by Reshma Jagasia, Ph.D., Scientist
by Nicole Tackmann, Ph.D., Clinical Strategy Intern
All clinical investigations conducted in the United States are subject to informed consent regulations under federal law (21 CFR Part 50 Subpart B). These regulations define the responsibilities of a clinical investigator to describe to a patient, or to his or her legally authorized representative (LAR), the details of an experimental treatment, including its potential risks and benefits, such that the patient or LAR may make an informed decision as to the patient’s participation in the study.
Under certain circumstances, subjects may not be able to provide consent for an investigational intervention. This inability to consent may arise from the nature of the illness or injury, such as a comatose disease state, or from the need for prompt medical intervention, precluding the time needed in which to inform and obtain consent. Most often, such patients have a life-threatening medical condition that necessitates urgent intervention. For clinical research in which (1) the investigational treatment has the prospect of direct benefit to the patient, (2) the investigational treatment needs to be administered quickly, before informed consent can be obtained, and (3) the prospective identification of individuals eligible for participation is not feasible, FDA recognizes a need for an exception from informed consent (EFIC). The laws governing EFIC are codified in 21 CFR 50.24 and are designed specifically to protect this most vulnerable population of study subjects.
EFIC procedures are not a means for clinical investigators to circumvent the need to inform and to obtain consent from a potential subject or LAR. On the contrary, EFIC procedures define the extra care and efforts that must be expended by the sponsor, clinical investigators, and Institutional Review Boards (IRBs) to protect patients who cannot consent at the time of treatment. Achieving the requirements of EFIC demands significant time, resources, and a concerted effort. The requirements for EFIC can be divided into three categories: investigational plan and consent, community consultation, and public disclosure.
Investigational Plan and Consent
Investigational plans that rely on EFIC must include justification for conducting the study in subjects who cannot consent. Justification for why the investigational intervention may be better than the available standard-of-care treatment must also be presented. These justifications should be specifically stated in the clinical study protocol.
Clinical investigators must also commit to try to contact a subject’s LAR or family member to obtain informed consent within the defined therapeutic window. This therapeutic window, which should be defined in the study protocol, is the time between onset of the event and the administration of the investigational intervention. FDA does not expect attempts to contact a LAR or family member to exhaust the entire therapeutic window. In fact, FDA recognizes that the therapeutic window for emergency research may be very brief or even non-existent.
Subjects in emergency research often do not have a designated LAR. In such cases, a LAR would need to be identified by the clinical investigator. LAR identification laws vary by state; for example, some states clearly define the hierarchy of individuals who may serve as a LAR while others do not address LAR identification at all. In the case of the latter, the IRB should define the hierarchy of who can serve as a LAR, the procedures for contacting a LAR or family member, how much time in the therapeutic window should be dedicated to these procedures, and what to do if two LARs disagree on consent. Attorneys should also review all study plans regarding the contact of LARs.
In the case that a LAR or family member cannot be reached to provide informed consent, the clinical investigator may enroll the patient under emergency research protocols. This emergency enrollment is the “exception” conferred by EFIC procedures. If at any time during the course of the study the subject becomes capable of consent (i.e., the subject is no longer comatose and is of sound mind), informed consent must be sought from the subject for continued participation in the study whether or not informed consent was obtained earlier from a family member or LAR.
The law also requires that any clinical investigation invoking EFIC be overseen by an independent data monitoring committee.
Because there is no reasonable, prospective manner in which to identify individuals likely to become eligible for participation in an emergency research investigation, sponsors and clinical investigators are required to reach out to communities-at-large from which potential subjects would be drawn to conduct community consultations. “Community” is the geographical area (i.e. city, region) that a clinical site services, but efforts can and should be made to target those members of the community that fit the demographics of the potential patient population. Community consultations should also include community leaders and representatives such as elected officials, local community activists, clergy, school officials, and other interested individuals.
During community consultations, members of the community assemble, and clinical instigators provide information about the proposed clinical trial to be conducted in the community, potential risks and benefits to prospective subjects, and methods, if any, as to how an individual may indicate his/her preference to be excluded from participation. Most significantly, community consultations are a two-way communication, and investigators are required to elicit feedback from the community about the proposed clinical trial.
Information offered in a community consultation should include:
- Summary of protocol, study design, and description of procedures to be followed, including the identification of any experimental procedures
- Summary of other available treatment options and their risks and benefits
- Estimated study duration and individual patient enrollment duration
- How potential study subjects will be identified
- Information about the study product, including risks, expected benefits, and potential adverse events
- Clear statement that informed consent will not be obtained for most subjects
- The rationale for the need of an exception from informed consent, and copies of the informed consent forms
- Description of the therapeutic window, and the portion of that window that will be used to contact the subject’s LAR or family member
All plans and materials (posters, presentations, pamphlets, etc.) employed to conduct community consultations must be reviewed by the IRB before community consultations can begin. The IRB will also review the feedback received from the community, which may lead to revisions of the study protocol and supporting documents. The IRB will determine the required amount of community consultation based on the unique circumstances of the study and the community. Typically, the less that is known about the safety and efficacy of an intervention, the greater the amount of community consultation that is required.
While community consultation is a two-way form a communication, public disclosure is a one-way transfer of information from the clinical investigator to the public. After community consultation and IRB approval of the study protocol, the investigator must publicly disclose the study before enrollment can begin. Information in public disclosures contain the same information provided in community consultations as well as identification of the sites or institutions that will be participating in the study. Public disclosure is designed to encourage public knowledge about the study.
At the completion of the clinical investigation, the results of the study must be publically disclosed to both the scientific community and the communities in which the study was conducted as part of the EFIC requirements. Reporting results on ClinicalTrials.gov alone is not sufficient to meet these disclosure requirements. Disclosure can be in the form of public service announcements, targeted mailers, press conferences, and information and links on a sponsor and clinic websites.
For more information on the EFIC process, please consult the FDA’s Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors: Exception from Informed Consent Requirements for Emergency Research (March 2011, Updated April 2013). For more information on LARs, see: “Legally Authorized Representatives in Clinical Trials” Katzen J. J Clin Res Best Pract. 2011; 7(3):1-5.