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Why Regulatory Convergence is Key to Global Development of Cell and Gene Therapies

There is growing excitement about the potential shown by cell and gene therapies, particularly in rare diseases. First, though, these therapies face challenges both in development and in aligning with regulatory guidance that was established long before the advent of advanced therapeutic medicinal products (ATMPs). Francesco Lanucara of PharmaLex explores the challenge of navigating guidelines that don’t always reflect the complexity of ATMPs and the importance of achieving regulatory convergence across different regions.

There have been significant advances in the field of cell and gene therapy in recent years with the approval of a growing number of therapies that target rare diseases. As knowledge is continuously gained on key aspects of the manufacturing processes and the quality attributes of cell and gene therapy products, regulatory guidance also continues to evolve. Both the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) have been busy in the past few years publishing new guidance for advanced therapeutic medicinal products (ATMPs). For example, the FDA produced two new guidances this year – one on CAR T cell products1 and one focused on products incorporating genome editing (GE) of human somatic cells.2

Largely, though, developers have had to find ways to work with long-established ICH guidelines that were designed with more conventional biotechnological products in mind, such as monoclonal antibodies. Due to the complexity of ATMPs, the regulatory framework has evolved differently in various jurisdictions, as is reflected by the diverse approaches from EMA and FDA to aspects of the development process, particularly with regard to the implementation of GMP compliance and the definition of starting materials. The evaluation and regulation of cell and gene therapy products would benefit from greater convergence and harmonisation of requirements and standards across different regions, supported by collaboration between industry, non-profit, academic and other organisations, and regulatory authorities.

Why ICH Harmonisation Guidelines Need an ATMP Update

The ICH was established more than 30 years ago as a global platform for the harmonisation of technical guidelines and requirements for the development and registration of pharmaceutical products. Today ICH has 20 members and 35 observers, and many health authorities worldwide now apply ICH guidelines to their regulatory framework. Some countries take ICH guidelines that don’t easily fit the complexity of ATMP medicines, resulting in developers of ATMPs struggling to meet expectations during the evaluation of their submissions. While ICH has developed some guidelines relevant to gene therapies, for example, guidance on nonclinical biodistribution studies in the development of gene therapies,3 many activities covered by well-established ICH guidelines don’t easily apply to cell and gene therapies. There is, therefore, a need for guidance to be updated to take into consideration the variety, complexity and challenges of cell and gene therapies.

As an example, requirements for batch-release testing cannot be applied in the same way to cell-based products as they are to an antibody. Typically, with cell-based products, tissue is taken from the patient, which is then genetically modified and returned to the patient. Cell-based products are often characterised by short shelf lives, challenging the execution of traditional release testing, such as sterility, in a time frame that allows delivery of the product to the patient without compromising the product quality. The challenges associated with ATMPs are recognised by schemes such as EMA’s PRIME programme, which provides developers of innovative ATMPs with options to adapt their CMC (chemistry, manufacturing and controls) development to the restricted timelines that are typically faced in the approval of these products. As an example, alternatives to the standard process qualification and validation as described in the ICH are described for ATMP programmes, where the number of batches manufactured at the time of submission of the Marketing Authorisation Application may be limited.