The COVID-19 pandemic has brought many issues to the public’s attention that used to be of interest only to clinical research and drug development communities: clinical trial design, efficiency and timelines of clinical research studies, drugs’ approval process, and pre-approval access to investigational therapies are just a few.
Pre-approval access drew considerable attention when President Trump was given the antibody cocktail REGN-COV2, a combination of two monoclonal antibodies directed against the spike protein of the SARS-CoV-2 virus, manufactured by Regeneron. Even before that, the individual-patient expanded access (EA) program for Gilead’s remdesivir provided the investigational agent to more than 1,700 COVID-19 patients before the number of requests and the administrative burdens of managing them prompted Gilead to move to a group expended access program. With this widespread use of individual EA requests far outstripping typical numbers (FDA received a total of 1449 requests in 2019), many hospitals and institutional IRBs were likely encountering this process for the first time.
Expanded access (EA), which is sometimes referred to as “compassionate use,” is a well-established pathway through which patients can get access to unapproved investigational therapies when they have no other treatment options and cannot enroll in a clinical trial. While requesting access to therapies through EA used to be a complex and time-consuming process for patients and physicians, the FDA has devoted substantial effort in the last several years to streamlining the request process and setting up websites and forms to be easier, more transparent, and more user-friendly.[i]
EA is considered treatment, not research, and the involvement of IRBs in the EA approval process has often been debated. The IRB should look carefully at the informed consent process and ensure an appropriate description of the potential risks, potential benefits and the many unknowns. Guidance put out by FDA provides a clear description of the role of the IRB, so the basics won’t be reviewed here; but for IRBs that are less experienced with this process or are creating internal policies for processing individual EA requests, there are a few points that are helpful to consider.
- As of January 2019, individual EA requests can be reviewed by the IRB chairperson or designee and do not need to be reviewed by the full board. However, the treating physician must specifically request this pathway, by checking a box on the individual IND application form (FDA Form 3926). Physicians who are unfamiliar with the IRB process may skip this box as the wording on the form implies that this is an “alternative process,” even though they may be fine with a chairperson review. It may be helpful for the IRB to be aware of potential requests early in the process, to help the physician complete this form.
- The EA regulations include procedures for both emergency and non-emergency EA requests; in the emergency setting, IRB approval can be obtained within 5 working days after the use of the agent “where there is not sufficient time to secure IRB review prior to beginning treatment” (21 CFR 56.104(c)). In practice, the phase “sufficient time” is subjective. We have sometimes seen physicians claim emergency use because they see post-use IRB approval as an easier pathway than pre-use approval, even though, for example, it took weeks for the pre-approval agent to be shipped to the physician to begin dosing. IRBs may want to define what they consider to be “sufficient time” in their policies so they and physicians have the same expectations.
- EA is intended only for agents that have not yet been approved for any indication; once a product is FDA-approved, it can be prescribed for off-label use for any indication that the physician believes is appropriate. However, insurance may not cover the off-label use. We have seen biopharma companies tell physicians to use the EA pathway to obtain treatment for patients who fall outside the approved label (for example, to treat a teenage patient when the drug is approved for adults only) so that the company can provide the drug at no cost to the patient. There are also a small number of agents to treat infections such as leprosy that are approved by FDA but not marketed in the US because the use is so rare, but the agents can be obtained through the EA pathway. So IRBs may see situations where EA is requested and used even for products that are technically FDA-approved but otherwise unobtainable.
[i] You may recall, in recent years, news about another pathway for accessing investigational products called Right to Try. Right to Try is codified in federal law but has been used in only a handful of cases over the last several years. It does not have a specific role for the IRB to play, so we do not cover it further in this post.
Sage Gustafson, MA, is a research associate in the Division of Medical Ethics at the NYU Grossman School of Medicine and the project manager of the NYU Working Group on Compassionate Use and Preapproval Access (CUPA).
Lindsay McNair, MD, MPH, MSBioethics has been working for more than 20 years in drug development and human subject protection; she is currently the Chief Medical Officer of WCG and the WCG IRB, and a member of the CUPA.