Surge in Cellular and Gene Therapies Challenges FDA

Wechsler,Jill;

With nearly a thousand research programs for cell and gene therapies moving through the regulatory pipeline, FDA’s Center for Biologics Evaluation and Research (CBER) is struggling to monitor and advance these critical treatments while also providing advice and oversight of the safety and efficacy of vaccines to combat the pandemic. Regulatory officials predict FDA will approve 10–20 cell and gene therapies during the next few years, for a total of some 40–60 innovative products over the decade. Many of these treatments fall under FDA’s high-profile program for vetting regenerative medicine advanced therapies (RMATs), which also calls on CBER’s Office of Tissues and Advanced Therapies (OTAT) to provide extra support for those cellular and gene products that meet standards for RMAT designation.

At BIO’s digital annual conference in June 2020, OTAT Director Wilson Bryan outlined the “huge escalation” in his office’s workload prior to the pandemic, with a tripling of investigational new drug applications (INDs) for gene therapies in the past three years. Back in January 2019, then-FDA Commissioner Scott Gottlieb said that FDA expected to receive more than 200 INDs a year for advanced therapies, building on its current total of more than 800 INDs for cell-based or directly administered gene therapies then on file (1). And while research in these categories has slowed in recent months due to COVID-19, Bryan noted that it has been offset by manufacturers looking to tap cellular therapies and intravenous immunoglobulin to combat the pandemic.

Continued advances in this field were seen with the July 2020 approval of tecartus from Gilead subsidiary Kite Therapeutics, a new treatment for rare mantel cell lymphoma in adults not responding to other treatment and Kite’s second CAR T therapy (2). Novartis’ Kymriah led the field with FDA approval in August 2017, followed by three other cutting-edge treatments. Sarepta Therapeutics is advancing a gene therapy for muscular dystrophy, but FDA has delayed approval of BioMarin’s much anticipated hemophilia treatment.

These and other development programs have been assisted by extensive guidance from FDA, as seen in a packet of six guidance documents published in January 2020. These advisories finalized agency policy on developing gene therapies to treat hemophilia, rare diseases, and retinal disorders and on providing long-term follow-up for these relatively untried products (3). A new draft guidance addresses the tricky issue of when similar gene therapies are sufficiently different for the purposes of gaining orphan drug designation and extended exclusivity (4). Manufacturers and other stakeholders recently filed comments on this proposal, seeking more specific examples and information from FDA on this important commercial policy.

A fairly lengthy final guidance addresses the need to provide sufficient chemistry, manufacturing, and control (CMC) information in applications, particularly on critical quality attributes and master cell banks (5). The advisory describes the importance of establishing manufacturing systems able to scale up from initial production of test products to commercial operation, noted CBER Director Peter Marks at the DIA virtual global annual meeting in June 2020. He observed that difficulties in establishing a reliable method for moving from laboratory production to a viable commercial process “without a hitch” can delay product approval. Strategies for dealing with variability and improved analytical methodologies can support product characterization, Marks added, as will efforts to establish standards in this area.

More resources for CBER?

For FDA to continue to oversee and advance these innovative and challenging development programs efficiently, industry, patient groups, and research organizations are urging policy makers to increase CBER funding (see Sidebar). So far, CBER has coped by shifting personnel and resources to meet user fee approval goal dates, Marks noted at the BIO conference. Some early meetings intended to assist sponsors in designing research programs for new therapies have had to be delayed or cancelled, he acknowledged, but most regulatory activities have moved forward.

FDA and Stakeholders Kick Off PDUFA Renewal Negotiations

At a public meeting in July 2020 to launch negotiations for renewing the Prescription Drug User Fee Act (PDUFA) before the current program expires in September 2022, patient advocates, research experts, and industry presented their preferences for tapping user fee revenues to support a range of FDA initiatives, including broader use of real-world evidence and innovative clinical trial methods to advance new therapies and for FDA to expand electronic communications systems in research and regulatory programs. A prominent theme is for the agency to incorporate innovations and program changes adopted for dealing with the COVID-19 pandemic into ongoing research policies and regulatory activities (1).

Several stakeholders also urged increased funding for the Center for Biologics Evaluation and Research (CBER) to support development of advanced therapies for rare diseases. Cartier Esham, executive vice-president of the Biotechnology Innovation Organization, cited the greater demand on CBER personnel for multiple meetings with sponsors and the need to clarify expedited pathways and expand standards for advanced manufacturing processes and technologies for gene therapies.

Over the coming months, FDA will seek input from industry leaders and representatives of consumer and patient organizations, research entities, and healthcare organizations to present Congress with a user fee agreement by the middle of next year so that the legislators can write and approve authorizing legislation by early 2022.

Reference

1. FDA, “Reauthorization of the Prescription Drug User Fee Act; Public Meeting; Request for Comments,” Notice, Federal Register, 85 FR 35096, 35096-35099.

—Jill Wechsler

However, CBER officials acknowledge that it will be difficult to maintain its schedule for supporting innovative therapies while also overseeing a growing number of COVID-19 vaccines moving into clinical trials, along with more new or updated vaccine manufacturing operations. All eyes are on FDA to fully assess the safety and quality of these critical preventives and to ensure the appropriate design and conduct of clinical studies.

CBER currently receives only a small portion of the annual user fee payments, about $135 million this year compared to $680 million for the Center for Drug Evaluation and Research (CDER), based on a much smaller number of biologics license applications CBER usually reviews compared to CDER (6).

But now the surge in INDs and applications for new cellular and gene therapies promises to narrow that disparity. Both CDER and CBER seek to recruit and train additional staff to assess the rising volume of innovative products and have been working to add some 200 agency reviewers and scientists to their offices. But efforts to expand staff in a very tight job market and through the agency’s cumbersome hiring process has been difficult, and the unique skills sought by CBER make recruiting particularly challenging.

References

1. S. Gottlieb, “Statement from FDA Commissioner Scott Gottlieb, MD and Peter Marks, MD, PhD, Director of the Center for Biologics Evaluation and Research on New Policies to AdvanceDevelopment of Safe and Effective Cell and Gene Therapies,” FDA.gov, Jan. 15, 2019.
2. FDA, “FDA Approves First Cell-Based Gene Therapy For Adult Patients with Relapsed or Refractory MCL,” Press Release, July 24, 2020.
3. FDA, Search for FDA Guidance Documents, FDA.gov.
4. FDA, Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations, Draft Guidance for Industry(CBER, January 2020).
5. FDA, Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs), Guidance for Industry(CBER, January 2020).
6. FDA, Five-Year Financial Plan, Fiscal Years 2018-2019-2020-2021-2022, 2020 Update for the Prescription Drug User Fee Act Program, Report (undated).

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When referring to this article, please cite it as J. Wechsler, "Surge in Cellular and Gene Therapies Challenges FDA," BioPharm International 33 (9) 2020.