What Does “Science Say” When the “Science” Is Rescinded?

Treatment research is challenging, so "following the science" is never easy.

Posted Dec 16, 2020

While we are all celebrating the remarkable scientific accomplishment of the rapid development of vaccines for SARS-Cov2 (COVID-19), it is instructive to review parallel accomplishments—and pitfalls—in the development of treatments for this deadly disease. In particular, the notion of "what the science says" has been—and continues to be—misunderstood and misused.

"What the science says" is, in fact, neither monolithic nor static because science itself and scientific findings are nuanced, specific, and subject to different interpretations—and often change whenever additional studies overturn previous interpretations. Also, because scientists are human, there must be safeguards against the bias that can intrude into scientific research.

This can be even more problematic in treatment research, especially when there is considerable variability in the natural history of an illness and when the data collection and data entry process are conducted at multiple sites—and as in COVID-19 studies—across multiple countries. Unfortunately, this situation is even more complicated when there is a worldwide public health crisis, as we have seen with COVID-19 because politics and shaping a political narrative can also have an impact on arguments about "what the science says."

For background, consider the scientific question of whether taking a particular medication is effective in treating illness. In a disease such as Ebola, wherein there is a very high mortality rate, whenever a medication is associated with a much higher survival rate, it is often a clear indication that the medication is effective.

But answering questions about treatment can be much more difficult when the untreated recovery rate without medication is much higher and if the goal of the medication is to reduce symptoms rather than to "cure" the disease. The U.S. Centers for Disease Control reports COVID-19 recovery rates are more than 90 percent in many age cohorts and even higher in young people,[1] so medications for COVID must be tested against a very high recovery rate (without medication), which is a much more difficult question for science to answer.

An antimalarial medication named hydroxychloroquine (HCQ) has been proposed as a possible preventative and as a treatment for patients infected with COVID-19. To be sure, there are many candidate medications, but this medication took on added significance in part because leaders of two large countries, who are themselves controversial, promoted HCQ as an effective drug in the spring of 2020.[2]

Shortly thereafter, a scientific paper appeared in a major medical journal—Lancet—indicating that not only was HCQ an ineffective treatment but that it is harmful and increased death rates.[3] At the time—in late May 2020—this was deemed sufficient scientific evidence to suspend clinical studies of HCQ.[4] The scientists reported (from the Lancet paper, p. 1): “We were unable to confirm a benefit of hydroxychloroquine or chloroquine, when used alone or with a macrolide, on in-hospital outcomes for COVID-19. Each of these drug regimens was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias when used for treatment of COVID-19.”[5]

In plain English, HCQ was proclaimed to be both ineffective and potentially harmful. The science had spoken! And this was used to discredit political leaders who touted HCQ.[6]

But what “science says” then took an interesting turn: In response to an open letter by more than 180 scientists raising concerns about the scientific integrity of the Lancet study on HCQ[7], the paper was withdrawn because several of the authors reported that they were unable to audit the data.[8] I would argue this audit should have occurred prior to the original publication. Regardless, “the science” was retracted!  

So what does the science now say about HCQ? It turns out that this is not so easy to determine. Because discovering effective treatments for COVID-19 is a very high priority, there are now dozens and dozens of studies on HCQ. This permits the aggregation of multiple studies into systematic reviews and meta-analyses, wherein “big-picture” scientific conclusions can be made. But it turns out that even these large aggregations yield different and sometimes conflicting results. Examples include the following conclusions:

  • HCQ doesn’t help and can be deadly when combined with another medication: “Hydroxychloroquine alone was not associated with reduced mortality in hospitalized COVID-19 patients but the combination of hydroxychloroquine and azithromycin significantly increased mortality.”[9]
  • Conflicting results in the same paper: “From the studies analyzed, it was found that groups treated with HCQ had an overall mortality rate that was 2.5 times greater than that of the control group. HCQ treated patients had higher rates of adverse clinical outcomes and side effects compared with the control populations. Lastly, there was a 1.2 times higher rate of improvement in the group of HCQ treated patients with mild to moderate symptoms as compared to the control group.”[10]
  • And, finally, that HCQ is effective in mild cases: “A total of 27 articles were found (N=44,684 patients, including N=7,803 from 5 randomized clinical trials (RCTs)). Overall, the use of HCQ was associated with a 22% lower mortality risk (pooled risk ratio: 0.78, 95%CI: 0.67 to 0.91; I2=80%, random effects).”[11] 

