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Everything You Wanted to Know About Expanded Access but Were Afraid to Ask, Part 3

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. Read Part 1 and Part 2.

Part 3: What’s an IRB to do?

EA is considered treatment, not research. EA was not established as a means to collect research data, even though certain safety data must be collected and shared with the FDA and the sponsor. But, once sponsors decide to capture/share EA-derived data above and beyond that needed to report SAEs, what should IRBs do when reviewing such plans: view this as research, and thus hold it to (higher) research standards, or continue to view this as treatment?  This distinction is important for patients’ rights and welfare.

When is it acceptable to collect RWD from EA?

In our view, collection/sharing of data from EA, even when this entails activities above and beyond the treatment itself, can be morally justifiable if those additional activities do not compromise the treatment mission of EA and if the data collected/shared provide societal benefit via the creation of generalizable knowledge.

At a minimum, IRBs should determine if the proposed data collection/sharing, above and beyond that pertaining to serious adverse events, is voluntary. In other words, can the patient say no to the data collection/sharing and still receive the requested medical product? If not, what justifies this constraint on a patient seeking treatment, who is not enrolled in research? That question applies to both single patient and cohort EA. When reviewing single patient or cohort EA in which RWD will be collected, IRBs should ensure patients’  rights and welfare are protected by distinguishing treatment procedures from any procedures to be conducted solely for the sake of data collection/sharing. IRBs should also be aware of why sponsors wish  to collect/share safety, efficacy, or other data, as well as how these data will be stored/shared.

Collection, sharing, and use of data from EA may raise questions about the protection of patients, and possibly of the scientific validity of the data. If what is proposed for the data collection/sharing effort goes beyond what seems appropriate for patients receiving treatment, an IRB may ask that the EA protocol be transformed into a clinical trial, subject to the oversight and regulation that accompany research studies. For example, if the patients receiving an unapproved medical product via EA are asked to undergo additional procedures, such as scans or lab work, that are being conducted solely for data-collection purposes, it may be reasonable for an IRB to deem this no longer EA but a research study. However, if data are being collected from activities that would be performed as a part of the administration and monitoring of the unapproved product, this may reasonably be seen as still EA, just with an expanded data collection component.

Ensuring RWD are fit for purpose

IRBs should keep in mind that EA lacks key features of RCTs, such as control groups, randomization, or blinding, that are essential to these studies’ ability to generate robust, generalizable findings. As such, ensuring that the collection/sharing of EA-derived data will lead to the creation of generalizable knowledge means reviewing the quality and rigor of the proposed data collection methods to ensure that attention has been paid to limiting bias, reducing sources of error, and avoiding missing data. In brief, if data are considered to be worth collecting, its collection and sharing should be done thoughtfully, with attention paid to minimizing the possibility of misinterpretation.

As such, IRBs should evaluate: (1) the purpose of the proposed data collection; (2) the population of interest from which data would be collected; (3) the likely reliability and accuracy of the data; and (4) the quantity of the data that would be collected. It may be that the data will not  be rigorous or the population not representative; for example, if a sponsor seeks to collect data from a number of single patient EA uses of its product in development. So long as the data collection/sharing component is voluntary (i.e., the patient’s access to the medical product is not dependent on their willingness to permit the collection and sharing of their data) and does not significantly increase risk or other harms to the patient, the IRB may decide the desired data collection and sharing is permissible, if the sponsor is able to provide a compelling rationale.

More questions arise when IRBs review cohort EA protocols, which more closely resemble clinical trials. For these, IRBs should determine if the protocol clearly defines the primary, secondary, and exploratory outcomes and specifies the reasons for the data use and sharing.

The key takeaway is that it should be permissible to collect voluntary RWD from both single patient and cohort EA under certain circumstances. These include that 1) the treatment mission of EA is not compromised, 2) the reason for the data collection/sharing is compelling, and 3)  the data will be suitable for the intended purpose. If these criteria are not met, the data collection/sharing is likely not appropriate for the EA setting; instead, the sponsor should be advised to  consider creating a clinical trial to obtain such data.

What IRB members should consider when reviewing EA submissions:

IRBs should ensure the consent process and documents (including surrogate permission) used in  EA meet the relevant regulatory requirements, the risk/benefit assessment is satisfactory, and relevant conflicts of interest are disclosed. As RWD collection/sharing increasingly becomes a part of EA, it may be that IRB forms will need to be updated to specifically inquire about data collection. When data collection/sharing extends beyond SAE reporting, the IRB should require information about the following:

  • the type of data to be collected/shared and how this will occur;
  • the extent to which data collection/sharing/use creates additional risks or benefits for patients;
  • whether the patient may refuse to participate in the data collection effort and still receive the desired product;
  • the procedures for maintaining confidentiality and protecting privacy; and
  • a quality assurance plan for data collection

If data beyond SAEs are collected from a cohort EA protocol, IRBs should review the (1) data collection methods, (2) statistical analysis and data management plan, and (3) subject inclusion/exclusion criteria.  The IRB may consider sources of bias, diversity of the population, and reproducibility of the results.

Key takeaway: RWD are increasingly being collected as part of EA, in both the single patient and cohort program types. Data collected from EA may be used for myriad purposes and more closely resemble research activities than the treatment endeavors that have classically constituted EA. To protect patients’ rights and welfare in these instances, IRBs should clarify which EA proposals have a data collection/sharing component beyond the required SAE reporting and carefully review these data proposals as described herein.

The authors would like to thank Jan Jaeger for her contributions to this work.

The Petrie-Flom Center Staff

The Petrie-Flom Center staff often posts updates, announcements, and guests posts on behalf of others.

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