This article is the fourteenth in our 2022 series, “Trends in Cell, Tissue, and Gene Therapies,” which aims to help you stay informed about the broad array of legal and regulatory issues affecting companies operating in the regenerative medicine space.

Background

In 2017, FDA published a regenerative medicine policy framework that would require developers of certain HCT/Ps to submit an investigational new drug application (IND) or biologics license application (BLA) with the agency, even if they were not previously required to do so; we summarized that framework online here. FDA initially provided a “grace period” of enforcement discretion to provide developers time to assess what they may need to do in order to come into compliance with the new framework. This enforcement discretion period ended on May 31, 2021, and the government is increasing its enforcement against regenerative medicine companies that are in violation of its policies, as we summarized online here.

To be clear, certain regenerative medicine manufacturers are still be able to market their products in the United States solely under the authority of section 361 of the Public Health Service Act (PHSA), which does not require pre-market review and FDA approval; we have analyzed some of those exceptions online here. However, for many companies in the regenerative medicine space, new clinical trials must be conducted – and BLAs containing those results approved by FDA – in order for their products to continue to be sold in the U.S. market.

Below, we have summarized six key strategies that regenerative medicine firms should consider as part of their registrational pathways and to enhance their chances of regulatory success.

1) Use data from previously marketed product

A regenerative medicine manufacturer that has been selling its product for several years – prior to the end of FDA’s enforcement discretion period – is likely to have data from the use of that therapy that might be eligible to aid in demonstrating the safety and/or efficacy of that product. At Hogan Lovells, we help advocate for clinical trial programs that fully leverage information that is already available, which can possibly minimize the size, length, and/or number of clinical trials needed to support a BLA approval. This, in turn, can lower the costs and time needed for registrational clinical study programs. FDA recognizes the importance of allowing sponsors to leverage data from electronic health records (EHRs), medical claims, disease registries, and digital DDTs, among other sources, under appropriate circumstances. 

For example, biologics sponsors can take advantage of FDA’s real-world evidence (RWE) program, which promotes the use of real-world data (RWD) relating to patient health status and/or the delivery of health care that is routinely collected from a variety of sources, and not merely collected through clinical trials. FDA Commissioner Robert Califf MD has stated that high quality RWE can provide a more efficient way to understand the risks and benefits of medical products when they’re used in practice, and has said that creating a system for RWE generation to support health care and regulatory decision-making will remain a top programmatic priority for the agency. We previously analyzed FDA’s top strategic priorities including leveraging RWE for regulatory decision-making online here. Although reliance on RWE is still evolving, the agency has issued several guidance documents on data considerations and contexts of use, and we have seen FDA permit reliance on RWE to reduce the need for pre-clinical animal studies, among other things.

FDA’s RWE guidance documents have explained how biologics sponsors should prepare protocols and statistical analysis plans ahead of meeting with FDA that explain the reliability, relevance, and comprehensiveness of their data sources, as well as the methodologies used to validate key design elements and maintain quality during data accrual, curation, and transformation to the final data set. Sponsors should also consider the potential impact of linking one or more registries or data systems on the overall integrity of the data used in the clinical trial.

2) Carefully design your potency assay

FDA requires potency testing to ensure the specific capability of a biological product, and the adequacy of a test to demonstrate potency is evaluated on a case-by-case basis. Sponsors of cellular therapies have experienced challenges in establishing biologic potency because FDA requires a potency assay for a final product to be as close as possible to the actual mechanism of action of that product; however, when a cellular product is tested, it is often not in the final form that it will be functionally when administered.

Proper potency assay design can allow sponsors to collect data that permits evaluation of whether their assays are suitable for their intended uses. This includes incorporating a sufficient number of replicates to allow for statistical analysis, using sample randomization to reduce biases (e.g., sources of bias associated with placement in a 96-well plate), and including appropriate controls. Assay design should also reflect knowledge of the factors that influence assay variability. At Hogan Lovells, we can help regenerative medicine sponsors anticipate and avoid problems with establishing sufficient potency assays that have proven to be landmines for other sponsors in the past.

3) Consider using investigator-sponsored trials

Data generated by investigator-sponsored research trials (ISTs) can also supplement the findings of company-sponsored clinical studies. ISTs can take a variety of forms, including situations where a company provides research support (in the form of drugs, funding, or both) to an investigator, who maintains control over the critical aspects of the trial. Among other things, an IST investigator will design the trial, draft the protocol, submit the IND, and serve as the sponsor. In exchange for providing the investigational product and/or funding, the company will typically obtain the rights to the data generated by the IST for use in regulatory submissions, such as an IND or BLA.

