Last month, the FDA issued six draft guidance documents specific to gene therapy development as their latest effort to update regulatory framework in the cell and gene therapy sector. This follows the release of a series of guidances and draft guidances in late 2017 also aimed at sponsors in this space. This most recent release of guidances target gene therapy manufacture (chemistry, manufacturing and control (CMC) information, long term follow-up (LTFU) and replication competent retrovirus (RCR) testing) and specific disease categories (hemophilia, rare diseases and retinal disorders).
The draft guidances for CMC, LTFU and RCR are intended to supersede existing guidances on these topics. The previous revisions of these guidances were in need of modification to be current with the industry today, as two of the previous versions were released in 2006 (RCR and LTFU) and one in 2008 (CMC). According to Ann Kemp, Senior Manager of Regulatory Compliance, Be The Match BioTherapies®, “The updates to the manufacturing documents provide needed clarity for the industry. A major highlight of these guidances is an update to the definition of gene therapy, which hadn’t been changed in over a decade. With so many gene therapies in development today, it definitely was time for the FDA to revisit.”
In addition to the new gene therapy definition, another change for the Chemistry, Manufacturing and Control (CMC) Information for Human Gene Investigational New Drug Applications (INDs) draft guidance is the reorganization of the document for consistency with the common technical document (CTD) format. This helps sponsors better understand what information is expected in different CTD modules (notably Module 3) and how the FDA envisions gene therapy product material fitting within the module headings.
“This will be very helpful for sponsors who are submitting INDs, because the modules provide a roadmap to the specific information the FDA is looking for in each section. The guidance also provides more details and examples for sponsors on how to provide sufficient information,” says Beth Kuker, Sr. Regulatory Compliance Specialist, Be The Match BioTherapies.
Regarding long term follow-up, initially the FDA did not fully understand the long-term implications of these new gene therapy products and were accordingly conservative with LTFU activities they were asking sponsors to perform. Now that the FDA has more data, they are updating their recommendations on how observational studies for LTFU should be designed per the Long Term Follow-Up After Administration of Human Gene Therapy Products draft guidance.
“A significant change to this document is the number of years that follow-up needs to occur. For most therapies, the FDA had recommended a 15-year follow-up period after administration of the therapy. In this guidance, the FDA says that companies can lessen the 15-year follow-up if there is sufficient evidence to support patient safety and therapy efficacy,” Ann says. “Additionally, they recommend sponsors establish a separate protocol for long-term follow-up with more focus on potential adverse events.”
The draft guidances for hemophilia, rare diseases and retinal disorders closely follow the draft guidances on CMC and LTFU recommendations and contain additional clarity on expectations for those product indications.
Overall, Ann says the steps that the FDA is taking are positive. “They really seem to be focused on open communication with gene therapy companies to promote the safe and efficient development of new therapies for patients, many of whom have no other therapy options. And that’s good for everyone involved.”
The FDA encourages feedback on the draft guidance documents. The public comment period is open until October 10, 2018.