Elsevier

Annals of Emergency Medicine

Volume 50, Issue 4, October 2007, Pages 448-455.e4
Annals of Emergency Medicine

Ethics/concepts
Implementing Emergency Research Requiring Exception From Informed Consent, Community Consultation, and Public Disclosure

https://doi.org/10.1016/j.annemergmed.2006.10.013Get rights and content

Conducting emergency research in the out-of-hospital and emergency department setting is a challenge because of the inability of patients to provide informed consent in many situations. Federal guidelines allowing research under an exception from informed consent for emergency research have been established (21 CRF 50.24). Community consultation and public disclosure, 2 required components of obtaining this exception, are seen by many as a barrier to resuscitation research. This article will provide a brief overview of the history of the exception from informed consent for emergency research and summarize our methods recently used to successfully complete community consultation and public disclosure for a trial evaluating 2 devices used during cardiopulmonary resuscitation in a large metropolitan area.

Introduction

Informed consent is the fundamental basis of research with human subjects. The Nuremberg Code begins with the statement that “Voluntary consent of the human subject is absolutely essential.”1 It is impossible to follow this standard when research is conducted in settings in which subjects are not able to provide informed consent, because of permanent mental disability or temporary impairment. To address this issue, the Declaration of Helsinki proposed that legal representatives be given the authority to consent for research subjects who are unable to provide their own consent.2

There are situations in which obtaining informed consent from the patient or a proxy is impossible. An exception from the general federal requirement of informed consent (21 CFR 50.23) was developed by the US Food and Drug Administration (FDA) in 1981. Before use of an unapproved device or drug on this subset of patients, the researcher must show that the subject is in a life-threatening situation, informed consent cannot be obtained, the therapeutic window is too short to obtain consent from a proxy decisionmaker, and no other equally efficacious therapy is available.3 An independent licensed physician must confirm the presence of all 4 of these criteria on an individual basis, and drug or device use must be reported to the institutional review board within 5 days. In 1983, the Department of Health and Human Services developed a waiver of consent process (45 CFR 46.116), in which patients can be enrolled in a study without their consent if the intervention is of minimal risk, there are no adverse effects with regard to patients’ rights, if the research cannot be practically carried out without the waiver, and when pertinent information is given to the patient when appropriate.4 A deferred consent process was also used by some investigators when the patient or the proxy was not able to provide prospective consent.5 If an attempt to locate the legal representative was unsuccessful, the patient was enrolled and consent was obtained afterwards. This form of consent was banned by the Office for the Protection of Research Risks in 1993 because of few existing safeguards for this vulnerable population.6

Large, randomized, prospective resuscitation research studies could not be conducted under those existing regulations. The Department of Health and Human Services waiver of consent relates only to research of minimal risk to the patient, which does not apply to new investigational devices. The FDA regulation applies specifically to one-time use of devices, precluding the opportunity to enroll large numbers of patients under this regulation. New, potentially lifesaving advances in resuscitation research were at a standstill until a federal rule (21 CRF 50.24) permitting an “exception from informed consent for emergency research” was published in 1996.7 This exception specifically applies to emergency research (1) for which an investigational new drug application or investigational device exemption is in effect; (2) involving human subjects who cannot give informed consent because of their emergent, life-threatening, medical condition (for which available treatments are unproven or satisfactory); and (3) when the intervention must be administered before informed consent from the subject’s legally authorized representative is feasible. Such studies may proceed only after a sponsor has received an investigational device exemption or investigational new drug application from the FDA and when the institutional review board has found and documented that specific conditions have been met (Figure 1).

Once it is determined that the study qualifies for an exception under 21 CFR 50.24, investigators must outline their plans to both the FDA and institutional review board for conducting community consultation and public disclosure before the start of the study, subsequently notifying all subjects of their involvement in the research and establishing an independent data safety and monitoring board to periodically review ongoing results. Community consultation is the process of actively engaging representative members of the community to provide feedback on the proposed trial before implementation. The purpose of this requirement is currently debated but has traditionally been seen as an attempt to assess the level of comfort the community has with the study and to address any concerns they may have. Public disclosure has traditionally referred to the efforts of researchers to notify and inform the public about the proposed project, which may be accomplished in a variety of ways: television, radio, or traditional print and online news media. The local institutional review board(s) must approve a suitable and comprehensive process for meeting these requirements, which may prove challenging because the FDA guidelines are general and the application of these guidelines is subject to interpretation. The complexity of this process has been suggested as a reason for an apparent decline of resuscitation research within the United States.8, 9