While taking advantage of IST data makes sense for many clinical trial sponsors – and could aid sponsors of regenerative medicines who find themselves suddenly needing to submit a marketing application to FDA – there are a number of potentially significant legal and operational risks associated with pursuing an aggressive IST strategy. At Hogan Lovells, we help companies to weigh the potential risks associated with ISTs, how the data from ISTs might be used in regulatory submissions, and – ultimately – whether to support proposed ISTs.

4) Making the most of nonconforming product

Out-of-specification (OOS) product is defined by its failure to meet established specifications or acceptance criteria for release of the product. FDA requires manufacturers to establish and maintain procedures and controls product that does not conform to specified requirements, and to address the identification, documentation, evaluation, segregation, and proper disposition of nonconforming product. Nonconforming product dispositions include “use as-is” decisions when the product does not affect the safety and effectiveness of the final product.

Regenerative medicine sponsors may consider whether there remains a way to utilize nonconforming product in clinical trials or expanded access programs. For example, if a product fails to meet a particular release specification, but the company and FDA nonetheless determine that the product does not present a risk patients and, in fact, may benefit certain patients, the company may be able to find other clinical uses of the product. FDA would expect the company to maintain documentation including justification for use of nonconforming product based on scientific evidence and to provide records upon request.

Accordingly, clinical trial sponsors should plan for these potential obstacles and discuss potential OOS situations with regulators prior to market authorization, and agree to a risk mitigation plan that applies to practical OOS situations where the potential benefit of receiving such product is greater than the potential risks.

5) Consider making product available under expanded access

An expanded access program (EAP), also called “compassionate use,” is a potential pathway for patients an immediately life-threatening condition or serious disease or condition to gain access to an investigational medical product for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available. Regenerative medicine sponsors that decide to open their product up for expanded access, as a parallel program to their clinical trial, should consider whether the additional data generated may be used to support their marketing application to FDA. It is possible that data from an EAP can be used as confirmatory data to support approval.

FDA’s support of EAPs had been demonstrated by its recent launch of the expanded access pilot “Project Facilitate,” a concierge call center under the Oncology Center of Excellence to facilitate the Single Patient IND request process for oncologists. Under the program, which we described online here, FDA staff help guide physicians through the process of applying for expanded access by answering questions, assisting with completing required paperwork, providing information on IRBs, and facilitating contact with the drug sponsor for submission of the expanded access request.

At Hogan Lovells, we regularly help clinical trial sponsors navigate expanded access program issues, and decide whether opening up parallel programs is advisable.

6) Carefully plan your Clinical Trial Agreement

FDA requires clinical trial sponsors to monitor the progress of studies, and the Clinical Trial Agreement (CTA) – among many other things – sets out the relationship between the sponsor and the clinical trial site for this monitoring process. We regularly advise regenerative medicine firms on contractual issues related to CTAs, and provide templates for clinical trial contracting, as well as specialized CTAs bespoke to clients’ needs.

For example, among other issues, we encourage sponsors to directly address remote monitoring of the clinical trial site in the CTA, in order to reduce the burden of in-person monitoring visits of every clinical trial site participating in the study. We recently summarized some of these concerns online here. In addition, smaller companies without a sizable in-house clinical operations team may prefer to outsource elements of the work that is required to ramp up a clinical trial operation.

Conclusion

Now that FDA’s period of enforcement discretion for regenerative medicines has ended, and the agency is cracking down on firms operating in the space that do not comply with its new policy framework, it is imperative that HCT/P manufacturers, as well as stakeholders that market HCT/Ps – including distributors, billing companies and consultants, health economics consultants, clinics, and health care providers – ensure they are in compliance with government standards.

If you have any questions on responding to the potential for stepped-up enforcement, need to evaluate whether your products and/or facilities comply with FDA’s regenerative policy framework, or are seeking help in conducting clinical trials and designing a registrational pathway, please contact any of the authors of this alert or the Hogan Lovells lawyer with whom you regularly work.

Authored by Robert Church, Michael N. Druckman, and Lowell Zeta

This article is the fourteenth in our 2022 series, “Trends in Cell, Tissue, and Gene Therapies,” which aims to help you stay informed about the broad array of legal and regulatory issues affecting companies operating in the regenerative medicine space. From clinical studies, to obtaining patents, to scaling up manufacturing, our global team will discuss novel issues arising in all parts of the world, including unique deal-making, litigation, and inspections concerns for CTGT companies. Ensure you are subscribed to Hogan Lovells Engage to receive these new insights weekly!