Regulatory Round-up - May 2024

UNITED KINGDOM

Health Research Authority (HRA)

Guidance on the use of the UK template Confidentiality Disclosure Agreements: model Confidentiality Disclosure Agreement (mCDA) and model Master Confidentiality Disclosure Agreement (mMCDA)

A study-specific CDA template and its associated guidance have been produced by a UK-wide partnership to help make the early sharing of information, for feasibility and site set-up purposes, clearer and more efficient in line with the UK Vision for Clinical Research Delivery. The recommended template aims to reduce negotiation time with sites, provide assurances to both parties that their rights and responsibilities are appropriate and facilitate compliance by sites with contract terms, replacing the inconsistency of terms to which NHS organisations are currently subject.

Please find further information, including access to the latest version of agreement (April 2024) here.

Medicines and Healthcare products Regulatory Agency (MHRA)

MHRA’s AI regulatory strategy ensures patient safety and industry innovation into 2030

On 30 April 2024, the MHRA set out its strategic approach to artificial intelligence (AI) which ensures patient safety and industry innovation into 2030. Since the publication of the Government’s white paper ‘A pro-innovation approach to AI regulation’ in 2023, the MHRA has taken significant steps in the past 12 months to adopt its recommendations on five key strategic principles:

• safety, security and robustness
• appropriate transparency and explainability
• fairness
• accountability and governance
• contestability and redress

This publication provides an update on the MHRA’s use of AI as a regulator of AI products, as a public service organisation delivering time-critical decisions and as an organisation making evidence-based decisions that impact public safety.

On 9^th May 2024 MHRA launched AI Airlock, its new regulatory sandbox for AI as a Medical Device. (AIaMD). A core difference between the AI Airlock and other regulatory sandboxes is the need for collaboration across many of the regulatory, governance and assurance organizations in healthcare. Using real-world products, the AI Airlock will bring together expertise from within the MHRA and key partners including the UK Approved Bodies, the NHS and other regulators. The outputs will inform subsequent AI Airlock phases in the short term, and future MHRA guidance and policy in the longer term, while exploring any limitations of existing approaches to demonstrating regulatory compliance.

AI Airlock - the Regulatory Sandbox for AIaMD in healthcare webinar will be held on 5^th June 2024 for developers and manufacturers of AI medical devices to hear early details of the MHRA AI Airlock project, which has been launched to help enhance understanding and accelerate solutions for the novel challenges of regulating AI medical devices.

The webinar will include presentations on the following topics:

• the challenges of regulating AI medical devices: context and overview
• an introduction to the aims and objectives of the AI Airlock project
• opportunities and timelines for developers and manufacturers to get involved.

There will also be a Question and Answer session aimed at answering questions from developers and manufacturers who are considering getting involved. Please find information on how to register here.

MHRA announces a proposed framework for international recognition of medical devices

The MHRA has published a statement of policy which describes how the UK Government intends to recognize regulatory approvals from Australia, Canada, the European Union and the United States of America depending on device type, class, and prior approval. The MHRA continues to review the list of comparable regulator countries and is in discussions with the Pharmaceuticals and Medical Devices Agency (PMDA) to explore the recognition of medical device approvals from Japan.

This initiative is an important step towards a new regulatory framework for medical devices in Great Britain which protects public health, ensures access to MedTech innovations, and maintains an attractive market for industry. The proposed framework is still in draft, and the final version would be integral with the future core regulations.

EUROPE

Regulatory Focus (RF)

European Directorate for the Quality of Medicines (EDQM)

New European Pharmacopoeia Commission approach to gene therapy

At its 178th session held in March 2024, the European Pharmacopoeia Commission EPC adopted the general monograph Gene therapy medicinal products for human use (1386) and the accompanying general chapter Additional information on gene therapy medicinal products for human use (5.34), which will replace general chapter 5.14.

In addition to a general requirements section containing provisions on the production of all GTMPs and specific requirements for recombinant vectors and genetically modified cells for human use, general monograph 3186 contains three individual sections describing additional requirements for the classes of GTMPs currently approved in Europe:

• genetically modified human autologous cells modified by integrating retroviral or lentiviral vectors;
• adeno-associated virus vectors for human use;
• oncolytic herpes simplex virus for human use

The accompanying general chapter 5.34 includes recommendations on product classes that are not yet on the European market to assist users and contains:

• the revised remaining sections of chapter 5.14, covering:
• plasmid vectors for human use;
• adenovirus vectors for human use;
• poxvirus vectors for human use;
• retroviridae-derived vectors for human use.
• a newly drafted section on genetically modified bacterial cells for human use.

In addition, general chapter 5.2.12. Raw material of biological origin for the production of cell-based and gene therapy medicinal products has also been revised to align it with this new approach. Please find further information here.

Public consultation on a new general chapter on cell-based preparations for human use in Pharmeuropa 36.2

In response to the need for a text covering the quality of cell-based preparations in the rapidly evolving field of advanced therapy medicinal products, the European Pharmacopoeia Commission is proposing a new general chapter, “Cell-based preparations for human use” (5.32), to its stakeholders. The chapter provides a framework of requirements for the production and control of cell-based preparations and comprises a definition, an extensive set of general requirements common to all cell-based preparations followed by four detailed individual sections describing additional specific requirements (for human haematopoietic stem/progenitor cells, human chondrocytes, human limbal stem cells and human mesenchymal stromal cells, respectively).

