Number 97-01

Human Subjects Protections

Revised (p. 2)

OPRR Reports

October 31, 1996

Subject: Informed Consent Requirements in Emergency Research

Dear Colleague:

This letter advises Institutional Officials and Institutional Review Board (IRB) Chairs of responsibilities related to informed consent when research subjects are enrolled in emergent circumstances.

As in the past, the regulations for protection of human subjects of the Department of Health and Human Services (HHS) at 45 CFR Part 46 stipulate requirements for obtaining (Section 46.116) and documenting (Section 46.117) informed consent. And, the regulations give IRBs authority to alter or waive the required consent in certain circumstances (Sections 46.116(c)-(d)).1 These provisions of HHS regulations remain unchanged and in full force.

On October 2, 1996 (Federal Register, Vol. 61, pp. 51531-51533), the Secretary, HHS, announced, under Section 46.101(i), a waiver of the applicability of the 45 CFR Part 46 requirement for obtaining and documenting informed consent for a strictly limited class of research, involving research activities that may be carried out in human subjects who are in need of emergency therapy and for whom, because of the subjects' medical condition and the unavailability of legally authorized representatives of the subjects, no legally effective informed consent can be obtained. This waiver, which provides a third route through which IRBs may approve research in this class, takes effect November 1, 1996.

This waiver applies to the Basic HHS Policy for Protection of Human Research Subjects (Subpart A of 45 CFR Part 46) and to research involving children (Subpart D of 45 CFR Part 46). However, because of special regulatory limitations relating to research involving fetuses, pregnant women, and human in vitro fertilization (Subpart B of 45 CFR 46), and research involving prisoners (Subpart C of 45 CFR Part 46), this waiver is inapplicable to these categories of research.

___________________
1A previous "Dear Colleague" letter (OPRR Reports 93-3, August 12, 1993) describes this authority of IRBs to alter or waive the requirement for informed consent.

Emergency Research Consent Waiver

Pursuant to Section 46.101(i), the Secretary, HHS, has waived the general requirements for informed consent at 45 CFR 46.116(a) and (b) and 46.408, to be referred to as the "Emergency Research Consent Waiver" for a class of research consisting of activities, each of which have met the following strictly limited conditions detailed under either (a) or (b) below:

• (a) Research subject to FDA regulations
  The IRB responsible for the review, approval, and continuing review of the research activity has approved both the activity and a waiver of informed consent and found and documented:
  

• (1) that the research activity is subject to regulations codified by the Food and Drug Administration (FDA) (see Federal Register, Vol. 61, pp. 51498-51531) at Title 21 CFR Part 50 and will be carried out under an FDA investigational new drug application (IND) or an FDA investigational device exemption (IDE), the application for which has clearly identified the protocols that would include subjects who are unable to consent, and
  

• (2) that the requirements for exception from informed consent for emergency research detailed in 21 CFR Section 50.24 have been met relative to those protocols, or
  

• (b) Research not subject to FDA regulations
  The IRB responsible for the review, approval, and continuing review of the research has approved both the research and a waiver of informed consent and has (i) found and documented that the research is not subject to regulations codified by the FDA at 21 CFR Part 50, and (ii) found and documented and reported to the OPRR that the following conditions have been met relative to the research:
  

• (1) The human subjects are in a life-threatening situation, available treatments are unproven or unsatisfactory, and the collection of valid scientific evidence, which may include evidence obtained through randomized placebo-controlled investigations, is necessary to determine the safety and effectiveness of particular interventions.
  

• (2) Obtaining informed consent is not feasible because:
  • (i) the subjects will not be able to give their informed consent as a result of their medical condition;
  • (ii) the intervention involved in the research must be administered before consent from the subjects' legally authorized representatives is feasible; and
  • (iii) there is no reasonable way to identify prospectively the individuals likely to become eligible for participation in the research.

• (3) Participation in the research holds out the prospect of direct benefit to the subjects because:
  • (i) subjects are facing a life-threatening situation that necessitates intervention;
  • (ii) appropriate animal and other preclinical studies have been conducted, and the information derived from those studies and related evidence support the potential for the intervention to provide a direct benefit to the individual subjects; and
  • (iii) risks associated with the research are reasonable in relation to what is known about the medical condition of the potential class of subjects, the risks and benefits of standard therapy, if any, and what is known about the risks and benefits of the proposed intervention or activity.

