Phase III Clinical Trials and Emergency Use Authoirzation (EUA)

On October 21, at the same time as the Phase 3 Covid-19 vaccine studies ended the recruitment of patients, Peter Doshi, assistant editor of the British Medical Journal, writes a column entitled: “Will covid-19 vaccines save lives? Current trials are not designed to tell us ». Doshi reviews in detail the parameters related to efficacy measures in the Covid19 vaccine studies where he concludes that as these studies are constructed with only 7 days follow-up after the last dose they will not be able to say anything about real clinical effect related to hospital admissions, deaths or possible reduction of risk of infection.

In the publication on the safety and efficacy of the Pfizer BionTech mRNA Covid-19 vaccine published in the New England Journal of Medicine on December 10, 2020, the authors conclude that the vaccine has a 95% efficacy .

In all ongoing phase III studies where details are provided, laboratory-confirmed cases, even with only mild symptoms, will meet the definition of the primary endpoint. Pfizer and Moderna’s studies, for example, have defined a positive laboratory test with an unspecified cough as a basis enough to count as a Covid-19 case. ” For the age group over 65, far too few people are included in this age group to be able to say anything about the end point.In the Pfizer-Biontech Phase III Study – The efficacy analysis includes only the first 170 cases reported with a SARS-CoV-2 RT-PCR positive test associated with mild symptoms.

On January 4, 2021 in BMJ Opinion Peter Doshi reveals the problem related to the concept of efficiency:

In this post , Doshi emphasizes his previous concerns with the choice of the primary endpoints that are in some way related to important clinical endpoints such as hospitalizations, death or injury or risk of infection.

“All attention has focused on the dramatic effect results: Pfizer reported 170 PCR-confirmed covid-19 cases, divided 8 to 162 between vaccine and placebo groups. However, these numbers are overshadowed by a group of patients “suspected covid-19” – those with symptomatic covid-19 who were not confirmed by PCR. According to the US Food and Drug Administration (FDA) report on Pfizer’s vaccine, there were “a total of 3410 cases of suspected but unconfirmed covid-19 in the total study population, 1594 occurred in the vaccine group against 1816 in the placebo group.”

Here, there is no statistically or clinically significant difference between vaccinated and non-vaccinated.

But regardless of the effect measure; when the follow-up period associated with the analysis of endpoints is only weeks and not months or years – in reality – these studies remain a biological experiment overshadowed by a possibly real, but unknown risk of so-called antibody-dependent amplification for those vaccinated as described in animal experiments.

Long term follow-up of clinical trials and FDA Approval

To fully understand the efficiency of any preventative or curative treatment long term follow-up of clinical studies must be undertaken and these studies should be available when Covid-19 Vaccines receive final approval.

It has become clear now, after some 10 months into the mass vaccination program, that adequate data to assess the impact of the SARS-Cov2 vaccinations in relation to effectiveness will not be forthcoming.

Does the FDA think these data justify the first full approval of a covid-19 vaccine?

The final efficacy timepoint reported in Pfizer’s preprint is “from four months to the data cut-off.” The confidence interval here is wider than earlier time points because only half of trial participants (53%) made it to the four month mark, and mean follow-up is around 4.4 months (see footnote).

This all happened because starting last December, Pfizer allowed all trial participants to be formally unblinded, and placebo recipients to get vaccinated. By 13 March 2021 (data cut-off), 93% of trial participants (41,128 of 44,060; Fig 1) were unblinded, officially entering “open-label followup.” (Ditto for Moderna: by mid April, 98% of placebo recipients had been vaccinated.)