A review of the literature highlights the scarcity of US trials conducted under 21 CFR 50.24.10, 11, 12, 13, 14, 15, 16, 17 Even less is known about the processes by which these studies satisfied the federal requirements for community consultation and public disclosure. The only articles documenting the community consultation process described the use of open public meetings.13, 18 Attendance at these meetings varied greatly, with approximately 20 to 25 attendees at each session. Public disclosure methods have been documented in 3 studies and are shown in Figure 2.13, 18, 19 The local media appeared to be the most common medium for notifying the community about the study.18, 19

Investigators involved in these studies reported the community consultation and public disclosure requirements to be time consuming and expensive, and although the lack of regulation may be beneficial to some degree, it was a hindrance to achieving the goals of each requirement. Investigators documented problems about defining “community” as it related to their studies, the dynamic nature of community and methods for notifying those who move into the community after community consultation and public disclosure are complete, difficulty identifying potential research subjects with any degree of certainty, and difficulty notifying or consulting with potential study participants when the pool of potential research subjects extended across an entire state or region.

Because of the paucity of information in the literature about community consultation and public disclosure logistics, we thought it was important to summarize our recent successful experience and provide logistic information to the research community on the processes that may be required by individual institutional review boards. We recognize the extreme variability in study populations, institutional review board review of these studies, and time and financial constraints of investigators; therefore, the information presented is intended to serve as a template that future investigators can use and tailor to their individual communities.

The ResQ Trial is a multicenter, randomized, prospective clinical trial conducted under an exception from informed consent for emergency research, examining the safety and effectiveness of 2 investigational devices (ResQPump® and ResQPOD®, Advanced Circulatory Systems, Inc., Minneapolis, MN) used during cardiopulmonary resuscitation (CPR).20 Survival in 3 groups of patients are being compared: patients receiving standard (conventional) CPR, patients receiving active compression-decompression CPR (performed with the ResQPump®) with the use of an impedance threshold device (the ResQPOD®), and patients receiving standard CPR with the impedance threshold device alone. The primary endpoint is survival to discharge with good neurologic outcome.

Treatment for cardiac arrest must be initiated immediately, making the therapeutic window virtually nonexistent. All patients who meet the inclusion criteria are automatically enrolled by emergency medical services (EMS) personnel in the field. If present, a patient’s legal representative has the right to request that the devices not be used on their family member. In this situation, EMS personnel would remove any devices in use and perform standard CPR. In accordance with 21 CFR 50.24(a)(6), family members are approached for consent for continued participation in the study, with an institutional review board–approved consent form only if the patient survives to hospital admission. This is the first feasible opportunity for the research team to approach family members, notify them of their relative’s enrollment, and ask for informed consent for continued participation in the study. This continued participation includes permission to access the patient’s medical record for study-related information and to conduct postarrest neurologic evaluations at discharge, 30 days, 90 days, and 1 year. If initial consent is obtained from the patient’s family, the patient is asked to provide consent for continued participation if or when he or she is physically or mentally able to do so. If the patient does not survive to hospital admission, the family is notified by the research team of enrollment in the study either by certified letter or telephone, and contact information for the principal investigator and study coordinator is provided.

The geographic borders of the study were defined by the primary service area of the sole EMS agency enrolling patients. The primary service area encompasses 55 square miles, including a large urban metropolitan area, an adjacent suburb, and the state fairgrounds. Sex and racial demographics of the primary service area are shown in Table 1. To identify the characteristics of the typical cardiac arrest patient in this area, we performed an audit of the past several years of cardiac arrest data collected by our quality assurance coordinator. This audit showed an average of 140 out-of-hospital cardiac arrests per year and a patient profile of a black or white man between 50 and 60 years of age.

The demographics of the primary service area and the cardiac arrest patient characteristics were used to identify a “surrogate community.” A list of 136 organizations, representing men’s and women’s groups, the homeless community, various ethnic and religious groups, members of the medical community, senior citizens, and nursing homes, was compiled (Appendix E1, available online at http://www.annemergmed.com). These groups were contacted with details of the study and were invited to the community consultation meetings (Appendix E2, available online at http://www.annemergmed.com).

