New recommendations for IRB review, informed consent and expanded access policies.

FDA recently announced the availability of a revised draft Guidance for industry on expanded access (EA) to investigational new drugs (INDs) for treatment use, which consists of recommendations presented in a questions-and-answers (Q&As) format. The initial Guidance was issued in June 2016 and updated in October 2017.

The newest draft version includes significant new recommendations related to the following:

• Institutional Review Board (IRB) review
• Informed consent
• Public and readily available Sponsor expanded access (EA) policies (requirements established by the Cures Act and the FDA Reauthorization Act of 2017 [FDARA])

New Questions Added to the Updated 2022 Draft Guidance

Incorporating Requirements for Investigators, Sponsors, and Sponsor-Investigators of Investigational Drugs

In its answer to question 2, “Are there safeguards in place for expanded access (EA) use of an unapproved drug?” FDA has pulled the definitions of “Sponsor,” “Investigator,” and “Sponsor-Investigator” into this document and specified that each must comply with the responsibilities for EA use under 21 CFR 312.

Investigator

• Definition: licensed physician that directs the administration or dispensation of the investigational drug
• Responsibilities: report adverse events to the Sponsor and maintain accurate case histories and drug disposition records, consistent with requirements of § 312.62

Sponsor

• Definition: individual or entity that submits an EA IND or protocol
• Responsibilities:
  • Remain in compliance with expedited IND safety reporting requirements and submit to FDA annual reports (§ 312.33)
  • Ensure that licensed physicians are qualified to administer the IND for the EA use and provide them with the information needed to minimize the risk and maximize the potential benefits of the IND
  • Maintain an effective IND for the EA use and retention of adequate drug disposition records (§ 312.57)

Sponsor-Investigator

• Definition: an individual (usually a licensed physician) who both initiates and conducts an investigation and under whose immediate direction the investigational drug is administered or dispensed
  • Responsibilities: report adverse events to the FDA and maintain accurate case histories and drug disposition records, consistent with requirements of § 312.62

IRB Review and Approval

IRB review and approval are required for treating a patient with an IND under EA per 21 CFR 56 before beginning treatment, except in an emergency (when there is not enough time for the treating physician to secure a prospective IRB review), provided the IRB is notified within five working days of such an emergency use per 21 CFR § 56.104(c). However, FDA does allow for waivers of particular aspects of this requirement, even for non-emergency individual patient EA IND requests.

Although full IRB review and approval may be waived, concurrence from the IRB chairperson or another designated IRB member is still required before treatment can begin. Note that these are only appropriate for individual patient EA; the FDA firmly believes that a waiver is “not appropriate” for intermediate and treatment INDs and protocols.

• Form FDA 3926
  • Treating physician must submit a signed completed Form FDA 3926 with the box in Field 10.b checked
  • Can also apply if amending an approved IND: must submit correspondence that clearly indicates the intent to request a waiver under 21 CFR § 56.108(c) and submit a signed completed Form FDA 3926 with the box in Field 10.b checked.
  • Physician will not receive notice from FDA that the waiver is granted
• Form FDA 1571
  • Treating physician must submit a separate waiver request to the application
  • FDA will issue a response to the waiver request

FDA responds to whether or not local IRB approval is required for physicians participating in another entity’s EA protocol in Q10 with a firm “maybe.” Physicians may not be required to obtain local IRB review and approval if the Sponsor already obtained it. However, a physician associated with an institution should not only verify that the sponsor has obtained IRB approval of the protocol but also consult the institution’s policies, as some institutions may require approval from a local IRB as well.

Informed Consent is Required to Allow Patients to Make an Informed Decision

EA submissions are subject to the informed consent requirements per 21 CFR § 50.1(a). One of the purposes of informed consent is to ensure that “patients are informed that they will be treated with an investigational product and that there may be uncertainty about the safety and effectiveness of the product.”

To facilitate adherence to the informed consent requirements, FDA has included a new informed consent template for individual patient EA as an appendix in the revised Guidance.

(Q13) To allow patients to make an informed decision about receiving experimental treatment, the consent form must include elements set forth in sections § 50.20 and § 50.25 (Q14), including a statement that treatment under EA “involves research” to satisfy the requirement in § 50.25(a)(1).

EA Policies Should Be Public

Under the newly added Section 561A(f) of the FD&C (Food, Drug, and Cosmetic) Act amended by FDARA, the manufacturer or distributor of INDs is required to make the EA policy readily available to the public.

In its answer to Question 35, FDA recommends that the pharmaceutical company or drug manufacturer who develops the IND for marketing makes its EA policy publicly available and complies with the requirement, rather than the distributor.

To comply with the requirement, the manufacturer or distributor must post the policy on a publicly available website (e.g., the manufacturer’s website or the Reagan-Udall Foundation EA Navigator web page). The policy must include contact information for the manufacturer or distributor, criteria the manufacturer or distributor will use to evaluate individual patients’ EA requests and responses to such requests, and a hyperlink to the relevant information on the ClinicalTrials.gov website.

If multiple INDs are under development at the same time, the pharmaceutical company/manufacturer should either publish one general EA policy covering all the INDs, or multiple individual EA policies for each IND.

To note: manufacturers and distributors of investigational medical devices are not required to comply with this requirement.

In question 36, FDA recommends that the pharmaceutical company/drug manufacturer (preferably) or the distributor of the investigational drug make its EA policy publicly available at the initiation of phase 2 or phase 3 study or at 15 days after the drug has been designed as breakthrough therapy/fast track product/regenerative advanced therapy, whichever is earlier.

FDA Provides Clarity on Additional Topics

In addition to these new questions and answers, FDA provides clarifying additional information throughout this document on a wide range of topics.  For example, when answering the question “How does FDA categorize and subcategorize EA submissions?” (Q6 in the draft guidance [previously Q8]), FDA has added additional text in their response to provide more clarity.

Some of these additions include:

• An additional example of emergency situations that may warrant an Individual patient EA IND for emergency use. In addition to situations where there is a need before a written submission can be made, FDA clarifies that this category applies to therapies expected to have a rapid effect in resolving an acute clinical emergency (and generally not to those intended for chronic administration to slow the progression of a disease)
• A statement indicating that single-patient protocols may still be subject to a clinical hold
• Rationale on when IP can be provided under intermediate-size patient population EA and treatment IND/protocols

Expanding Treatment Access to Patients

EA for treatment use can be a lifesaver for patients with serious or immediately life-threatening diseases who have exhausted all available treatment options and are not eligible for (or able to participate in) a clinical trial or that do not have a clinical trial available for their disease.

With the new changes, such as by mandating the availability of EA policies publicly posted by the manufacturers or distributors of INDs, the FDA directly enables the patients and their physicians to make informed decisions about receiving the treatments they most need.

Click here to see a list of the questions included in the guidance.

If you have any questions or would like further information, email info@mmsholdings.com to speak to a regulatory expert.

Learn more about MMS regulatory experts here.

By: Nancy Hsu, Regulatory Affairs Associate, Maria Clara Liuzzi, Medical Writer, and Supriya Perambakam, Global Regulatory Affairs Manager

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