January was a gangbuster month for the FDA’s Center for Biologics Evaluation and Research (CBER) with regard to publication of gene therapy (GT) guidance documents!  A total of six final guidelines and one draft guideline on GT products were issued.  These included:

  • Chemistry, Manufacturing, and Control Information for Human Gene Therapy Investigational New Drug Applications (here)
  • Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up (here)
  • Long Term Follow-Up After Administration of Human Gene Therapy Products (here)
  • Human Gene Therapy for Rare Diseases (here)
  • Human Gene Therapy for Retinal Disorders (here)
  • Human Gene Therapy for Hemophilia (here)
  • Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations (here)

These guidances will be extremely valuable to the exploding field of gene therapeutics, especially to those companies that are in the early development and clinical study phases.

For today’s blog, I’ll be reviewing the final guidance at the top of the list (i.e., CMC information for GT IND Applications).  As this guidance is packed with critical details regarding the content of IND applications for gene therapy products, firms looking to enter this field are encouraged to become familiar with the entire final guidance document.  However, in the interest of space, this blog installment will focus specifically on the content changes relative to the draft guidance document of the same name that was issued in July 2018.  These changes are tabulated below.

CTD Section New Information in Final Guidance Document
Module 2 Provide a general introduction to the gene therapy product, including a description of the active ingredients, the mode of action, and proposed clinical use.
Identify whether the product is a combination product.
Describe how the product will be handled at the clinical site prior to administration to the patient.  This information should be hyperlinked to the Drug Handling and Preparation for Use instructions in Module 5.
Drug Substance (3.2.S) The Agency recommends that sequence data and data supporting genetic stability be submitted in the “Regional Information (3.2.R)” section of the CTD.
For cells that are genetically modified ex vivo, a separate DS section should be provided for the vectors used for transduction of the cells.
Control of Materials (3.2.S.2.3) The requirement to establish a materials qualification program has been added.
Also, in the subsection on control of allogeneic cells, screening of the donors for variant Creutzfeldt-Jakob disease has been added, as well as a requirement that testing for viral contaminants be performed by a laboratory that is either certified to perform such testing on human specimens under the Clinical Laboratory Improvement Amendments of 1988 and 42 CFR Part 493 or has met equivalent requirements as determined by the Centers for Medicare and Medicaid Services (21 CFR 1271.80(c).
Drug Substance Impurities (3.2.S.3.2) A requirement for testing products produced in HeLa cells for the presence of E6/E7 genes has been added.
Analytical Procedures for Control of Drug Substance (3.2.S.4.2) A requirement for a description of the system suitability controls for analytical methods, as well as a recommendation for trending of assay performance to gain further understanding of the method and method improvements during product development, have been added.
Batch Analysis (3.2.S.4.4) The Agency has added a strong recommendation for sponsors to gain adequate experience with new clinical manufacturing processes, or after transfer of manufacturing to a new facility prior to making material for clinical studies.
Reference Standards or Materials (3.2.S.5) The requirement for establishing a protocol for evaluating the stability of reference materials and for retaining sufficient reference material to bridge to a new reference material has been added.
Compatibility (3.2.P.2.6) The Agency has added a strong recommendation to understand in-use and in-device stability and the potential impacts on product performance.
Analytical Procedures for Drug Product Control (3.2.P.5.2) The final guidance includes endotoxin limits for intraocularly-administered drugs (i.e., 2.0 EU/dose/eye for injected or implanted products and 0.5 EU/mL for ophthalmic irrigation products).
Facilities and Equipment (3.2.A.1) The Agency specifies the duties of the manufacturer’s Quality Unit to include establishing procedures to qualify reagents and critical materials, and prevent microbial contamination, cross-contamination, and product mix-ups.  In addition, the Quality Unit should have procedures in place to investigate lot failures, out-of-specification results, and ways to implement corrective actions as product development progresses.  It is also expected that the IND will describe how the quality control testing and oversight are separated from the manufacturing unit.