Given the scale of investments made to support these development efforts and advancements possible, drug sponsors have looked to the U.S. FDA to consider accelerating gene and cell therapy development. The regulatory body has responded by shifting its departmental structure to streamline approvals.
By understanding the manufacturing hurdles and development timelines for cell and gene therapy, drug sponsors can be better prepared to keep projects on track.
Challenges with cell and gene therapy
Gene and cell therapies are routinely lumped together, but they have some key differences. Gene therapy is a technique that treats, prevents or cures diseases or medical conditions, most often by adding or replacing a defective gene. Nearly all gene therapies use one of three vector types: adeno-associated-virus (AAV) vectors, adenovirus vectors or lentivirus vectors.
Cell therapy, on the other hand, injects living cells (either autologous or allogeneic) into a patient to treat a condition or disease. Cell therapies span immunotherapy, oncology and regenerative medicine. Popular variations of cell therapies include CAR T-cell therapies and natural killer (NK) cell therapies.
Manufacturing challenges present one of the biggest barriers to advancing development for cell and gene therapies. Materials, e.g., lentiviruses, are scarce and expensive enough to be prohibitive in some circumstances. Specifically, autologous CAR T-cells must be manufactured at a U.S. FDA-approved facility.
Current shortages and import challenges with non-human primates (NHPs) also present a challenge for pre-clinical testing, particularly for gene therapies where NHPs are often considered a relevant species. (NHPs are typically not used for pre-clinical testing for cell therapies.) Lineage and poaching concerns have led to increased oversight by U.S. regulatory agencies.
Target toxicity is another area that drug sponsors should consider carefully. High toxicity in early pre-clinical trials can indicate that the therapy is targeting healthy cells in addition to tumor cells. Autogenic and allogeneic cell therapies also have varying considerations. Drug sponsors need to carefully consider on- and off-target toxicity concerns to preempt additional inquiries from regulators.
Given the numerous obstacles drug sponsors face when developing a cell or gene therapy, in addition to nonclinical testing and manufacturing concerns, it is important to build a partnership in preparing for an IND submission.
Structural changes to streamline regulatory processes
It is important to understand the structure of the U.S. FDA in order to have deeper insight into regulatory timelines that affect cell and gene therapies. While traditional drugs are governed by the Center for Drug Evaluation and Research (CDER), gene and cell therapies are governed by CBER.
CBER consists of several offices, including the Office of Tissues and Advanced Therapies (OTAT). OTAT is being renamed to the Office of Therapeutic Products (OTP) and elevated to the status of being a “super office.” These changes aim to improve the agency’s functional alignment, increase review capabilities, and enhance expertise on new cell and gene therapies.
Consult with regulatory bodies to keep gene and cell therapy development on track
In an effort to accelerate development timelines for cell and gene therapies, the U.S. FDA has outlined new steps to increase communication between drug sponsors and regulators. These include four different types of pre-submission meetings, which are outlined in the reauthorization of the Prescription Drug User Fee Act (PDUFA VII) for 2023 through 2027. Meetings are categorized as Type A through Type D and designed to address varying issues and concerns.
- Type A meetings are researched for otherwise stalled drug development projects, such as in the case of a clinical hold. The meeting will be scheduled by the U.S. FDA within 30 days and the background package is due at the time of request.
- Type B meetings are also known as “milestone meetings,” and they occur either prior to or at the conclusion of phase 3 of drug development. The scheduling time frame for these meetings is 50- 70 days of request, depending on the type, and background packages are due 30-50 days prior.
- Type C meetings are a catch-all category that includes any type of meeting that does not fall within the scope of Type A or Type B meetings. Drug sponsors may request a written response for Type C meetings in lieu of a video conference or in-person meeting. The U.S. FDA will schedule the meeting within 75 days of request and the background package is due 47 days prior to the meeting.
- Type D meetings are a new type of meeting outlined in PDUFA VII. These are a very focused type of meeting that might address specific questions about toxicology, for instance, in the absence of other information. This new type of meeting affords drug sponsors an opportunity to gain regulatory feedback early on in the drug delivery process.
Drug sponsors can leverage these meetings to ask basic questions about assays and to delve into details including what species of animals, how many animals, how often dosing will take place, what analytes will be measured, how frequently blood will be taken, etc.
Engaging a laboratory testing partner to assist in these meetings can help set expectations between regulators and drug sponsors around what is practical and possible. A laboratory partner will be able to speak to the availability of testing species or the viability of particular testing protocols.
A final word on cell and gene therapies
Cell and gene therapies are a rapidly growing field of development, but this popularity has also contributed to manufacturing, testing and regulatory challenges. By understanding the barriers at hand and communicating with regulators through pre-submission meetings, drug sponsors can mitigate delays and keep development timelines on track for cell and gene therapies.
Mary Ellen Cosenza, PhD, DABT, ATS, RAC is a regulatory consultant with over 30 years of senior leadership experience in the biopharmaceutical industry in the U.S., Europe and emerging markets.
Filed Under: Cell & gene therapy, Drug Discovery, Immunology