By Dr. Paula Vaccarello and Dr. Jörg Schneider, on behalf of PharmaLex

With more innovator companies targeting cell and gene therapy, it’s not surprising that investigational new drug (IND) applications are increasing. Data from the Food and Drug Administration (FDA) show that the Center for Biologics Evaluation and Research (CBER) received 777 original IND applications in fiscal year 2021 (October 2020 to end of September 2021), compared to 396 original INDs in 2015. This includes many biologics such as vaccines, blood products, and cell and gene therapies.

With this increase, there has also been a rise in the number of clinical holds for products regulated by the CBER. As CBER director Peter Marks has noted, there is an evident lack of experience or knowledge about the type and level of data required for an IND.

“We see a variety of different types of INDs, some of which are missing key pieces, and sometimes those can be fixed with interactive discussions during the 30 days. But 30 days is not a lot of time if someone doesn’t have a manufacturing section to their IND.”

Peter Marks, CBER Director at the Biopharma Congress in Washington, DC, February 2023

Addressing hold issues

The FDA has a default position that allows manufacturers to initiate their clinical trial if no response from the agency is received within 30 days. During this time, the FDA will review the application to ensure patient safety.

Any questions from the agency fall under two categories: non-hold issues where the sponsor is asked to provide more information, but where the clinical trial can continue; and more serious issues where the agency places a hold on the product moving into clinical trials until additional requested information is submitted and deemed acceptable. The most common issues are related to clinical safety, pre-clinical safety and efficacy, and CMC (Chemistry, Manufacturing and Control), which arise largely due to the lack of understanding of complex CMC requirements by inexperienced developers, but also from big players in the pharmaceutical industry.

We reviewed recent biologics IND holds by the FDA – spanning gene therapy, cell therapy, proteins, microbiome therapies and vaccines – and found that most holds were lifted after four to five months. However, some products have been on hold for as much as 18 months, either because the data requested by the FDA has not yet been submitted, the program was put on hold, or the submitted data was rejected by the agency.

This review included several interesting examples that emphasize the types of issues developers face. For example, VERVE-101 from Verve Therapeutics was placed on hold in November 2022 as the FDA requested more data. VERVE-101 is a single-source, investigational gene editing medicine that turns off the PCSK9 gene in the liver to durably lower low-density lipoprotein cholesterol (LDL-C). Specifically, the FDA requested data on potency differences between human and non-human cells, the risks of germline editing, and off-target analyses in non-hepatocyte cell types. The agency also requested the company to share data from the ongoing heart-1 trial in the United Kingdom (UK) and New Zealand.

The fact that a product candidate is on clinical hold in the US, whilst clinical trials are ongoing elsewhere is testimony to the different perspectives regulatory agencies across the globe can have. This may be factored into a regulatory product strategy. UK´s MHRA (Medicines and Healthcare products Regulatory Agency) recently issued an innovation passport for Heart-1, which is designed to evaluate the safety and tolerability of VERVE-101 administration in patients with heterozygous familial hypercholesterolemia (HeFH).

In cell therapies, one product that was placed on hold by the FDA for a year is Bluebird bio’s lovo-cel (lovotibeglogene) to treat sickle cell disease. That hold was lifted in December 2022 after an investigation into an adolescent patient who developed persistent anemia after treatment with lovo-cel. The company presented results from the investigation at the American Society of Hematology (ASH) Annual Meeting and Exposition in December 2022, as well as details of another patient, this time an adult, with persistent anemia after treatment with the therapy. It was found that both patients had two α-globin gene deletions known as alpha-thalassemia trait and were the only patients in the study with this specific genotype. As a result, this genotype was added to exclusion criteria for further studies, and the clinical trial was allowed to resume.

Another interesting example from FDA holds is MaaT Pharma’s MaaT013, donor-derived microbiome therapy for the treatment of steroid-resistant acute graft-versus-host disease. The initial hold was issued in August 2021 due to clinical and manufacturing issues and the approval was rejected again a year later. While the answers to the original concerns were satisfactory, further concerns were raised about the safety and efficacy of mixing samples from several donors. The FDA has requested more information on the safety and efficacy to standardize the product, as well as data on how the product was developed.

Navigating agency interactions

Bringing biologics to market is extremely complex for many reasons and requires an understanding of the regulatory environment and health authority expectations. Cell and gene therapies, with their complex manufacturing processes and non-clinical programs and highly diverse product classes, are particularly challenging, whilst protein-based therapeutics face fewer issues benefiting from their more established market position. While issues such as clinical safety will always result in holds, having professional regulatory advice is key when trying to navigate complex issues such as CMC requirements.

Furthermore, when working with the regulators to address issues raised, it is important to know how to manage that communication. Getting the right advice from the outset can ensure issues are addressed before an IND application is made or that issues related to an IND hold can be resolved quickly.