EMERGENCY USE 03/02/2016

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1 DUKE UNIVERSITY HEALTH SYSTEM Human Research Protection Program EMERGENCY USE 03/02/2016 Emergency Exemption for an Investigational Drug or Biologic or Unapproved Device Emergency use of an investigational drug or biologic (emergency exemption) is defined as the use of an investigational drug or biological product for a human subject in a lifethreatening situation in which no standard acceptable treatment is available, and in which there is not sufficient time to obtain DUHS IRB approval (21 CFR (d)). The emergency use provision of the FDA regulations (21 CFR (c)) is an exemption from prior review and approval by the IRB. The exemption may not be used unless all of the conditions previously mentioned exist. Emergency use of an unapproved device is defined as the use, with a human subject in a life-threatening situation, of an unapproved device for a purpose or condition for which the device requires, but does not have, an approved application for pre-market approval (FDA approval for marketing). An unapproved device may be used in human subjects only if it is approved for clinical testing under an approved application for an investigational device exemption (IDE). However, emergencies may arise where an unapproved device may offer the only possible life-saving alternative, but an IDE for the device does not exist, or the proposed use is not approved under an existing IDE, or the physician or institution is not approved under the IDE. A. Definitions Life-threatening, for these purposes (21 CFR (d)), includes the scope of both life-threatening and severely debilitating, as defined below: Life-threatening means 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 endpoint of clinical trial analyses is survival. The criteria for life-threatening do not require a 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 of an IRB protocol at a convened meeting of the IRB is feasible. Severely debilitating means 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. 1

2 B. Criteria for Emergency Use To ensure that the emergency use will occur in compliance with FDA regulations and guidance, the investigator must establish and document that: 1. The patient is in a life-threatening situation. 2. No standard acceptable treatment is available. 3. There is not sufficient time to obtain a review and approval of the proposed use by a convened IRB. For devices, because of the immediate need to use the device, there is no time to use existing procedures to get FDA approval for the use. The emergency use will be reported to the IRB within five working days. 4. Any subsequent use of the investigational product will have prospective IRB review and approval. 5. The use does not involve a systematic investigation designed to develop or contribute to generalizable knowledge. 6. Consent will be sought from each prospective participant or the participant s legally authorized representative, in accordance with and to the extent required by 21 CFR 50 and will be appropriately documented, in accordance with and to the extent required by 21 CFR OR the situation meets the 21 CFR exception to the requirement for consent. In the event that a device is to be used in circumstances meeting the criteria described above, IRB would expect the investigator to follow as many subject protection procedures as possible. These include: 1. Obtaining an independent assessment by an uninvolved physician. 2. Obtaining informed consent from the patient or the patient s legally authorized representative. 3. Notifying the IRB. 4. Obtaining authorization from the IDE holder, if an approved IDE for the device exist. C. Investigator s Communication with the IRB The IRB is required to review the emergency use of an investigational drug or biologic in a life-threatening situation in order to assess investigator compliance with FDA regulations and guidance. Either before or within five (5) business days after the emergency use, the investigator must provide a formal submission, via the emergency use pathway in eirb, to the IRB for review. The submission must include the items described below in Section F. Investigators are advised to contact the IRB Office at the earliest feasible opportunity to document that an emergency exists and the seven required conditions (listed above) exist. An IRB Chair may be contacted 24 hours a day/7 days a week by calling the main IRB telephone number ( ), and then following the instructions to contact the Chair on call. The IRB will assist the physician in ensuring that appropriate recipient protections are contemplated, as in Section D below, and will remind the physician of the reporting 2