The draft general chapter has now been published in Pharmeuropa 36.2, where it will remain open for public consultation until 30 June 2024.

Draft guideline on ‘Content of the dossier for sterile substances’ released for public consultation

EDQM has drafted a guideline ‘Content of the dossier for sterile substances’ (PA/PH/CEP (23) 54) which is now available for public consultation until 15 August 2024. It is intended for applicants as a guide for compiling a dossier in order to obtain a Certificate of Suitability (CEP) for a sterile substance. This guidance document can be downloaded here.

European Medicines Agency (EMA)

Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials

This draft guideline addresses development, manufacturing and quality control as well as non-clinical and clinical development of investigational ATMPs. It describes requirements for exploratory trials (including First in Human studies) and confirmatory trials as well as provides a perspective towards Marketing Authorization Application (MAA).

Meeting Report Of The Joint EMA/EORTC Workshop on Soft Tissue And Bone Sarcoma Workshop

EMA and the Soft Tissue and Bone Sarcoma Group (STBSG) of the European Organisation of Research and Treatment of Cancer (EORTC) held a workshop on 12^th January 2024 to address the question on how to develop new treatments in ultra-rare sarcomas, as a model for ultra-rare tumours.

The aims of the workshop were to:

• Discuss the needs and points to consider for developing treatments in rarest cancer types using ultra-rare sarcomas as a model;

• Facilitate interactions among relevant stakeholders aiming at global collaboration;

• Explore a framework for regular meetings between the adult sarcoma community and regulatory agencies, in particular EMA and FDA, to work side by side in the development of new approaches and clinical studies tailored for this purpose.

The video recording and report of the 12 January 2024 meeting are now available here.

Reflection Paper On Use Of Real-World Data In Non Interventional Studies To Generate Real-World Evidence

This reflection draft document discusses methodological aspects of non-interventional studies (NIS) using real world data (RWD) in order to generate real-world evidence (RWE) for regulatory purposes. Given the large amount of information that NIS using RWD can generate for regulatory purposes, it is important to understand their limitations as well as how some of these limitations could be overcome or mitigated to increase the reliability of the evidence. This reflection paper is therefore relevant to all stakeholders involved in the planning, conduct and analysis of NIS using RWD to generate RWE for regulatory purposes, including Marketing Authorisation Holders (MAHs) and Applicants, regulatory authorities, HTA bodies, payers, academia, RWD holders and healthcare professionals’ and patients’ associations. Comments can be submitted until 31 August 2024.

Concept paper on revision of the Guideline on Risk Assessment of Medicinal Products on Human Reproduction and Lactation: from Data to Labelling

Most data regarding human pregnancy exposures are collected after marketing authorisation by spontaneously reported post-authorisation data, in patient/pregnancy registries, and via epidemiological studies undertaken in such data sources. In its Regulatory Science Strategy to 2025, the EMA highlights their commitment to advance access to better understanding and communication of benefits, risks, and uncertainties of medicines use in pregnancy and breastfeeding, throughout the product lifecycle.

The Pharmacovigilance Risk Assessment Committee (PRAC) and Committee for Medicinal Products for Human Use (CHMP) are optimising close cooperation for the revision of the ‘CHMP Guideline on risk assessment of medicinal products on human reproduction and lactation: from data to labelling (EMEA/CHMP/203927/2005)’.

This concept paper outlines the areas in this guideline which are planned to be updated.

EATRIS CONNECT

EATRIS-CONNECT Project Launches To AccelerateTranslational Medicine

EATRIS is the European Infrastructure for Translational Medicine; a non-profit organisation that brings together resources and services for research communities to translate scientific discoveries into benefits for patients. EATRIS focuses on improving and optimising preclinical and early clinical development of drugs, vaccines and diagnostics, and overcoming barriers to health innovation.

EATRIS-CONNECT is an EU-funded initiative that will use digital transformation as a tool to accelerate translational medicine. Led by EATRIS, the 3-year project (1 May 2024-30 April 2027) unites 21 organisations from across Europe, backed by a budget of €3.9 million from the Horizon Europe program. Please find further information here.

USA

Food and Drug Administration (FDA)

FDA grants accelerated approval to Breyanzi (lisocabtagene maraleucel) for follicular lymphoma

On 15 May 2024, the FDA granted accelerated approval to lisocabtagene maraleucel for adults with relapsed or refractory follicular lymphoma (FL) who have received two or more prior lines of systemic therapy. Please find further information here.

