Consideration For CMC For Human Gene Therapy for Rare Diseases: FDA Guidance

FDA Guidance on Human Gene Therapy for Rare Diseases


The general chemistry, manufacturing, and controls (CMC) considerations for product manufacturing, testing, and release of GT products for rare diseases are the same as those described for other GT products.  However, some aspects of the development programs for rare diseases, such as limited population size and fewer lots manufactured, may make it challenging to follow traditional product development strategies. In traditional product development, critical quality attributes (CQAs) of the product are evaluated during each phase of clinical development, and characterization data from many drug product lots are correlated to clinical outcomes. 

Smaller study populations may result in the need for fewer manufacturing runs, which can make it difficult to establish the critical process parameters (CPP) necessary for ensuring CQAs. In addition, GT products may have CQAs with higher variability than drugs or well-characterized biologics, which can add to CQA uncertainty. However, demonstrating process control to ensure a consistent product with defined CQAs for potency, identity, and purity is required to demonstrate compliance with licensure and regulatory requirements

 These factors make it even more critical that a sponsor of a GT product for a rare disease establish a well-controlled manufacturing process along with suitable analytical assays to assess product CQAs for product concentration, potency, identity, and purity as early in development as possible, optimally before administration of the GT product to the first subject. When changes to the manufacturing process are necessary, a comparability assessment may be needed. Importantly, as the Phase 1 study may provide evidence of safety and effectiveness for licensure, we recommend that sponsors characterize the product’s CQAs, and implement manufacturing CPPs, before initiating clinical studies. Innovative strategies for understanding CQAs may include applying prior knowledge from other similar products, leveraging product characterization data from nonclinical studies, evaluating CPPs during engineering runs, or the production of multiple small lots versus a single large product lot. Sponsors developing GT products for rare diseases are strongly encouraged to contact the Office of Tissues and Advanced Therapies (OTAT) in the Center for Biologics Evaluation and Research (CBER) prior to investigational new drug application (IND) submission and during product development to discuss their product-specific considerations, which may include:

 • Product-related variations may have a pronounced effect on the interpretability of clinical data in rare disease studies. Examples of product variations include impurities such as empty and wild-type viral particles in viral vectors and variability in genetically modified cell therapies caused by intrinsic differences among subjects’ cells. The establishment of assays for the characterization of product-related variants and impurities will be important for program success. 

• Potency assays are critical to assess product functional activity, consistency, and stability, and to provide evidence of comparability after changes to the manufacturing process. To better understand product function(s), we strongly encourage the evaluation of multiple product characteristics before initiating clinical studies. These characterization studies may in turn be used to establish a potency test, which is critical to successful product development. 

Therefore, we recommend that a potency test that measures a relevant biological activity be qualified for suitability (i.e., accuracy, precision, sensitivity, specificity) prior to conducting trials intended to provide substantial evidence of effectiveness for a marketing application and validated prior to licensure. 

• It can be challenging to develop and validate a manufacturing process or perform comparability studies and develop suitable assays to measure CQAs when there is limited availability of starting materials (e.g., autologous cells), a lack of reference materials, or limited process understanding. Sponsors are encouraged to consider, where possible, implementing manufacturing changes needed for commercial-scale production and demonstrating product comparability prior to the initiation of clinical trials intended to provide substantial evidence of effectiveness for a marketing application. 

Importantly, if product comparability cannot be demonstrated, additional clinical data may be needed. 

For details, visit