Wednesday, July 28, 2021

All You Will EVER Know About This mRNA Goo Is What We Choose To Tell You!!!

bmj  |  Duration of protection is not the only question that longer, placebo controlled trials can address. They also address vaccine safety.

“Very often, it’s the fact that we have that placebo controlled follow-up over time, that gives us the ability to say that the vaccine didn’t cause something at a longer period of time after vaccination,” the FDA’s Philip Krause explained last December.13

Yet there is a gap—currently of unknown size but growing—between any expectation of blinded placebo controlled data, and the reality that within weeks of the vaccines receiving an EUA the unblinding of trials commenced as placebo recipients were offered the chance to get vaccinated.

Steven Goodman, associate dean of clinical and translational research at Stanford University, told the FDA in an invited presentation last December, “Once a vaccine is made widely available and encouraged, maintaining a double blinded control group for more than a nominal period is no longer in the investigator’s (or regulator’s) control and undue pressure to do so may undermine the entire vaccine testing enterprise.”14

Goodman’s recommendation was to rapidly convert the trials into crossover studies, enabling those on placebo to get vaccinated (and vice versa), while maintaining the blind. The companies challenged the feasibility, calling it “onerous,” and a crossover never occurred.15

The BMJ asked Moderna, Pfizer, and Janssen (Johnson and Johnson) what proportion of trial participants were now formally unblinded, and how many originally allocated to placebo have now received a vaccine. Pfizer declined to say, but Moderna announced that “as of April 13, all placebo participants have been offered the Moderna covid-19 vaccine and 98% of those have received the vaccine.”2 In other words, the trial is unblinded, and the placebo group no longer exists.

Janssen told The BMJ: “We do not have specific figures on how many of our study participants have received a vaccine at this time.” But the company confirmed it was implementing an amended protocol across all countries to unblind all participants in its two phase III trials, the earlier of which passed the median of two month follow-up mark in January.

How the FDA will weigh the loss of blinding and placebo controlled follow-up is unclear, but just months ago the agency said these trial properties were vital.

“Continuation of placebo controlled follow-up after EUA will be important and may actually be critical to ensure that additional safety and effectiveness data are accrued to support submission of a licensure application as soon as possible following an EUA. … Once a decision is made to unblind an ongoing placebo controlled trial, that decision cannot be walked back. And that controlled follow-up is lost forever,” the FDA said last October.3

At its next advisory committee in December 2020, the FDA reiterated the importance of the placebo group: “Placebo controlled follow-up can be very important in showing that whatever happened in the vaccine group also happened in the placebo group. Because that’s our best way of knowing.”13

What’s the rush?

The US’s “Operation Warp Speed” delivered on its promise to get a novel vaccine into arms in record time (box). Millions of doses of vaccines are being administered daily across the US, making clear that lack of FDA approval is no barrier to access. So just what benefit is there in seeking, and granting, a BLA?

The BMJ asked the manufacturers why they were seeking a BLA. Moderna did not respond and Janssen only confirmed it intended to apply for a BLA “later in 2021.” Pfizer likewise did not answer but instead quoted an FDA webpage on medical devices, which stated: “Sponsors of EUA products are encouraged to follow up the EUA with a pre-market submission so that it can remain on the market once the EUA is no longer in effect.”16 But EUAs have no built-in expiry date—in fact, 14 EUAs for Zika diagnostic tests remain active despite the public health emergency expiring in 2017.17

Cody Meissner told The BMJ he saw some distinct advantages of a BLA over EUA. An approved vaccine, for one, would provide “an element of assurance,” increasing public trust in the vaccines, particularly for those currently sitting on the fence. It would also pave the way for claims of vaccine injury to be routed through a more established compensation programme, and for adding the vaccine to government funded schemes to reach children in financial need.18 Finally, it may affect the potential for vaccine mandates: “It is unlikely these vaccines will be mandated while an EUA is in place. Remember that currently these vaccines are still considered experimental.”

While still under EUA, an increasing number of educational and other institutions have already mandated vaccines, but debates over the legality of these actions has hinged on the distinction between authorisation and approval.19

But approving a vaccine in order to legally support mandates or convince people of its safety arguably puts the cart before the horse. Meissner responded that a BLA would not be issued until the FDA is convinced of the short and long term safety of these vaccines.