FDA issued another COVID-related guidance for immediate implementation last week. Citing a substantial increase in the number of requests for individual patient expanded access requests for COVID-19 investigational drugs (which we will use here to include biological products), on June 2, 2020, FDA released a guidance for investigational review boards (IRBs) and clinical investigators entitled “Institutional Review Board (IRB) Review of Individual Patient Expanded Access Requests for Investigational Drugs and Biological Products During the COVID-19 Public Health Emergency Guidance for IRBs and Clinical Investigators”.
As in many of the other guidances issued during the ongoing COVID-19 public health emergency, FDA states that it intends this guidance to remain in effect only for the duration of the emergency, but notes that the within 60 days following termination of the public health emergency, the agency intends to review and revise the guidance taking into consideration its experience with implementation and any comments received.
As its title suggests, the guidance applies only to requests under FDA’s individual patient expanded access pathway (21 C.F.R. §312.310), sometimes referred to as “compassionate use,” and does not apply to expanded access programs for intermediate-size or treatment expanded access requests (under 21 C.F.R. § 312.315 or 312.320). Under the regulation, individual patient expanded access allows a patient with a serious or immediately life-threatening disease or condition to gain access to an investigational drug when there is no comparable or satisfactory alternative therapy, the potential benefits to the patient justify the potential risks, and the requested use will not interfere with clinical investigations that could support marketing approval. The primary purpose of providing individual access to an investigational drug under this pathway is for diagnosing, monitoring, or treating the patient, rather than generating scientific safety or effectiveness data.
A request for individual patient expanded access can be submitted to FDA by a licensed physician as a new investigational new drug application (IND) or by the sponsor of an existing IND as a protocol amendment. An emergency request does not require prior IRB approval, but the IRB must be notified within 5 working days of treatment initiation, and subsequent use is subject to IRB review. Prior IRB approval is required for non-emergency requests for individual patients. A physician submitting a non-emergency request may request a waiver from the ordinary requirement for full IRB approval. As FDA has outlined in previous guidance (“Expanded Access to Investigational Drugs for Treatment Use – Questions and Answers”), such a waiver is appropriate when the physician obtains concurrence from the IRB chairperson or another designated IRB member.
FDA states that it is providing recommendations about the key factors and procedures IRBs should consider when reviewing individual patient access requests, including IRB reviews conducted by an individual member, because the agency has become aware that during the existing public health emergency IRBs are seeking clarity on how to comply with their obligations under 21 C.F.R. part 56.
FDA recommends that IRBs consider establishing procedures for a single IRB member to review an expanded access submission for an individual patient when a waiver from full IRB review is requested, including procedures that outline relevant factors to be reviewed and procedures for documenting the decisions made.
FDA suggests that review of an expanded access request for an individual patient focus on assessing the risks and benefits for the patient involved, and notes that the information must be adequate to assess whether these risks have been minimized and are reasonable in relation to the anticipated benefits. FDA does not expect that a protocol will be necessary to provide sufficient information to determine if those criteria are satisfied (although if the request is submitted by the sponsor it is likely that a protocol is already available).
FDA lists the following as information that should be included, noting that the information may be included in a thorough patient history and treatment plan:
- proposed daily dose, route, and frequency of administration, duration of planned treatment, criteria for discontinuation of treatment, and planned dose modifications for adverse events;
- planned monitoring for adverse events, response to treatment, and changes in clinical status, as well as proposed modifications to the treatment plan to mitigate risks to patients if appropriate;
- key details of the patient’s history, including diagnosis and summary of prior therapy (including response to such therapy), and information regarding a patient’s relevant clinical characteristics (such as comorbid conditions and concomitant medications); and,
- summary of the known risks of the drug.
The guidance also provides that the IRB’s review of an expanded access request for an individual patient should include:
- an assessment of the qualifications of the requesting physician submitting the individual patient expanded access request;
- if the request is for a pediatric patient, confirmation that adequate provisions are included for soliciting age-appropriate assent from children and permission from a parent or guardian; and,
- confirmation that the informed consent document contains the information required under 21 C.F.R 50.25. Given that the drug used under expanded access is investigational, FDA considers a statement in the informed consent document indicating that although the primary use of the drug is for treatment, the drug is investigational and FDA has not determined that the drug is safe or effective for use in treating COVID-19, to satisfy the requirement under 21 C.F.R §50.25(a)(1) that the informed consent provide a statement that the use of the product “involves research.”