By Mark Levi, PhD, PAREXEL® Consulting
In July 2018, FDA published updated draft guidance on the complex topic of “Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)”.
It took 27 years from the treatment of the first patient with an experimental gene therapy (for ADA-SCID) to the first FDA approval. Long considered risky and a therapy of last resort, gene therapies have recently come to the forefront of biologic therapies for diseases such as retinal dystrophy, which can now be treated with one dose of Luxturna®.
The FDA’s draft guidance revises that issued in April 2008 and outlines just what types of information applicants should submit in each new IND application reviewed by the Center for Biologics Evaluation and Research (CBER). Gene therapies are unlike even the most complex biosimilars and so the guidance identifies what CMC information is sufficient to assure product safety, identity, quality, purity, and strength (including potency) of the investigational product (21 CFR 312.23(a)(7)(i)).
Even making the distinction between DS(s) and DP in gene therapies can be difficult requiring a lengthy explanation in eCTD Module 2. Should the gene therapy be a part of a combination product, the manufacturing (drug) and engineering (device) information must be provided.
The required Manufacturing Process and Control Information (eCTD Module 3) is almost as detailed as that required for a BLA. However, FDA now recommends that even at early stages (toxicology and first clinical lots) of manufacture, the sponsor anticipate and describe how proposed manufacturing changes (process optimization) could potentially affect product performance. Even for first-in-human studies, FDA recommends that any differences between toxicology lots and clinical lots be assessed for any impact on safety. Impurities must be reduced and quantified, especially those that may be tumorigenic. Safety testing is also different from any other product in that it includes testing for replication-competent viruses and the wild-type oncolytic virus.
While analytical procures for original INDs do not usually have to be validated for Phase I studies, the test methods need appropriate controls and need to be qualified and the protocol submitted in the IND. Additionally, a qualified method is needed to quantitate preclinical and clinical lots for dose comparison.
It is noteworthy that this draft guidance goes into great detail on the types of testing needed on the DS and DP illustrating just how complex gene therapies are and how they differ from every other biologic product regardless of complexity. FDA outlines the critical and relevant CMC data necessary even to conduct a Phase I study of a gene therapy.
PAREXEL is currently supporting clients in developing regulatory strategies and submissions for cell and gene therapy products, which take into account their many differences from even biosimilars.