Expanded access, which is treatment access to experimental drugs (also referred to as “compassionate use” or “pre-approval access”), has generated increasing interest and debate over the last several years. Currently, US federal regulations allow manufacturers to provide Investigational New Drugs (INDs) to patients with serious diseases or conditions who have exhausted approved therapeutic options and cannot participate in a clinical trial. As key players in the pre-approval access process, IRBs must review and approve expanded access protocols in accordance with FDA guidelines. Moreover, the new “Right to Try” laws currently taking effect on both the federal and state levels make it especially crucial that IRB members stay informed about ongoing developments and potentially thorny ethical issues.

On March 7, PRIM&R hosted a webinar, Pre-Approval Access to Drugs in Development: Navigating the Changing Regulatory, Ethical, and Legal Landscape, to educate HRPP professionals on FDA guidance, recent legislation, and ethical questions related to expanded access. The panel featured Richard Klein, the former director of the FDA’s Patient Liaison Program in the Office of Health and Constituent Affairs, and Beth E. Roxland, JD, MBioethics,
an Attorney, Bioethicist, and Senior Advisor on Law, Health Policy and Ethics at Roxland Consultants, Ltd.

After the webinar, Mr. Klein responded to some of the attendee questions time didn’t permit us to address live. We’re pleased to share those responses with the readers of Ampersand.

Do expanded access programs need to be listed in ClinicalTrials.gov?
Richard Klein (RK): Yes. New regulations require that sponsors list any expanded access program on ClinicalTrials.gov.

If a 3926 is submitted, is a 1571 required as well?
RK: No. The 3926 is the form of choice for single patient use. It substitutes for the 1571. A 1571 can be used, but it is longer and tends to be more confusing for those unfamiliar with the form. It also requires attachment of another form, 1572 (investigator qualification form). So, only the 3926 need be submitted. Some doctors are used to using the 1571, and continue to use it. Only one or the other is required for single patient access.

Why even involve the IRB in the expanded access review process?
RK: Because these are investigational products, and ethical oversight is part of patient protection. IRBs are the front line in assuring that patients understand the investigational nature of the product and that there are certain potential risks (often unknown) associated with such products.

Does the IRB need to review the consent form rather than just a clinical consent?
RK: I’m not certain I understand the distinction. The IRB should review the informed consent form to ensure it adequately informs the patient of the investigational nature of the treatment product. It should also ensure the process of consent is adequate.

Why would a company require individual INDs (and not an IND for an intermediate size population) for use of a drug when a subspecialty clinic might have multiple patients who could benefit from the drug? An individual IND is required in the case of clofazimine used to treat serious mycobacterial infections, for example. Thus, our IRB sees repeated protocols that seem to be a waste of time for the physician and the IRB.
RK: I think that’s a good question. I’ve seen this with other drugs as well. It is at the discretion of the company how they want to provide access (if at all). The agency often encourages cohort programs when there are multiple patients, to lighten the paperwork burden on everyone involved, but again, it’s up to the company. It might provide more control over the distribution of the product and the qualifications of individual physicians administering the product on the part of the company than a cohort study would. 

What is the difference between an IRB’s letter of concurrence vs. approval?
RK: It essentially demonstrates that the treatment use and informed consent were reviewed, and that the IRB representative concurs with the treatment use.

I read that a physician-sponsor does not have to wait for FDA approval of an IND application but can start using the drug after so many days. How does/should that impact IRB review?
RK: I think this refers to the 30-day waiting period for new INDs. FDA has a 30-day window within which to review and make a decision on any IND application. Generally, the agency responds to these EA requests much sooner (average of about four days for non-emergency single patient IND requests). The agency may respond with questions for additional information or clarification, or may deny a request. But if FDA does not respond within 30 days, a researcher or physician can proceed. Presumably, the physician/investigator will submit a request to an IRB around the same time they submit the request to FDA, and the IRB should review the materials so that the treatment may begin as soon as FDA allows it to proceed.

If the IRB reviews an expanded access application and approves it prior to FDA approval (can they or should they do that?), what happens if the FDA does have extra stipulations? I assume the physician-investigator would need to take it back to the IRB.
RK: The IRB can review and act on the request prior to final FDA decision. If there are added stipulations or changes based on the FDA response, the IRB should most certainly be informed and have the opportunity to reconsider.

If an IRB chair or member reviews a single patient access request, should it be a clinician?
RK: The requirement is that the chair, or a member of the committee designated by the chair. There is no requirement that the reviewer be a clinician.

Does an IRB need to wait for a physician to get an IND approval from the FDA before reviewing?
RK: No. In fact, prospectively reviewing can speed access by the patient. The FDA requires that the treating physician have IRB approval/concurrence in hand before treatment begins.

Are there any special concerns that the IRB should have about expanded access requests- especially for single patients?
RK: Primarily that the patient is well informed about the investigational nature of the treatment/product, that there are potentially unknown risks, etc. 

Does a physician with his own IND need to report any adverse events or data to the company providing the drug?
RK: Usually, the company stipulates the information reporting requirements for the physician. There are certain reporting requirements to the FDA spelled out in the Code of Federal Regulations, but reporting to the company depends on the specific agreement between the company and the physician.

Should a sponsor share a treatment protocol with a physician applying for a single patient IND?
RK: Often the company recommends, and sometimes stipulates, treatment regimen, dosing, etc. There is no regulatory requirement, but companies may have important information related, for example, to pediatric dosing, and may have specific recommendations depending on the underlying health history of a patient, based on their accumulated data on safety from animal and previous human experience.

Can a physician ever use a pharmaceutical’s expanded access IND for a single patient, or would a physician always need to obtain an IND for single patient treatment?
RK: Yes. If there is an existing IND for treatment access – either an intermediate patient population IND or Treatment IND, the physician should treat under the existing IND. Existing INDs are often listed in ClinicalTrials.gov.

Can continuing review for treatment use be conducted through expedited procedures?
RK: The answer is yes. If continuing review is required for an individual patient IND, it can be performed by the chair or a designated member of the committee. This only applies to individual/single patient INDs. Cohort programs (e.g., intermediate size patient population or treatment IND) require full board review.

PRIM&R thanks Mr. Klein for sharing his expertise.

The recording of this webinar is available for individuals to purchase in PRIM&R’s online store. If you would like to purchase the webinar for group viewing, please download the order form (PDF) and send it to registration@primr.org.

For more information about Right to Try legislation, please see PRIM&R’s recent blog post, Taking a Closer Look at the New Federal “Right to Try” Law, co-authored by Beth E. Roxland, JD, MBioethics, and Elisa A. Hurley, PhD.