FDA Issues “Cliffs Notes”-style Guidance on Cell and Gene Therapy; What CMC Questions Did They Answer? (Part 2)

We recently published the first part of our review of FDA’s draft guidance titled “Frequently Asked Questions – Developing Potential Cellular and Gene Therapy Products.” Questions and Answers Guidance (see previous coverage here).  In this post we focus in on the draft guidance document’s chemistry, manufacturing, and controls (“CMC”)-specific content.  In eight pages we get a string of high-level regulatory questions that provide a nice roadmap for CMC product development, which largely align with opportunities to engage with CBER as you progress through the development of cellular and gene therapies (“CGT”).

As you review these questions and answers, nothing that CBER provides in this guidance is “new.”  In fact, nearly all of the CMC comments are directing us to existing guidance documents.  This does not mean that there is no value in this recent publication. What can be gained from this new guidance from a CMC perspective is more nuanced.  The guidance documents that CBER has issued in recent years in the CGT space have been important steps forward.  Each provides high-level considerations for a field that spans a mind-boggling number of indications and therapeutic modalities that CBER is responsible for reviewing.  This is best exemplified by CBER’s description of characterization tests in this guidance:

The appropriate characterization tests depend on the unique features of the product type. For example, characterization testing of a cell-based product may include extended assessment of cell surface phenotypic markers, such as those associated with immune-cell activation, differentiation, and exhaustion. For adeno-associated viral vectors, examples may include characterization of non vector DNA impurities in capsids by next-generation sequencing, vector genome size analysis, and detection of capsid amino acid modifications by mass spectrometry. For tissue-engineered medical products, examples may include biomechanical testing to assess the ability of a vascular graft to tolerate repeat access without leaking, permeability testing to assess the characteristics of a skin graft, or cellular distribution throughout a cell scaffold construct.”

This broad span of products can limit CBER’s ability to give meaningful details or examples in guidance, leaving the Center to make more general recommendations:

• “FDA recommends that sponsors evaluate a number of product characteristics during early clinical development to help identify and understand CQAs”
• “There is no fixed number of lots recommended for PPQ. In general, a greater understanding and knowledge of the product and manufacturing process can reduce the number of PPQ lots that should be sufficient to qualify the performance of the manufacturing process.”

If you make a tissue product you may produce one lot per patient where a gene therapy may only need a handful of lots through Phase 3.  It is harder to execute full testing programs on lots containing one unit.  As a result, how you approach your PPQ will be drastically different.

Key takeaway for CMC:  What makes a successful CMC section for an IND or BLA looks very different for every development program.  In this draft guidance, CBER is walking sponsors through the options available to them to ask program-specific questions as sponsors will only get one shot at some meeting types (INTERACT, Pre-IND, Pre-BLA). It is important that sponsors do not miss an opportunity to engage with CBER on CMC topics. This is even more so in rare disease CGT programs where clinical development can be more streamlined, so CMC product development is expected to happen at a more rapid rate.  This new guidance will help ensure that sponsors get the most out of their interactions with CBER by ensuring they do not have major blind spots.  From there, it is up to sponsors to take every opportunity to ask product-specific CMC questions to CBER.  As this and other CGT guidance documents illustrate, there is no one-size-fits-all approach to CMC.