available in the release notes and the Lists of known issues and proposed workarounds).

The Clinical Trials Coordination Group (CTCG) published a Q&A document on complex clinical trials, to support sponsors submitting or transitioning their complex trials to CTIS.

UK and MHRA News

1. The HRA has welcomed a response to a consultation on clinical trial regulations by the MHRA. The HRA has already made it easier to register studies using automatic registration for clinical trials approved through their combined review process on the ISRCTN registry. It will now be a legal requirement to register trials in a World Health Organisation (WHO) public register. There will also be a requirement to publish a summary of results within 12 months of the end of the trial. Sharing trial findings with participants in a timely manner and suitable format will also be required by law. For the full article click here.

2. On 21 March 2023 the UK drug regulator, MHRA, announced that the UK government will introduce a legal requirement to make public the results of all clinical trials within 12 months of trial completion. Any company or university breaking the law will be refused permission to start new trials. Read TranspariMED’s short article for further details.

3. The UK’s revamped clinical trials framework should offer faster application review timelines than the EU. Transparency, patient involvement, and diversity are high on the agenda according to this article in Pink Sheet.

FDA Guidance and News

1. The deadline to submit comments via the US FDA on ICH M11 guideline on harmonised protocols (released for consultation on 21 October 2022) was 21 Feb 2023 and all comments received via the US FDA docket can be viewed. Comments from TransCelerate based on their  experience with the CPT are included.   

2. A virtual public meeting on ClinicalTrials.gov Modernization will be held on 25 April 2023, 12:30 to 3 pm ET to provide updates on the current beta websites. Registration is open. The meeting’s recording and slides will be available on the ClinicalTrials.gov Modernization webpage after the meeting.
3. FDA has issued a draft guidance ‘Electronic Systems, Electronic Records, and Electronic Signatures in Clinical Investigations: Questions and Answers’ that provides recommendations on the use of electronic systems, electronic records and electronic signatures, and when final, will supersede the May 2007 guidance.
   

   With the evolving use of electronic systems in clinical investigations, the draft guidance: 

   1. Updates recommendations for applying and implementing data integrity and data security controls, including the use of audit trails and the protection of records in the current environment of electronic systems used in clinical investigations. 
   2. Provides additional recommendations on the risk-based approach to validation of electronic systems described in the September 2003 guidance for industry Part 11, Electronic Records; Electronic Signatures--Scope and Application." 
   3. Facilitate the use of electronic systems, electronic records, and electronic signatures to improve the quality and efficiency of clinical investigations. 
   
   

   For more information on the draft guidance and how to submit comments, see the Federal Register Notice. Comments should be submitted by 15 May 2023.

4. FDA has issued the Framework for the Use of Digital Health Technologies in Drug and Biological Product Development. The Digital Health Technology (DHT) framework document will guide the use of DHT-derived data in regulatory decision-making for drugs and biological products. For information on the DHT program, visit the Digital Health Technologies for Drug Development webpage. For information on the framework and how to comment, please see the Federal Register Notice. 

5. US FDA has issued draft guidance to clarify which pharmacogenomic study findings and data should be included in regulatory submissions for investigational new drug applications (INDs), new drug applications (NDAs) and biologics license applications (BLAs).  In addition, the document provides recommendations on the format and content of the pharmacogenomic data submissions. Comments on the draft guidance can be submitted until 20 June 2023 to regulations.gov and labelled as Docket No. FDA-2022-D-2856. When finalised, this guidance will replace the 2005 guidance.
6. FDA has issued draft guidance, Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics, regarding clinical trial design considerations to support accelerated approval applications. The draft guidance discusses the design of clinical trials, and ways to improve the data available at the time of accelerated approval and reduce clinical uncertainty for patients by initiating post-marketing confirmatory studies in a timely manner. Specifically, the draft guidance addresses the design, conduct and analysis of data through two RCT approaches – conducting two separate RCTs or using one trial for both accelerated approval and to verify clinical benefit. It also provides considerations for sponsors to determine the adequacy of single-arm studies to support an application. 
   

   In a commentary in NEJM in 2022, Oncology Center of Excellence staff outlined the concepts included and expanded upon in the draft guidance. The Oncology Center of Excellence has also launched Project Confirm, as an initiative that promotes the transparency of outcomes related to accelerated approval for oncology indications and fosters discussion and research on the accelerated approval program. The project developed a searchable database with information on the status of all oncology accelerated approvals, a model that was then adopted by FDA’s Center for Drug Evaluation and Research for all accelerated approvals.

7. The latest release notes regarding the ClinicalTrials.gov Beta and PRS Beta websites are available along with a guest blog on the modernization efforts.

