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

November 14, 2018

Re: Docket No. FDA-2008-D-0205: Chemistry, Manufacturing, andControl (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)

Dear Sir/Madam:

The Biotechnology Innovation Organization (BIO) thanks the Food and Drug Administration (FDA or Agency) for the opportunity to submit comments on FDA’s Draft Guidance for Industry “Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)” (Draft Guidance or Guidance).

BIO is the world’s largest trade association representing biotechnology companies, academic institutions, state biotechnology centers, and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial and environmental biotechnology products.

General Comments

We commend the FDA for an excellent job in drafting the Draft Guidance; overall, it is well written and comprehensive. It effectively provides guidance on a range of CMC topics relevant to gene therapy products. However, BIO notes that the Draft Guidance is quite prescriptive and does not necessarily match modern manufacturing. BIO would like to see a better balance between the information that FDA needs to see in order to allow an IND to move forward and over-reporting of information that may be unnecessary. On the whole it seems that much of the information required in the Draft Guidance is more appropriate for a BLA filing, an approved product, or post approval changes to a product rather than an IND.

More specifically, several sections in the Guidance (lines 65-66, 117-118, 376-377) directly or indirectly seem to suggest that CMC information provided in the IND represents a “commitment” and “is subject to FDA review prior to releasing a new lot of clinical trial material”. The terms “commitment” and “lot release” are generally used in the context of licensed products and in this regard could be interpreted that CMC changes made during clinical development are subject to review and prior approval before implementation. Such a requirement could potentially restrict and delay development including continuous improvement of products under clinical development, which critically depends on regulatory flexibility while process and product knowledge are accumulated. BIO would appreciate if FDA could clarify the meaning of the terms “commitment” and “lot release” in this context or consider removing this language from the Guidance to avoid possible misinterpretation.

BIO finds that the scope of the document is not clear. The Guidance states in line 25 that the scope of the Guidance covers gene therapy applications generally. However, some recommendations, such as those regarding shipping and handling, are specific to ex vivo gene therapy and are not appropriate for in vivo gene therapy products. In addition, we would appreciate clarification regarding the quality expectations on gene modifying agents, such as viral vectors.  When used in the ex vivo manufacture of gene therapy products, the vector should be considered a critical starting material, which should be well characterized and appropriately controlled but not necessarily to the same extent as a drug substance. We ask FDA to provide specific recommendations for the product type and differentiate recommendations for ex vivo gene therapy products from in vivo gene therapy products.

We find that the Draft Guidance recommendations are unclear for which stage of development they would apply to. For some recommendations, the Draft Guidance specifies the expectation for the timing (e.g., information expected with the original IND submission), however; for most of the recommendations, the timing of application of the recommendations needs to be clarified. Additionally, the Draft Guidance includes recommendations for different stages including initial IND submission, during IND stage of clinical development phases, and CMC information to be submitted at the time of BLA submission. We ask FDA to clarify and specify when the individual recommendations in the Guidance would apply at the time of original IND submission.

The Guidance seems to suggest that analytical assays should be qualified/validated to be fit for their intended use. In this regard, the Guidance recommends assay qualification during early phases of product development, with an increasing expectation that assays be fully validated for late stage development and licensure. It would be greatly appreciated if FDA could provide more clarity, and perhaps examples, to differentiate between the terms “assay qualification” and “assay validation” in the context of specific ICH Q2 validation parameters (e.g., accuracy, linearity, precision), and explain how this applies to early versus late stages of product development.

It is BIO’s understanding that FDA, per Draft Guidance considers, a gene vector employed as an ex vivo gene therapy product a "Drug Substance" (e.g., lines 181-183, 230-231, etc.). BIO believes this would provide for a novel interpretation of the term "Drug Substance" (per 21 CFR 207.1, 207.3, 314.3, etc.) subjecting gene vectors used as intermediates for subsequent manufacture (i.e., ex vivo gene vectors) and gene vectors intended as Active Pharmaceutical Ingredients (i.e., in vivo gene vectors) to equal quality standards (see 21 CFR 312.23(a)(7)). In this regard, while the Guidance provides the definition of the term Drug Substance (i.e., 21 CFR 314.3(b)), it is silent on the rationale for interpretation of an ex vivo gene vector as a Drug Substance. BIO believes it is important to define and differentiate quality control and release expectations for gene vectors with different end-uses. To that end, it would be equally beneficial and greatly appreciated defining and differentiating testing expectations for the other materials referenced in this (or other similar) guidances as follows: raw materials, starting materials, and Drug Substance Intermediate.

BIO believes a section in the Guidance discussing how Sponsors can leverage and reference existing knowledge and data, for example, when same technology or manufacturing process features such as same vector are used for a subsequent gene therapy product, would be beneficial.

Finally, BIO believes that the Guidance would benefit from a glossary for consistent interpretation of terminology used in the Guidance. 


BIO appreciates this opportunity to comment on the Draft Guidance for Industry “Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs).” Specific, detailed comments are included in the following chart. We would be pleased to provide further input or clarification of our comments, as needed.