Addressing the unique regulatory challenges of gene therapies

Francesco Lanucara | Senior Consultant, Regulatory Affairs CMC, Biopharma Excellence

Gene therapies have the potential to transform the treatment of disease by correcting an underlying genetic disorder. However, given the complexity of gene therapies and how rapidly the field is evolving, there are many regulatory and development challenges to overcome.

Just as gene therapy science continues to develop, so too do the regulations. Guidance is still being defined by regulatory authorities, with different expectations around the level of control of the safety, quality and efficacy of these products between the various health authorities.

The lack of harmonized regulations is understandable, given that there is still relatively little knowledge about gene therapies compared with more conventional biotherapeutics. For viral vector-based gene therapy products, which are a combination of protein and genetic payload, the interplay with the genome of the patient makes overall understanding of the critical quality attributes of these molecules and their overall mechanism of action much more challenging.

Since the underlying feature of many gene therapies is to manipulate the patient’s genome, it’s also important that companies can demonstrate to the health authorities that there are no unexpected adverse events – not just in the short-term but longer term, and that means more extensive follow up of patients after clinical trials.

The manufacturing side presents gene therapy companies with another set of challenges. First is sourcing the materials. The fact that materials are usually specifically sourced, often with unique cell lines developed by a contract development and manufacturing organization (CDMO), can make sourcing materials from different suppliers challenging. In addition, showing the same level of quality might be difficult, especially when moving from preclinical to clinical and commercial manufacturing. And there’s the question of whether the CDMO is able to assist the sponsor moving from pre-clinical through manufacturing scale up, including providing information for the regulatory filing.

The timelines involved are particularly daunting. Gene therapies very often target rare diseases and fall under regulators’ expedited programs, which can put sponsors under huge time pressure since it means getting everything done twice as fast despite having half the knowledge.

Engage early and stay informed

Gene therapy innovators undoubtedly face challenges; however, it should be remembered that regulators are eager to support the development of products that address an unmet medical need. Health authorities have implemented various programs aimed at facilitating ongoing engagement and support for developers of innovative products, such as the PRIME scheme from the EMA, the Innovative Licensing and Access Pathway (ILAP) program from the UK’s MHRA and FDA’s Breakthrough Therapy Designation.

Often with gene therapies, however, innovators don’t have the clinical evidence needed to be accepted for some of these programs. Regardless of the process followed, sponsors should reach out to the agencies early on and make the most of their interaction with regulators. Early scientific advice before filing an investigational new drug (IND) or investigational medicinal product dossier (IMPD) application is fundamental because it helps the sponsor to understand how much more they might have to do to demonstrate their product is safe before initiating a first-in-human trial, based on the knowledge accumulated.

Take the opportunity to describe the intended manufacturing process and the control strategies to the agency and seek agreement on alternative ways to meet certain regulatory expectations down the line, such as different approaches to process validation that might include concurrent validation or decoupling the validation of the drug substance from the drug product. By engaging early and providing clear information to the authorities, sponsors are less likely to face barriers later on when it might be more difficult to put mitigation measures in place.

Sponsors also need to be proactive when it comes to staying ahead of new regulatory guidance. EMA has published two updates in the last two years for investigational advanced therapeutic medicinal products (ATMPs), as well as questions and answers on comparability considerations for ATMPs.

FDA recently joined the Bespoke Gene Therapy Consortium, a collaboration of sponsors, regulatory agencies and the National Institutes of Health, with the objective of trying to develop a standard set of analytic tests to apply to the manufacture of viral vectors made by consortium researchers in order to improve and accelerate manufacturing processes. The consortium is also striving to streamline regulatory requirements to simplify the overall regulatory approval process.

There is new guidance on the role of the qualified person in releasing ATMP products for clinical trials or for commercial purposes in the EU, which is a very different approach to the FDA and can create some confusion for US sponsors, where a qualified person does not form part of the release of the material. This is another example of where early engagement with the agencies can be invaluable as they may waive import release testing for products coming into Europe if sponsors can demonstrate enough relevant data and show why repeat quality testing could be too onerous. That was the case for Luxturna and Zolgensma, where sponsors were able to demonstrate that, because of the small volume of production, it was not feasible for them to repeat the quality testing to release the product in Europe.

CMC preparation

In addition to working with the regulators, a priority should be to invest time and effort into gathering the CMC data needed to get a product into the clinic.

The amount of CMC work that sponsors can do is limited by development timelines and by the analytics toolbox available to them. Indeed, the analytics for the best methodology to address regulatory questions regarding gene therapies are still being developed and some methodologies that were previously considered to be acceptable have been found to have shortfalls as the knowledge develops.

As these developments show, gene therapy innovators need to not only think outside the box but also think long term. Upscaling or transferring the manufacturing process to a new site after the exploratory clinical trial is a common situation and requires a comparability study to demonstrate that the product generated for the pivotal clinical study is comparable to the product used in the exploratory trial.

A new wave of medicines

The reality with gene therapies, which are tailor-made to the patient, is that it is very difficult to standardize the manufacturing process because there can never be a one-size-fits-all approach. Flexibility is therefore important when dealing with products that are so patient-specific. However, as industry and regulators gain more knowledge about gene therapy processes and products, there will inevitably be greater clarity around requirements, as well as more breakthroughs in this exciting new wave of innovation.

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