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115.FDA Regulations: Treatment or Emergency Uses of Investigational Drugs

FDA allows flexibility in the expanded use of investigational drugs for treatment for persons with serious or life-threatening diseases or conditions (Subpart I) and for persons with life-threatening and severely-debilitating illnesses (Subpart E). See HRPP policy 100 for an overview of and hyperlinks to FDA regulations, information sheets, and guidance; and FDA Information Sheet Guidance for IRBs and Clinical Investigators: Emergency Use of an Investigational Drug or Biologic

IMPORTANT NOTE: At this time, neither the University nor its Affiliate sites actively conduct or manage planned emergency research; therefore, the University does not have policies in place for such research. Investigators interested in conducting planned emergency research must contact the RIO to discuss the possibility of engaging in this type of research. As warranted, the IRB will develop and publish policy for planned emergency research.

Expanded Access (Treatment) Uses of Investigational Drugs

Subpart I of FDA regulations describes the requirements for the use of investigational and approved drugs where availability is limited by a risk evaluation and mitigation strategy when the primary purpose of the use is to diagnose, monitor, or treat a patient's disease or condition (i.e., expanded access uses). By authorizing such expanded access uses, FDA aims to facilitate the availability of such drugs to patients with serious or life-threatening diseases or conditions when there is no comparable or satisfactory alternative therapy.

General Requirements for Expanded Access Uses

The following requirements apply to FDA and IRB determinations for expanded access uses, whether under a new IND or a protocol amendment to an existing IND (per §312.305, (a) Criteria).

  1. The patient or patients to be treated must have a serious or immediately life-threatening disease or condition, and there must be no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition.
  2. The potential patient benefit must justify the potential risks of the treatment use and the risks of treatment use are not unreasonable in the context of the disease or condition to be treated.
  3. Providing the investigational drug for the requested use must 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.

The following additional requirements (at §312.310) apply to use of investigational drugs for treatment of an individual patient by a licensed physician, including for emergency use.

  1. The treating 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
  2. The patient cannot obtain the drug under another IND or protocol.

If the drug is the subject of an existing IND, the expanded access submission may be made by

  • the sponsor, by amending the IND to include the expanded access for the individual patient; or
  • a licensed physician, by obtaining permission from the sponsor for FDA to refer to information in the IND to support the expanded access request and FDA with any other required information not contained in the IND (e.g., information specific to the individual patient).

All expanded access uses are subject to FDA regulations for

  • the protection of human subjects (§50), including requirements for informed consent, unless the emergency use meets the criteria for FDA exception from general requirements for informed consent (as specified below);
  • IRB approval (§56) unless the emergency use meets the criteria for the exemption from the requirements for IRB review for emergency use (as specified below);
  • IND applications (§312); and
  • applications to market a new drug; (§314), and biological products (§600).

See §312.305 for more information about FDA requirements for submission for expanded access use, safeguards, and when treatment may begin.

Criteria for FDA Exceptions from General Requirements for Informed Consent for Emergency Use

FDA regulations describe exceptions to general requirements for informed consent. The following two exceptions are relevant to emergency uses of test articles. The required documentation for both of these requirements must be submitted to the IRB within 5 working days after the use of the test article.

FDA Exception per §50.23, item (a): Informed consent is deemed feasible unless before use of the test article, both the investigator and a physician who is not otherwise participating in the clinical investigation certify (in writing) all of the following are true:

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

FDA Exception per §50.23, item (b): If it is the opinion of a clinical investigator that immediate use of the test article is required to preserve the life of the subject, and time is not sufficient to obtain the determination of an independent physician as described above prior to using the test article, the article may be used if within 5 working days after the use of the article, the clinical investigator's determinations are reviewed and evaluated in writing by a physician who is not participating in the clinical investigation.

FDA Exemption from Requirement for Prior IRB Review and Approval for Emergency Use

FDA regulations at §56.104, item (c) exempt emergency use of an FDA-regulated test article from requirements for prior IRB review and approval as long as

  • the use meets all requirements for the expanded access use (see above); and
  • the physician using the test article reports the emergency use to the University IRB within 5 working days.

NOTE: Any subsequent use of the test article at the University is subject to IRB review.

Investigator and Sponsor Responsibilities for Expanded Access Uses

Investigators' and sponsor' responsibilities (Subpart D of FDA regulations) apply as follows to the extent the requirements are relevant to the expanded access use:

  • A licensed physician who administers an investigational drug for an expanded access use is considered an investigator (i.e., physician-investigator) and must comply with the responsibilities for investigators as itemized below.
  • An individual or entity that submits an expanded access IND or protocol under Subpart I is considered a sponsor and must comply with the responsibilities for sponsors as itemized below.
  • A licensed physician who submits an IND for expanded access use under is considered a sponsor-investigator and must comply with the responsibilities for sponsors and investigators.

