How should we regulate genome editing for pharmaceutical applications?

by Dr. Diane Seimetz

Genome editing technologies are not only having a game-changing effect on research. They also have the potential to transform health care by curing diseases for which there are currently no or no satisfactory therapies available.

In particular with the emergence of novel gene editing technologies such as CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats) in the pharmaceutical arena the question arises how to best regulate these technologies.

On 18 October 2017 the European Medicines Agency (EMA) organized an expert meeting on genome editing technologies used in medicinal product development. Diane Seimetz contributed to the meeting as invited expert and has summarized the discussion and critical aspects in this article.

Genome editing technologies are not only having a game-changing effect on research. They also have the potential to transform health care by curing diseases for which there are currently no or no satisfactory therapies available.

In particular with the emergence of novel gene editing technologies such as CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats) in the pharmaceutical arena the question arises how to best regulate these technologies.

On 18 October 2017 the European Medicines Agency (EMA) organized an expert meeting on genome editing technologies used in medicinal product development.

The expert panel comprised experienced stakeholder from academia, industry and regulators. Diane Seimetz contributed to the meeting as invited expert. The outcome of the EMA expert meeting on genome editing is scheduled to be discussed during the upcoming Committee for Advanced Therapies (CAT) Strategic Review and Learning meeting.

One of the most important questions regarding the development genome edition technologies are related to the specificity and precision of editing at the intended genetic loci, i.e. “on-target”. The potential for so called “off-target” effects, e.g. insertions or deletions outside of the intended genetic loci, has been identified as a key concern. These questions will need to be carefully addressed during product development and will impact the duration of clinical follow-up time to assess long term effects. As genome editing technologies progress towards clinical stage different tools are being developed to assess on-target editing and potential off-target effects. No gold standard is available yet. Nor are regulatory guidance documents in place addressing the particularities of genome editing. However, the principles of existing guidance documents for cell and gene therapy should be considered as applicable.

In the EU genome editing products are being regulated as Advanced Therapy Medicinal Products (ATMPs). ATMPs comprise Gene Therapy Medicinal Products (GTMP), Cell Therapy Medicinal Products (CTMP) and Tissue Engineered Products (TEP). It is likely to assume that the majority of genome editing products will be regulated in as GTMP.

The US FDA regulates human medical products that apply genome editing under the existing framework for biological products, which include gene therapy products. The first genome editing product that has been announced as being applied in US clinical trials employed zinc finger nuclease (ZFN) mediated genome editing. Proposals for human gene therapy clinical trials are discussed and reviewed by the NIH’s Recombinant DNA Advisory Committee (RAC). The RAC has already discussed the first clinical protocol to use CRISPR/Cas9-mediated genome editing. No objections were raised.

In the EU, the Clinical Trial Application (CTA) for the first company-sponsored clinical trial of a CRISPR/Cas9 genome-edited therapy is currently under review.

As with any new therapeutic approach not all questions can be perfectly answered in particular during early development. Experience will be gained over time as the technologies are being applied. To some extent the situation with genome editing today is comparable to the time where genetic modifications with viral vectors emerged. Therefore a science-based approach for the assessment and regulation of genome edited products is essential. For sponsors diligent design of editing tools with high on-target efficiency and no/low off-target activity is important. For residual risks and uncertainties arising from either the genome editing itself or the associated therapeutic procedure a well thought out risk assessment and mitigation strategy should be in place.

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