October 2021

Medicines and Vaccines

ICH Guidelines

1. Read the final ICH E8(R1) Guidance here, adopted on 06 October 2021. General principles include participant protections; scientific approach to trial design, planning, conduct and reporting; and patient input into drug development.

It is good to see reference to estimand and transparency and disclosure throughout.

2. The ICH E6 Guideline for Good Clinical Practice (GCP) Public Web Conference (held on 18 and 19 May 2021) Report is available here.

EMA Publish Statements and Guidances

1. Read the EMA Statement on Clinical Data Privacy here.

2. Read the EU Guidance on Good Lay Summary Practice published on 04 October 2021 here.

3. On 21 October 2021, EMA released a guide on access to unpublished documents relating to EMA Policy 0043.

CTIS News

Issue 5 of CTIS Highlights is out now (October 2021). Events and training are covered, as well as new ways of working in CTIS for Sponsor organisations.

These two documents published by EMA on 30 September 2021 describe CTIS user personas: Sponsor and Member State. These contain visual models to describe different types of users in CTIS:

1. Clinical Trial Information System (CTIS) - Member state user personas
2. Clinical Trial Information System (CTIS) - Sponsor user personas

On 07 October 2021, this ‘Go-live Planning’ document on ‘Summary of key areas in preparation of the operation of CTIS’ was published.

FDA Guidances and News

1. FDA have opened Draft Guidance ‘Benefit-risk assessment for new drug and biological products’ for comment until 29 Nov 2021.

2. FDA Draft Guidance Sept 2021 is available: ‘Real-World Data: Assessing Electronic Health Records and Medical Claims Data To Support Regulatory Decision-Making for Drug and Biological Products’

3. FDA Draft Guidance Oct 2021 is available: ‘Data Standards for Drug and Biological Product Submissions Containing Real World Data’ for comment until 21 Jan 2022.

4. The FDA has warned companies for GMP violations and conducting clinical trials without an IND.

Transparency and Disclosure Resources

1. Most major European research institutions are now uploading missing clinical trial results. Read about the improvement in uploads to EudraCT in this StatNews article and in this TranspariMed article.

2. d-wise and Vivli have announced a partnership to offer anonymization services and software for institutions and researchers contributing to clinical research data sharing.

3. Clinicaltrials.gov resources:

• Read the Modernization Report here.
• Glossary is updated. Newly added Definition: ‘Results First Posted with QC Comments’.
• Materials from the Train the Trainer, 21 August 2021 are now available.

4. The Berlin Institute of Health will run a workshop on uploading clinical trial results to EudraCT on Tues 04 Nov 2021.

5. The UK NHS will hold its ‘Make it Public’ annual conference on 03 and 04 Nov 2021. The focus is on transparency.

Publications and News Related to Clinical Study Reporting and Transparency

1. This TranspariMED article shows that the UK pharma industry is lobbying government to overhaul the UK’s clinical trial regulation to bring it into line with international reforms.

2. This TranspariMED article shows that TranspariMED has filed an ethics complaint with the University of Texas MD Anderson Cancer Center over its refusal to disclose the outcomes of a clinical trial involving patients with brain tumour metastases.

3. Flanagin et al’s Guidance published in August 2021 in JAMA titled ‘Updated Guidance on the Reporting of Race and Ethnicity in Medical and Scientific Journals’ updates earlier guidance following solicitation of comments, further research and discussion. This updated guidance will be added to the ‘American Medical Association (AMA) Manual of Style: A Guide for Authors and Editors’. The updated guidance is aimed at journals, but the principles hold for clinical trial documentation such as protocols, CSRs and IBs.

4. Recent reviews by King-Kallismanis et al (June 2021) and Fernandes et al (August 2021) show that PROs are used inconsistently across cancer trials and that there is room for improvement. This is well-timed and illustrative given the Draft FDA Guidance on ‘Core PROs in Cancer Clinical Trials’ published in June 2021.

5. In this CMAJ paper titled ’Optimizing Data Available via Health Canada’s Clinical Information Portal’, the authors report that despite 160 submissions to the Health Canada portal including CSRs, data utility appears low, and they encourage increased use of the data.