Responsibilities of Physician-Investigators

Physician-investigators must obtain prior IRB approval for any expanded access use unless following three conditions are true:

  1. The use of the test article is for a human subject in a life-threatening situation, no standard acceptable treatment is available, and time is insufficient to obtain prior IRB approval (see definition of "emergency use" at §56.102, item (d)).
  2. The emergency use is reported to the IRB within 5 working days (per §56.104, item (c)).
  3. Any subsequent use of the test article at the institution is subject to prior IRB review.

Physician-investigators must obtain legally effective informed consent as required by the IRB (unless  an FDA exception for informed consent at CFR 50.23 (a) or (b) applies) (as described above);

Physician-investigators must report adverse drug events to the sponsor.

Physician-investigators must maintain and retain accurate records that include a case history of the patient and the disposition of the drug as required.

Responsibilities of Sponsors

Sponsor responsibilities are beyond the scope of this policy. Information about sponsor (and investigator) responsibilities are codified at §312 Subpart D.

Investigator-Sponsor Requirements for Expanded Access Uses

Investigator-sponsors must

  • ensure physician-investigators are qualified to administer the investigational drug for the expanded access use;
  • provide the physician-investigator with the information needed to minimize risk and maximize the potential benefits of the investigational drug (e.g., Investigator's Brochure);
  • maintain an effective IND for the expanded access use;
  • maintain and retain adequate drug disposition records in accordance with FDA and institutional requirements; and
  • comply with FDA requirements for submission of IND safety and annual reports.

Types of Expanded Access Uses of Investigational Drugs

Single Patient Treatment Use of an Investigational Drug by a Licensed Physician

FDA regulations at §312.310 specify the two criteria under which a licensed physician may administer or dispense an investigational drug for treatment use, including emergency use, for an individual patient.

  1. A licensed physician determined the probable risk to the person from the investigational drug is not greater than the probable risk from the disease or condition.
  2. FDA determined that the patient cannot obtain the drug under another IND or protocol.

Requires prospective IRB approval and informed consent unless the use is for emergency treatment and the relevant conditions have been met for expanded, emergency use and/or exception from general requirements for informed consent.

NOTE: The IRB may determine it would be inappropriate to deny emergency treatment to a second individual if the only obstacle is that the IRB has not had sufficient time to convene a meeting to review this use of the test drug.

If the drug is the subject of an existing IND, the expanded access submission may be made by the sponsor or a licensed physician as follows:

  • The sponsor amends an existing IND to include a protocol for expanded access for an individual patient.
  • A licensed physician submitting an expanded access obtains permission from the sponsor for FDA to refer to any information in the IND that would be needed to support the expanded access request and provides any other required information not contained in the IND (e.g., information specific to the individual patient).

If there is an emergency that requires the patient to be treated before a written submission can be made, FDA may authorize the expanded access use to begin without a written submission. The FDA reviewing official may authorize the emergency use by telephone. The licensed physician or sponsor must provide FDA with an expanded access submission within 15 business days of FDA's authorization of the use.

Treatment use for a single patient is generally limited to a single course of therapy for a specified duration unless FDA authorizes multiple courses or chronic therapy.

At the end of treatment, the licensed physician or sponsor must provide FDA with a written summary of the results of the expanded access use, including adverse effects.

FDA may require the sponsor to monitor expanded access uses of extended duration.

NOTE: Under DHHS regulations, emergency use of an investigational drug is not considered research. Patients receiving the drug are not considered research participants and the outcome of emergency use of an investigational drug cannot be included in any report of a research activity subject to DHHS regulations. Under FDA regulations, the emergency use of an investigational drug is a clinical investigation, the patient is a participant, and the FDA may require data from an emergency use to be reported in a marketing application.

Treatment Use of an Investigational Drug by a Licensed Physician in an Intermediate-sized Population

Under specific conditions (see §312.315), FDA allows use of an investigational drug for the treatment of more than one patient when the population is smaller than that typical of a treatment IND or treatment protocol (as described below). For example, when a significant number of requests arise for individual patient expanded access to an investigational drug for the same use, FDA may ask a sponsor to consolidate the expanded access uses.

Requires prospective IRB approval and informed consent.

Treatment uses for intermediate populations may arise when a drug

  • is not being developed (e.g. rareness of disease/condition restricts recruitment);
  • is being studied in a clinical trial but patients requesting use of the drug are unable to participate in the trial; or
  • is approved but is no longer marketed for safety reasons or is otherwise unavailable through marketing.

