An emergency can mean different things depending on the context and people’s perception, but for the use of investigational products, it can mean life or death. The U.S. Food and Drug Administration (FDA) regulations have two defined pathways for emergency research: the use of an investigational product for one person in an emergency in accordance with 21 CFR 50.23 (hereafter 50.23 studies) and research on an investigational product in emergency situations accordance with 21 CFR 50.24 (hereafter 50.24 studies).
Studies conducted under both 50.23 and 50.24 can be controversial and due to the nature of the study there may be increased regulatory risk. One of the controversial aspects of both pathways is that they allow for a waiver of consent. The Institutional Review Board (IRB) must carefully balance the need to advance critical clinical research in traumatic and emergent care settings with the need to maintain the autonomy of choice for the patient, especially in light of past abuses and missteps in medical research.
Obtaining Consent
Informed consent remains the bedrock principle upon which almost all clinical trials are built. Through the informed consent process, an individual, or their legally authorized representative (LAR), can decide if they want to participate in the research. In some cases, there may be other alternatives they wish to pursue, or the individual does not want any additional treatment, or the individual has questions they need answered before agreeing to participate.
In an emergency situation, time is limited and it may not be feasible to obtain consent from the individual or the LAR prior to when treatment needs to be provided. In some cases, the individual will either be unconscious or of limited mental capacity at the time treatment is required, and delaying treatment while attempts are made to contact someone legally authorized to provide consent on the individual’s behalf could have deadly consequences. The ethical challenge is then balancing treating an individual with an investigational product in a life-threatening situation and ensuring they have the autonomy to decide if they want to participate in research.
Special Considerations Under 50.23 – Emergency Use
Under the current system, the IRB is tasked with trying to strike an appropriate balance and ensure the rights and welfare of the participant are protected. However, treating an individual patient using an investigational product under 50.23 may occur without prior IRB review. If a provider believes there is no alternative option that presents equal or greater likelihood of saving the individual’s life, the provider can use the investigational product. If there is sufficient time, the provider must obtain confirmation from another physician, independent of the research, that the use of the investigational product is appropriate. If there is not sufficient time to get confirmation from a second physician, then the only person involved in the decision is the provider. Even if there is a second physician involved, due to the shortage of time, there may not be much time to review the medical records and determine if there are equally effective alternatives or if this is truly the best and only option for the individual.
The underlying issue involving consent is that the individual did not freely consent. In this situation, the issue can be framed as would the individual, or their LAR, have consented, if they could. Most of the time we can assume the patient or their LAR would agree to receive the investigational product if they could because it may be the only option to save their life. For example, if the individual is having a heart attack due to a blocked coronary artery and the only available stent that can be used with this individual is investigational, but it is fairly similar to approved stents. It is reasonable to assume that the individual would not have any concerns with using the investigational stent.
In contrast, some people may have strong personal beliefs and would not choose to receive an investigational product if given the opportunity. However, if there are no other options to save the individual’s life they may be given the investigational product regardless of what they would want.
Regulatory Issues
Providers are required to notify the IRB within five working days of the justification for using an investigational product along with confirmation by a second physician. WCG’s process is that if the IRB agrees that the use of an investigational product was appropriate for a particular individual, then the IRB simply acknowledges the use. However, the IRB may, in rare circumstances, see the situation differently. If the IRB has significant issues with the use meeting the regulatory requirements under 50.23, they could determine the provider to be in Serious Non-Compliance and report the issue to the regulatory agencies . This action could lead to an inspection by the FDA and/or Office for Human Research Protections (OHRP), which could then result in further observations of non-compliance or a Warning Letter.
Special Considerations Under 50.24 – Research in Emergency Situations
For research that requires the study of products used in emergency situations, under 50.24, the normal Investigational New Drug (IND) and Investigational Device Exemption (IDE) requirements still apply, with specific additional steps in place to safeguard participants. These additional steps include community consultation, public disclosure, data monitoring committee (DMC) oversight, and a commitment by the investigator to attempt to contact a family member who is not a legally authorized representative.
Community Consultation and Public Disclosure
In lieu of obtaining consent from each participant, the regulations provide for an exception to informed consent, when the community is aware of the emergency research and agrees the study can be done in that community. Community consultation, as interpreted by the FDA, is meant to be a two-way communication between the research team and a wide group of community representatives. This ensures that the community or communities in which this emergency research is being conducted has an opportunity to be informed about the research, its potential risks and benefits, and that community members are given an opportunity to ask questions and provide feedback.
Public disclosure means disclosure of the study and any trial results to the community and the research team by the sponsor. This is meant to be a one-way dissemination of information by the sponsor and occurs prior to the start of the research, after completion of the research, and at any time the IRB determines there is something necessary to disclose.
In both community consultation and public disclosure, the disseminated information must include information about the clinical trial including its risks and any expected benefits, a summary of the protocol and trial design, how to opt out of participation, and who to contact for any additional questions or information. These can be conducted via radio announcements, television ads, random telephone surveys, public meetings, and focus groups, among others.
