What is an Adverse Event in a Clinical Trial?

Blog by Thomas Milovac

Kow and colleagues have recently addressed the lack of quality in reporting adverse events (AEs) in trials of remdesivir, basing their analysis on guidelines recommended by the Consolidated Standards of Reporting Trials (CONSORT).1 For example, none of the trials defined an AE, and only one trial noted how researchers collected AE related data. Such lack of transparency in clinical trials makes it reasonable to ask: What is an adverse event? The trial for another Covid-19 antiviral heightens the relevance of this question. Hammond and colleagues pitted nirmatrelvir plus ritonavir against a placebo in participants who had recently contracted Covid-19.2 Without commenting on trial success, the researchers observed that the experimental arm participants experienced less AEs overall, less dropout, and less severe AEs than the placebo arm participants. How can this incongruity be explained?

One explanation for how a placebo could produce similar or more AEs is the nocebo effect, which occurs when participants experience negative effects of medications because of their anticipation of such effects.3 More aligned with Kow et al.’s point regarding the unclear definition of AEs, another explanation is that adverse events are any negative event experienced by trial participants. A case in point is Hammond et al.’s Supplementary Appendix, which included “Covid-19” (a precondition for enrolment in the study), “wrist fracture,” “eye injury,” “influenza,” “hand fracture,” and “road traffic accident,” all occurring more often in the control group.4 However, the researchers distinguished “events that emerged during [the] treatment period,” from “events considered to be related to [the] drug or placebo.”5 Furthermore, Beigel and colleagues documented adverse events unrelated to their trial, where there is a differentiation between “at least one adverse event,” and “at least one related adverse event.”6 AEs, therefore, appear to be either something manufactured by the nocebo effect or any potential negative experience encountered by a trial participant.

Neither of these explanations adequately details the safety profile of the medication under investigation. Moreover, both explanations leave future patients worse for wear because they hinder their decision-making capacity. When patients cannot distinguish causally related AEs from unrelated AEs, they cannot properly adjudicate whether a drug is right for them. More importantly, if researcher analyses do not make such distinctions between the data explicit, the effect snowballs across the entire medical system. Physicians cannot properly counsel patients, and therefore cannot fulfill their role as experts responsible for patient care and provision of treatment. Trial data on AEs ought to accurately detail the negative effects brought about by a drug, so that the data can be reasonably used by patients and physicians alike; researchers should avoid cataloguing negative events that are not causally related to the drug because doing so decreases the relevant safety information patients and their physicians have at their disposal.

The lack of relevant safety information in clinical trials also compromises patients’ ability to consent to treatment. Consent requires adequate information because patients ought to know what the risks of treatment are as well as what could happen if they forego treatment. More plainly, relevant information is necessary to consent because patients need to know what they are agreeing to. If they lack this vital understanding, then the consent obtained is void. Therefore, problematic reporting of AEs in clinical trials has the negative, down-stream effect of preventing patients from supplying informed consent.

 

Works Cited

[1] Chia Siang Kow, Mamoon Aldeyab, and Syed Shahzad Hasan. “Quality of Adverse Event Reporting in Clinical Trials of Remdesivir in Patients with COVID-19. European Journal of Clinical Pharmacology 77 (October 2020): 435–7, http://dx.doi.org/10.1007/s00228-020-03008-6.

[2] Jennifer Hammond et al. “Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19.” New England Journal of Medicine 386 (February 2022): 1397–408, http://dx.doi.org/10.1056/nejmoa2118542.

[3] Luana Colloca and Franklin G. Miller. “The Nocebo Effect and Its Relevance for Clinical Practice.” Psychosomatic Medicine 73 (September 2011): 598-603, https://doi.org/10.1097/psy.0b013e3182294a50.

[4] Hammond et al., “Oral Nirmatrelvir,” table S5.

[5] Hammond et al., “Oral Nirmatrelvir,” table 2.

[6] John H. Beigel et al. “Remdesivir for the Treatment of Covid-19—Final Report.” New England Journal of Medicine 383 (October 2020): Supplementary Appendix, table S17, http://dx.doi.org/10.1056/nejmoa2007764.

 

Thomas Milovac is a PhD candidate at the University of Waterloo in the department of philosophy. Thomas is currently working on his dissertation focusing on environmental bioethics and how the provision of healthcare can harm humans and the biosphere.

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