Conducting research using the emergency exception from informed consent: the Public Access Defibrillation (PAD) Trial experience

Abstract

Background: The Public Access Defibrillation (PAD) Trial, a prospective, multicenter, randomized clinical trial comparing two prehospital resuscitation strategies, was conducted under the regulations for exception from informed consent (21CFR50.24) in 24 communities in North America. These regulations place additional requirements for human subject protection on investigators and Institutional Review Boards (IRBs), including conducting community consultation (CC) and public disclosure (PD). Objective: To describe the IRB approval process at study sites and the number and types of community consultation and public disclosure activities conducted. Methods: The 24 study sites in the United States and Canada submitted IRB applications, CC and PD plans, and a structured report on IRB process and investigator perceptions to the Clinical Trial Center at the University of Washington. Results: The primary IRBs for all 24 trial sites and a total of 101 IRBs approved the study. The median interval from submission to approval was 108 days (IQR 43–196), and the mean number of revisions was two (range 0–7). Investigators conducted nearly 12,000 activities to achieve CC and PD; activities varied greatly from site to site in both type and quantity. Conclusion: The length of time to obtain IRB approval and the extent of community consultation and public disclosure varied greatly among trial sites in meeting the current regulations for conducting emergency research with exception from informed consent. This suggests that more specific guidance may be useful and that determination of effective strategies for community consultation and public disclosure is needed.

Sumàrio

Contexto: O ensaio relativo ao acesso do público à desfibrilhação de (PAD), multicêntrico, aleatorizado comparando duas estratégias de reanimação pré-hospitalar, está a ser feito ao abrigo das regras para isenção de consentimento informado (21CFR50.24) em 24 comunidades na América do Norte. Estas regras colocam exigências adicionais aos investigadores e aos Comités Institucionais de Revisão (IRBs) para protecção de pessoas e incluem consultas à comunidade (CC) e informação ao público (PD). Objectivo: Descrever os processos de aprovação dos IRBs nos locais de estudo e o número e tipo de consultas à comunidade e actividades de informação pública dos locais de estudo que foram efectuadas. Métodos: Os 24 locais nos Estados Unidos e Canadá submeteram pedidos ao IRB e planos de CC e PD e apresentaram um relatório estruturado do processo nos IRB e da percepção dos investigadores ao Clinical Trial Center na Universidade de Washington. Resultados: Aprovaram IRBs primários para os 24 locais e um total de 101 IRBs. O tempo médio de apresentação até á aprovação foi de 108 dias (IQR 43–196) e o número médio de revisões foi dois (intervalo de 0–7). Os investigadores realizaram quase 12 000 actividades para conseguir CC e PD; as actividades variaram muito de local para local quer em tipo quer em quantidade. Conclusão: O intervalo de tempo para obter aprovação do IRB e a extensão das consultas à comunidade e informação pública variaram muito entre os locais de estudo para assegurar os regulamentos actuais para condução de pesquisa em emergência com isenção de consentimento informado. Isto sugere que pode ser útil orientação mais especı́fica e que é necessário a determinação de estratégias eficazes para consulta à comunidade e informação pública.

Resumen

Antecedentes: El estudio de desfibrilación de acceso público(PAD), un estudio clı́nico prospectivo multicéntrico randomizado que compara dos estrategias de resucitación, está siendo conducido bajo regulaciones para excepción de consentimiento informado (21CFR50.24) en 24 comunidades en Norte América. Estas regulaciones ponen regulaciones adicionales para protección de sujetos humanos en investigadores y comités de revisión de investigadores (IRBs), incluyendo conducir consultas a la comunidad (CC) y difusión pública (PD). Objetivo: Describir el proceso de aprobación IRB en los sitios de estudio, y el número y tipo de consultas realizadas y actividades de difusión pública conducidas en los sitios de estudio. Métodos: Los 24 sitios de estudio en los Estados Unidos y Canadá enviaron aplicaciones a IRB, planes de CC y PD, y un reporte estructurado sobre el proceso de IRB y las percepciones de los investigadores al Centro de Estudios Clı́nicos en la Universidad de Washington. Resultados: Los IRBs primarios para todos los 24 sitios de estudio y un total de 101 IRBs aprobaron el estudio. La mediana del intervalo desde el envı́o hasta la aprobación fue 108 dı́as (IQR 43–196), y el número promedio de revisiones fue de 2 (rango 0–7). Los investigadores condujeron casi 12000 actividades para conseguir CC y PD; las actividades variaron ampliamente entre un sitio y otro tanto en tipo como en calidad. Conclusión: El tiempo para obtener la aprobación de IRB y la extensión de consulta a la comunidad y difusión comunitaria varió ampliamente entre los sitios de estudio al tratar de cumplir los regulaciones para conducir investigación de emergencia con excepción del consentimiento informado. Esto sugiere que puede ser útil guı́a mas especı́fica y es necesaria la determinación de estrategias efectivas para consultas a la comunidad y difusión pública.