In addition to the criteria for all expanded uses (above), expanded uses in intermediate-sized populations require there is

  1. enough evidence that the drug is safe at the dose and duration proposed for the expanded access use to justify a clinical trial of the drug in the approximate number of patients expected to receive the drug under expanded access; and
  2. at least preliminary clinical evidence of effectiveness of the drug, or of a plausible pharmacologic effect of the drug to make expanded access use a reasonable therapeutic option in the anticipated patient population.

(See §312.315 for more information about submission requirements, and safeguards for this type of expanded access use.)

Wide-spread Treatment Use of an Investigational Drug by a Licensed Physician

In addition to provisions for expanded access use for treatment of an individual patient and intermediate-sized populations, FDA regulations at §312.83 and §312.320 allow for wide-spread treatment use of an investigational drug via a treatment protocol or Treatment IND.

Requires prospective IRB approval and informed consent.

Requirements for FDA Approval of a Treatment IND

  1. Trial status. The drug must be under investigation in a controlled clinical trial under an IND designed to support a marketing application for the expanded access use or all clinical trials of the drug have been completed.
  2. Marketing status. The sponsor of the IND supporting marketing must be actively pursuing marketing approval of the drug for the expanded access use with due diligence.
  3. Evidence. Sufficient clinical evidence must be available to provide a reasonable basis for concluding the investigational drug may be effective for the expanded access use without exposing patients to an unreasonable and significant risk of illness or injury.

The sponsor is responsible for monitoring the treatment protocol to ensure that licensed physicians comply with the protocol and the regulations applicable to investigators.

Open Label Protocol or Open Protocol IND

When a controlled trial has ended, treatment may be continued to allow participants to continue to receive the benefits of the investigational drug until marketing approval is obtained. These are considered uncontrolled studies that are carried out to obtain additional safety data (Phase 3 studies).

Requires prospective IRB approval and informed consent.

Group C Treatment IND

FDA established the "Group C" treatment IND as an agreement between FDA and the National Cancer Institute (NCI). The Group C program allows distribution of investigational agents to oncologists for the treatment of cancer under protocols outside the controlled clinical trial. Group C drugs are distributed only by the National Institutes of Health under NCI protocols.

Treatment is the primary objective. Patients treated under Group C guidelines are not part of a clinical trial. The University likely would accept the FDA waiver from the requirement for approval for Group C drugs, but recognizes the University IRB may opt to review the project under its policies/procedures. Investigators wishing to provide treatment under a Group C IND must submit the "Guideline Protocol" for the use of the Group C drug and the FDA-approved informed consent document.

Parallel Track

Through its Parallel Track policy, FDA permits wider access to promising new drugs for AIDS/HIV related diseases under a separate "expanded access" protocol that "parallels" the controlled clinical trials that are essential to establish the safety and effectiveness of new drugs. It provides an administrative system that expands the availability of drugs for treating AIDS/HIV.

These studies require prospective IRB review and informed consent.

Emergency Use IND

The need for an investigational drug may arise in an emergency situation that does not allow time for submission of an IND in the usual manner. In such cases, FDA may authorize shipment of the drug for a specified use with the requirement for the sponsor to file an appropriate application as soon as practicable.

Prospective IRB review is required unless

  • all of the conditions for "emergency use" described above and at §56.102, (d) are met; and
  • all of the conditions are met for an FDA exemption at §56.104, (c).

FDA regulations require that any subsequent use of the investigational product at the institution have prospective IRB review and approval.

FDA and the University IRB acknowledges, however, that it would be inappropriate to deny emergency treatment to a second individual if the only obstacle is that the IRB has not had sufficient time to convene a meeting to review the issue.

Informed consent must be obtained unless the conditions for exception from general requirements for informed consent at §50.23 are met.

Drugs for Treatment Uses for Persons with Life-Threatening and Severely-Debilitating Illnesses

Subpart E of FDA regulations for Investigational New Drug Applications (IND), describes procedures to expedite the development, evaluation, and marketing of new therapies intended to treat persons with life-threatening and severely-debilitating illnesses, especially where no satisfactory alternative therapy exists. (See life-threatening and severely debilitating in the HRPP online Policy Manual Definitions.) The decision to allow treatment or expanded uses of drugs for life-threatening and severely-debilitating illnesses for a single subject or a group of subjects is based on the following considerations:

  • When no satisfactory alternative treatment exists, subjects are generally willing to accept greater risks from test articles that may treat life-threatening and debilitating illnesses.
  • Benefits of a drug should be evaluated in light of the severity of the disease being treated.

See Subpart E for the scope, and procedures and requirements (including requirement for early consultation of sponsor with FDA) for drugs intended to treat life-threatening and severely-debilitating illnesses. Contact the RIO for information about submitting a request to use an investigational drug for a persons with life-threatening and severely-debilitating illnesses.

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