As we await our nation’s State of the Union address, FDA’s own Commissioner Scott Gottlieb and Center for Biologics Evaluation and Research (CBER) Director Peter Marks issued a joint statement providing a state of union of sorts on the development and regulation of cell and gene therapy. This comes at a time when we are seeing exponential growth in the number of cell and gene therapies entering clinical development (see previous coverage of the first gene therapy that was approved here). The statement both provides an update on the advancement of these technologies and FDA’s actions and activities intended to further support their development.
An Inflection Point
Assessing the current pipeline and trends in incoming INDs, FDA views this as an inflection point in cell and gene therapy technology and innovation. As such, FDA attempts to project the volume of cell-based or directly administered gene therapy products in development and gaining approval in coming years:
- Currently 800+ active INDs
- Anticipate receipt of 200+ new INDs per year by 2020
- Predict approval of 10-12 cell and gene therapy products per year by 2025
Drawing an analogy to the platforms for humanizing antibodies that accelerated the mainstreaming of human monoclonal antibody drugs in the late 1990’s, FDA credits the advent of safe and effective vectors (e.g., AAV vectors) for the delivery of gene therapy products as enabling this progress.
To accommodate these increases, CBER is expanding its review group dedicated to reviewing these applications, with the hope of adding about 50 additional clinical reviewers to the CBER Office of Tissues and Advanced Therapies (OTAT).
Developing New Policy
To support the advancement of cell and gene therapies, Commissioner Gottlieb and CBER Director Marks underscored the importance of FDA developing a comprehensive framework for these technologies. This is consistent with the work FDA has done over the last 1+ years, already weighing in on aspects of development through a series of guidance documents issued in December 2017 (see previous coverage here), followed-up with another release of guidances in July 2018 (find the full list of cell and gene therapy guidances here).
The two FDA officials used this opportunity to preview what additional draft and final guidance documents the Agency is currently developing, which include the following topics:
- Different areas of active product development (e.g., products for inherited blood disorders like hemophilia). FDA previously issued a draft hemophilia drug development guidance, as well as retinal- and rare disease-specific guidances in July 2018.
- Development of gene therapies for certain neurodegenerative diseases. In February 2018, the Agency released a series of neurology-focused drug development guidances for ALS, Duchenne muscular dystrophy, Alzheimer’s disease, partial onset seizures, and migraines (see previous coverage here), so this could be a key opportunity to see how FDA’s views on gene therapy development differ from traditional drug development.
- Manufacturing of cell-based gene therapies, such as CAR-T cells. Guidances on this topic will recommend parameters for introducing advances in manufacturing without requiring costly new clinical investigations, as well as propose alternative ways to ensure safety and effectiveness of resulting products. This area of guidance will also cover critical quality attributes and other factors related to product manufacturing, with the goal of specifying when minor changes are allowable without clinical bridging studies. FDA is planning a public meeting in the coming months to discuss expediting clinical bridging studies when more than minor changes are introduced to the manufacturing process, but do not represent a transformation to a fundamentally different product.
- Promote efficient development of safe and effective cell-based regenerative medicine products. For small sponsors, including academic investigators, who may not be able to conduct a clinical trial on their own, FDA intends to encourage these sponsors to pool clinical data to demonstrate safety and effectiveness of a product that is (a) manufactured with a similar manufacturing protocol and product quality specifications and (b) is used for a common clinical purpose.
Noticeably absent from the statement is any indication that the guidance documents will discuss the implications of the product quality policies on biosimilar development of cell and gene therapies.
Insights into FDA’s Evolving Regulatory Approach
While the Commissioner and CBER’s statement was mostly forward-looking, setting expectations for future policy development, a few key takeaways emerged.
The Role of Accelerated Approval
First, the statement notes that expedited programs, such as RMAT designation and accelerated approval are key to cell and gene therapy development. Specifically, the statement sets out that accelerated, or Subpart E, approval can represent a faster route to approval when a gene therapy targets an underlying monogenetic change such that it could alter or cure the underlying genetic defect that leads to, and causes advance of, a disease. This expedited development timeframe is able to be counterbalanced by post-marketing evaluation of the risks associated with gene therapies (i.e., durability and rare off-target effects), which require longer-term follow-up than traditional clinical trials allow. This represents a great opportunity for FDA to more systematically utilize the accelerated approval pathway in an area outside of oncology, which has been the only area where FDA has had a well-established policy for use of this approval pathway.
In the same vein, the statement also distinguishes when CBER may view traditional approaches to drug development to be more appropriate. FDA lays out that, where a gene therapy instead creates a genetic alteration aimed at treating the symptoms of a disease, or potentially altering the expression of a protein or enzyme believed to play a role in the advance of a disease (i.e., alter course and symptoms but not “cure” the disease), a more traditional clinical study is more appropriate.
Enforcing Pre-Market Approval of HCT/P’s
The statement expresses a continued concern by FDA that certain cell-based products that the Agency views as being subject to pre-market approval are being marketed outside of regulatory compliance and are even posing potential significant safety concerns to patients. This refers to FDA’s ongoing attempt to reign in HCT/P manufacturing where it believes the products, primarily stem cell products, do not meet all four criteria for regulation solely under 21 CFR Part 1271. In December 2018, the Agency issued a press release expressing its disappointment in the dearth of HCT/P manufacturers that have reached out to the Agency during the first 14 months of the enforcement discretion period (see previous coverage here).
In an apparent follow-up to last month’s press release, this statement announced FDA’s intent to undertake enforcement actions in 2019 for those products that pose a significant risk of potential harm to patients. However, the statement did not specify what those enforcement actions would be, nor how this policy differs from what CBER’s enforcement posture has been to date regarding purportedly violative HCT/Ps.