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Fears about overly accelerated development programs has heightened demands for wider access to information on study protocols, statistical analysis plans, and early results.
With all eyes on efforts to research and test potential vaccines and therapies to combat the coronavirus pandemic, fears about overly accelerated development programs has heightened demands for wider access to information on study protocols, statistical analysis plans, and early results. One aim is to address concerns that political pressure from the White House might lead to FDA authorization or approval of a COVID-19 vaccine before Phase III data have been fully evaluated.
Leading vaccine manufacturers have responded by taking the unusual step of disclosing full clinical study protocols for their late-stage randomized, blinded, placebo-controlled studies. After the CEO’s of nine companies pledged to collect sufficient data to demonstrate product safety and efficacy before seeking FDA approval, Moderna CEO Stephane Bancel made public its 135-page protocol specifying its plan for randomization of 30,000 patients, how they are selected based on age and likely risk, and listing of all recruitment sites in the United States. The document specifies the plan for blinding, randomized assignment to placebo, efficacy assessments, and statistical analysis plan for determining when the study meets its endpoints and that an independent data monitoring committee is slated to compare efficacy of vaccine to placebo initially when 53 and 106 cases are confirmed, and then after 151 cases of infection. An independent data monitoring committee is slated to compare efficacy of vaccine to placebo initially when 53 and 106 cases are confirmed, and then after 151 cases of infection.
Pfizer and AstraZeneca similarly released their trial protocols, acknowledging the need for greater transparency in COVID-19 vaccine research. The Pfizer document specifies the vaccine candidate and dose for Phase II/III testing and the number of trial participants, including age groups and evidence of infection before vaccination. It describes dosing schedule, adverse event assessment, and the plan for interim analyses of data. Here, the sponsor will utilize an internal Pfizer committee to review data plus an external data monitoring committee to review cumulative unblinded data throughout the study. Pfizer expects to assess a total of nearly 44,000 participants, half receiving the vaccine, in anticipation that this will yield 164 primary-endpoint cases within six months.
And AstraZeneca’s protocol indicated a goal of 50% effectiveness, with statistical confidence to be met when 150 trial participants become ill. The plan calls for only one interim analysis, compared to more for the other manufacturers, and it might be halted early if the vaccine is 50% effective with fewer cases of contamination.
These disclosures came on the heels of efforts to resolve a report of a serious adverse event in the AstraZeneca trial that halted its Phase III study, generating criticism of the company for failing to reveal specifics on the safety issue, which outside clinicians termed a rare spinal inflammatory disorder called transverse myelitis. Although clinical trials for the vaccine resumed quickly in the United Kingdom, Brazil, and South Africa, US studies remained on hold as officials at the National Institutes of Health (NIH) urged delay pending further investigation into the cause and nature of the adverse event and whether it was triggered by the vaccine or an unhappy coincidence. US authorities said they wanted to examine tissue or blood samples from the British patient to evaluate the case further and hopefully avoid increased vaccine hesitancy in the US.
The disclosure of usually confidential details on research plans responded to concerns raised by leading scientists and research authorities about the need for more transparency in vaccine studies to promote public confidence in the independence and reliability of clinical research on pandemic vaccines and therapies. Although vaccine developers were providing the usual public information on study sites and enrollment plans, experts continued to seek more details on statistical analysis plans that would allow more public assessment of adverse events and research outcomes. And they wanted to know when sponsors were likely to seek input from independent data safety monitoring boards on whether to stop a trial early—either to assess a safety issue or to file an emergency use authorization (EUA) with FDA. With the federal government providing billions in support of vaccine development programs, independent scientists insist that the public should have that kind of information.