By Alison Bateman-House, Hayley M. Belli, and Sage Gustafson
This series is adapted from a webinar hosted by PRIM&R on August 5, 2021: IRB Review of Expanded Access Protocols that Collect Real World Data: Considerations and Guidance.
Part 1: What is Expanded Access and How Does it Work?
Expanded Access (EA) is a regulatory mechanism that allows patients, through their physicians, to request the use of an unapproved medical product in a treatment setting.
The goal of EA is to provide potentially beneficial investigational interventions in an expeditious manner to seriously ill patients who have no other treatment options. Expanded Access is not intended to produce generalizable knowledge; however, it involves reporting of serious adverse events (SAEs) to the entity developing the product (the “sponsor”) and the regulatory agency (the U.S. Food and Drug Administration or FDA), which contributes to the development of knowledge about the unapproved product’s safety.
Other regulatory mechanisms that provide ways for patients to access investigational medical products prior to FDA approval and outside of clinical trials include Emergency Use Authorization (EUA) and Right to Try (RTT). However, EUAs are limited to public health emergencies, and RTT is only rarely used, so we concentrate here on EA, which is used by thousands of U.S. patients each year.
Expanded Access, historically known as “compassionate use,” permits treatment use of an unapproved, investigational medical product by either an individual patient (single patient EA) or a group of similar patients (cohort EA), if the sponsor is willing to provide the product.
Who qualifies for EA, and how does it work?
Patients seeking to use a product via EA must have a serious or life-threatening condition for which there are no comparable FDA-approved treatments or clinical trial options available. For example, patients may experience difficulty participating in a clinical trial of an investigational product if that trial is not yet accruing, has met its target enrollment, or the patient does not meet the trial’s eligibility criteria or cannot travel to a trial site.
The proposed intervention must have a positive risk/benefit assessment, as determined by the patient’s treating physician, and its use via EA must be reviewed and permitted by the FDA and an institutional review board (IRB). While EA is intended for treatment and is not research, federal regulations require IRBs to review and approve EA protocols and requests, the consent process, consent documents, surrogate consent, and related documents. Additionally, the patient or a surrogate decision-maker must provide valid consent.
There are two types of EA that may come before an IRB:
Cohort EA: A cohort EA program is similar to an open label, single arm clinical trial in structure; however, unlike in a clinical trial, the overall intention is to provide a group (defined as two to many) of similar patients access to an unapproved intervention for treatment purposes, not to collect generalizable knowledge. The IRB is responsible for the review and approval of the cohort EA protocol, the informed consent form, the consent process, and other materials. Full committee review is appropriate.
Single patient EA: Single patient EA involves one patient and one treating physician. The FDA permits one member of an IRB, as opposed to the full committee, to review and approve a single patient EA treatment plan. In emergencies, single patient EA may proceed without obtaining IRB approval; in such cases, the IRB must be notified within 5 business days of the use of the unapproved medical product.
The identification and reporting of serious adverse events (SAEs) to sponsors and the FDA is required from both single patient and cohort EA.
EA requires collaboration amongst stakeholders, including commitment from a physician to prepare the single patient EA application or review a patient’s eligibility for a cohort EA program; a sponsor to provide the investigational agent; the FDA and the IRB to provide independent review and oversight; a pharmacy to accept, prepare, and dispense the product; and the patient to provide voluntary informed consent or a surrogate decision-maker to give legal authorization in lieu of the patient. The IRB is responsible for conducting a risk/benefit assessment, ensuring the patient’s rights and welfare are protected, and assessing relevant conflicts of interest. In the case of cohort EA, the FDA and IRB proactively review a protocol, as would be the case for a clinical trial; in the case of single patient EA, the FDA and IRB review a treatment proposal for an individual patient. Again, in emergencies, the requirement for IRB review for single patient EA may be waived and replaced by a requirement to notify the IRB after the fact.
Key takeaway: Unapproved medical products in development may offer some benefit to patients who lack other treatment options. EA was created to permit certain patients the option of trying these products outside of clinical trials for which they are unable to participate, if the sponsor is willing to provide the requested item. Patients, physicians, sponsors, the FDA, and IRBs all have roles to play in EA.
The authors would like to thank Jan Jaeger for her contributions to this work.