Regulatory Round-up - November 2022

EUROPE

European Commission (EC)

Amendment to the CTR on IMP Labelling

As previously reported in the September 2022 Regulatory Round-up, the European Commission (EC) revised the current labelling requirements provided in the Clinical Trials Regulation (CTR) for investigational medicinal products (IMPs) regarding expiry dates by means of a Delegated Regulation. On the 15^th November 2022 the regulation has been published in the Official Journal of the European Union (DelegatedRegulation 2022/2239). The regulation will enter into force 20 days from its publication.

European Medicines Agency (EMA)

DARWIN EU^® welcomes first data partners

EMA has selected the first set of data partners to collaborate with DARWIN EU^®, the Data Analysis and Real-World Interrogation Network. The data available to these partners will be used for studies to generate real-world evidence that will support scientific evaluations and regulatory decision making; one of the three initial studies, of particular interest to the cell and gene therapy community, is focused on the epidemiology of rare blood cancers to inform on their prevalence in Europe. Real-world evidence refers to information derived from analysis of real-world data, which is routinely collected data about a patient’s health status or delivery of healthcare from a variety of sources other than traditional clinical trials. Please find details here.

New Quality Innovation Expert Group (QIG) supports medicine innovation

EMA has established a Quality Innovation Expert Group (QIG) to support innovative approaches for the development, manufacture, and quality control of medicines for the benefit of patients in the European Union (EU). These include, but are not limited to, new technologies, digitalisation, novel materials and novel devices, in line with the priorities highlighted in EMA’s Regulatory Science Strategy to 2025. The Quality Innovation Expert Group was set up in September 2022 and is composed of eight members with a background in chemical, biological quality assessment and GoodManufacturing Practice (GMP) inspections.

The expertise of the QIG can also be called upon in the assessment of medicines using these innovative technologies in regulatory submissions such as scientificadvice, marketing authorisation applications and related post-authorisation lifecycle changes. Please find details here.

EMA: Q&A Documents on Centralised Procedures updated

The Questions & Answers (Q&A) documents relating to centralised marketing authorisation procedures, last revised in June, have now been updated and published on the European Medicines Agency (EMA) website. These Q&As are intended to provide guidance and guidelines for marketing authorisation holders and applicants of centralised procedures and provide answers to potential questions at different stages of the centralised marketing authorisation application process.

The new versions of the "Q&A" documents for central procedures can be found at:

• Topics before and during application
• Topics after marketing authorisation has been granted

Revision of the EU GMP Guide Annex 11 "Computerised Systems" – Presentation of Concept Paper

The current EU GMP Guidance Annex 11 "Computerised Systems" has been in force since 2011. On 16^th November 2022, the EMA (European Medicines Agency) published a 5-page "Concept-Paper on the revision of Annex 11 of the guidelines onGood Manufacturing Practice for medicinal products - Computerised Systems" to revise annex 11 in order to meet current technological and regulatory developments. Comments on this concept paper can be submitted until 16^th January 2023.

Presentation of Concept Paper on platform trials

The EMA is proposing a reflection paper to support the planning of platform trials, so they can be used as pivotal trials. The aim of the reflection paper is to complement existing guidance documents, e.g., on multiplicity and adaptive design, and not to replace or revise them.

A draft concept paper has been adopted by the Committee for Medicinal Products for Human Use (CHMP) for release for public consultation. Comments on this concept paper can be submitted until 31^st January 2023.

European Medicines Agency (EMA) Patients' and Consumers' (PCWP) and Healthcare Professionals' (HCPWP) Working Parties meeting with all eligible organisations

This meeting (held on the 15^th November 2022) brought together all eligible patient and consumer and healthcare professionals organisations and members of the Patients' and Consumers' Working Party (PCWP) and Healthcare Professionals' Working Party (HCPWP). The meeting discussed: patient involvement in medicines development and regulation including feedback from Patient Experience Data workshop and CIOMS report; Health Technology Assessment – interconnection of regulatory and HTA activities and role of patients and HCP. Please find details here.

