FDA Finalizes 6 Gene Therapy Guidances, Unveils a New Draft

Regulatory NewsRegulatory News | 28 January 2020 |  By 

The US Food and Drug Administration (FDA) on Tuesday finalized six guidance documents on gene therapy development and released a new draft guidance on interpreting the sameness of gene therapies under the orphan drug regulations.

The guidance release comes as more than 900 investigational new drug applications are ongoing for gene and cell therapy clinical studies, and as FDA has struggled to hire enough experts to tackle the related challenges. The release of the six final guidances and the new draft were expected as FDA’s list of guidance documents from last July explained.

Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, explained: “Scientific development in this area is fast-paced, complex, and poses many unique questions during a product review; including how these products work, how to administer them safely, and whether they will continue to achieve a therapeutic effect in the body without causing adverse side effects over a long period of time.”

Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations

The new draft guidance on sameness is not quite four pages long but explains (with examples) how FDA will decide if orphan exclusivity will be awarded if two gene therapy products are intended for the same use or indication.

The draft notes how FDA’s determination of “sameness” will consider, per 21 CFR 316.3(b)(14)(ii), the principal molecular structural features of the gene therapy products, although the regulations do not explain how the “same drug” definition applies to gene therapies.

So for the purposes of granting orphan designations and exclusivity, the guidance explains three different scenarios:
  • “If two gene therapy products express different transgenes (e.g., transgenes that encode different enzymes for treatment of the same rare disease), and have or use different vectors, FDA generally intends to consider them to be different drugs for purposes of 21 CFR 316.3(b)(14)(ii) because they will not contain the same principal molecular structural features.
  • If two gene therapy products express different transgenes, FDA generally intends to consider them to be different drugs for purposes of 21 CFR 316.3(b)(14)(ii) because they will not contain the same principal molecular structural features, regardless of whether they have or use the same vector.
  • If two gene therapy products have or use vectors from a different viral class (e.g., gammaretrovirus vs. adeno-associated virus (AAV)), FDA generally intends to consider them to be different drugs for purposes of 21 CFR 316.3(b)(14)(ii) because they will not contain the same principal molecular structural features, even if they express the same transgene (e.g., a transgene that encodes the same enzyme for treatment of the same rare disease).
But FDA also said that it “intends to make the determination of whether two vectors from the same viral class (e.g., adeno-associated virus 2 (AAV2) vs. adeno-associated virus 5 (AAV5)) are the same or different on a case-by-case basis.”

The agency further says it will consider additional features of gene therapies, explaining, “If two gene therapy products express the same transgene and have or use the same vector, determining whether the gene therapy products are the same drug for purposes of 21 CFR 316.3(b)(14)(ii) may also depend on additional features of the final product that can contribute to the therapeutic effect. These additional features may include regulatory elements, or for genetically modified cells, may include the cell type that is transduced. In these cases, FDA generally intends to consider requests for designation and exclusivity of gene therapy products to evaluate whether such additional features may be considered to be “principal molecular structural features” within the meaning of 21 CFR 316.3(b)(14)(ii).”

Final Guidance

The six final guidance documents, meanwhile, finalize drafts from July 2018 and focus on developing hemophilia, rare disease and retinal disorder gene therapies, and include one on chemistry, manufacturing and control (CMC) information, one on long term follow-up observational studies collecting data on adverse events and one on the testing of retroviral vector-based therapies.

Human Gene Therapy for Hemophilia

The final version of this guidance includes updated explanations on efficacy endpoints, noting the FDA’s ability to use factor activity levels as validated surrogate endpoints that could support traditional approval “is currently limited by several scientific considerations.

“One of these considerations is that discrepant results may be obtained when using conventional factor assay methodology to assess the plasma factor levels in patients treated with GT products in comparison to the assessment of levels following the administration of their recombinant or plasma-derived counterparts. Another consideration is the lack of molecular characterization of the protein translated in vivo (e.g., factor VIII produced by hepatocytes), in contrast to recombinant factor concentrate products produced in vitro. Additional uncertainty exists regarding the extent of clinical benefit introduced by genetically engineered modifications that increase the specific activity of coagulation factor protein (e.g., factor IX Padua constructs),” the guidance adds.

In addition, further details in the final guidance also explain what traditional approval vs. accelerated approval would mean.

Human Gene Therapy for Rare Diseases

This final guidance includes new phrasing that was not included in the draft, as well as some new details on when to use placebo controls (i.e. “If a study has multiple dose-level cohorts, consider randomizing some subjects in each cohort to receive placebo.”) and when to use intra-subject comparisons to “avoid the problem of variability among subjects that occurs with inter-subject controls.”

Other new details in the final version discuss identifying relevant biomarkers and concomitant medicines.

Human Gene Therapy for Retinal Disorders

This final version remains largely similar to the draft, with some new details on safety considerations and further explanation of why a single administration of a gene therapy product in each eye may not always be sufficient.

The final version also adds information on the separation of clinical evaluators and personnel involved in product administration and the sham procedure.

Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)

Similar to the others, this 54-page final guidance also includes editorial changes, as well as new information on critical quality attributes (CQAs) and references to other guidances on CQAs.

The final draft also includes new recommendations on bacterial master cell banks (MCBs), which the agency says can provide a consistent starting material for the manufacture of plasmids or microbial vectors.

“However, MCBs may not be necessary for all manufacturing situations if the plasmid intermediate is appropriately qualified (e.g., for early phase studies when the plasmid is used to make a vector for ex vivo modification of cells),” the final guidance says. FDA also includes a new subsection on replication competent viruses.

Long Term Follow-up After Administration of Human Gene Therapy Products

This 35-page final guidance remains almost exactly the same as the draft version, with some minor edits and additions, such as the note that, “If at the time of BLA approval FDA determines it is necessary to initiate LTFU observations, you should submit the study protocol to your existing IND, with a cross-reference letter to the BLA submission explaining that the protocol was submitted to the IND.”

Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up

The final version of this 16-page guidance is also almost identical to the draft, with a new subsection on vector producer cell working cell bank, in addition to revised recommendations on assays for testing (section III. C).


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