Considerations for the Use of Human-and Animal-Derived Materials in the Manufacture of Cell and Gene Therapy and Tissue-Engineered Medical Products

FDA has issued a draft guidance which provides recommendations regarding assuring the safety, quality, and identity of materials of human and animal origin used in the manufacture of cellular and gene therapy (CGT) and tissue-engineered products (TEP). This guidance applies to reagents, feeder cells and excipients and other inactive ingredients in the drug product that are in direct contact with the starting material, intermediates, final products, and any materials used to manufacture reagents, feeder cells, and excipients, and materials incorporated in tissus engeneered medicinal products (TEMPs). Human cells used as starting material to manufacture human cells, tissues, and cellular and tissue-based products, including TEMPs are excluded.

The considereations include donor screening and testing, adventitious agent testing and screening, risk assessment, and materials management. This guicance also provides recommendation regarding the chemistry, manufacturing, and control (CMC) information submitted in an investigational new drug application (IND) relating to the use of human- and animal-derived materials.

This guidance supplements the following two final guidances:

• “Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs); Guidance for Industry,” dated January 2020 and

• “Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs),” dated April 2008.

Public consultation is open until 30 Jul 2024.

Safety Testing of Human Allogeneic Cells Expanded for Use in Cell-Based Medical Products

FDA has issued a draft guidance intended to sponsors of allogeneic cell-based medicinal products, to provide recommendations for determining the appropriate cell safety testing to support an Investigational New Drug Application (IND) or a Biologics License Application (BLA). Cell safety testing should be based on a risk analysis that considers the expansion potential of the cells, the reagents that are used to expand the cells in culture, and the number of individuals the cell-based medical product is capable of treating.

This guidance supplements the following two final guidances:

• “Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs); Guidance for Industry,” dated January 2020 and

• “Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs),” dated April 2008.

Comments can be submitted until 30 July 2024.

Risk Evaluation and Mitigation Strategy Logic Model: A Framework to Link Program Design With Assessment; Draft Guidance for Industry

A Risk Evaluation and Mitigation Strategy (REMS) is a drug safety program that the FDA can require for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks. REMS are designed to reinforce medication use behaviors and actions that support the safe use of that medication. While all medications have labeling that informs health care stakeholders about medication risks, only a few medications require a REMS. FDA can require a REMS before initial approval of a new drug or after the drug has been approved should FDA become aware of new safety information about a drug and determine that a REMS is necessary to ensure that the benefits of the drug outweigh its risks. The purpose of this draft guidance is to describe the FDA’s REMS logic model which is a framework that provides applicants with a systematic, structured approach to the design, implementation, and evaluation of a REMS. Comments can be submitted until 6 August 2024.

EPA, FDA, and USDA Issue Joint Regulatory Plan for Biotechnology

In response to President Biden’s Executive Order 14081, “Advancing Biotechnology and Biomanufacturing Innovation for a Sustainable, Safe, and Secure American Bioeconomy,” the U.S. Environmental Protection Agency (EPA), the FDA, and the U.S. Department of Agriculture (USDA) have developed a plan for Regulatory Reform under the Coordinated Framework for the Regulation of Biotechnology to update, streamline, and clarify their regulations and oversight mechanisms for products of biotechnology.

The agencies will focus on five major areas of biotechnology product regulation:

• Modified plants
• Modified animals
• Modified microorganisms
• Human drugs, biologics, and medical devices
• Cross-cutting issues

EPA, the FDA and USDA intend to implement the following joint efforts:

• clarify and streamline regulatory oversight for genetically engineered (GE) plants, animals and microorganisms
• update and expand their information sharing through a memoranda of understanding(MOU ) to improve and broaden communication and coordination of oversight of modified microbes
• undertake a pilot project focused on modified microbes to explore and consider the feasibility and costs of developing a web-based tool that informs developers about which agency may regulate a given product category.

Please find further information here.

Improved Online Regulatory Science Tools Catalog

The Office of Science and Engineering Laboratories launched an improved online Regulatory Science Tool (RST) Catalog to enhance search and browse capability as well as allow for long-term growth in published tools. The RST Catalog is now organized by research program and device type, cross referenced by both program and RST category, and an online portal for many OSEL-developed applications including the Device and Material Safety Evaluation Library. The RST Catalog will continue to provide peer-reviewed resources for medical device companies and innovators.

FDA Announces The Establishment Of The OCE Equity Program

FDA Oncology Center of Excellence (OCE) announced the formation of The OCE Equity Program to improve access to clinical trials of oncology medical products for populations that have been historically underrepresented in clinical research, such as racial and ethnic minorities, individuals who live in rural areas, sexual and gender minorities, and individuals with economic, linguistic, or cultural barriers to healthcare services. The OCE Equity Program seeks to advance equitable access to clinical trials for all patients with cancer through policy, research, and education.

The Aims of The OCE Equity Program to :

• Develop and promote policies to ensure adequate enrollment of historically underrepresented and vulnerable subgroups in oncology clinical trials intended to support FDA approval to evaluate any differences that may exist across the population.
• Engage and collaborate with internal and external stakeholders on research, policy, and educational initiatives to promote access to and advance equity in clinical trials.
• Conduct and present analyses of data generated through clinical trials and other data sources to evaluate outcomes across subgroups.

Please find further information here.

European Medicines Agency (EMA)

Food and Drug Administration (FDA)

Therapeutic Goods Administration (TGA)

Click here to download the PDF.