3 requirements in Section F below. The IRB Chair will review the information provided by the investigator to determine if the plans of the investigator would follow FDA regulations and guidance. In the event that the plan does not comply with FDA regulations and guidance, the Chair will provide information to the investigator for how to comply with these regulations and guidance. Some sponsors or manufacturers will agree to allow the use of the investigational drug or biologic or device, but their policy requires "an IRB approval letter" before the investigational drug or biologic will be shipped. If it is not possible, within the time available, for the investigator to prepare an IRB protocol and the IRB staff to convene a quorum of the IRB to review the protocol, an IRB Chair will provide for the sponsor a written statement that the IRB has acknowledged the proposed use and considers the use to meet the requirements of 21 CFR (c). This is not an "IRB approval," but the acknowledgment statement may be acceptable to the manufacturer for allowing the shipment to proceed. The IRB will not approve a request for an emergency use unless it does so at a convened meeting. Short of this, the IRB will acknowledge that such a use will occur/has occurred, and if true, that the emergency use will be/was in compliance with FDA regulations and guidance. See Section F below. D. Informed Consent Requirements Investigators are required to obtain the informed consent of the subject or the subject's legally authorized representative in an emergency use situation. Informed consent must be sought from each prospective participant or the participant s legally authorized representative, in accordance with and to the extent required by 21 CFR 50 and informed consent is appropriately documented, in accordance with and to the extent required by 21 CFR All of the basic elements of informed consent (and any applicable additional elements) are to be provided, unless the situation meets the conditions for exception (described below). 1. A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental. 2. A description of any reasonably foreseeable risks or discomforts to the subject. 3. A description of any benefits to the subject or to others which may reasonably be expected from the research. 4. A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject. 5. A statement describing the extent to which confidentiality of records identifying the subject will be maintained and that notes the possibility that the Food and Drug Administration may inspect the records. 6. An explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained. 3

4 7. An explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights, and whom to contact in the event of a research-related injury to the subject. 8. A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled. 9. A statement that FDA may inspect the records associated with this research. When appropriate, the following elements of information shall also be provided to each subject in this emergency setting: 1. A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable. 2. Anticipated circumstances under which the subject's participation may be terminated by the investigator without regard to the subject's consent. 3. Any additional costs to the subject that may result from participation in the research. 4. The consequences of a subject's decision to withdraw from the research and procedures for orderly termination of participation by the subject. 5. A statement that significant new findings developed during the course of the research which may relate to the subject's willingness to continue participation will be provided to the subject. 6. The approximate number of subjects involved in the study. The investigator may adapt a consent form from a previously approved research study involving the use of the investigational drug or biologic to be suitable for this emergency use by removing all references to that research study but retaining all references to the research use of the investigational drug or biologic. Or the investigator may develop a new consent form that includes all of the above elements of informed consent. An IRB Specialist, Medical Writer or a Chair may assist the investigator in this process. The consent form must be printed on the Duke MO 345 form for inclusion in the subject s medical record. E. Waiver of Informed Consent The investigator is expected to obtain the written consent of the subject or the subject s legally authorized representative for this emergency use. However, if 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)), then the investigational use may proceed without the consent of the subject or the subject s legally authorized representative. 1. The subject is confronted by a life-threatening situation necessitating the use of the drug or biologic or device. 2. Informed consent cannot be obtained because of an inability to communicate with, or obtain legally effective consent from, the subject. 4

5 3. Time is not sufficient to obtain consent from the subject s legally authorized representative. 4. 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 investigational drug or biologic 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 have been met, the investigator should make the determination and, within five (5) business days after the use of the drug or biologic or device, have the determination reviewed and evaluated in writing by a physician who is not participating in the clinical investigation. The investigator must notify the IRB within five (5) business days after the use of the drug or biologic or device (21 CFR 50.23(c)) See Section F. F. Investigator s Report To The IRB and Its Review Investigators are required to submit to the DUHS IRB a notification of anticipated emergency use of an investigational drug or biologic prior to its use, or a report on the emergency use of the investigational drug or biologic within five (5) business days following its use. The notification or report must contain the following information: 1. A description of the emergency and the use of the investigational drug or biologic or device. 2. Documentation that the seven required conditions (see Section B. above) were met. 3. A statement from the investigator that no new use of the investigational drug or biologic or device will occur without prior IRB review and approval. 4. A copy of the unsigned informed consent document used for the research, when applicable. 5. When the emergency use occurred without prior consent of the subject or the subject s legally authorized representative, a copy of the letter from the independent physician that the four required conditions were met (see Section E above). G. IRB Review Once the report is received in the IRB Office, the Executive Director and Lead Chair are informed of the submission via automated from the eirb. That information, the Investigator s report and any related documents, e.g. informed consent document, emergency IND/IDE, are assigned to an IRB Chair for review to ensure that the emergency use will follow/followed FDA regulations and guidance. In the event that the use does not comply with FDA regulations and guidance, the Chair will include this information in the report of the emergency use to the convened IRB. The report will be presented by the reviewing Chair to a convened IRB. The convened IRB will be notified of the emergency use and the Chair s findings. If the emergency use event and/or investigator s actions did not comply with FDA regulations and 5

