New and Emerging Regulatory Guidance for Cell and Gene Therapy Product Development

In this post, Chelo Tudela, regulatory affairs manager; Giulia Detela, regulatory affairs principal specialist; and Ilse-Maria Nolan, senior director of regulatory intelligence, policy and advocacy, discuss considerations for cell and gene therapy development based on recent updates to regulatory guidance published by the European Medicines Agency (EMA) and the U.S. Food & Drug Administration (FDA). PPD’s cell and gene therapy regulatory experts last issued a comprehensive review and comparison of the EU and U.S. regulatory frameworks in an overview in RAPS Regulatory Focus November 2020 issue.¹ Here, we highlight a brief summary of the newly published guidance for those involved in developing cell and gene therapy programs.

Background

Cell and gene therapies (CGT), known in the EU as Advanced Therapy Medicinal Products (ATMPs), are widely considered a ground-breaking field of innovative therapies. While these therapies are viewed to have great promise, they are a complex category of biological products requiring sophisticated pre-clinical and clinical development. Accordingly, an extensive volume of legislation and guidance has been published to foster advanced therapy product development. In both the EU and U.S., the legal basis for development falls under the regulatory framework of biological products with supplemental advanced therapy-specific legislation and guidance:

• In the EU, Regulation (EC) No. 1394/2007 establishes the overall legal and regulatory framework for ATMPs, classifying them into three main types: gene therapy medicines, somatic-cell therapy medicines and tissue-engineered medicines. In addition, a fourth category exists for ATMPs incorporating a medical device component, referred to as combined ATMPs.

• In the U.S., advanced therapies are regulated under section 351 of the Public Health Services (PHS) Act and Title 21 of the Code of Federal Regulations (CFR). They are classed as either cellular or gene therapy products. In 2016, the 21st Century Cures Act established a new expedited designation for a subset of CGT products, under the Regenerative Medicine Advanced Therapy (RMAT) program, which is part of the U.S. advanced therapy classification, although not a classification itself.

The first advanced therapy approvals occurred in 2009 in the EU² and 2010 in the U.S.³ To-date, 15 advanced therapy products have received approval for use in the EU and 19 in the U.S.

Recent guidance updates

Staying current with evolving regulatory intelligence and a proactive regulatory strategy is critical to development of advanced therapies due to the rapidly evolving science and regulatory framework.

European Union

EMA Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells⁴:

• The updated guideline will become effective June 2021 and incorporates scientific developments, regulatory experience and current thinking in the area of genetically modified cells. Updates to the quality section focus on starting materials, comparability and validation. A new non-clinical section focuses on chimeric antigen receptor and T-cell receptor-modified T cells, induced pluripotent stem cell derived cell-based products and cell-based products derived from genome editing, and an Annex has been included on clinical aspects specific to CAR-T cells. ATMP developers, particularly early stage companies developing investigational products, should incorporate appropriate aspects in their development strategy.

EMA Guideline on registry-based studies⁵:

• Post-authorization efficacy and safety studies are typically necessary for ATMPs licensed in the EU, and frequently performed based on existing disease registries. In fact, the EMA required post-authorization registry-based studies for nine of the 10 currently authorized ATMPs.

• In September 2020, the EMA published a draft guideline on registry-based studies including considerations for ATMPs. It recommends early discussions with regulatory authorities at both the national and EMA level. The guideline suggests strategy for post-authorization activities be developed during the pre-authorization phase, discussed in scientific advice and EMA PRIority MEdicines (PRIME) procedures if applicable. These early discussions should involve the concerned Rapporteurs or Lead Member States (and concerned EMA Committees) as well as registry holders and health technology assessment bodies, as relevant.

• The public consultation closed on 31 December 2020 and we await the final publication, which we expect will support regulators, registry holders and applicants, as well as establishing a structured approach for early dialogue. In the interim, we recommend applicants embrace its recommendations by planning inclusion of registry-based studies in their clinical development programs and leveraging consultation tools such as national and central Scientific Advice, procedural pre-submission meetings as well as the PRIME scheme, if applicable, during the pre-authorization phase.

United States

Human Gene Therapy (GT) for Neurodegenerative Diseases⁶:

• The FDA has published several disease specific CGT guides. In January 2021, FDA published a new draft guidance outlining considerations for development and approval of gene therapy products for neurodegenerative diseases affecting adult and pediatric patients. It provides recommendations for chemistry, manufacture & control, pre-clinical and clinical trials, in addition to expedited approval pathways and FDA communication. It outlines different meeting types that may be used for discussions, depending on the stage of product development and the issues to be considered to avoid approval delays. In our view, the recommendations in this guidance are critical for developers of gene therapy for neurodegenerative diseases.

Manufacturing Considerations for Licensed and Investigational Cellular and Gene Therapy Products During COVID-19 Public Health Emergency⁷:

• This guidance, published 5 January 2021 and effective immediately, outlines risk-based recommendations to minimize potential transmission of COVID-19 during manufacturing of CGT products during the pandemic. To ensure compliance with current good manufacturing practice (CGMP) requirements, CGT manufacturers are expected to evaluate potential risks to facilities, processes, manufacturing controls, donors, products, and the number of subjects that can be treated with the product. For example, an allogeneic product that is manufactured using a newly established cell bank and/or may be used to treat a large number of subjects or patients, would be associated with a higher infection risk than an autologous product. A description of the risk assessment and mitigation strategies, including scientific justification and literature references, should be included in the appropriate FDA submission (e.g., investigational new drug application (IND), biologics license application (BLA), or master file). It is important that CGT developers embrace recommendations of this guideline to avoid potential compliance issues.

A common thread throughout these and other advanced therapy guidance is the importance of agency communication throughout product development. We expect the regulatory environment of the fast-moving field of advanced therapies to continue to evolve at a fast pace as regulators incorporate new experience and scientific progress to inform development strategy. Staying current with evolving regulatory intelligence and engaging in frequent interactions with regulatory agencies are crucial activities to inform regulatory strategy and achieve the most efficient path to approval and market access.