Gaps Persist in Understanding the Fundamentals of Informed Consent

Maurie Markman, MD

This has been an interesting and complex year in the realm of clinical trials. The results of multiple COVID-19 studies provide a remarkably powerful testimony to support well-designed, well-conducted trials and highlight the importance of interpreted investigative studies in optimizing the health of our society. Within the hierarchy of clinical trials, phase 3 randomized studies remain the gold standard, though some argue that appropriately designed meta-analysis of multiple studies provides even more definitive and meaningful insight.

Despite the remarkable success associated with the monumental double-blind, placebo-controlled COVID-19 vaccine studies, there has been considerable criticism of investigative approaches that examined potential therapeutic strategies to treat or prevent complications of this infection. In fact, the results of an extensive review of the topic document a number of concerning features. The report cites the use of underpowered, inadequately designed and conducted randomized studies; investigators leveraging large but poorly understood databases believed by some to be sufficient to avoid randomization; and, finally, the publication of results in high-impact medical journals by internationally recognized academics of observational data employing dubious or perhaps, nonexistent population-based sources for which stunningly inadequate vetting was employed.¹

Execution Gaps Lead to Missed Opportunities

The advent of rapid online coverage of research that has not undergone peer review has enabled widespread reporting of observational research and clinical trial efforts, the stated conclusions of which may be grossly overstated or, frankly, wrong.

Further, consider that in early 2020, COVID-19 was rapidly spreading, affecting both the developed and the developing world. The unfortunate absence of widespread international cooperation in the design and conduct of pragmatic clinical trials to definitively answer simple yet critical questions (eg, quickly defining the benefits or lack thereof for hydroxychloroquine, dexamethasone, and immune serum from survivors of a COVID-19 infection to treat or prevent complications) must be seen as a lost opportunity. However, it should be noted that countries with more centralized public health and research infrastructures mounted impressive controlled clinical trials that helped define clinical efficacy.^2,3 Consider just how much could have been rapidly learned if these efforts were conducted on an international rather than a national scale.

Missing the Mark on Informed Consent

A recent report regarding the informed consent process for patients enrolled on COVID-19 vaccine trials adds another element of concern, one that is highly relevant for clinical studies in the cancer domain.⁴ Considering the highly experimental nature of the initial phase 3 trial efforts of these vaccine products, including lack of solid knowledge of both efficacy and toxicity, one would have anticipated and hoped for considerable clarity in the informed consent document required from all participants. This would include material written at a reading level appropriate for the majority of individuals being asked to participate in this essential societal effort.

Unfortunately, investigators reported that the informed consent forms for 4 of the phase 3 COVID-19 randomized studies examined fell short of what would be considered optimal.4 First, each document was excessively long requiring at least 30 minutes to read at a pace of 240 words a minute. Second, each document exceeded the reasonable standard of ninth-grade reading ability and was overall rated as “difficult.”

Finally, because of the truly experimental nature of these vaccine products, a placebo-controlled study design was essential. In the opinion of this commentator, there can be no objectively valid objection to this decision for the initial study designs. However, considering the fact that, by definition, approximately half of the study population would not receive the active product, it is perhaps more than a little surprising that just 1 of the 4 consent forms specifically stated that “participants with the placebo group might receive vaccine.” Further, the investigators noted, “the reference was oblique and failed to specify timeline or other details.”⁴

Can the points described here regarding future plans of study participants randomized to the placebo arms possibly be considered appropriate informed consent? Of course, at the time consent was obtained, it was unknown if the various vaccines would be demonstrated to be safe and effective. However, that was always a realistic possibility; otherwise, why conduct the study?

There is a widely held perspective among members of the academic research community that participation in a clinical trial is fundamentally different from clinical care, and the researcher’s obligations to a “research subject” differ from those of a physician providing care to an individual patient. If this argument is accepted, one might conclude that the COVID-19 vaccine trials were specifically designed to answer a scientifically important question rather than provide protection from this dangerous virus for individual participants. Further, carrying the argument to its logical conclusion, investigators would not have an obligation to participants in the placebo arm, assuming the trial had a favorable outcome. Their only responsibility would be to conduct an excellent trial and report the results, which would, hopefully, be relevant to future individuals or patients.

In striking contrast, if we acknowledge both the critically import-ant scientific aims of the study and its potential effect on participants, a plan for future management of individuals randomized to placebo—assuming a positive outcome—is ethically mandated. For example, this might have prospectively included a decision to offer active vaccination to this group once the vaccine received FDA approval for noninvestigative use.

Finally, it must be noted that the experience with informed consent described is potentially relevant for cancer investigative efforts whenever it is deemed appropriate to include a placebo-controlled study arm.

References

1. Ferreira JP, Epstein M, Zannad F, et al. The decline of the experimental paradigm during the COVID-19 pan-demic: a template for the future. Am J Med. 2021;134(2):166-175. doi:10.1016/j.amjmed.2020.08.021
2. Horby P, Mafham M, Linsell L, et al; RECOVERY Collaborative Group. Effect of hydroxychloroquine in hospi-talized patients with Covid-19. N Engl J Med. 2020;383(21):2030-2040. doi:10.1056/NEJMoa2022926
3. Cavalcanti AB, Zampieri FG, Rosa RG, et al; Coalition Covid-19 Brazil I Investigators. Hydroxycloroquine with or without azithromycin in mild-to-moderate Covid-19. N Engl J Med. 2020;383(21):2041-2052. doi:10.1056/NEJMoa2019014
4. Emanuel EJ, Boyle CW. Assessment of length and readability of informed consent documents for COVID-19 vaccine trials. JAMA Netw Open. 2021;4(4):e2110843. doi:10.1001/jamanetworko-pen.2021.10843