FDA Guidance to Industry Streamlines Physician Compassionate Use Requests

By Jordan Paradise

The Food and Drug Administration (FDA) published draft guidance for industry last week detailing a streamlined process for physician submissions of individual patient requests for compassionate use of experimental drugs undergoing active clinical trials. Entitled Individual Patient Expanded Use Access Applications: Form FDA 3926, this guidance builds on a well-established system of assessment by the FDA and provides a specific format for submissions.

Compassionate use requests are routinely channeled through the FDA’s Expanded Access Program, which provides access to investigational new drugs (INDs) in certain circumstances. Expanded access assessments focus on whether and to what extent individuals facing serious or life-threatening diseases or disorders should be able to access experimental drug treatments that have not yet received FDA approval under the touchstone measures of safety and effectiveness. The federal statute provides for such access to INDs, which is further set forth in FDA regulations, 21 C.F.R. 312. As the recent guidance states:

Under the applicable criteria in 21 CFR 312.305(a), FDA must determine that:

• The patient to be treated has a serious or immediately life-threatening disease or condition, and there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition;
• The potential patient benefit justifies the potential risks of the treatment use and those potential risks are not unreasonable in the context of the disease or condition to be treated; and
• Providing the investigational drug for the requested use will not interfere with the initiation, conduct, or completion of clinical investigations that could support marketing approval of the expanded access use or otherwise compromise the potential development of the expanded access use.

Under the applicable criteria in 21 CFR 312.310(a):

• The physician must determine that the probable risk to the person from the investigational drug is not greater than the probable risk from the disease or condition; and
• FDA must determine that the patient cannot obtain the investigational drug under another IND or protocol.

While the federal statute and implementing FDA regulations set forth basic requirements for the FDA’s assessment of such requests, the procedure has long been fraught with complaints about process, transparency, and outcomes. Despite these complaints, the FDA reports that it allows 99% of requests. However, even if access is granted by the FDA, neither the statute nor the regulations mandate that the drug sponsor actually provide the drug. A January 2015 New England Journal of Medicine article succinctly details these complaints, including extensive preparation time for physicians, lengthy FDA review times, a lack of reporting on drug sponsor determinations, uncertainty on coverage for the drugs, effect on clinical trial enrollment, and liability issues.

The outcomes of two legal cases have largely shaped the developing debate in this area. Nearly a decade ago, in Abigail Alliance v. von Eschenbach, 495 F.3d 695 (2007), the D.C. Circuit held that terminally-ill patients had no fundamental right to experimental therapy that had not yet received approval by the FDA. The Abigail Alliance had petitioned the FDA to promulgate new regulations allowing drug sponsors to market investigational new drugs that had completed Phase 1 safety trials to terminally-ill patients. After the FDA denied the petition, the Alliance filed a lawsuit alleging violation of a Constitutionally-protected right. The D.C. Circuit’s decision flows from a previous Supreme Court case, U.S. v. Rutherford, 422 U.S. 544 (1979), where the Court held there was no special right for terminally-ill patients to access a drug subject to a pending new drug application where safety and efficacy had not yet been established by the FDA.

National coverage of the rights of patients to access INDs has been prominent in the last few years due to several factors, including patient advocacy campaigns through social media and federal and state “right to try” bills. The highly-publicized Josh Hardy social media campaign for access for a sick 7-year old to the drug brincidofovir, an anti-viral in Phase 3 clinical development by Chimerix, is detailed in an August 2014 Health Affairs blog post here. The New England Journal of Medicine has an excellent synopsis of the five state “right to try” laws passed in Arizona, Colorado, Louisiana, Michigan, and Missouri here. Federal legislation, H.R. 5805, has also been introduced to amend the compassionate use process.

The goal of the new draft guidance process and accompanying form is to make the submission process easier on physicians requesting access for patients. The FDA’s draft guidance document provides that the physician must first confirm that the manufacturer is willing to supply the drug. The physician must include a letter of authorization (LOA) in their request which then allows right of reference to information submitted to the FDA by the drug sponsor. Contents of a request include: patient initials, date of submission, clinical information, patient treatment information, the LOA from the drug manufacturer, a physician’s qualification statement and name, address, contact information, a request for authorization to use Form FDA 3926, and a certification statement and signature. The physician is then considered a sponsor-investigator and subject to human subject protections contained in 21 C.F.R. 50 and Institutional Review Board (IRB) requirements contained in 21 C.F.R. 56. Both informed consent and IRB authorization must be obtained prior to initiation unless the request is for an emergency individual use. Treatment with the IND may proceed once the FDA notifies the physician, or within 30 days after FDA receives the completed draft form (once finalized by the FDA). The draft guidance includes a draft Form 3926 as Appendix I.

For further coverage of the FDA’s new draft guidance, see the Regulatory Affairs Professional Society post here.