EMA Guidance and News

1. EMA releases an overview of key performance indicators (KPIs) to monitor the European clinical trials environment in respect of clinical trial applications (CTAs) – Metrics on the Clinical Trials Regulation and Clinical Trials Directive - each month. Read the latest reports (Edition 10 and Edition 11)  and access past reports here. 

2. The EMA has issued Q&A guidance to address sponsors’ questions on  pilot testing the review of raw clinical trial data for marketing authorization applications (MAAs) and post-authorization applications. The newly released document provides answers to commonly asked questions about the proof-of-concept (PoC) pilot on the submission and analysis of ‘raw data’ from clinical studies as part of selected initial marketing authorisation applications (iMAAs) and post-authorisation applications. PoC information released by the EMA in Oct 2022 states that raw data (also called Standardised Study Data) means “individual patient data from clinical studies in structured format from which statistical analyses are derived. Raw data includes the datasets in Study Data Tabulation Model (SDTM) and Analysis Data Model (ADaM) formats.”

3. EMA Management Board highlights from the March 2023 meeting shared experience with mandatory use of CTIS: over 320 clinical trials authorised under the Clinical Trials Regulation are available in CTIS. Next steps include upcoming system releases planned for the first quarter of 2023 and enhancements through 2023 aimed at further improving the CTIS user experience.

4. EMA has published a revised version of the Q&A document providing preliminary guidance to users on how to protect personal data and commercially confidential information (CCI) in CTIS. The new Q&A item 1.9 clarifies that documents with track changes can only be submitted in CTIS in the slot ‘not for publication’.

Transparency and Disclosure Resources and News

Health Canada has developed a draft guidance document on the Registration of Clinical Trials and Public Disclosure of Results and is proposing a clinical trials search portal. This portal would help make more Canadian authorised trial information available to the public and improve accessibility of this information.
Health Canada is seeing public feedback on the draft guidance along with proposed mock-ups of the new clinical trials search portal. Consultation closes to new input on 24 April 2023.

Development Strategy News

1. Johnston et al have published a research letter ‘FDA Approval of Drugs Not Meeting Pivotal Trial Primary End Points, 2018-2021’ where they identified 21 drug approvals with null findings or 1 or more primary efficacy endpoints. Success of other pivotal studies, positive findings from secondary/exploratory endpoints and favourable post hoc analysis were the most common grounds for acceptance. The work not only highlights the complexity of regulatory decision making, but also the need to be mindful of secondary and exploratory objectives outcomes.

2. Mayo and Kim published ‘What can be Achieved with the Estimand Framework?’ It provides the perspective of regulatory statisticians in reviewing IND protocols and SAPs for studies used to support "substantial evidence of effectiveness" in NDAs and BLAs. The article clearly explains the value of adopting an estimand framework - and what is needed when one is not in place (e.g., scanning multiple sections of the protocol including "educated guesswork" for omitted elements).

3. International Clinical Trials has published a Medical Writing Supplement dedicated to the importance of well-written clinical study protocols. The February 2023 supplement is entitled “Clinical Study Protocols: The Pillars of Clinical Development.”

4. European Patient-CEntric ClinicAl TRial PLatforms (EU-PEARL) will have a closing event on 25 April 2023 entitled “Paving the Way to Innovative and Patient-Centered Clinical Research.” Register to follow the all day event online. High-level discussion topics will include:

• The results of EU-PEARL, and how they benefit patients, researchers, and the broader health ecosystem
• How Integrated Research Platforms (IRPs) can accelerate clinical research, especially in therapeutic areas with unmet medical needs
• What infrastructure and methodological changes are needed to unlock the pathway to innovative clinical research, and how EU policy makers can support this.

News from Asia Regulators

1. The Japan Registry of Clinical Trials (jRCT) announced in early March 2023 that the registered data from two registries – the Japan Medical Association Clinical Trial Registry System (JMACCT-CTR) and the Japan Pharmaceutical Information Center Clinical Trial Information (JapicCTI) – have been migrated to jRCT.
   jRCT is a WHO-recognized primary registry in Japan, it is mandatory to register the protocol and post results in jRCT, except for bioequivalence studies.
2. In early March 2023, the International Traditional Medicine Clinical Trial Registry (ITMCTR) was added to the WHO’s Primary Registries Network of the International Clinical Trials Registry Platform (ICTRP). The ITMCTR is a non-profit online cross-regional registry that enables voluntary registration of clinical trials conducted in China and globally in the field of traditional medicine such as Chinese medicine, acupuncture, tuina massage, herbal medicine, ayurveda, homeopathy, and complementary and alternative medicine.
3. China NMPA adopts ICH S1B(R1) guideline for carcinogenicity studies initiated from 22 March 2023; the ICH S1A, S1B, and S1C(R2) guidelines have been adopted since 2019 and are still valid for use. (Page in Mandarin)
4. China NMPA adopts ICH E14/S7B Q&A Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for clinical studies initiated from 31 July 2023. (Page in Mandarin)

Medical Devices

Medical devices information is kindly compiled by Raquel Billiones.

