The authors have declared that no competing interests exist.
Conducting research in an emergency situation, such as an outbreak of disease, poses ethical challenges. These challenges differ according to the type of research: epidemiologic or clinical, and for the latter, whether the disease outbreak can be anticipated in advance. We address these three situations, proposing different potential solutions for each.
In an outbreak situation, public health authorities undertake a rapid response in an effort to document the existence and magnitude of a public health problem in the community and to implement appropriate measures to address the problem
For researchers and public health agencies, therefore, the question is how to comply with the ethical requirement that research be approved by a properly constituted, independent ethical review committee (ERC) but still enable a prompt response when an outbreak occurs. If we concede that existing methods of ethical review are too protracted to be useful in outbreak situations, can alternative mechanisms be employed to ensure that such investigations undergo some type of ethical review? How can the rights and welfare of individuals be protected during investigations of disease outbreaks, and at the same time enable such investigations to be carried out expeditiously?
In addition to review by a research ethics committee, a fundamental ethical requirement in research is to obtain informed consent from participants. Although not all research requires the informed consent of individual subjects, the vast majority of clinical research, most social and behavioral research, and some epidemiologic research must be carried out with the voluntary, informed consent of participants or their legally authorized representatives. In contrast, in many instances of public health practice, collection and use of information or human biological specimens can be conducted without a written informed consent document and without obtaining permission to store the samples for future use. However, a problem could arise if an investigator wants to use these samples, collected initially for public health purposes, for research. Current research practice calls for obtaining consent for the use of specimens in future research that may not be known at the time they are collected. Samples obtained in a non-research context without such provisions may require going back to get consent from sampled individuals, which could be logistically difficult, if not impossible. For example, samples with no identifying information could not be traced back to the individuals from whom they were obtained. Additionally, if a considerable time has elapsed between the collection of identifiable samples and the plan to use them in research, it could be difficult to locate the individuals. If researchers intend to use previously collected samples without going back to get consent, they must provide a justification in the protocol submitted to the research ethics committee.
It is hard to see, even in non-research contexts, how human biological specimens could be obtained or even how individuals could be surveyed without first obtaining their permission to draw blood or to ask questions that may intrude on their privacy. Nevertheless, procedures for obtaining consent from individuals in an outbreak situation could depart from those typically used in other investigations and still be ethically acceptable. It is surely not necessary to include all 26 items listed as “essential information for prospective research subjects” in the CIOMS
It might be thought that the problems related to obtaining consent from people in an outbreak situation could be overcome by an appeal to the clause in the US Code of Federal Regulations that permits a waiver of informed consent for research conducted in an emergency, the so-called final rules
In addition, nothing in the Food and Drug Administration (FDA) final rules exempts the research from review by an IRB or ERC. On the contrary, the IRB review and logistical requirements needed for approval of studies under the final rules have been described as so burdensome that they may be impeding much needed resuscitation research
Another requirement in the FDA rules is community consultation before the research can be initiated. A plan for such consultation must be included in the protocol submitted to the IRB. Clearly, in the case of most outbreaks, affected communities probably cannot be identified in advance, precluding the very possibility of conducting such research. For all these reasons, the FDA emergency rules are inapplicable to research conducted in disease outbreaks.
What solutions are available to ensure that public health research in disease outbreaks can proceed without undue delays and yet protect the rights and welfare of human beings who are surveyed, whose blood is drawn, or who receive experimental or off-label drugs? It might be argued that approval of a proposed investigation by a Ministry of Health can serve this purpose. However, approval by a Ministry of Health is not the equivalent of ethical review and clearance by a duly constituted committee. Both types of approval are necessary in research in non-emergency situations, but a governmental office is not equipped to do the same sort of review as a committee with expertise and experience in research ethics.
An appropriate solution would be to seek an alternative mechanism to that of full review of a complete research protocol by an IRB or ERC. Different strategies would be appropriate for epidemiologic research, on the one hand, and clinical trials, on the other.
The methodology used in epidemiology can be the same whether an activity is characterized as research or public health practice. In regard to research, a well-established procedure for ethics review already exists that would apply to almost all epidemiologic research conducted in a disease outbreak. That mechanism is expedited review by an ERC. Such investigations pose no more than minimal risk, as the most invasive procedures involving human beings are likely to be blood drawing and survey completion. Expedited review is typically conducted by committee chairs or someone they designate, and can be accomplished within a day or two. Committees could establish a policy for disease outbreak investigations in which a full, detailed protocol need not be submitted. A shorter document describing the background, the purpose of the research, informed consent procedures, and steps to protect the confidentiality of information obtained from the individuals should be acceptable in such a policy. As for the need to obtain informed consent from participants, in epidemiologic research, the requirements for informed consent typically are guided by whether identifiable information is collected and how it is collected. A duly constituted oversight body could decide to waive the requirement for signed consent forms in favor of oral consent depending on the specifics of a research proposal.
Research involving experimental medications or new uses for approved drugs is considered more than minimal risk, and therefore cannot be reviewed by the expedited mechanism. Two situations call for somewhat different solutions. The first situation is that of repeat occurrences of an outbreak of a known disease, such as cholera
The second situation, somewhat more problematic, is an outbreak of a disease heretofore unknown. Probably the best recent example is that of severe acute respiratory syndrome (SARS)
The SARS epidemic highlights the major difficulties in conducting clinical research in disease outbreaks involving novel disease-causing agents. Unlike a disease like cholera, where an outbreak and a population can be predicted with some certainty, SARS occurred in a population that was impossible to pre-identify. Furthermore, the causative agent of SARS was initially unknown, and no existing approved treatment protocols were in place. Despite the logistical and methodological difficulty of conducting clinical trials in outbreaks of new diseases, it is precisely these situations where clinical studies are most needed. Unfortunately, the use of “model protocols” to enable the more rapid IRB or ERC review described above may not be sufficient for outbreaks of new diseases. However, in the case of pandemic influenza, a model protocol could still be developed even though the particular strain of the virus may not be known in advance. Existing antiviral medications could be used in initial studies until new preventive vaccines or therapeutic medications can be manufactured and used in subsequent clinical trials.
The most urgent concern at the time of an outbreak of any disease is to implement public health measures to contain its spread. What those measures should be, and to what extent they may involve limitations on individual liberty and other social distancing mechanisms, pose different ethical challenges. We have described a mechanism whereby epidemiologic research can commence immediately, under the conditions of expedited review outlined above. In the meantime, investigators will have to develop clinical research protocols to address a previously unknown disease and seek IRB approval in the usual manner or through the use of “model protocols.”
Some form of ethical oversight is needed to conduct an investigation of a disease outbreak, be it predictable or unanticipated. The mechanism and procedures can vary from that of an established ERC, acting in an expedited manner for minimal risk research, to development of a model protocol submitted to a committee for full review in advance of an anticipated future outbreak. Such safeguards can help to ensure that the rights and welfare of individuals are protected in disease outbreaks and that communities maintain trust in public health research and practice.