HIGHLIGHTS:

  • The U.S. Food and Drug Administration (FDA) has issued three final guidance documents that address FDA's rules and regulations governing "expanded access" to investigational drugs.
  • The expanded access process is designed to facilitate the availability of unapproved new investigational treatment options to patients with serious or immediately life-threatening diseases or conditions who lack therapeutic alternatives.
  • The three guidance documents aim to provide clarification of these criteria to those seeking expanded access and to make the required application to FDA less burdensome for doctors and patients.

The U.S. Food and Drug Administration (FDA) issued three final guidance documents on June 2, 2016, that address FDA's rules and regulations governing "expanded access" to investigational drugs. The expanded access process – often referred to as "compassionate use" – is designed to facilitate the availability of unapproved new investigational treatment options to patients with serious or immediately life-threatening diseases or conditions who lack therapeutic alternatives.

While FDA has promulgated regulations governing the availability of unapproved drugs outside of clinical trials for treatment purposes, the issue has become even more salient as patients, physicians, life sciences companies and policy makers have expressed frustration with continuing difficulty in gaining access to certain drugs. Indeed, several legislative proposals intended to address this issue are pending in Congress. These guidance documents do not change current FDA regulations; rather, they are FDA's attempt to streamline the process, at least in part as a response to these developments.

Brief Background on Expanded Access

Under regulations issued in 2009, FDA may permit expanded access to an investigational new drug outside of a clinical investigation, or to an approved drug where availability is limited by a limited by a risk evaluation and mitigation strategy (REMS), for an individual patient when certain criteria are all met:

  • 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
  • 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 use1

Additionally:

  • the patient's 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
  • FDA must determine that the patient cannot obtain the investigational drug under another IND or protocol2

A subset of this type of expanded access is emergency expanded access for an individual patient. In an emergency situation that requires immediate treatment before a written submission to FDA can be made, FDA may grant expanded access by telephone or other rapid means of communication. The treating sponsor must then submit an expanded access application within 15 working days of the initial authorization.

The three guidance documents issued on June 2 aim to provide clarification of these criteria to those seeking expanded access and to make the required application to FDA less burdensome for doctors and patients.

FDA's Final Guidance Documents

The first guidance document, "Individual Patient Expanded Access Applications: Form FDA 3926," streamlines the process for physicians to request use of an investigational new drug to treat individual patients who have exhausted other treatment options, including for emergency use. In its guidance, FDA expresses concern that some physicians requesting expanded access for individual patients have encountered difficulty completing required documentation because the existing forms are not tailored to requests for individual patient expanded access.

The current Form 1571 is used by sponsors for all types of Investigational New Drug (IND) submissions, including for large clinical trials, while the new Form 3926 is designed specifically for individual patient expanded access requests.3 FDA anticipates that physicians will be able to complete the new form in 45 minutes. Form FDA 3926 may also be used for certain follow-up submissions to an individual patient expanded access IND, such as safety reports, changes to treatment plans and after-treatment summaries. The process for emergency use expanded access will not change, but the physician will use the new Form 3926 instead of Form 1571.

The guidance document also provides some clarification of existing requirements. FDA instructs that when a physician would like to obtain an investigational drug outside of a clinical investigation for an individual patient, the physician should first ensure that the investigational drug can be obtained. If so, the physician needs to obtain a Letter of Authorization (LOA) from the sponsor of the referenced IND (e.g., commercial sponsor or drug manufacturer). The LOA permits FDA to refer to information that the sponsor of the IND has submitted to FDA. In cases where it is not possible to obtain an LOA (e.g., the entity supplying the drug does not have an IND filed with FDA), FDA instructs the physician to contact the relevant review division at FDA to determine what information is needed to support the expanded access submission. Physicians should also contact the review division if the requested individual patient expanded access IND is for an approved drug for which availability is limited by a REMS. The physician should then submit an individual patient expanded access IND to the appropriate FDA review division and may choose to use Form FDA 3926.

The other two guidance documents do not provide new policies or processes but rather are designed to answer questions about FDA's broader expanded access program and provide more details regarding the rules governing charging for investigational drugs provided under early access programs or under other INDs.

In its "Expanded Access to Investigational Drugs for Treatment Use – Questions and Answers" guidance document, FDA responds to frequently asked questions about the entire expanded access program. The document addresses not only requests to FDA for individual patient expanded use under a new IND (i.e., requests under the new Form 3926) but also requests for individual patient expanded use under a new protocol to an existing IND, as well as expanded access for intermediate and large populations.

Highlights of common issues addressed in the guidance by FDA include:

  • clarifying the roles played by the patient, the treating physician, the FDA and the IND sponsor in making expanded access decisions.
  • explaining the difference between expanded use for individual patients under a new IND versus a protocol to an existing IND. A new IND is typically requested when the original IND sponsor does not wish to be the sponsor of the expanded access use. In this case, the physician acts as sponsor under the new expanded access IND.
  • clarifying that Institutional Review Board (IRB) approval and informed consent are required for expanded use submissions. For emergency expanded use, treatment may begin before IRB approval, but must be reported to an IRB within five days. Additionally, FDA recognizes in the document the competing concerns of ensuring IRB oversight and providing timely access to treatment for patients in need. FDA states that it has recommended the use of central IRBs for review of expanded access uses, but acknowledges that additional options may be needed.
  • outlining the timing for initiation of treatment under various expanded access approvals.
  • addressing complex situations such as the ability for a patient to be treated under more than one expanded access IND, or to be treated with multiple courses of therapy or treated for a chronic condition under an IND.

Finally, FDA issued "Charging for Investigational Drugs under an IND – Questions and Answers" to address common questions related to the implementation of FDA's regulations in such situations. This includes charging for expanded access use as well as clinical trial use. In 2009, FDA revised its 1987 regulations governing circumstances under which a sponsor may charge for investigational drugs. The 2009 revision was meant to address: 1) circumstances regarding charging for investigational drugs in a clinical trial that were not anticipated under the original rule, 2) criteria for charging under all categories of expanded aces, and 3) types of costs that can be recovered when charging under an IND. This guidance document provides additional clarification on the 2009 regulations, including the criteria for charging for an investigational drug, the process for seeking FDA approval to charge for the drug and allowable cost recovery calculations.