Clinical Researcher—December 2024 (Volume 38, Issue 6)

PEER REVIEWED

Muhammad Waseem, MBBS, MS, FAAP, FACEP, FAHA, FSSH, CPI

 

 

 

Informed consent, a cornerstone of ethical research involving human subjects, presents a unique challenge in emergency medical cases. The Nuremberg Code, a pivotal document that originally defined informed consent, and the Declaration of Helsinki, which underscores the ethical dilemma and provides regulations for exceptions to informed consent, are not just crucial but carry significant weight in understanding the complexities of clinical investigation for potentially life-threatening interventions in emergent conditions. These documents emphasize that specific reasons must exist to justify the inclusion of research subjects with a condition that renders them unable to provide informed consent, particularly in emergencies with a significant threat to the patient’s well-being or life.

Research without permission can be done when enrollment decisions must be made immediately and the patient’s wishes are unknown because of the situation. This reiteration of the importance of informed consent in emergency medical cases reinforces the ethical considerations in such situations.{1}

Emergency research often necessitates Exemption from Informed Consent, a regulatory mechanism that allows research to be conducted without the explicit consent of the research subjects (see Table 1). This exemption, as outlined in the 1996 release of 21 CFR Part 50.24 of the Code of Federal Regulations by the U.S. Food and Drug Administration (FDA) for human subject research, is pivotal. The FDA and the U.S. Department of Health and Human Services are crucial in providing the regulatory oversight to allow “emergency research” without informed consent. Their diligent oversight ensures that emergency research is conducted ethically and with the subjects’ best interests in mind, thereby reassuring the medical community and the public.{2}

Utilizing exceptions to obtaining informed consent in emergency research offers significant benefits. It provides the potential for broader subject recruitment and ensures the possibility of obtaining informed consent later. This approach can enhance the feasibility and effectiveness of emergency research, ultimately benefiting the patients involved. Emergency research can be conducted without consent through community disclosure or consultation, followed by notification and obtaining permission from the subject or their family for continued participation after the intervention is applied. The community’s involvement in the research process through disclosure and consultation is crucial and significant to the success of emergency research.

Prospective Consent

Prospective consent, a method for ensuring informed consent from research subjects, holds promise in addressing the challenges of obtaining informed consent in emergency medical cases. It involves identifying an at-risk population and acquiring consent from as many of them as possible before an emergency arises. This approach provides a framework for ethical research in such situations. A “consent in advance” model already exists for specific conditions, such as organ donation, and its potential in emergency cases is worth exploring, offering a hopeful solution to the challenges of emergency research.

The critical challenge, however, is recruiting an adequate number of individuals in at-risk groups to ensure enough will present with the emergency condition of interest. This approach raises the following question: Given the unlikelihood of any individual developing the emergency condition of interest, can their consent be truly informed? Will the identified potential subject pool consider all the risks of participation? Might individuals be convinced to volunteer when they would not have otherwise?

Because the chance of participating in the trial is so low, many will likely give little thought to the potential consequences. For example, if a new medication was in clinical trials to be provided within a three-hour window to patients who come to the Emergency Department having had a mini stroke, all patients being followed in the hospital with prior transient ischemic attacks could be asked for prospective consent should they present with the condition again.

There must also be a robust mechanism for differentiating those who have consented from those who have either refused or have not been approached. Another issue to be considered is the Hawthorne Effect, which states that a person’s behavior may be influenced purely by observing their behavior. In the research context, this effect could lead to subjects altering their behavior or responses because they know they are being followed, potentially skewing the results. This effect is essential to consider when designing and conducting research, as it can impact the validity of the results and the ethicality of the research process. For instance, if subjects are aware that their behavior is being observed, they may alter their behavior to conform to what they believe the researchers want to see, thereby compromising the accuracy of the data collected.

