The US Food and Drug Administration is willing to grant regulatory flexibility for manufacturers of cell and gene therapy products from certain chemistry, manufacturing and controls (CMC) requirements in biological license applications. An agency official acknowledged that the difficulties in manufacturing these products demand such flexibility, which will make it easier to move them from the research lab to patients. Yet such flexibility will only be granted on a case-by-case basis.

One example of this flexibility would be allowing the release of batches for distribution before completion of process validation studies; another would be relaxing certain stability testing requirements and allowing the use of prior knowledge to substitute for such testing.

Steven Oh, deputy director of the division of cellular and gene therapies in the FDA’s Center for Biologics Evaluation and Research, made this pronouncement on 10 June at a CASSS meeting in Bethesda, MD, on cell and gene therapy products. He also discussed some of the unique challenges to manufacturing these products, provided an update on the agency’s RMAT program for expediting review of designated regenerative medicine advanced therapies, and offered some suggestions for getting novel cell and gene therapies approved.

Oh said that the biopharmaceutical industry is continuing to show strong interest in developing cell and gene therapy products; the agency expects to receive more than 500 investigational new drug applications and investigational device applications for these products by the year’s end. This is more than double the 187 INDs and IDEs submitted in 2014. In anticipating a glut of new INDs for cell and gene therapies in the coming years, FDA announced earlier this year plans to add 50 additional clinical reviewers to deal with the growing workload. (Also see “Shutdown Bite Tightens At US FDA, But Gene Therapy To Get 50 More Reviewers” – Pink Sheet, 15 Jan, 2019.)

Manufacturing Difficulties Acknowledged
Despite this explosive growth in INDs, Oh acknowledged the difficulties in manufacturing these products compared with other types of biologics, and cited a long laundry list of challenges. For one, he said that “these products have a short shelf life and stability data is not always available.”

Other challenges include limited product manufacturing experience prior to licensure, the fact that critical quality attributes are not entirely understood due to limited knowledge of the in-process material. There is also greater product variability arising from the source starting materials, and there is a shortage of qualified reagents and materials. In addition, assays are not always fully developed and qualified.

Conducting comparability studies is also difficult because reliable reference standards and validated assays are hard to find.

Oh said that “because of the way that cell and gene therapy products are manufactured and the technical difficulties of making cell and gene therapy products, this requires a new manufacturing paradigm.”

Relaxed Controls Needed
In light of these difficulties, Oh told the meeting that the agency is willing to confer some flexibility in its  CMC requirements.

Oh said that “when a gene or a cell therapy enters in development, the central goal for all stakeholders is to ensure a quality product can be consistently produced and be available. In light of this, FDA may exercise some flexibility in terms of the type of manufacturing information submitted at the time of approval.”

This flexibility will be conferred on a case-by-case basis, and will depend on the type of manufacturing process, the product’s characteristics, the seriousness of the condition and the unmet medical need, the robustness of the quality system and the strength of the risk-based quality assessments.

In a general sense, he said this flexibility may allow the concurrent release of the product before the completion of process validation studies, especially in cases where there is limited manufacturing available at the site.

FDA is also considering relaxing certain stability testing requirements. Oh said that prior knowledge or other supporting data may be used as a substitute for stability data.

In addition, FDA may allow rolling submissions of Common Technical Document modules in which applicants can file Module 3 last. That’s the module with all the details on quality.

Earlier Calls For Flexibility
There have been earlier calls for the FDA to ease some of the burdens in getting cell therapies approved for early stage clinical studies. At a 17 May meeting, two groups, the Friends of Cancer Research and the Parker Institute for Cancer Immunotherapy, presented the FDA with a white paper that urged the agency to ease some of the procedural and manufacturing burdens on early studies of cell therapies in a white paper. (Also see “Cell Therapies: US FDA Asked To Clarify Development Standards For Early-Phase Trials” – Pink Sheet, 22 May, 2019.)

The paper calls for, among other things, flexibly applying phase-appropriate GMPs to the manufacture and testing of plasmids, viral vectors, ancillary materials and reagents and T-cell based infusion products for early exploratory trials, and adopting regulatory pathways that allow for manufacturing process changes based on patient-specific raw materials information to maximize product quality without having to conduct costly and lengthy clinical studies.

Steep Hurdles In Getting RMAT Designations Approved
Oh said that seeking RMAT designation is one way to ensure rapid review of an investigational new drug application for a cell or gene therapy product; yet the numbers show that getting designation requests approved is not easy.

The agency has been approving just one out of three requests for RMAT designation. As of 31 May, the agency received 102 requests and granted 32 approvals. Similarly, as of February, the FDA had approved 30 of 91 RMAT requests. (Also see “Regenerative Medicine Therapies: Manufacturing Changes May Not Impact RMAT Designation” – Pink Sheet, 18 Feb, 2019.)

Gene therapy products stand a better chance than cell therapy products of winning RMAT designation. As of 31 May, FDA had approved roughly half, or 24 of the 51 requests for gene therapies, while only approving four of the 27 requests made for cell therapies. Applicants submitted 21 requests for breakthrough designation of other types of products; the FDA approved only four.

The RMAT designation was created by the 21st Century Cures Act as an expedited regulatory pathway for sponsors developing regenerative medicine therapies that are intended to treat, modify, reverse or cure a life-treating disease or conditions, and for which preliminary clinical evidence indicates that the product has the potential to address unmet medical needs. Products with the designation may be eligible for accelerated approval. (Also see “Woodcock, Califf Give Thumbs Up To Certain 21st Century Cures Provisions” – Pink Sheet, 14 Dec, 2016.)

Oh said that RMAT designations are denied for administrative reasons such as having an inactive IND, or if there is no preliminary clinical evidence submitted to support the designation. Or designations can also be denied if the clinical data is not based on the same IND product or the product does not qualify for RMAT designation.

Early Meetings Encouraged
Oh recommended that sponsors meet with the FDA early in the development cycle for cell and gene therapies to identify and resolve potential problems early on to ensure smooth IND reviews. He said that the FDA’s INTERACT program is an especially valuable mechanism for meeting with the agency and ironing out potential deficiencies early on.

The INTERACT program, established by CBER in June 2018, is a formal program that allows industry to meet with FDA reviewers during early pre-clinical development stages to allow sponsors to ask the FDA questions about manufacturing and other technical issues to help streamline development. (Also see “CBER Implements Pre-Clinical Meeting Program For Biologics, Gene Therapy Sponsors” – Pink Sheet, 22 Jun, 2018.) The program is intended to help accelerate development and approval of novel biologics and other products reviewed by the center.

Can The FDA Keep Up With Meeting Requests?
At the end of Oh’s presentation during a question and answer session, he was asked by a meeting participant whether the FDA’s staff can keep up with all of the requests for early interaction meetings.

Oh said previously in his remarks that more sponsors are taking advantage of early meetings with the FDA before submitting INDs. In 2018, CBER’s Office of Tissues and Advanced Therapies had 395 meeting with sponsors, compared to 295 in 2017 and 269 in 2016.

Oh said that “we do have a lot of meetings requested and because of the importance of this to stakeholders we do get requests for advice. Many of these meetings are optional … yet as things progress to a product license application we need to see something and we would definitely encourage you to take advantage of these early interaction meetings. Before you start phase 3 [studies] you definitely want to have a meeting with FDA.”