To develop a guideline for an investigator to use in the event he/she needs to administer an investigational agent to an individual in a life threatening situation prior to securing Institutional Review Board approval.
In certain situations, an investigator may need to administer, as soon as possible, an investigational agent or biological product to a patient in a life threatening situation. The use of the agent may or may not be outlined in a study protocol that is open at another institution. When the PI does not have the time to open the study at Cottage Health System using the required IRB approval process before the patient necessitates treatment with the agent, federal regulations have allowed for the one-time use of the intervention prior to securing IRB approval (see guidelines at 21 CFR 56.104).
Emergency use: The use of an investigational drug or biological product with a human subject in a life-threatening situation in which no standard acceptable treatment is available and in which there is not sufficient time to obtain IRB approval [21 CFR 56.102(d)].
Life Threatening: Diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted and diseases or conditions with potentially fatal outcomes, where the end point of clinical trial analysis is survival. The criteria for life threatening do not require the condition to be immediately life threatening or to immediately result in death. Rather, the subjects must be in a life-threatening situation requiring intervention before review at a convened meeting of the IRB is feasible. Life threatening, for the purposes of section 56.102(d), includes the scope of both life threatening and severely debilitating, as defined below.
Severely Debilitating: Diseases or conditions that cause major irreversible morbidity. Examples of severely debilitating conditions include blindness, loss of arm, leg, hand, or foot, loss of hearing, paralysis, or stroke.
I. Investigator Responsibilities
A) An investigator may administer a test article without first securing IRB approval if all of the following conditions are met:
- The subject is in a life-threatening or severely debilitating situation.
- No standard acceptable treatment is available.
- There is not sufficient time to obtain IRB approval.
B) When an investigator wishes to use this provision for a hospitalized patient (or for treatment be given in the hospital), he/she must:
- Notify and receive permission from at least one of the following individuals prior to administration of the test article: the IRB Chair; the Institutional Official; the Chief of Staff, or the Chair of the Pharmacy & Therapeutics Committee.
- Contact the IRB Administrator in order to request the CHS Emergency Use Reporting Form (see attachment A). The completed form is due no later than 5 days after the intervention has taken place [21 CFR 50.23 (c)]. As outlined in the form, if it is not possible to obtain consent, a written report by a physician (who is not participating in the patient’s treatment) is required to evaluate the determination made by the treating investigator.
II. Emergency Exemption From Prospective Institutional Review Board Approval
All research involving humans as subjects at Cottage Health System requires prospective review by the Institutional Review Board (IRB). However, situations may arise where the use of an unapproved, investigational drug or device may offer the only possible life-saving alternative. Furthermore, there may not be sufficient time to obtain the approval from the Institutional Review Board. Nothing in the Cottage Health System policies regarding the use of humans as research subjects is intended to limit the authority of a physician to provide emergency medical care, to the extent the physician is permitted to do so under applicable federal, state, or local law (see Section V).
The emergency use provision in the FDA regulations [21 CFR 56.104( c)] is an exemption from prior review and approval by the IRB. The exemption, which may not be used unless all of the conditions described in 21 CFR 56.102(d) exist, allows for one emergency use of a test article without prospective IRB review. FDA regulations require that any subsequent use of the investigational product at the institution have prospective IRB review and approval. FDA 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.
The FDA regulations do not provide for expedited IRB approval in emergency situations. Therefore, “interim,” “compassionate,” “temporary” or other terms for an expedited approval process are not authorized. An IRB must either convene and give “full board” approval of the emergency use or, if the conditions of 21 CFR 56.102(d) are met and it is not possible to convene a quorum within the time available, the use may proceed without any IRB approval.
Some manufacturers will agree to allow the use of the test article, but their policy requires “an IRB approval letter” before the test article will be shipped. If it is not possible to convene a quorum of the IRB within the time available, some IRBs have sent to the sponsor a written statement that the IRB is aware of the proposed use and considers the use to meet the requirements of 21 CFR 56.104( c). Although, this is not an “IRB approval,” the acknowledgement letter has been acceptable to manufacturers and has allowed the shipment to proceed.
