On February 4, 2015, The U.S. Food and Drug Administration (“FDA”) issued a draft guidance titled “Individual Patient Expanded Access Applications: Form FDA 3926” (the “Guidance”). This Guidance1describes the streamlined application process for requesting “expanded use” of investigational agents for patients suffering from serious and life threatening disease conditions, who have no viable alternative treatments.

The expanded use pathway provided for under the FDA regulatory framework has received heighted attention in recent years as more patients are making their plight to obtain investigational agents public. For such patients, gaining timely access to investigational agents is critical and perhaps the last hope for a cure. Accordingly, the draft Guidance is an indication that the FDA is seeking ways to streamline the approval process, and to customize the regulatory submission requirements for qualifying individual patients. This recent Guidance introduces both a new process and a streamlined submission form specifically for physicians seeking expanded access on behalf of individual patients.

"Compassionate Use2" under the FDA Framework

Certain critically ill patients find themselves in a precarious situation when either they do not qualify for an active clinical study in which investigational drugs are being tested, or the trials are complete, yet the drug is not yet commercially available. In light of these dire situations, the FDA has created an “expanded access program” pathway for patients seeking treatment with investigational drugs (1) under a “treatment IND,” (2) under an IND for an intermediate-size patient population (smaller than typical for a treatment IND) or (3) an IND for individual patients, including under emergency situations. The final regulations that establish the current expanded access pathway balance two potentially competing interests: providing access to patients for life-threatening diseases versus avoiding interfering with the development of investigational drugs for marketing under approved applications.

With respect to access for individual patients, the current FDA regulatory framework requires the treating physician to determine that the probable risk to the patient from the investigational drug is not greater than the probable risk from the disease or condition, itself. Furthermore, prior to approving such expanded access the 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 benefit justifies the potential risks for 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 use; and
  • The patient cannot obtain the investigational drug under another existing IND or protocol.

The Form

The Guidance includes a draft Form FDA 3926, which serves as an alternative route to receive IND approval for individual patients. When applying for expanded access pursuant to FDA regulations3, the treating physician can submit the Form FDA 3926 in lieu of Form 1571, the form traditionally used by sponsors when applying for Investigational New Drug Applications (“IND”) to conduct clinical investigations. This is a welcomed change for physicians who reported difficulty using the 1571 as it was not “tailored to request for individual patient expanded access.”

This newly proposed process allows the treating physician to get an exemption from providing certain IND filing requirements under the Federal regulations, when they file an Form FDA 3926, provided that, (1) the physician-sponsor certifies that for all future requests for expanded access under the issued IND, the physician will file the FDA Form 1571; and (2) the physician receives permission from the drug manufacturer to provide the FDA access to an existing IND. With regard to the second requirement, information typically required for an IND application such as description of the manufacturing factory, chemistry, manufacturing controls information, and pharmacology and toxicology information is not required to be submitted when the physician has obtained a letter of authorization from the manufacturer to allow FDA access to such information under other existing INDs described more fully below.

Procedure

The Guidance sets forth the process for obtaining an investigational drug for a individual patient’s use, including completion of the Form FDA 3926. A licensed physician should first receive agreement from the drug manufacturer to provide the drug. A manufacturer should document such approval on a letter of authorization, and if applicable, the manufacturer’s permission should include allowing the FDA to refer to the manufacturer’s existing IND for specific information related to the investigational drug. The physician may then file the completed Form FDA 3926, which will serve as the application for an expanded access application. Under the expanded access IND, the physician is considered the sponsor- investigator and must comply with applicable regulations set forth in 21 CFR part 312, Subpart D.

Except in emergencies, the patient must also sign an informed consent that complies with 21 CFR part 50 and an Institutional Review Board (“IRB”) must approve the experimental treatment in accordance with 21 CFR part 56 before any treatment set forth under the Protocol for the expanded access IND is provided. Treatment under the expanded access IND may occur once the IND goes into effect at the earlier of (i) the receipt of IND approval from the FDA either by telephone or in writing or (ii) thirty days following submission of the completed application (FDA Form 3926) to the FDA.

Procedure in Emergency Situations

In an emergency situation when a patient must be treated immediately, there may be no time for filing an expanded IND, or obtaining IRB review and approval. In such cases, the request to access the drug may be made to the FDA by telephone. An FDA official can provide approval over the telephone, provided that the treating physician explains how the scenario complies with the FDA regulatory framework related to expanded access. Following the emergency treatment, that physician has 15 working days to submit the expanded access application from the date on which the FDA authorized the investigational use. In addition, the physician must notify the applicable IRB of the emergency treatment within five days of the treatment. With regard to obtaining informed consent, the physician must obtain consent that is consistent with 21 CFR part 50, unless the investigator and a physician who is not otherwise participating in the in the treatment certify in writing the following:

  1. The patient is confronted by a life-threatening situation necessitating the use of the test article.
  2. Informed consent cannot be obtained from the patient because of an inability to communicate with, or obtain legally effective consent from, the patient.
  3. Time is not sufficient to obtain consent from the patient's legal representative.
  4. There is no alternative method of approved or generally recognized therapy that provides an equal or greater likelihood of saving the life of the patient.

This certification must be submitted to the IRB within 5 working days after the use of the investigational drug.

On the other hand, if immediate use of the investigational drug is required before an independent physician's opinion can be obtained, within 5 days of the use of the investigational drug, the treating physician's (investigator) determination to use the drug must be reviewed and evaluated in writing by an independent physician who is not participating in the treatment.

Implications for Pharmaceutical Manufacturers

This draft Guidance brings hope to patients and their treating physicians for faster access to experimental therapies. For pharmaceutical manufacturers, providing faster access to experimental therapies will require additional infrastructure to support such requests and navigation of regulatory restrictions that arise related to promotion of off-label use of drugs. This Guidance is a reminder that manufacturers need to consider what processes and policies are in place to allow them to receive, review and respond to requests for expanded use access. While some companies have created policies and procedures and have been very public about the availability of their products for expanded use programs; there is concern raised by others that such publicity might result in fines and penalties imposed for promoting drugs that have not been approved as safe and effective by the FDA.

Although the FDA published guidance to address the need for pharmaceutical manufacturers to only respond to physicians' unsolicited requests for more off-label information4, it failed to address a manufacturer's ability to make public the existence of

expanded access programs for patients populations or advocacy groups.

Therefore, pharmaceutical manufacturers should consider the following when creating internal processes to honor such expanded access requests:

  1. Solicitation in any form may be seen as off-label promotion.
  2. Companies should not permit the sales organizations to promote expanded access programs.
  3. Medical Affairs should be the point for all requests, and should consider eligibility for existing clinical trials when request are made.
  4. Companies should have a mechanism to allow Medical Affairs to coordinate with regulatory and legal departments to allow for rapid decision making, proper documentation of the basis for decision to honor a request, and ensure that legal and regulatory requirements are satisfied.
  5. Companies should consider whether regulations permit the patients or their insurers to be charged for the cost of the investigational drug, as well as the administrative costs associated with assisting in drafting a treatment protocol, monitoring the investigational use and shipping the investigational agent.

Comments to the Draft Guidance

The FDA is seeking public comment on the draft Guidance, which is due no later than March 31, 2015.