EMA and EATRIS webinar on support for academic and non-profit ATMP developers

EMA and European Infrastructure for Translational Research (EATRIS) organised a webinar on 1^st December 2022 titled ‘Support for academic and non-profit ATMP developers’, for the Erasmus-funded ADVANCE project. Patrick Celis (EMA Advanced Therapies Scientific Lead) gave an overview of the support tools in place at EMA for medicine developers from the academic sector, and provided insights into the recently announced academic ATMP development support pilot.

The European Federation of Pharmaceutical Industries and Associations (EFPIA)

Euro Roundup: EFPIA proposal seek to reverse EU’s shrinking share of R&D pie

A new report published by Charles River Associates for the European Federation of Pharmaceutical Industries and Associations (EFPIA) paints a challenging picture of falling competitiveness in Europe, with the global share of pharmaceutical R&D investment, clinical trials and manufacturing output all decreasing. The situation is most acute for Advanced Therapies Medicinal Products (ATMPs) – tissue, gene and cell therapies – used to prevent, treat and cure rare conditions, including some cancers. Clinical trial activity for ATMPs is twice as high in the US and almost three times as high in China than in Europe. The number of ATMP trials conducted in the US and Asia-Pacific region grew by 70% and 67%, respectively from 2014-21, while Europe remained stagnant.

The report highlights a number of challenging areas and makes policy recommendations – which could be implemented at National Government level – or EU level through the revision of the pharmaceutical legislation. Please find details here.

UNITED KINGDOM

Medicines and Healthcare products Regulatory Agency (MHRA)

Horizon Scanning Case Study: Developing standards for Adeno-associated virus gene therapies

MHRA horizon scanning identified a need for standardisation of AAV products to support developers and manufacturers of these gene therapy medicinal products. AAV reference materials are required to establish the concentration (copies or particles per mL), and the particle empty/full ratio of AAV products.

CGT Catapult in collaboration with MHRA secured funding from the Regulators’ Pioneer Fund (RPF) to support a 6-month project to produce, and perform initial analyses on, a batch of AAV2 material manufactured at the CGT Catapult Braintree facility. The AAV2 material is now being evaluated by multiple external collaborators, from industrial stakeholders to academic laboratories, and its ‘fitness for use’ as a reference material is being assessed. Please see here for more details and information on the network concerned with AAV standardisation.

Return to International GMP Inspections

At the start of the Covid 19 pandemic, in March 2020, the MHRA Inspectorate published a blog post in which it was announced that until further notice they would only conduct on-site inspections linked to the UK Government’s COVID-19 response or any other potential serious public health risk.

Since April 2022, GMP Inspectors have been taking part in a pilot programme to look at a possible return to international GMP on-site inspections.

On the 8^th of November 2022 the MHRA announced that the pilot was successful, and they are now resuming their programme of international onsite GMP inspections, albeit with restrictions. A risk-based approach will be taken. Please here for more details.

Access Consortium Good Manufacturing Practice (GMP) Statement

The "Access Consortium" consists of representatives of regulatory authorities from Australia (Therapeutic Goods Administration), Canada (Health Canada), Singapore (Health Sciences Authority), Switzerland (Swissmedic) and recently also from the UK (Medicines and Healthcare Products Regulatory Agency, MHRA). The aim of this consortium is to promote international cooperation, reduce duplication of work and increase the capacities of the individual authorities.

On 15^th November 2022, the heads of the agencies represented in this consortium published an "Access Consortium Good Manufacturing Practice (GMP) Statement", in which the commitment to demonstrate greater inspection reliance and accept GMP inspection outcomes was made. The reliability of inspection results will be based on the review of inspection reports or other evidence carried out by Access Consortium members in their territory. This is to avoid additional GMP inspections. Please see MHRA notice here.

British Pharmacopoeia (BP)

Guidance on the Characterisation of the particle population in AAV products

The BP has prepared, a draft authoritative, non-mandatory, best practice guidance on the Characterisation of the particle population in AAV products for population in AAV products. BP is seeking feedback through public consultation, which is open until 31^st January 2023. The draft document, including background and the draft guidance can be found here.

USA

Food and Drug Administration (FDA)

FDA Approves First Gene Therapy to Treat Adults with Hemophilia B

On the 22^nd of November 2022, FDA approved Hemgenix (etranacogene dezaparvovec), an adeno-associated virus vector-based gene therapy for the treatment of adults with Hemophilia B (congenital Factor IX deficiency) who currently use Factor IX prophylaxis therapy, or have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes. Please find more details of the announcement here.

