Jessica Huening

by Jessica Huening

FDA Publishes Three New Guidance Documents: A Good Move, Part 1

On June 2, 2016, the Food and Drug Administration (FDA) published three new final guidance documents related to expanded access1 and charging for investigational drugs under an IND.  The new guidance documents are informative, and effectively address areas that often cause confusion within the clinical research community.

Expanded Access to Investigational Drugs for Treatment Use – Questions and Answers

This Q&A document provides answers to frequently asked questions regarding expanded access and clarifies several points:

  • General topics, including distinctions between expanded access protocols from continuation of open-label safety protocols, and how to consider individuals who have participated in a clinical trial that continue to receive the investigational agent but no longer meet inclusion criteria
  • Criteria and procedures for the two application types for expanded access: expanded access of a protocol as an amendment to an existing IND (e.g., expanded access protocol), and the creation of a new IND submission intended for treatment (e.g., expanded access IND)
  • The forms required in the submission process
  • The logistics of who should make the submissions

For example, FDA recommends sponsors submit individual patient expanded access protocols to an existing IND to optimize safety concerns, administrative burden, and product review.  Explanation is provided on FDA’s process and rationale to grant or deny expanded access requests in various situations.2

Responsibilities for obtaining IRB review and informed consent requirements are also reviewed.[3]  Given full board review requirements may deter patient access where IRB review is not readily accessible, FDA encourages the use of central IRBs for expanded access review.  Limited access to IRBs should not curtail innovative clinical research. For those physicians without an IRB, finding the right central IRB with a mechanism for handling expanded access research is critical.

Individual Patient Expanded Access Applications: Form FDA 3926

Sponsor-investigators can use Form FDA 3926 for an initial individual patient expanded access application, as well as many follow-up submissions.4  Form FDA 3926 is tailored to individual patient expanded access as an alternative to Forms FDA 1571 & 1572, which are used by commercial sponsors for a variety of IND submissions.5

In this guidance, FDA outlines numerous expectations and regulatory criteria applicable to sponsor-investigators, FDA, and IRBs in order to authorize, implement, and complete ongoing reporting requirements related to individual patient expanded access.6  For example, sponsor-investigators are instructed to provide a letter of authorization to access IND information from the investigational drug’s commercial IND holder, if applicable.

The guidance outlines various conditions which establish non-emergency treatment may proceed.  FDA also clarifies they may authorize emergency use over the phone or by “other means of rapid communication” with the expectation that a subsequent application for expanded access is submitted.

The areas addressed by these guidance documents are often confusing for researchers. The clarifications offered in the documents further accuracy and ultimately participant protection—a good move by the FDA.



[1] Expanded access facilitates the use of investigational treatments to primarily diagnose, monitor, or treat patients with serious or immediately life threatening diseases or conditions who lack therapeutic alternatives. This includes when a withdrawn drug has been removed for safety reasons but remains a viable treatment option for a patient population, the use of a foreign unapproved drug similar to an approved drug during a drug shortage, and when use of an approved drug where availability is limited due to a risk evaluation and mitigation strategy (REMS) for patients who cannot obtain the drug under the REMS.

[2] Of note, FDA generally considers subsequent uses of an investigational drug used under emergency procedures at the same institution to require IRB review.  The FDA highlights, however, they do not intend to deny subsequent expanded access emergency use at an institution when IRB review is not feasible.

[3] Investigators are responsible for ensuring IRB review of the expanded access has been obtained consistent with 21 CFR 56 (21 CFR 312.305(c)(4)).  Informed consent requirements in 21 CFR 50 apply to expanded access INDs, including emergency use, unless an exception to informed consent in 21 CFR 50 applies.

[4] Per the guidance, Form FDA 3926 can be used for the following individual patient IND follow-up submissions as identified in 21 CFR 312: Initial Written IND Safety Report (§ 312.32(c)); Follow-up to a Written IND Safety Report (§ 312.32(d)); Annual Report (§ 312.33); Summary of Expanded Access Use (treatment completed) (§ 312.310(c)(2)); Change in Treatment Plan (§ 312.30); General Correspondence or Response to FDA Request for Information (§ 312.41); and Response to Clinical Hold (§ 312.42(e)).

[5] FDA notes the Agency considers a checked box in field 10 of the FDA 3926 as part of a signed submission to be a request to waive any additional requirements in part 21 CFR 312 for an IND submission consistent with 21 CFR 312.10 which is appropriate for individual patient expanded access INDs as physician noncompliance with these requirements would not pose a significant and unreasonable risk to individuals patients, and compliance with these requirements is not necessary for the FDA to evaluate the IND.

[6] Applicable regulatory criteria for FDA to permit expanded access generally are found in 21 CFR 312.305(a).  Applicable regulatory criteria that delineate physician responsibilities are found in 312.310(a).  Submission requirements for all expanded access requests are found in 21 CFR 312.205(b) with additional requirements for individual patient expanded access located in 21 CFR 312.310(b).  FDA cites Safety Reporting Requirements for INDs and BA/BE Studies as guidance related to submitting IND safety reports.  FDA cites Investigator Responsibilities—Protecting the Rights, Safety, and Welfare of Study Subjects as guidance in identifying sponsor and investigator responsibilities.  Investigators are responsible for ensuring IRB review of the expanded access has been obtained consistent with 21 CFR 56 (21 CFR 312.305(c)(4)).


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