Deferred or “Delayed” Consent

In this case, subjects are recruited without consent using the deferred consent approach, and consent is obtained later. Deferred consent is a process where subjects are enrolled in a study without their initial consent, but consent is sought at a later, more appropriate time. If implemented correctly, this approach can ensure that consent is only for the patient’s continued research participation. However, a key consideration is the impact on data analysis if consent is required for this review but not granted. If missing data are omitted from complete data, then the analysis may be susceptible to bias. Therefore, it’s crucial to consider the implications of deferred consent on data analysis and the potential for bias in the results.{3}

Although it is plausible that using deferred consent may result in more scientifically rigorous research, several concerns remain. Subjects cannot refuse or consent to something that has already happened. This raises important ethical questions and requires further discussion. Would it be ethically permissible to enroll subjects in research without their consent? Are there times when researchers should forego consent? Also, several patients might need help to discuss their research participation. What should be done with the data collected from these subjects? Can it be included in the analysis? Many believe it should be considered as something other than a tactic to improve recruitment.{4} 

Proxy Consent

This principle allows a proxy to act on behalf of another individual who cannot decide. A proxy can provide authorization for care and research participation. However, this approach also has its inherent challenges. For example, could a proxy accurately represent the wishes of another individual? If they can do this, they must decide what decision they believe the subject would make. The difficulty lies in ensuring that the health proxy represents the subject’s wishes and not the proxy’s.

Addressing Ethical Concerns

Research quality depends on ethics, a well-designed protocol that addresses patient safety, and appropriate data collection tools. Research is only valid if it is conducted ethically. Various approaches can be used to address ethical issues; however, it’s important to note that public disclosure and community consultation requirements may be specific to people’s cultural values in the United States.{5} Medical professionals, researchers, and institutional review board (IRB) members play a crucial role in ensuring that research is conducted ethically, that participation in studies empowers patients, and that researchers are held accountable for the validity and ethical conduct of the study.

Community Consultation

Addressing the ethical concerns intrinsic to the emergency research context is vital when considering exceptions to informed consent. Requiring community consultation could be a significant step in this direction. Emergency research with a waiver of consent requires trust between research professionals and society. This consultation should include two-way communication, in which the communities are educated on the content of the research study and the meaning of and need for consent exceptions.{6} The purpose of community consultation is not to provide community consent or disapproval but to foster a sense of shared responsibility and understanding, thus highlighting the ethical considerations in emergency medical research and making the audience feel trusted and part of a collective effort.

Public Disclosure

This is a viable and inexpensive way to inform a large target population about emergency medical research. Furthermore, reporting clinical trial results to the appropriate registries could strengthen research transparency.{7} The availability of results in the public domain helps inform medical judgment and advance medical science.{8}

IRB Practices and Intensive Oversight

A diligent IRB review of study proposals is a vital protection for research subjects. Mechanisms exist to safeguard the rights of prospective medical research subjects and promote their protections for particularly vulnerable participants and specific circumstances. Although the minimum frequency of continued review is no less than once per year, the degree of risk involved in research procedures should determine the frequency of continued review. Also, studies that are greater than minimal risk require full committee review.

IRBs should choose the most appropriate method for obtaining informed consent under challenging situations.{9} There may be variations in the interpretation of waiver of informed consent regulations among the IRBs.{10} However, the extent of protection should depend upon the risk of harm and the likelihood of benefit to the subjects. It is essential to recognize that the judgment that any individual lacks autonomy should be periodically reevaluated.

Sponsor Role and Responsibilities

The sponsor is responsible for a clinical investigation and is generally responsible for ensuring informed consent is obtained before enrolling participants in research studies. Sponsors are required to take extra steps to protect human subjects. They must monitor the progress of all research involving an exception from informed consent.

FDA Guidance

On December 21, 2023, the FDA expanded informed consent exceptions with a final rule permitting the IRB to waive or alter elements for specific FDA-regulated minimal-risk clinical investigations (see Table 2). This document provides an exception from the requirement to obtain informed consent when a clinical investigation poses no more than minimal risk to the human subject and includes appropriate safeguards to protect the rights, safety, and welfare of human subjects. This clarified the FDA’s guidance and reduced confusion about when emergency research can proceed without obtaining an individual subject’s informed consent.

However, this is a narrow exception to the requirement for obtaining and documenting informed consent. This applies to a limited class of research activities involving human subjects who need emergency medical intervention but who cannot give informed consent because of their life-threatening medical condition. The exceptions involve critical situations such as emergencies or public health crises.