The media relations department at our institution sent a press release to 4 metro-area television stations, 4 talk radio stations, the 2 large metropolitan newspapers, and a large number of the community newspapers within the primary service area. This press release included general information about the study, the anticipated start date of the study, and the date and times for the community consultation meetings (Appendix E3, available online at http://www.annemergmed.com). The principal investigator was interviewed by 3 of the 4 television stations, 2 of the 4 radio stations, 1 of the large metro newspapers, and 1 of the community newspapers. All of the interviews were either aired on television or radio or published in print newspaper articles. The newspaper article published by the metropolitan newspaper was distributed to the Associated Press Wire Service and was reprinted in several newspapers across the nation, including the online version of The Washington Post. All of these interviews were free publicity that required a minimal amount of coordination from the principal investigator and the media relations staff.

In addition to these efforts, paid public notices were placed in 10 newspapers: the 2 large metro newspapers and 8 community newspapers (Appendix E4, available online at http://www.annemergmed.com). These newspapers were chosen according to their projected coverage area of the primary service area, average demographic readership numbers, and cost. The total cost of these notices was approximately $1,700. The principal investigator also gave 2 presentations to the city council and county board of commissioners. These presentations served 2 primary purposes: to make public officials aware that the study was going to be conducted with their constituents and to notify the public of the study and upcoming community consultation meetings through the live broadcasts and rebroadcasts of the meetings on public access television free of charge. The free publicity reached an estimated 3,000 viewers per broadcast.

An additional complementary method of public disclosure involved the use of internal publications at our institution. The weekly online newsletter, distributed to approximately 9,000 employees, included information about the study and an invitation to attend the community consultation meetings. A final public disclosure tool involved the broadcast of 75 30-second public service announcements aired on 5 cable stations in the metro area (available online at http://www.advancedcirculatory.com/Video/ResQ.wmv). The 5 stations (HGTV, Fox News Channel, CNN, Lifetime, and AMC) were chosen to match the demographics of potential study subjects. Members of the EMS agency enrolling patients were filmed in a mock scenario showing the use of the study devices, with a voiceover describing when the devices would be used. Contact information for the study coordinator was also included for viewers who had additional questions about the project. The cost for producing, editing, and airing these announcements was $2,450.

Our institutional review board believes community consultation necessitates face-to-face interaction between community members and the research team. Using the primary service area demographic information, invitation letters were sent to 136 community organizations approximately 3 weeks before the date of the meetings. Addresses and telephone numbers for these organizations were obtained from Web sites and the local telephone book. The invitation letters were mailed with a reply card, requesting a response regardless of intent to attend one of the meetings (Appendix E2, available online at http://www.annemergmed.com). If no response was received 1 week before the meeting, a telephone call was placed to each organization’s contact person, and when e-mail was available, a reminder was also sent. The invitation to the general public was provided in conjunction with the television, radio, and print public notices.

Two town-hall-style public meetings were held on a single day, one in the morning and one in the evening. A total of 84 people attended the 2 meetings (Table 2). Attendees representing community organizations, EMS and public health agencies, and the IRBs reviewing the study were asked to sign in and were given an information packet containing the PowerPoint presentation slides and a questionnaire. The questionnaire requested demographic information from the attendee, as well as an evaluation of their understanding of the study, the format of the presentation, and the question-and-answer session. The meeting consisted of a brief introduction and a scripted PowerPoint presentation, followed by an open question-and-answer session led by the principal investigator. Each session lasted approximately 90 minutes, and both sessions were videotaped for documentation. The presentation content focused on the meaning of the exception from informed consent for emergency research and information about the study protocol. It also included a videotaped demonstration of the 2 investigational devices being used by EMS personnel. All the material presented had been approved by the institutional review board. To confirm understanding of the study and the exception from informed consent, the principal investigator requested a show of hands for those who felt comfortable with the study enrollment process, and 100% of attendees indicated that they were comfortable. The results of the questionnaire also showed that 98% of the attendees agreed or strongly agreed that they understood the purpose of the study (Table 3).

Using the viewership and readership numbers supplied by the various media outlets, as well as the numbers from direct contact that we were able to track, we estimate that a potential 3 million people nationwide and 1.9 million people in the metropolitan study area were informed of this study in some form. After a final review of all community consultation and public disclosure processes, the institutional review board gave final approval for study commencement and enrollment began in October 2005.

