Grand Rounds April 26, 2024: Waiver or Alteration of Informed Consent for Minimal Risk Clinical Investigations – FDA Regulation Development and Research Landscape (Lauren Milner, PhD; Jonathan Casey, MD, MSCI; Matthew Semler, MD, MSCI)

Posted on by Elizabeth Mccamic

Speakers

Lauren Milner, PhD
Office of Clinical Policy
U.S. Food and Drug Administration (FDA)

Jonathan Casey, M.D., MSCI
Assistant Professor, Division of Pulmonary and Critical Care Medicine
Vanderbilt University Medical Center
Director, Coordinating Center Pragmatic Critical Care Research Group

Matthew Semler, M.D., MSCI
Associate Professor, Division of Pulmonary and Critical Care Medicine
Vanderbilt University Medical Center
Director, Steering Committee Pragmatic Critical Care
Research Group
Co-Director, Vanderbilt Center for Learning Healthcare

Keywords

Food and Drug Administration, FDA, Waiver of Consent, Alteration of Informed Consent, IRB, Ethics, Regulatory

Key Points

  • Section 3024 of the FDA 21st Century Cures Act (2016) amends the Food, Drug and Cosmetics Act and provides the U.S. Food and Drug Administration (FDA) with the authority to permit an exception from informed consent requirements when the proposed clinical testing poses no more than minimal risk to the human subject and includes appropriate safeguards to protect the rights, safety, and welfare of participants.
  • In 2018, FDA issued the Proposed Rule that would allow an IRB to waive or alter certain informed consent elements, or to waive the requirement to obtain informed consent, under limited conditions, for certain minimal risk clinical investigators.
  • The Final Rule (2023) finalizes 4 criteria for waiver or alteration of consent with minor edits and adopts a 5th criterion for waiver or alteration of consent for identifiable information and biospecimens.
  • The Final Rule is not new for IRBs and investigators familiar with the minimal risk waiver/alteration provision in the Common Rule. It has the same criteria, same process. It is relatively new to FDA’s regulated community. Previously, FDA regulations allowed waiver only for certain types of emergency research.
  • The goal of the Final Rule is to advance medical product development without compromising the rights, safety and welfare of people participating in clinical research. FDA will develop a draft guidance to accompany the final rule and communicate with researchers, IRBs, patient communities and other interested parties about the rule.
  • To understand how the regulations are being applied currently, a team at Vanderbilt systematically reviewed all studies meeting the NIH definition of clinical trial, published in the last year (May 2023 to April 2024) in JAMA and the New England Journal of Medicine (NEJM). Each trial was reviewed to determine whether informed consent prior to enrollment was required.
  • During that time period, 33 trials were published in JAMA or NEJM that did not require informed consent. The reasons they did not require informed consent fell into 3 buckets: 1. Emergency and critical care studies (19 RCTs enrolling more than 15,000 patients where informed consent before enrollment was considered impracticable because of the urgency of the intervention and the condition of the patient); 2. Cluster-level: Infection Prevention (11 RCTs enrolling almost 3 million patients where consent was considered impracticable because the intervention was delivered to a group of patients different than the patients who would experience the outcomes (i.e. infection control) and due to the scale); 3. Interventions to promote communication and facilitate care (3 RCTs).
  • In all, the systematic review found that 13% of trials did not require informed consent before enrollment, and 89% of patients (more than 3 million) in trials that did not require informed consent before enrollment.
  • Upcoming FDA guidance on waiver and alteration of consent could provide the first regulatory guidance for minimal risk interventional research. While U.S. federal regulators do not currently provide guidance on minimal risk for interventional trial, trials are occurring with waiver and alteration.
  • Upcoming FDA regulations present an important opportunity for the NIH Collaboratory’s goal of facilitating Learning Healthcare Systems capable of using embedded pragmatic trials to improve patient outcomes

 

Discussion Themes

-What is next from FDA in terms of the release of any further guidance? The timeline is challenging. It is under development and the FDA is working through the process.

–How does one judge the minimal risk criteria? For example, there are a lot of people who treat patients with diabetes with various medications. They may vary in terms of side effects, some of which might be rare. How do you identify if it is minimal risk? You have to meet 2 criteria to be considered for waiver of informed consent, both minimal risk and impracticability. Regardless of how you assess risk for a modestly sized study of a non-urgent intervention, then it would be conceivable to do it under consent and you would not need a waiver. If you are talking about health care system level studies, and for example, a study where these medications are already being used commonly and they are considered to be equivalent, that might be a case where people could consider choices like that. The framework of thinking is always “compared to what” and who is making the decisions. In clinical care is this something where the data is already good enough that physicians feel confident most of the time about one choice or would the patient have a strong preference about or a situation where the patient and clinician are not making the decision and there’s a spectrum in between. The question what does it look like now in clinical care can give a qualitative sense about the risk.

 

Tags

#pctGR, @Collaboratory1