On August 5, 2021, PRIM&R hosted a webinar titled IRB Review of Expanded Access Protocols that Collect Real World Data: Considerations and Guidance. During this webinar, Alison Bateman-House, PhD, MPH, MA (a bioethicist) and Hayley Belli, PhD, MS (a biostatistician), from the NYU Grossman School of Medicine Working Group on Compassionate Use and Preapproval Access, discussed ethical and analytical considerations when collecting real world data from Expanded Access protocols. Today, they provide further information and answer follow-up questions.

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 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 any serious adverse events (SAEs) to the entity developing the product (the “sponsor”) and the FDA. While EA is for treatment purposes 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.

In addition to the mandatory collection and sharing of data related to serious adverse events, many sponsors, regulators, and patients believe that real world data (RWD) gleaned from Expanded Access—in other words, data obtained from these treatment uses—may offer value for regulatory, clinical, and research uses. Therefore, sponsors increasingly seek to gather data beyond that which is required. It is likely that IRB members reviewing EA protocols (for multiple patients) will encounter plans for the collection of real world data, and data collection might even be a part of single patient EA requests. While IRBs are used to reviewing EA requests, there are several additional key questions to consider when reviewing EA that collects RWD. These include:

1. Does this proposal maintain EA’s treatment mission?
2. Are the burdens of data collection/sharing on different stakeholders, including clinicians and patients, minimal?
3. Is the proposed data collection (beyond the required safety reporting) voluntary, or is it required to obtain access to the desired unapproved medical product? Is the data collection strategy able to answer the sponsor’s question, or would these data more appropriately be collected through a rigorous clinical trial?

In this post, we answer questions that were raised by the audience. We also explore more questions and topics on Expanded Access protocols that collect real world data in this free  guide, which you can download by logging into the PRIM&R Knowledge Center (if you don’t already have a PRIM&R account—it’s the same one you use to register for programs and renew PRIM&R membership—you can create one for free). We invite you to contact us with follow-up questions or thoughts.

Q: I’d be interested in your recommendations for managing treating investigator conflict of interest (COI) in EA. I’m curious about managing COI when approached to approve for EA. 

A: The management and treatment of investigator COI is institution specific, typically requiring input from various institutional officials. Generally, COIs in research must be disclosed to the IRB and other institutional entities, as required and managed accordingly, and this provides a template for handling COI in Expanded Access. At a minimum, treating clinicians can be asked if they have financial or other stakes in the unapproved product that would be used and if these have been disclosed to the patient in the informed consent process. Alternatively, an institution could develop a policy stating that clinicians with COIs must allow a non-conflicted peer to manage the patient’s care as related to the unapproved product.

Q: Is FDA saying anything about how IRBs should approach these reviews, particularly when data collection involves procedures that are not standard of care, and we are really starting to include a research component in the protocol? There are significant contractual implications for indemnification and concerns related to reciprocity for the data, which can slam the brakes on actually getting these protocols up and running, which we want so patients can get care.

A: Some IRBs do review the research component of an EA protocol separate from the treatment component of the EA protocol. The FDA provides some guidance for IRB review of EA protocols, but they do not make specific recommendations for how IRBs should manage this specific issue.

Q: Do you recommend adding a HIPAA Authorization, along with consent, to disclose the potential that more than just clinical safety information will be provided to the sponsor?

A: HIPAA authorization may be included with the single and cohort EA ICF. However state laws, institutional and IRB policies may vary.

Q: Is the question about giving the patient the option to decline data collection beyond SAEs an implication that it should be optional from an ethical standpoint?

A: Ethically, patients should be informed of all anticipated procedures, including the collection, sharing,  and use of their data. The process of consent and the consent forms should include the type of data being collected and if it is for research and/or treatment purposes. Clinigen, a large contract research organization involved in the creation and execution of EA programs, has a policy that all non-SAE-related data collection in EA must be voluntary and that products should not be withheld from patients unwilling to agree such data collection. It remains to be seen if this becomes the prevailing stance across industry.

PRIM&R thanks Alison Bateman-House and Hayley Belli for sharing their expertise and for creating and sharing the this follow-up guide. The recording of this webinar is available for purchase in the Knowledge Center. You can also download the webinar follow-up guide at no cost by logging into the Knowledge Center—if you don’t already have a PRIM&R account (it’s the same one you use to register for programs and renew PRIM&R membership) you can create one for free.

Alison Bateman-House, PhD, MPH, MA, is an assistant professor in the Division of Medical Ethics at NYU Grossman School of Medicine. She is co-chair, with Arthur Caplan PhD, of the Working Group on Compassionate Use and Preapproval Access (CUPA), an academic group that studies ethical issues concerning access to investigational medical products and which is composed of patient advocates, clinicians, members of industry, former FDA staffers, lawyers, and academics. She also co-chairs, with Lesha Shah MD, the Pediatric Gene Therapy and Medical Ethics (PGTME) working group, which includes academics, patient advocates, industry representatives, and a wide array of clinical and research professionals. Bateman-House serves as the non-voting, non-paid chair of the NYU/Janssen Pharmaceutical Compassionate Use Advisory Committees (CompACs) for Infectious Diseases and Neurology/Psychology. CompAC won the Reagan-Udall Foundation for the FDA’s 2019 Innovation Award. Bateman-House has published and spoken extensively on how to best handle requests for non-trial access to investigational drugs and on related ethical issues. She has also written and spoken frequently on the history and ethics of using humans as research subjects and on clinical trial accessibility.

Hayley Belli, PhD, MS, is an assistant professor of biostatistics within the Department of Population Health at NYU Grossman School of Medicine, where she conducts research in the design, conduct, and analysis of pragmatic and adaptive clinical trials, including studies embedded within electronic health records, and methods for extracting evidence from real world data in the context of Expanded Access programs. She is a member of the Working Group on Compassionate Use and Pre-Approval Access within the NYU Division of Medical Ethics, and co-chairs the Ethics and Real-World Evidence Research Project.