My own reading of the literature is that although there are certainly many studies that show that HCQ is not helpful, we currently do not know with certainty whether it is helpful or harmful. But please note that I am not a physician and am not rendering medical advice. I am simply presenting my interpretation of complex and nuanced scientific literature. As a clinical translational scientist who studies treatments to support communication abilities in Autism, Down Syndrome, and other complex developmental profiles, I can say from experience that determining “what the science says” is challenging and that the inconsistent results for HCQ are not surprising in such a complex discovery space.

Science can—and does—provide credible answers and amazing discoveries, such as the COVID-19 vaccines. So, as more data come in, I am confident science will indeed answer the hydroxychloroquine question and other questions about COVID-19 with increasing precision. But until then, “what the science says” and “following the science” is a naturally progressing story that can change and should not be politicized.

References

[1] https://www.cdc.gov/coronavirus/2019-ncov/hcp/planning-scenarios.html?fbclid=IwAR3DvH5umpJxiObUDTKBckeBAfqudrtvzWfQhYiUfHeEhCFeg5UXzalabGg. Accessed December 14, 2020

[2] https://www.theguardian.com/science/2020/apr/06/coronavirus-cure-fact-check-hydroxychloroquine-trump. Accessed December 16, 2020

Coronavirus: World leaders' posts deleted over fake news. https://www.bbc.com/news/technology-52106321. Accessed December 14, 2020

[3] https://www.statnews.com/2020/06/04/lancet-retracts-major-covid-19-paper-that-raised-safety-concerns-about-malaria-drugs/ Accessed December 14, 2020

[4] WHO’s Hydroxychloroquine Trial Suspended Pending Safety Data. https://www.bloomberg.com/news/articles/2020-05-25/who-s-hydroxychloroquine-trial-suspended-pending-safety-data. Accessed December 14, 2020

[5] Mehra, M. R., Desai, S. S., Ruschitzka, F., & Patel, A. N. (2020). Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. The Lancet.

[6] https://thehill.com/policy/healthcare/500236-massive-hydroxychloroquine-study-raising-health-concerns-about-the-drug. Accessed December 15, 2020.

[7] https://www.documentcloud.org/documents/6933411-Open-Letter-the-Statistical-Analysis-and-Data.html. Accessed December 16, 2020.

[8] Mehra MR, Desai SS, Ruschitzka F, Patel AN. RETRACTED: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020 May 22:S0140-6736(20)31180-6. doi: 10.1016/S0140-6736(20)31180-6. Epub ahead of print. Retraction in: Lancet. 2020 Jun 5;:null. Erratum in: Lancet. 2020 May 30;: PMID: 32450107; PMCID: PMC7255293.

[9] Fiolet, T., Guihur, A., Rebeaud, M. E., Mulot, M., Peiffer-Smadja, N., & Mahamat-Saleh, Y. (2020). Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis. Clinical Microbiology and Infection.

[10] Hussain, N., Chung, E., Heyl, J. J., Hussain, B., Oh, M. C., Pinon, C., ... & Babu, B. (2020). A Meta-Analysis on the Effects of Hydroxychloroquine on COVID-19. Cureus, 12(8).

[11] Di Castelnuovo, A., Costanzo, S., Cassone, A., Cauda, R., de Gaetano, G., & Iacoviello, L. (2020). Low Dose Hydroxychloroquine is Associated with Lower Mortality in COVID-19: A Meta-Analysis of 27 Studies and 44,684 Patients.

[12] https://www.ama-assn.org/system/files/2020-10/nov20-handbook-addendum.pdf p. 18