There is no cookbook method for gaining institutional review board approval for a study conducted under 21 CFR 50.24. The following are some general suggestions that we believe can be helpful to investigators required to conduct community consultation and public disclosure:

  • 1

    Identify the Appropriate Staff Members to Coordinate the Process

    • The best way to accomplish the necessary tasks in a timely fashion is to identify and assign specific people to the various tasks that must be accomplished. A study coordinator or research associate can be invaluable as a point person for coordination and organization.

  • 2

    Carefully Identify Your Study’s Target Population

    • Determine the demographics and geographic boundaries of the potential research subjects and target marketing efforts at these people. Make sure this information is accurate and quantitative if possible (quality assurance data, census information).

  • 3

    Work Closely With the Institutional Review Board(s) That Will Be Reviewing the Project

    • Community consultation and public disclosure and the initial and final institutional review board reviews are time consuming. All institutional review boards must review and approve all press releases, flyers, and other material before release to outside agencies. Establish and maintain frequent contact with administrative personnel in the institutional review board offices throughout the review process. These people can be valuable liaisons between researchers and institutional review board members. If they are fully informed of your intentions and understand your plans, they can expedite matters greatly.

  • 4

    Familiarize Yourself With the Requirements of 21 CFR 50.24

    • Variability will exist in interpretation of the requirements, but if you understand them well, you will be able to discuss issues with the institutional review board constructively.

  • 5

    Plan Your Meeting Location With Several Factors in Mind

    • If you are holding an open public meeting, find a central location for your study population that is accessible to public transportation and has adequate and free parking. Make sure there are no large events held in the same area on the same date that may affect turnout. For every 100 people directly invited, approximately 10 will show up. It may be appropriate to plan 2 meetings on the same day or 1 meeting on several days. Use multiple methods of communication for inviting the general public and community organizations because written invitations may not be enough.

  • 6

    Do Not Reinvent the Wheel

    • Although the process may be new to you, it is fundamentally a combination of public relations and event planning. Use public relations personnel to send out press releases and schedule interviews. If you are working with another agency (police, fire, ambulance), involve their public relations personnel as well. These agencies often have tremendous influence with local news organizations, which can be very helpful in getting the message to the general public. Use multiple avenues to disseminate information according to the target population. Take advantage of people at your institution who plan events regularly to provide information about catering and venues that would suit your needs.

  • 7

    Community Consultation and Public Disclosure Do Not Have to Break the Bank

    • If your institution is in a central location for the study population, schedule the meeting(s) there and use the existing conference space for free. Contact the local public access cable company about advertising the study free and see if they would be willing to record and rebroadcast your community consultation meeting. Contact city and county officials and give a brief presentation about the study. Request permission to place a study summary and an invitation to the community consultation meeting in community organization newsletters. Online postings are an inexpensive way to advertise, but consider the study population when doing so. The elderly, for example, may be less likely to have a computer and online access. Finally, many neighborhood organizations have a monthly online calendar in which events can be posted free. The direct cost to conduct community consultation and public disclosure was approximately $5,000, although the $2,450 spent on public service announcements was more than our institutional review board required. Salary support for study personnel was not included in the cost estimate.

  • 8

    Take Your Show on the Road

    • Realize that you do not have much control over who will attend your meetings. To increase awareness of a project, it may be more appropriate to physically bring the information to key groups. Presenting at a standing monthly meeting is a great alternative to inviting groups to an open meeting that may conflict with work or personal time.

Section snippets

Discussion

There are inherent bioethical and logistic problems surrounding community consultation and public disclosure. Specifically, defining the term “community” and identifying the goals of community consultation and public disclosure are areas of debate within the research community. Because the purpose of these requirements continues to be debated without much consensus, we believe that it is important to establish the goals of community consultation and public disclosure and the tools to evaluate

Conclusion

Understanding the key elements of community consultation and public notification and collaborating with the institutional review board will aid investigators in completing the requirements under 21 CFR 50.24. Although challenges exist, demonstrating due diligence on the part of the investigator can result in a successful process. Obtaining an exception from informed consent requires patience and cooperation between the investigators and the institutional review board. Focusing efforts on

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Supervising editor: Keith T. Ghezzi, MD

Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article, that may create any potential conflict of interest. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement. Supported by grant 2-R44-HL65851-03, National Institutes of Health, Heart, Lung and Blood Institute, HealthPartners Research Foundation Internal grant 04-032, Metropolitan 911 Board grant, Guidant Foundation grant, and Local 21 grant.

Publication dates: Available online January 12, 2007.

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