Time Required to Address Scientific Questions Generates an Information Dilemma

Maurie Markman, MD

One of the more perplexing issues surrounding scientific questions is the extended time required to provide an answer. Even once a well-considered and vetted conclusion is obtained, an additional interval of time may be required to modify or reverse the answer because of new, relevant data.

A partial explanation for increasingly distressing difficulties with communication between public health officials and the public may be explained by the timelines associated with rigorous scientific investigation, including the conduct and analysis of clinical trials. This was seen especially during the COVID-19 pandemic. Definitive answers to questions relevant to governmental policy to optimize societal health and economic welfare, employer guidance, or individual safety are needed but often what is available in response are no more than reasonable suggestions based on limited and frequently changing data.

The role and benefits of mask mandates or the need for school closures to help ensure public safety in the early days of the pandemic are excellent examples of the dilemma faced by the scientific, medical, and public health communities. In an era of immediate access to information (or in some cases misinformation) provided to society through a variety of social media outlets, the sometimes less than adequate or scientifically supported recommendations/mandates from national or regional scientific and public health officials have not inspired societal confidence.

Further, when questions were raised regarding the safety and effectiveness of the several COVID-19 vaccines, early reassurance had to be based on limited clinical trial data and, admittedly, short follow-up. Critical safety and efficacy features of the products have now been unequivocally documented including observations that specific vaccines appear to possess unique adverse effects. These features would not have been known or available for discussion when the products were initially provided to the public because clinical trials of the agents had not been completed.

A recent report from France has provided data regarding the risk of stroke, pulmonary embolism, or myocardial infarction following review of 46.5 million adults aged 18 to 74 years who received a COVID-19 vaccine between December 27, 2020, and July 20, 2021.¹ Although no association was found between these events with mRNA-based vaccination, a potential risk was observed with the administration of an adenoviral-based vaccine product. Again, this information was available only through examination of this large, population-based database after more than 1 year of follow-up.

Similarly, the question of if the risk of developing myocarditis after COVID-19 vaccination vs COVID-19 infection has required time to document in large patient populations. In a recently published report from England, investigators examined individuals who developed myocarditis following adenoviral-based or mRNA-based vaccination or following a positive SARS-CoV-2 test from December 1, 2020, and December 15, 2021.² The findings revealed that, overall, COVID-19 infection was associated with a greater risk of experiencing this potentially serious cardiac event compared with vaccination.

Another large population-based study from England and Wales examined electronic health records from January to December 2020 to understand the risk of the development of arterial or venous thrombotic disease following the diagnosis of a COVID-19 infection.³ Individuals with confirmed COVID-19 infection had a relatively high risk for experiencing a major arterial or venous thrombotic event that persisted for almost 1 year after diagnosis compared with a noninfected control population.

Other studies that followed the effect of COVID-19 infection or vaccination over time have addressed the risk of psychiatric and neurological complications,⁴ the potential for the development of chronic fatigue syndrome or myalgic encephalomyelitis in infected children,⁵ and the benefits of a booster dose.⁶

In each of the studies patient populations were required to be followed over an extended period to reach clinically meaningful and scientifically (statistically) valid conclusions, including the relative risk of serious adverse effects associated with vaccination. It is also relevant to note that decisions to restrict use of a COVID-19 vaccine product following initial approval have been made based on evolving data.⁷ This emphasizes how the nature of rigorous regulatory science holds the potential for unanticipated negative outcomes, which can arise despite proper conduct and interpretation of results of clinical trials that led to drug licensing.

Of course, the cancer arena is not immune to the late effects of clinical research efforts that may substantially alter our understanding of both the science and implications for patient treatment. There is no better example of this phenomenon than the recent decision by the FDA and pharmaceutical manufacturers to withdraw prior approval for the use of several commercially available PARP inhibitors as later-line therapy in recurrent epithelial ovarian cancer.⁸

These decisions were based on data generated from several randomized phase 3 trials that suggested a potential negative effect of the drugs on overall survival compared with a cytotoxic drug treatment study control arm. It is interesting to note that until these outcomes were seen, the major concern among clinicians had been for the possible late development of myelodysplastic syndrome or acute leukemia in heavily pretreated patients with ovarian cancer. However, the effects noted in this analysis do not appear to be related to a secondary malignant hematologic process.

These disquieting results were not anticipated and only observed with extended follow-up of the trial population, which again emphasizes how, over time, conclusions of scientifically valid investigative efforts may substantially change.

Maurie Markman, MD, editor in chief, is president of Medicine & Science at Cancer Treatment Centers of America, a part of City of Hope.

References

1. Botton J, Jabagi J, Bertrand M, et al. Risk for myocardial infarction, stroke, and pulmonary embolism following COVID-19 vaccines in adults younger than 75 years in France. Ann Intern Med. 2022;175(9):1250-1257. doi:10.7326/M22-0988
2. Patone M, Mei XM, Handunnetthi L, et al. Risk of myocarditis after sequential doses of COVID-19 vaccine and SARS-CoV-2 infection by age and sex. Circulation. 2022;146(10):743-754. doi:10.1161/CIRCULATIONAHA.122.059970
3. Knight R, Walker V, Ip S, et al; CVD-COVID-UK/COVID-IMPACT Consortium and the Longitudinal Health and Wellbeing COVID-19 National Core Study. Association of COVID-19 with major arterial and venous thrombotic diseases: a population-wide cohort study of 48 million adults in England and Wales. Circulation. 2022; 146(12):892-906. doi:10.1161/CIRCULATIONAHA.122.060785
4. Taquet M, Sillett R, Zhu L, et al. Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1 284 437 patients. Lancet Psychiatry. 2022;9(10):815-827. doi:10.1016/S2215-0366(22)00260-7
5. Song AL, Becht S, Jank M, et al. Association of SARS-CoV-2 seropositivity with myalgic encephalomyelitis and/or chronic fatigue syndrome among children and adolescents in Germany. JAMA Netw Open. 2022;5(9):e2233454. doi:10.1001/jamanetworkopen.2022.33454
6. Ridgway JP, Tideman S, French T, et al. Odds of hospitalization for COVID-19 after 3 vs 2 doses of mRNA COVID-19 vaccine by time since booster dose. JAMA. 2022;10.1001/jama.2022.17811. doi:10.1001/jama.2022.17811
7. Barouch DH. Covid-19 vaccines - immunity, variants, boosters. N Engl J Med. 2022;387(11):1011-1020. doi:10.1056/NEJMra2206573
8. Tew WP, Lacchetti C, Kohn EC; PARP Inhibitors in the Management of Ovarian Cancer Guideline Expert Panel. Poly(ADP-ribose) polymerase inhibitors in the management of ovarian cancer: ASCO guideline rapid recommendation update. J Clin Oncol. 2022;10.1200/JCO.22.01934. doi:10.1200/JCO.22.01934