Current Vaccine Conundrums Demonstrate Why You Do Real Phase II Trials

1 Shot, 2 Shot, 3 Shots? This should have been studied prior to entering pivotal phase III registration studies.

Generally when a therapeutic is tested in humans, there are a series of three phases of clinical trials. The first is basically to make sure there are no big safety problems and might give you some preliminary data on efficacy. In phase 2, you are looking to get better data on how it is used in the real world and if there are enough hints at efficacy so you can make a good decision to spend the massive amounts of money for the final phase. That phase, phase 3, represents the very large randomized double blinded placebo controlled trials that are powered to show both safety and efficacy in a large population. The approval decisions are primarily based on these results.

When I worked on Wall Street, Genentech was the most respected therapeutic manufacturer in the industry. Their success on phase 3 trials was incredibly impressive.

But this was not an accident. Most drug and biotechnology companies try to rush their drugs to market as fast as possible, trying to dispose of the phase 1 and phase 2 trials as quickly as possible to start enrolling their pivotal phase 3 registration studies. Genentech, on the other hand, put a lot of thought and effort into their phase 2 trials so they had a really good idea of if the drug really worked and how best to use it before moving into the final phase. Thus, it is not surprising their phase 3 success rate was so high.

What we are seeing with vaccines now is an example of what not to do with clinical trials. Not only did they basically jump right into humans with very little animal data, they went from phase I right into phase 2/3 in a matter of months. And the scientific community is witnessing the consequences right now.

First of all, we really do not even know if the second dose is necessary. Better data on relative efficacy should have been done in well done phase II trials with actual clinical follow up. We know from the reactogenicity studies that patient reactions were much worse on the second shot compared to the first shot. That might translate into higher adverse event rates. It would be reasonable to assume so, but thanks to that study not being done, we will probably never know.

Indeed if you look at the efficacy data, the severe COVID-19 outcome looksbetter starting from dose 1 as compared to starting with dose 2. This difference very well could be random error, but that zero versus 6 cases data does make you wonder.

Source: SUPPLEMENTARY APPENDIX to Six Month Safety and Efficacy of the BNT162b2 mRNA COVID-19 Vaccine, Page 15, Table S6

We cannot say dose 1 works as well or better than dose 2 from this, because on the long term results most of the patients got both doses in addition to the small numbers. But it does make you think that “Maybe one dose was all you needed.” The risk reward might have looked much better if that change had been implemented. It appears that Pfizer and BioNTech investigators just “guessed” two would be better and went forward without substantial validation in proper phase 2 studies.

And now we are in the worst possible situation. Hundreds of millions of people worldwide have received experimental vaccines on basically about 4.5 months of follow up of all the patients enrolled. That is all we will ever get because Pfizer decided to cross people over and unblind the study.

Now breakthrough infections are (predictably) a problem and there might very well be antibody-dependent enhancement at work. How do we deal with this?

Well now people are suggesting a third jab. We have no data at all if that is safe or effective. But we have these millions of people who could be facing antibody-dependent enhancement (ADE) and we have no idea if it is better to give them a third boost, roll out a new better tailored vaccine for the new variants, or find some other way of dealing with this problem.

If proper Phase II studies were done prior to the Phase III registration studies, we would have a good idea what to do.

Here is how things should have worked. A smaller cohort of patients should have been given one versus two doses and followed up for about 9 months. That would show you the relative advantage of both vaccines and allow you to analyze what happens when antibody titers normalize to baseline.

At the end of that period you might have saw evidence of breakthrough infections like we see now. Then before you went into larger number of patients, you could take the people in the phase II studies and extend it into another placebo controlled study testing if giving the patients in both arms a maintenance dose actually improved outcomes. If it was not effective you could then strategize on other Phase II studies to do to improve the overall outcomes for patients. The company might even decide the long term therapeutic benefit did not justify moving into phase 3 with this vaccine type.

Once the properly done phase 2 studies were completed, there would hopefully be a scientifically validated hypothesis as to what the right dosing regimen would be. That dosing regimen would then be used to conduct larger registration studies that would demonstrate to physicians the real world outcomes when the best possible strategy from a risk reward scenario (at least as per data you have at that point).

And that trial should be carried out for at least 2 years to determine the long term consequences of the treatment before giving it to large numbers of population. We have no earthly idea if other problems might arise with proper followup. That currently statistically insignificant 24% increase in death rate over placebo might actually become statistically significant over time due to underlying cardiovascular injuries caused by the vaccines (such as myocarditis). There is no way of knowing until the studies are done.

But now we are left in no man’s land with hundreds of millions of people in the world’s most ill-advised medical experiment, with people running around desperately trying to figure out how to deal with the “breakthrough cases,” recommending strategies for masses of people supported by no prospective randomized controlled trials. History I predict will not look kindly on public health officials from this error; it will be up there with medieval blood letting and cytotoxic chemotherapy drugs that mainly enhance cancer stem cells. These extra jabs literally could result in massive severe adverse events (SAEs) due to prior immune priming to the vaccine. We have no earthly idea. The studies have not been done.

But We HAD TO Get This Out There…You Know, COVID!

The facts do not bear this out. Pfizer has the most data of anyone, and the latest data we have seen (I want the latest breakdown of deaths on the HIDDEN 21 versus 17 data) suggests a one year morbidity of 0.025% from COVID-19. The death rate in the vaccine is actually 24% higher than control. This is partly driven by a cardiovascular disease rate that has a than 0.11% annual mortality in the vaccine arm the last data we saw (could be higher now, this is based on 15 deaths vaccine vs 14 control we have seen), the degree to which is meaningful we do not yet know. If this is a pressing health emergency, why have we not treated cardiovascular disease with the same alacrity given the apparent risk, approving every new medicine with shoddy and rushed trials when the mortality rate in the Pfizer trial for these events was over 4 times higher (in the vaccine arm) than the placebo COVID-19 risk?

We knew before the EUA was even reviewed by the FDA panel, the mortality and morbidity from COVID-19 was overestimated based on Pfizer’s data submitted to VRPAC. They did not even meet the minimum criteria for EUA approval with no deaths and per pre-established secondary endpoint with 1 severe COVID-19 versus only 3 in the control. That is 1/17,411 = 0.006% severe COVID-19 in the vaccine arm and 3/17,511=0.017% severe COVID-19 in the placebo arm over 1.5 months. Not exactly terrifying…

Source: VRBPAC Briefing Document, Page 31, Table 11

And maybe if they did those phase 2 studies, maybe they would have chosen the dose 1 endpoint instead, and it would have looked better.

And, even if the FDA’s estimate of 0.2% per year was correct, that still is not a pressing health need when you consider the negative effects from a therapeutic that is not properly studied could easily be above that rate.

How many people are these vaccines potentially going to kill due to antibody-dependent enhancement? What about if there is an underlying cardiac morbidity due to massive T cell reactions to mRNA that made its way to the heart after injection? It is hard to tell when you do not have controlled follow up past 4.5 months for the entire study population.

This is not evidence based medicine. This is every bit of scientific quackery that shady supplement companies are accused of.