Conclusions

Informed consent is not always feasible in emergency research, and a waiver of informed consent gives directions for engaging effectively in emergency medical research. Such consent waivers are only permitted under highly restricted and specific circumstances, and the intent of waiving the requirement for prospective, voluntary consent should be in the interests of the patient’s safety and rights and that of the public.

When obtaining consent is not feasible, the research should pose no more than the minimum risk. Regulatory exceptions where any procedures conducted to save the subject’s life are available and require prompt reporting to IRB for review.  Hence, the protection of the rights and welfare of individuals involved in the research process should be adequate. Researchers should commit to developing context-appropriate strategies and flexible approaches to ensure they are conducting ethical research in such situations.

Table 1: Informed Consent Exception Requirements for Emergency Research {11}

• A life-threatening condition or situation exists
  • Available treatments are either not tested or unproven or unsatisfactory
  • Need exists for research to evaluate the safety and efficacy of treatment
• Obtaining informed consent is not feasible
  • The subject is unable to consent because of a medical condition
  • There is no time to contact a subject’s legally authorized representative
• Possibility must exist that the subject will benefit from treatment
• The research could not practically be carried out without the waiver

                                                                                                                                               

Table 2: Common Rule Criteria to Permit a Waiver or Alteration of the Informed Consent

• The research is designed to ensure that subjects are exposed to no more than minimal risk, providing a high level of safety and reassurance.
• The requested waiver or alteration is a necessary and justified step, without which the research could not practically be carried out.
• If research involves identifiable private information or identifiable biospecimens, it could not practicably be carried out without using such information or biospecimens in an identifiable format.
• The waiver or alteration ensures that subject rights and welfare are not adversely affected, demonstrating  commitment to ethical research.
• Whenever appropriate, the subjects or legally authorized representatives will be provided with additional pertinent information after participation.

References

1. Silbergleit R, Dickert NW. 2020. Context and principles must drive alternatives to consent in emergency research. Lancet Neurol 19(12):968–9.
2. McRae AD, Weijer C. 2002. Lessons from everyday lives: a moral justification for acute care research. Crit Care Med 30(5):1146–51.
3. Nichol G, Powell J, van Ottingham L, Maier R, Rea T, Christenson J, Hallstrom A. 2006. Consent in resuscitation trials: benefit or harm for patients and society? Resuscitation 70(3):360–8.
4. MacKay CR, Torguson R, Waksman R. 2015. Delayed consent: will there be a shift in approach for US primary percutaneous coronary intervention trials? Lancet 15;386(9994):714–6.
5. U.S. Department of Health and Human Services. Code of Federal Regulations Title 46, Protection of Human Subjects. 2010. http://hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm
6. Dickert NW, Metz K, Fetters MD, Haggins AN, Harney DK, Speight CD, Silbergleit R. 2021. Meeting unique requirements: Community consultation and public disclosure for research in emergency setting using exception from informed consent. Acad Emerg Med 28(10):1183–94.
7. Munshi R, Pilliwar C, Maurya MR. 2023. Public disclosure of clinical trial results at Clinical Trial Registry of India—Need for transparency in research! Perspect Clin Res 14(2):81–5.
8. Strahlman E, Rockhold F, Freeman A. 2009. Public disclosure of clinical research. Lancet 18;373(9672):1319–20.
9. Verma S. 2021. Exemption from informed consent: When it is possible in investigational product and drug trials? Saudi J Anaesth 15(4):428–30.
10. Polito CC, Cribbs SK, Martin GS, O’Keeffe T, Herr D, Rice TW, Sevransky JE. 2014. Navigating the institutional review board approval process in a multicenter observational critical care study. Crit Care Med 42(5):1105–9.
11. Mosesso VN Jr, Cone DC. 2005. Using the exception from informed consent regulations in research. Acad Emerg Med 12(11):1031–9.

Muhammad Waseem, MBBS, MS, FAAP, FACEP, FAHA, FSSH, CPI, is a Professor at Weill Cornell Medicine and an Attending Physician and Research Director for Emergency Medicine at Lincoln Medical & Mental Health Center, where he is also Vice Chair of the Institutional Review Board. Among other organizations, he is active with the Society for Simulation in Healthcare, Public Responsibility in Medicine and Research, the American College of Emergency Physicians, American Academy of Pediatrics, and the American Heart Association.