Introduction

The ethical principles for human research are embodied in the Nuremburg Code [1], [2] and the Helsinki Declaration [3]; in the United States these are formalized in the Code of Federal Regulations (CFR) [4]. The primary principles of autonomy, beneficence, and justice are upheld through the rigorous implementation of informed consent. As stated in the Belmont Report, the ethical conduct of research requires that “… subjects, to the degree that they are able, be given the opportunity to choose what shall or shall not happen to them” [5]. No method of protecting the research subject’s rights is equal to obtaining prospective consent from the informed individual [6], [7]. However, it has long been recognized that research can be conducted ethically without informed consent in some situations [8]. The Declaration of Helsinki discussed conditions for both proxy and waiver of consent [3].

The emergency medical setting warrants consideration for modification of the individual informed consent standard. A person with a medical emergency may not have the capacity to provide informed consent due to physical, psychological or emotional duress [9]. Yet, such individuals are among those most in need of effective treatment [9], [10], [11]. Healthcare providers have an ethical obligation to determine the most effective therapy through carefully conducted research while maintaining individual rights [8].

In 1993, the United States Food and Drug Administration (FDA) issued a memorandum placing a moratorium on all research without prospective informed consent (except for research with minimal risk) [8]. This remained in effect until 1996, when the FDA and the Department of Health and Human Services (DHHS) published regulations (21CFR50.24) enabling the conduct of emergency research with exception from informed consent (Fig. 1) [4], [12], [13], [14]. Despite these regulations, there is a growing concern that little emergency research is being performed in the United States when circumstances preclude prospective informed consent [15]. Some researchers believe that the regulations are unnecessarily burdensome and that Institutional Review Boards (IRBs) may be uncertain about how to interpret them [1], [6]. These concerns are heightened by recent incidents that have generated intense governmental and public scrutiny of the research process [17], even though none of these incidents have specifically involved exception from informed consent.

The Public Access Defibrillation (PAD) Trial was an international, multi-center, randomized controlled study of two strategies for the initial care of patients with out-of-hospital sudden cardiac arrest (OOH-CA) [18]. The control strategy consisted of training on-site, non-medical, lay volunteer responders to call 9-1-1 and perform basic cardiopulmonary resuscitation (CPR), while the intervention strategy added training and on-site deployment of automated external defibrillators (AEDs). The primary outcome measure was the number of survivors of OOH-CA. This trial involved two sets of subjects. The first are the volunteer layperson responders who received CPR or CPR/AED training; prospective, written informed consent was obtained from these subjects. The second set of subjects was comprised of persons who suffer a suspected OOH-CA at study locations. These subjects, who were unresponsive and suspected to be in cardiac arrest, were incapable of providing consent at the time of enrollment, and the interventions being evaluated must be applied immediately to be effective, thus prohibiting any delay to obtain proxy consent. The PAD Trial Investigators identified two potential mechanisms for addressing the issue of informed consent from this second set of subjects. The study could be considered “minimal risk,” requiring IRB approval but obviating the need for patient subject consent (45CFR46), or it could be conducted under the regulations for exception from informed consent for emergency research (21CFR50.24).

Discussions were held among investigators, the Clinical Trial Center (CTC) at the University of Washington, the FDA, the National Heart, Lung, and Blood Institute (NHLBI), the primary sponsor, and the American Heart Association (AHA), an additional sponsor. Specifically considered was whether “minimal risk” refers to the probability and magnitude of harm normally encountered in patients with the respective disease or condition (i.e., a relative standard) or to that encountered in the daily life of a member of the general public (i.e., an absolute standard). CPR performed by laypersons is a currently accepted treatment for OOH-CA, and the use of the AED fell within FDA approved indications. Thus, the trial presented no significant additional risk than what would typically be encountered by victims of OOH-CA. The FDA held that the absolute standard should apply, and subsequently most parties to the discussion agreed. Thus, the PAD Trial had to precede under the exception for emergency research regulations (21CFR50.24). An IDE was obtained for the trial, but subsequently the FDA advised the CTC that it was not required since all devices used in the trial had received FDA clearance.

This paper describes the experiences of the PAD Trial Investigators in obtaining IRB approval to conduct research using the exception from informed consent regulation and the number and types of community consultation (CC) and public disclosure (PD) activities study sites reported to the CTC.