Assessing Genetic Heterogeneity in the Context of Genome Editing Off-Targets in Gene Therapy Products

FDA is holding public workshop on 16^th December 2022 to discuss the impact of individual genetic heterogeneity on genome editing, and best practices for validating off-target editing events in the context of human genetic heterogeneity. The workshop will bring together academia, industry, and other stakeholders involved in research, development, and regulation of genome edited gene therapy products. Register here (attendance is free and available on a first come basis).

Patient-Focused Drug Development Listening Meeting — Patient Perspectives on Gene Therapy Products

Patients and caregivers can provide valuable input into the discussion of investigational therapies by describing their experience with a disease or condition, and by defining meaningful change in terms of their specific disease and the risks they are willing to accept. With the potential for more gene therapies to become available to patients in the future, it is important to understand patient and caregiver perspectives on these products.

The FDA’s Center for Biologics Evaluation and Research (CBER) Office of Tissues and Advanced Therapies (OTAT) hosted a virtual patient-focused drug development listening meeting to better understand patient perspectives on gene therapy products, including cell-mediated gene therapies. The recording can be viewed here.

Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps): Small Entity Compliance Guide

FDA has announced the availability of the final version of the small entity compliance guide (SECG). It is intended to help small entity establishments that manufacture HCT/Ps better understand the comprehensive regulatory framework for HCT/Ps set forth in the regulations and comply with certain HCT/P-related rules. However, it also includes a useful reference to the subparts of 21 CFR part 1271 that apply to biologic products (including cell and gene therapy products).

Studying Multiple Versions of a Cellular or Gene Therapy Product in an Early- Phase Clinical Trial – Guidance for Industry

FDA has published this final guidance intended to provide recommendations to sponsors interested in studying multiple versions of a cellular or gene therapy product in an early-phase clinical trial for a single disease.

The objective of these early-phase clinical studies is to guide which version(s) of the product to pursue for further development in later-phase studies. Thus, these studies are not intended to provide primary evidence of effectiveness to support a marketing application and generally are not adequately powered to demonstrate a statistically significant difference in efficacy between the study arms. Recommendations include how to organise and structure the investigational new drug (IND) applications, submit new information, and report adverse events.

FDA OTAT Town Hall: Gene Therapy Chemistry, Manufacturing, and Controls – Transcript now available

Subject matter experts from the Division of Cell and Gene Therapy at the Office of Tissues and Advanced Therapies (OTAT) within the FDA’s Center for Biologics Evaluation and Research (CBER) hosted a virtual town hall to answer stakeholder questions related to gene therapy chemistry, manufacturing, and controls on Thursday

29 September. The transcript is now available here.

Expanded Access to Investigational Drugs for Treatment Use Questions and Answers – Draft Guidance for Industry

The US Food and Drug Administration (FDA) has updated its guidance for industry on expanded access to investigational drugs under an investigational new drug (IND) application. The guidance now includes new frequently asked questions about how expanded access should be implemented given new regulatory access and statutory requirements through the 21^st Century Cures Act (Cures Act) and FDA Reauthorization Act of 2017 (FDARA).

While the guidance remains largely the same from 2017, FDA added new recommendations for Institutional Review Board (IRB) review, informed consent and new requirements in Cures Act and FDARA to publicly share sponsor policies on evaluating and responding to expanded access requests.

FDA Warning Letters of the Fiscal Year 2022: the "Top Ten" GMP Deficiencies

In the fiscal year 2022 (Oct. 2021 - Sept. 2022), a total of 42 Warning Letters were sent to medicinal product manufacturers, each explicitly describing the GMP deficiencies in connection with the paragraphs of 21 CFR 211. The analysis of these
"Drugs" Warning Letters, by Concept Heidelberg shows that most violations of basic GMP rules are closely related to the quality unit's failure to take responsibility.

For additional information please refer to the ECA Academy issue.

Public consultations

European medicines agency (EMA)

Medicines and Healthcare products Regulatory Agency (MHRA)

Food and Drug Administration (FDA)

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