Updates from MDCG

MDCG 2023-3: Questions and Answers on vigilance terms and concepts as outlined in the Regulation (EU) 2017/745 on medical devices was released in February 2023.

Updates from MedTech Europe

1. MedTech Europe released their public report in February 2023, describing the Survey Results for October 2022 on the transition to the IVDR.
2. MedTech Europe released in February 2023 the 3rd edition of the ebook Clinical Evidence Requirements under the In Vitro Diagnostics Regulation (IVDR). The ebook is a  Q&A guide to performance evaluation requirements of the new IVDR 2017/746.

Updates from the International Medical Device Regulators Forum (IMDRF)

1. The IMDRF Group on Good Regulatory Practice released the IMDRF/GRRP WG/N71 Medical Device Regulatory Review Report: Guidance Regarding Information to be Included. The report details documentation of the Conformity Assessment Body's assessment, whether specified requirements have been met. It provides a consistent way for the body to assess compliance and facilitates sharing information between Regulatory Authorities.
2. The IMDRF opened the public consultation on the In Vitro Diagnostic Device Regulatory Submission Table of Contents (IVD ToC). Consultation closes on 15 April 2023.
3. The IMDRF released the Edition 6 of the IMDRF Terms of Reference which describes the body’s scope and nature of activity.

Updates from the Notified Bodies

Team-NB published the position paper Best Practice Guidance for the Submission of Technical Documentation under Annex II and III of In Vitro Diagnostic Medical Devices Regulation.

Updates from Switzerland

1. Swissmedic released a new guidance document that sets forth regulations on the use of mobile technologies in human and veterinary medicinal products.
2. Swissmedic published their official position to grant extension for the certification of medical devices, in line with the extension of the equivalent European regulation. These measures ensure that devices marketed in the EU continue to be available for Swiss patients.

Updates from the UK

1. An output of the UK’s Health Technology Regulatory and Innovation Programme (HealthTRIP) has been released. The report presents data from these 350 SME engagements; shows insights and findings from these data; and provides recommendations for interventions to help support and grow the UK HealthTech Industry.
2. In March, MHRA released the guidance on Crafting an Intended Purpose in the Context of Software as a Medical Device (SaMD). The guidance defines the intended purpose for SaMD to help SaMD manufacturers meet their statutory obligations.

Updates from the EU

1. The European Commission released the Q&A on practical aspects related to the implementation of Regulation (EU) 2023/607 - Extension of the MDR transitional period and removal of the “sell off” periods.
2. The EMA launched a pilot program in February to provide scientific advice on the intended clinical development strategy and proposals for clinical investigations for certain high risk medical devices (class III devices and class IIb active devices intended to administer and/or remove medicinal products.) through medical device expert panels. A Letter of Interest template for online application was released in March.
3. The European Institute of Innovation and Technology (EIT) Health recently released the new Think Tank Report on Digital Medical Devices: Paths to European Harmonisation Summary Report.

Updates from the US FDA

The US FDA released end of March two guidance documents on: 

• Marketing Submission Recommendations for a Predetermined Change Control Plan for Artificial Intelligence/Machine Learning (AI/ML)-Enabled Device Software Functions.
• General Considerations for Animal Studies Intended to Evaluate Medical Devices 

EMWA Conference Prague May 2023

Don’t forget you can register for your free place to join us:

The CORE Reference Team will host a face-to-face open introductory and Q&A session on CORE Reference and the CPD resources during the EMWA May 2023 conference in Prague. See you on Friday 12 May 2023 at 17.15-18.15. 

Title: The CORE Reference Project - Value for the Global Regulatory MW Community

Abstract: The CORE Reference EMWA Special Project provides Continuous Professional Development (CPD) for regulatory medical writers through open access resources and intelligence dissemination on clinical study reporting and public disclosure of clinical-regulatory documents. The team will present a 60-minute open session including a full web tour; demonstration of the CPD resources, including the RPD content published monthly; a PDF open-book demonstration of CORE Reference and its practical utility; insights on the ICH M11 Step 2 draft protocol template; and we will take questions from the audience.

Presenters names (with affiliations): Chair, Sam Hamilton (Freelance); Committee - Alison McIntosh (Freelance), Vivien Fagan (IQVIA).