6 guidance, the convened IRB committee will determine if the investigator will be evaluated for serious or continuing noncompliance as required by DUHS IRB policy. The investigator is informed by the Chair in writing that if the investigator anticipates the need to use the investigational drug or biologic or device in additional subjects, prospective review by the IRB is required. If the IRB finds that the investigator has not complied with FDA regulations and guidance, the Institutional Official or designee will notify both the investigator, the sponsor, and the FDA of the IRB s finding of investigator noncompliance. This exemption allows for one emergency use of an investigational drug or biologic or device without prospective IRB review, provided that such an emergency use is reported to the IRB within five (5) business days. After the emergency use, the investigator should evaluate the likelihood of a similar need occurring again, and if future use is likely, submit an IRB protocol requesting approval for such future use. If a second individual requires identical treatment and the only obstacle is that the IRB has not had sufficient time to convene a meeting to review the submitted protocol, the investigator may follow the procedures described above for notification of the IRB about the proposed use. According to FDA, a person treated under FDA s emergency use provision is considered to be a research subject (21 CFR (e)). Therefore the outcome of the emergency use, including any unanticipated problems, must be reported to FDA. (This report may be via the drug or biologic sponsor. If the investigator is also the sponsor, the sponsor-investigator will comply with the procedures described in Responsibilities of an Investigator Who Is Also a Sponsor.) However, OHRP views the person differently (OHRP Guidance (May 15, 1991). OHRP agrees that emergency medical care for patients may be provided without regard to IRB review and approval. Whenever emergency care is initiated without prior IRB review and approval, OHRP holds that the patient may not be considered to be a research subject, and such emergency care may not be claimed as research, nor may the outcome of such care be included in any report of a research activity sponsored or funded by a DUHS entity. Note that the conduct of planned research in life-threatening emergency situations where obtaining prospective informed consent has been waived, as provided by 21 CFR 50.24, differs from this emergency use provision. That research plan must be approved in advance by the FDA and the IRB, and publicly disclosed to the community in which the research will be conducted. Community consultation must also be sought. Specifically for Unapproved Devices: Note that a physician may not conclude an emergency exists in advance of the time when treatment may be needed based solely on the expectation that IDE procedures may require more time than is available. Physicians should be aware that the IRB expects them to exercise reasonable foresight with respect to potential emergencies 6

7 and to make appropriate arrangements under the IDE procedures far enough in advance to avoid creating a situation in which such arrangements are impracticable. After an unapproved device is used in an emergency, the investigator should: (1) Evaluate the likelihood of a similar need for the device occurring again, and if future use is likely, immediately initiate efforts to obtain IRB approval and an approved IDE for the device s subsequent use. (2) If an IDE for the use does exist, notify the sponsor of the emergency use, or (3) If an IDE does not exist, notify FDA of the emergency use and provide the FDA with a written summary of the conditions constituting the emergency, subject protection measures, and results. Subsequent emergency use of the device may not occur unless the investigator or another person obtains approval of an IDE for the device and its use. If an IDE application for subsequent use has been filed with the FDA and the FDA disapproves the IDE application, the device may not be used even if circumstances constituting an emergency exist. Developers of devices that could be used in emergencies are expected to anticipate the likelihood of emergency use and obtain an approved IDE for such uses. Reference: Food and Drug Administration Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors: Exception from Informed Consent Requirements for Emergency Research, March Previous Version Date(s): 02/02/2016, 5/19/2011, 5/30/2008 7