The Research Challenge
To study the efficacy of the proposed MATH+ protocol against COVID-19, a collective decision was made to do so via the formation of a patient registry to measure and compare the outcomes of patients treated with MATH+. This was done not only against the prevailing “supportive-care only” strategy, but also against other novel proposed treatment approaches employed throughout the country and world.
A randomized or placebo-controlled trial (RCT) design was decided against given that such trials require investigators to possess “clinical equipoise”, which is the belief by the investigator that neither intervention in the control or experimental group is more effective. With respect to each of the individual “core” therapies of MATH+, all authors understood the medical evidence base in support of their use to be well established, and thus superior to any placebo. This was based not only on the rapidly accumulated knowledge and insight into COVID-19, but also from their collective knowledge, research, and experience with each of the component medications in critical illness and other severe infections.
Furthermore, our experts were troubled by editorials in major peer-reviewed medical journals, arguing that such treatments were “experimental”, and that use should therefore be restricted to only within such RCT’s. Truly “experimental” medicines, defined best as therapies with near nil clinical familiarity or published evidence base in critical illness or ICUs, such as hydroxychloroquine, liponivir/ritonavir, remdesivir, and tocilizumab, should indeed be studied within an RCT, largely because clinical equipoise could reasonably be held by many investigators.
However, in regards to the core MATH+ therapies, there are extensive published clinical studies and meta-analyses demonstrating positive outcomes in treating patients with similar diseases and conditions. Moreover, some of the authors’ facilities already include these therapies in standard treatment protocols for severe sepsis and ARDS. Thus, a placebo-controlled trial could not have been ethically conducted by members of the FLCCC Alliance due to a lack of clinical equipoise around the core therapies – in particular, corticosteroid therapy. In contrast, the investigators behind the RECOVERY trial of corticosteroid use in COVID-19 did indeed possess clinical equipoise. They were thus able to randomize over 4,000 patients to receive a placebo, and consequently demonstrated statistically significant mortality benefits in the patients who received the steroid.
Evidence-based medicine vs. RCTs in a pandemic
August 14, 2020 | USA
The randomized control trial controversy
“Medicine’s Fundamentalists” by Norman Doidge on tabletmag.com
August 3, 2017 | USA
Evidence for health decision making — beyond randomized, controlled trials
by Thomas R. Frieden – New England Journal of Medicine
June 1964 | Finland
WMA Declaration of Helsinki
The World Medical Association’s Ethical Principles for Medical Research Involving Human Subjects (amended by several WMA General Assemblies from 1975 to 2013)
Excerpt from the WMA Declaration of Helsinki
The World Medical Association’s ethical principles for medical research involving human subjects.
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964
Extracts from the WMA Declaration of Helsinki, supporting our position that it is unethical to treat patients with a placebo (alone) when an effective intervention (like MATH+) exists:
- The health of my patient will be my ﬁrst consideration
- A physician shall act in the patient’s best interest when providing medical care
- The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best proven intervention
- The use of placebo will not subject the patient to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention
- Extreme care must be taken to avoid abuse of the use of placebos
For the complete WMA Declaration of Helsinki please see link in the section above.