III. Exception From Informed Consent Requirement
Even for an emergency use intervention, the investigator is required to obtain the informed consent of the subject or the subject’s legally authorized representative, unless both the investigator and a physician who is not otherwise participating in the clinical investigation certify in writing all of the following [21 CFR 50.23(a)]:
- The subject is confronted by a life-threatening situation necessitating the use of the test article.
- Informed consent cannot be obtained 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 subject's life.
If, in the investigator’s opinion, immediate use of the test article is required to preserve the subject’s life, and if time is not sufficient to obtain an independent physician’s determination that the four conditions above apply (prior to administration of the test article), the clinical investigator must state this in writing using the CHS Emergency Use Reporting Form. The independent physician’s evaluation is still required to substantiate the treating physician’s actions.
FDA regulations allow for one emergency use of a test article in an institution without prospective IRB review, provided that such emergency use is defined as a single use (or single course of treatment, e.g., multiple doses of antibiotic) with one subject. “Subsequent use” would be a second use with that subject or the use with another subject.
If it is anticipated that the test article may be used again, the IRB requests that a protocol and consent document be developed so that an approved protocol would be in place when the next need arises. In spite of the best efforts of the clinical investigator and the IRB, a situation may occur where a second emergency use needs to be considered. FDA believes it is inappropriate to deny emergency treatment to an individual when the only obstacle is lack of time for the IRB to convene, review the use, and give approval.
IV. Emergency Use of a Test Article versus Emergency Research
HHS regulations do not permit research activities to be started, even in an emergency, without prior IRB review and approval (see 45 CFR 46.103b and 46.116f and OHRP guidance at http://ohrp.osophs.hhs.gov/humansubjects/guidance/hsdc91-01.htm .
When emergency intervention is required due to a life threatening or severely debilitating event, whether or not the intervention involves the use of a test article or an FDA approved agent, no data collection is permitted and the intervention may not be deemed as research. The regulations have made the allowance for emergency use of a test article in order to enable patients in critical situations, for whom time is of the essence, to receive treatment without the requirement to follow the normal, time-consuming channels of IRB review and approval.
However, emergency use of a test article must be distinguished from emergency research (research which is designed to measure the results of interventions in emergency situations). Emergency research must have prior IRB approval and uses the normal enrollment and consenting guidelines as set forth in the regulations. Such research is designed to collect data and provide generalizable information. For example, research on patients in life threatening situations, such as research conducted in Emergency Departments or Intensive Care Units, must have prior IRB approval in order to allow the collection and reporting of data.
V. Emergency Medical Care
Nothing in the regulations is intended to limit the authority of a physician to provide emergency medical care. However, when emergency medical care is initiated without prior IRB review and approval, the patient may not be considered a research subject. Such emergency care may not be claimed as research, nor may any data regarding such care be included in any report of prospectively conceived research activity. When emergency care involves investigational drugs, devices, or biologics, U.S. Food and Drug Administration (FDA) requirements must be satisfied.
If a test article is not involved (i.e. the intervention is FDA approved), the physician does not need to report the use of the intervention to the IRB when such administration was done to provide emergency medical care. The emergency care may be conducted in accordance to a research protocol for which the investigator has not received prior IRB approval (one that has not been opened or approved locally), even though the method of administration of the product may be described in a research protocol being conducted elsewhere. Again, such emergency care may not be claimed as research. The investigator should open the research protocol following the use of the intervention, if he/she feels that use of the intervention may be required again in the future.
If there is no research protocol describing the use of the product as intended by the physician, and he/she wishes to provide a patient with the intervention in a manner that is not consistent with the product’s labeling, it is within the scope of the physician’s medical license to treat the patient with the product if he/she feels it is in the best interest of the patient and that the patient’s condition is likely to improve as a result of such off-label use of the product.
Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgment. If physicians use a product for an indication not in the approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product’s use and effects. Use of a marketed product in this manner when the intent is the practice of medicine does not require the submission of an Investigational New Drug Application (IND) or Investigational Device Exemption (IDE) with the FDA. One-time off-label use of an FDA approved product does not require IRB review or approval.