Health Letter, September 2021
By Michael Carome, M.D.
On June 8, 2021, Public Citizen urged federal regulators to immediately investigate an already completed National Institutes of Health (NIH)-funded clinical trial involving patients with life-threatening prolonged seizures because of serious ethical and regulatory violations. Public Citizen detailed its allegations about the trial in a letter to the U.S. Department of Health and Human Services’ Office for Human Research Protections (OHRP) and the U.S. Food and Drug Administration (FDA) following an analysis of the trial’s design.
For the Established Status Epilepticus Treatment Trial (ESETT), researchers in emergency departments at 58 hospitals across the U.S. enrolled 462 children and adults suffering an episode of status epilepticus — a seizure lasting longer than five minutes — that had not resolved after standard initial treatment with a benzodiazepine (for example, diazepam) and randomly assigned them to receive one of three FDA-approved seizure medications intravenously: levetiracetam, fosphenytoin or valproate. The goal was to determine which of the three drugs would result in better seizure resolution and responsiveness within 60 minutes after initiation of the assigned drug.
According to Public Citizen’s Health Research Group, the troubling flaws in ESETT’s design exposed some of the subjects to unacceptable and avoidable risks and thus violated regulatory and ethical norms for human research. These lapses are even more disturbing given that the subjects were enrolled without providing informed consent.
The trial was conducted without the informed consent of the subjects (or in the case of children, their parents’ or guardians’ permission) under an FDA regulation that allows an exception to the requirements for informed consent for certain emergency research.
Public Citizen’s analysis of ESETT, which enrolled subjects from November 2015 to December 2018, identified major flaws in the design of the study that resulted in all three trial groups potentially exposing some subjects to care that was significantly different from the usual care for status epilepticus patients. These deviations from usual care predictably could have delayed resolution of some subjects’ status epilepticus that had not responded to a benzodiazepine, increasing the risk of adverse neurological outcomes and death.
Public Citizen highlighted key flaws in ESETT’s design, including the following:
- Under usual care for status epilepticus, which was well-documented by the ESETT researchers before the start of the trial, selection of seizure-drug therapy for status epilepticus that has not resolved with a benzodiazepine is based on patient-specific factors, including a patient’s long-term seizure-drug use and compliance, age, underlying medical conditions and known responsiveness to a given seizure drug during any prior episodes of status epilepticus. But in ESETT, subjects were randomized to receive any one of three seizure drugs regardless of these individualized usual-care practice considerations.
- Because of dosing limits imposed by the trial’s design, some of the one-third of enrolled subjects who weighed more than 165 pounds likely received inadequate doses of the assigned seizure drug.
- The trial was blinded, meaning doctors caring for the subjects did not know which of the three drugs was given to each subject. The trial protocol strongly discouraged doctors from finding out which drug was used until 60 minutes after treatment with the assigned drug was started. Sixty minutes was an exceptionally long time to discourage unblinding in a patient with persistent status epilepticus.
Each of these flaws potentially contributed to a dangerous delay in resolution of status epilepticus in some subjects.
Public Citizen also expressed concern that selection of subjects enrolled in ESETT was not equitable, as required by federal regulations and the basic ethical principle of justice. Specifically, ESETT enrolled a disproportionately high number of Black subjects — 42% of all subjects — compared with the proportion of patients hospitalized in the U.S. for status epilepticus who are Black — about 27%.
The fact that ESETT successfully passed through multiple levels of review and was approved by officials at the NIH and by institutional review boards at participating institutions is yet another troubling example of the dysfunction — at multiple levels — of the U.S. system for protecting human subjects enrolled in complex clinical trials.
In the letter to the OHRP and FDA, and in a separate letter to NIH Director Francis Collins, Public Citizen noted that the failure to incorporate usual-care clinical practices into the design of randomized clinical trials in critically ill patients has been a recurring problem with large multicenter clinical trials funded by the NIH over at least the past two decades. ESETT was just the latest example of these problems.
Public Citizen urged the OHRP and NIH to promptly conduct an audit of all ongoing or soon-to-be-initiated NIH-funded clinical trials involving critically ill subjects and assess whether usual-care clinical practices were rigorously characterized and appropriately incorporated into the design of these trials. For trials for which this was not done, subject enrollment should be immediately suspended or delayed.