The IRB must review the plans for both community consultation and public disclosure prior to the implementation of either. If any concerns or objections were raised during a community consultation session, those objections and concerns should be considered by the IRB when deciding whether to approve or modify an emergency research clinical trial. The IRB may decide to invite members of the community to a meeting, add board members who are members of the community, use community members as consultants, request additional community consultations by the investigator and sponsor, or conduct community consultations on its own, if the board decides additional information is necessary.
Knowledge of the community make up, including religious and cultural groups, socioeconomic factors, racial composition, whether it is urban or rural community, and understanding the beliefs and practices of the population with respect to medical care are critical in determining the means of outreach and who may attend the public meetings. As such the community consultation plans could vary widely from one community to another, even in similar geographic areas.
Possible pitfalls in community consultation relate to the diversity of audience and method of information dissemination. Researchers and IRB members alike must remain aware of the makeup of the people who attend the community consultations, the population of the community where the research takes place as a whole, and the methods of communication. Often the method of dissemination of information is itself a barrier, leading to situations wherein a very small subset of the community is actively engaged in making decisions for the population at large, leading to disparity. For example, a more rural area might not have widespread access to the internet, depending on infrastructure, leading to those in the urban center representing the population in public discourse. The local newspaper or radio station might appeal to a specific racial, political, age, or economic demographic, while largely failing to reach the rest of the community. In addition, the people who attend in-person meetings and public presentations frequently are not representative of the community as a whole and may not even be those most likely to be in the research. Historical barriers to attendance at public forums and focus groups, such as transportation needs, work schedules, disabilities involving the ability to see and hear, and community sentiment toward medical research are all to be considered.
There are a couple major challenges with community consultations, including getting people to attend the public meetings on the emergency research project and that those who do attend may not be representative of the community as a whole. This means that a few hundred people, who may not be representative of the population as a whole, could decide that an emergency research study can be conducted in a community of several thousand or hundreds of thousands of people.
Ensuring that community members know that opting out is an option, and how to do so effectively, should be a priority. Generally, any advertisements or public disclosures will provide information for how members of the community could opt out of the research. One common method would be to request a medical alert bracelet indicating that the individual chooses not to participate in the emergency research.
Separate IND and IDE
It is important to note that any research conducted under 50.24 requires the submission of a separate IND and IDE for each study conducted under 50.24 even if an IND or IDE already exists. Information previously submitted in support of other applications may be included as reference. For instance, if a drug is being studied under both 50.24 and the normal IND procedures, there will be one IND for the study conducted under 50.24 and another IND for any other studies for that particular drug product. For the FDA to allow a study to proceed under 50.24, the study must meet the regulatory requirements under 50.24 in addition to the IND or IDE requirements.
Placebo Controlled Studies
One of the more controversial aspects of conducting research in an emergency situation is the use of placebo-controlled studies. In order to determine if the intervention is effective, the FDA requires that there be well-controlled studies, for which placebo is often the most effective, and most of the interventions used in an emergency situation cannot be adequately tested except in an emergency situation. If there is no current treatment, then the participants would be in the same position as if they were not in the study. However, if there is an approved therapy, participants could be denied effective treatment if they are randomized to the placebo arm. Even if the treatment is only marginally effective or there are serious side effects from the treatment, in a life-threatening situation, getting some treatment is likely going to better than getting a placebo.
Obtaining Consent
Each emergency protocol will include a therapeutic window of when the intervention needs to be initiated to be effective. During the therapeutic window, the study team must try to obtain consent from the participant, an LAR, or a close family member. For some conditions, like a heart attack, the therapeutic window may only be a few minutes, and it would not be practical to get consent during this time and in this instance the intervention begins immediately. In contrast, some conditions such as traumatic brain injury or stroke may have a therapeutic window that is several hours long. However, these interventions are generally more efficacious the earlier they are administered. If the therapeutic window is several hours long, the study staff are expected to attempt to get consent, but not to the extent that effective treatment for the participant may be delayed.
Even if the participant is able to consent or there is an LAR available, it may be difficult to determine if consent is truly freely given. The participant is in a stressful, life-threatening situation and there is not time to stop and think about the consequences of being in the study or considering other alternatives. Participants, or their LAR, may feel like being in the study is their only option, even if there are other alternatives. In contrast to non-emergent clinical trials, the participants, or their LAR, can review the study, ask questions, and possibly discuss participation in the study with another physician or trusted individuals.
Conclusion
When conducting research in an emergency situation it is necessary to evaluate interventions to be used to save lives during similar situations. However, these studies are complex, regulatorily risky, and generally deny autonomy to the individual by including them in research they may not have agreed to otherwise. When conducting research under 50.24, the sponsor and IRB must pay particular attention to the community consultation plan to ensure the community is well represented and the researchers obtain feedback from different community groups and populations.