• (4) The research could not practicably be carried out without the waiver.
  

• (5) The proposed research protocol defines the length of the potential therapeutic window based on scientific evidence, and the investigator has committed to attempting to contact a legally authorized representative for each subject within that window of time and, if feasible, to asking the legally authorized representative contacted for consent within that window rather than proceeding without consent. The investigator will summarize efforts made to contact representatives and make this information available to the IRB at the time of continuing review.
  

• (6) The IRB has reviewed and approved informed consent procedures and an informed consent document in accord with Sections 46.116 and 46.117 of 45 CFR Part 46. These procedures and the informed consent document are to be used with subjects or their legally authorized representatives in situations where use of such procedures and documents is feasible. The IRB has reviewed and approved procedures and information to be used when providing an opportunity for a family member to object to a subject's participation in the research consistent with paragraph (b)(7)(v) of this waiver.
  

• (7) Additional protections of the rights and welfare of the subjects will be provided, including, at least:
  
  • (i) consultation (including, where appropriate, consultation carried out by the IRB) with representatives of the communities in which the research will be conducted and from which the subjects will be drawn;
  • (ii) public disclosure to the communities in which the research will be conducted and from which the subjects will be drawn, prior to initiation of the research, of plans for the research and its risks and expected benefits;
  • (iii) public disclosure of sufficient information following completion of the research to apprise the community and researchers of the study, including the demographic characteristics of the research population, and its results;
  • (iv) establishment of an independent data monitoring committee to exercise oversight of the research; and
  • (v) if obtaining informed consent is not feasible and a legally authorized representative is not reasonably available, the investigator has committed, if feasible, to attempting to contact within the therapeutic window the subject's family member who is not a legally authorized representative, and asking whether he or she objects to the subject's participation in the research. The investigator will summarize efforts made to contact family members and make this information available to the IRB at the time of continuing review.

In addition, the IRB is responsible for ensuring that procedures are in place to inform, at the earliest feasible opportunity, each subject, or if the subject remains incapacitated, a legally authorized representative of the subject, or if such a representative is not reasonably available, a family member, of the subject's inclusion in the research, the details of the research and other information contained in the informed consent document. The IRB shall also ensure that there is a procedure to inform the subject, or if the subject remains incapacitated, a legally authorized representative of the subject, or if such a representative is not reasonably available, a family member, that he or she may discontinue the subject's participation at any time without penalty or loss of benefits to which the subject is otherwise entitled. If a legally authorized representative or family member is told about the research and the subject's condition improves, the subject is also to be informed as soon as feasible. If a subject is entered into research with waived consent and the subject dies before a legally authorized representative or family member can be contacted, information about the research is to be provided to the subject's legally authorized representative or family member, if feasible.

For the purposes of this waiver "family member" means any one of the following legally competent persons: spouses; parents; children (including adopted children); brothers, sisters, and spouses of brothers and sisters; and any individual related by blood or affinity whose close association with the subject is the equivalent of a family relationship.

On October 2, 1996 (Federal Register, Vol. 61, pp. 51498-51531), the FDA published a final rule which amends FDA regulations to authorize a waiver of informed consent in research which is regulated by FDA. The joint publication of these actions permit harmonization of the HHS and FDA regulations regarding research in emergency circumstances. The HHS waiver, just as the FDA regulatory change, provides a narrow exception to the requirement for obtaining and documenting informed consent from each human subject or his or her legally authorized representative prior to initiation of research if the waiver of informed consent is approved by an IRB. The waiver authorization applies to a limited class of research activities involving human subjects who are in need of emergency medical intervention but who cannot give informed consent because of their life-threatening medical condition, and who do not have available a legally authorized person to represent them. The Secretary, HHS, is authorizing this waiver in response to growing concerns that current regulations, absent this waiver, are making high quality research in emergency circumstances difficult or impossible to carry out at a time when the need for such research is increasingly recognized.

Sincerely,

/s/	/s/
Gary B. Ellis, Ph.D. Director Office for Protection from Research Risks	Melody H. Lin, Ph.D. Deputy Director Office for Protection from Research Risks

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