6. The UK’s Health Research Authority (HRA) has partnered with the ISRCTN registry to help researchers fulfil transparency responsibilities. On 19 Oct 2021, the HRA announced that “Clinical trials will be automatically registered to guarantee a full picture of research taking place in the UK, thanks to our world-first partnership with ISRCTN”. Read HRA’s news here.

EU CTR 536/2014 Definition Relevant for Utility of CORE Reference

Refer to CORE Reference Section 9.4.1.2 ‘Non-Investigational Product(s)’ on page 25. Please be advised that the term ‘non-IMP’ – which was appropriately used in CORE Reference (published 2016) - has been renamed in the EU to ‘Auxiliary Medicinal Product’ per the EU Clinical Trial Regulation GMP Annex 13 and (EU) 536/2014.

The CORE Reference Section header 9.4.1.2 and supporting comment A139 (which gives examples on ‘non-IP’) both remain current because the change of definition applies only in the EU. Examples of non-IP given in CORE Reference continue to align with examples of Auxiliary Medicinal Product per the EU CTR 536/2014.

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Medical Devices

The implementation of the EU Medical Device Regulation (MDR) and In Vitro Device Regulation (IVDR) is ongoing. One of the key requirements of these two regulations is increased transparency and public disclosure. Below are some recent updates:

EUDAMED Updates

The EU is making good progress in the set-up of the European Database for Medical Devices (EUDAMED). In addition to the Actors Module, which was functional in December 2020, two additional modules went live in October 2021. The EUDAMED modules UDI/Devices Registration and Notified Bodies and Certificates are fully operational! Three additional modules - Clinical Investigations and Performance Studies, Vigilance and Post-market Surveillance, and Market Surveillance - are expected to be launched in May 2022.

Guidance documents on the use of the EUDAMED are being developed. The guide for the actor registration module for economic operators was updated in September 2021. The guide for Notified Bodies is also now available.

Proposed Delay for IVDR

Delay to the full roll-out of the new IVDR is being considered. In July 2021, the Competent Authorities for Medical Devices (CAMD) Task Force on Certification Capacity Monitoring conducted a survey across the industry to assess the impact of IVDR on the availability of IVDs when the regulation comes into force in May 2022. Analyses of the survey results by MedTech Europe indicate that a significant proportion of IVD tests may be discontinued when the IVDR comes into force. One of main reasons for this problem is the shortage of Notified Bodies for IVDs. The European Commission has released a proposal to extend the transitional timelines of some IVD classes. A progressive rollout is foreseen. Check out the Q&A document for more details.

MDCG Updates

The EU Medical Device Coordinating Group (MDCG) recently released two new guidance documents:

• MDCG 2021-24 provides guidelines on the classification of medical devices, with information on the purpose of classification, the methods of classification and the application of classification rules.
• MDCG 2021-25 describes the setting up of an ad hoc task force regarding the application of transitional provisions, especially with regards to legacy medical devices.

Notified Body Opinion Template

The European Association Medical Devices - Notified Bodies (Team-NB) has proposed a notified body opinion template. The aim of the template is to have a harmonised reporting method by different NBs across Europe.

Outside of the EU: Updates on Machine Learning-enabled Medical Devices

FDA Virtual Public Workshop - Transparency of Artificial Intelligence/Machine Learning-enabled Medical Devices

The US FDA organized a virtual workshop on 14 October 2021 on transparency of Artificial Intelligence/Machine Learning (AI/ML)-enabled medical devices aimed at patients, caregivers, and providers. If you missed it, you can view the webcast recording.

Tripartite Regulatory Guiding Principles on Good Machine Learning Practice

The US FDA, Health Canada, the UK MHRA have released a new document on Guiding Principles on Good Machine Learning Practice for Medical Device Development. These 10 guiding principles are aimed to “help promote safe, effective, and high-quality medical devices that use artificial intelligence and machine learning”. In particular, two principles are focusing on patients: # 3 Clinical Study Participants and Data Sets Are Representative of the Intended Patient Population and # 9 Users Are Provided Clear, Essential Information.