In every drug trial, the third and final stage is the most dramatic and fraught with risk. It involves administering an experimental medicine to human beings to test its efficacy and safety. During a pandemic, the stakes of a Stage III vaccine trial are about as high as clinical trial stakes can get: in the balance is the health of hundreds of millions, if not billions, of people. For this reason, it was controversial among public health experts when the U.S. companies with rights to the earliest and most promising vaccine candidates rejected calls for comparative global trials overseen by the WHO, and instead hired private contractors to run closed human tests in parallel with those conducted by the U.S. National Institutes of Health.
Moderna contracted the North Carolina firm PPD, who in turn subcontracted out the management of dozens of trial centers to smaller companies. One of these, Velocity Clinical Research, made headlines when news broke of its failure to recruit sufficient numbers of minority subjects to provide sufficient data on diverse population groups, thus slowing down the trials and requiring government-run trial centers to “make up” the difference, as one NIH investigator told NBC. More consequentially, neither Moderna nor Pfizer tested on pregnant women during their phase III trials, creating a data gap that officials blame for seeding ongoing vaccine hesitancy among pregnant women. “I think it hurt us to not be able to strongly come out of the gate and recommend these vaccines,” Linda Eckert, the CDC liaison at the American College of Obstetricians and Gynecologists, told Politico.
Earlier this month, the medical journal BMJ added another piece to our understanding of privately administered COVID-19 vaccine trials. The story involves systemic malfeasance by the Texas-based Ventavia Research Group, a contractor hired by Pfizer to manage several vaccine trial sites. A former regional director for Ventavia named Brook Jackson provided the magazine with photo, audio, and email documentation of the contractor covering up employee incompetence and failure to enforce basic protocols during the most important drug trial of the century. According to the BMJ,
the company falsified data, unblinded patients, employed inadequately trained vaccinators, and was slow to follow up on adverse events reported in Pfizer’s pivotal phase III trial. In September 2020, [Jackson] repeatedly informed her superiors of poor laboratory management, patient safety concerns, and data integrity issues. After [she] emailed a complaint to the US Food and Drug Administration (FDA)... Ventavia fired her later the same day.
The story features evidence that Jackson, a veteran clinical research manager, was not telling the Ventavia brass anything they didn't already know. The story quotes one company official telling his fellow executives, “In my mind, it’s something new every day.” This comment, regarding major breaches of protocol and sloppy procedures, was made before Jackson's hiring in the summer of 2020. Also that month, company executives circulated a to-do list that included meetings with three site staff members on the subject of “falsifying data, etc.” One of these staffers was “verbally counseled for changing data and not noting late entry,” a note indicates. According to the BMJ, “Staff who conducted quality control checks were overwhelmed by the volume of problems they were finding.”
Due to FDA staffing shortages, whistleblower complaints like Jackson’s are often belatedly investigated, if they are investigated at all. “There’s just a complete lack of oversight of contract research organizations and independent clinical research facilities,” Jill Fisher, a medical school professor and author of Medical Research for Hire: The Political Economy of Pharmaceutical Clinical Trials, tells BMJ.
The problems brought to light by Jackson point to the larger question raised by allowing companies to control trials in which they have a vested interest in the outcome. As with so much else, COVID-19 has offered a dramatic context for examining these issues, beginning with a forgotten blueprint prepared by the WHO experts that gave the disease caused by SARS-CoV-2 its name, weeks before it officially became a pandemic.
On February 11, 2020, the world knew enough to be worried about the novel coronavirus that emerged in Wuhan, China the previous December. But for much of the public, it was just a simmering anxiety. The virus known as 2019-nCoV was officially still only classified as a Public Health Emergency of International Concern. Yet professional in the field strongly suspected what was to come. In Geneva that week, several hundred infectious disease and public health experts gathered with a sense of borrowed time for a two-day Research and Innovation Forum convened by the WHO and the EU-funded Global Research Collaboration for Infectious Disease Preparedness, a consortium of dozens of leading research institutes.
After returning home, attendees produced a research roadmap for what they feared might be required to contain a pandemic. It covered a wide ambit, including the state of science around coronaviruses, how to put that science on tracks to develop diagnostics, treatments, and vaccines, and how to build and broaden channels of communication and information-sharing between scientists around the world to accelerate innovation.
The sixth item of the roadmap involved a blueprint for global comparative trials of vaccines and treatments. The reasoning was straightforward and seemingly obvious: in a pandemic, global trials would allow for a rapid comparative analysis of vaccines and medicines across a genetically variant population of nearly eight billion people. A trial pitting vaccine versus vaccine is better than one that measures a vaccine versus placebo. “Rapidly developing master protocols for clinical trials,” the blueprint stated, “will accelerate the potential to assess what works and what does not, improve collaboration and comparison across different studies, streamline ethics review and optimize the evaluation of new investigational drugs, vaccines and diagnostics.”
The protocol for what became known as the WHO vaccine “Solidarity trials” was published that summer. However, none of the companies with vaccine candidates in development expressed any interest in participating; nor did their patron governments include any mention of the WHO trials in their funding contracts. In September, the WHO committee that drafted the protocol took to the pages of The Lancet to explain the benefits of a multi-country vaccine trial involving dozens of hospitals and hundreds of trial sites around the world, including “pop up” sites in places with high infection rates.
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“In comparison with individual trials for each of the many different vaccines, a global multivaccine trial with a shared control group could provide more rapid and reliable results,” wrote the group, who included U.S. officials from NIH and the FDA, as well as WHO scientists and dozens of leading academic researchers.
The group explained how the WHO trial would not only yield more and better information, but would also save time and effort in comparison to the individual commercial trials preferred by the drug companies. “High enrollment rates facilitated by flexible trial design and hundreds of study sites in high-incidence locations could yield results on short-term efficacy for each vaccine within just a few months of including that vaccine,” they wrote. Relying on commercial contractors to conduct black box studies on uniform populations risked presenting a partial, flawed picture of the vaccine candidate’s value. This flawed picture presented a danger, insofar as it “might not provide sufficient evidence of safety or efficacy in other populations.” Based on the results, the WHO vaccine coalition would fast-track the most promising candidates for Phase II and III clinical trials.
As the vaccines moved forward toward human trials, calls for putting mRNA vaccines under the purview of the Solidarity vaccine trial went nowhere. The reason for Moderna and Pfizer's silence was not hard to guess. Although participation would not have required they give up any proprietary information related to the production of the vaccines, it would have resulted in transparent trial data, which drug companies consider a valuable category of intellectual property. It also risked exposing the benefits of the competition—or the dangerous side effects on its own candidate—in front of the entire world.
“The rejection of the Solidarity trial showed the companies were willing to put profits above people, above containment of the virus, and even above the efficacy of their own products,” says Dr. Satyajit Rath, a former researcher at India’s National Institute of Immunology.
He continued, "Companies like Pfizer and Moderna laughed it out of court. They basically said, ‘Are you nuts? Why would we subject our candidate to a comparison that could reveal its limitations?’ There’s no question comparative trials would have yielded more precise information about relative strengths and limitations of each vaccine candidate. But it went against the profit-maximizing approach by taking the trial into a public, transparent space. Damned if they were going to do that.”
On October 6, 2020, weeks after the Lancet appeal, Reuters broke the story of a pause in Moderna’s vaccine trial due to the above-mentioned shortcuts taken by its private contractor, Velocity Clinical Research. The testing company had enrolled 30,000 people at a single test center, and fallen short of needed racial and ethnical proportion requirements by nearly fifty percent. Racial outreach is “not something that is part of the business model of commercial research organizations,” the co-director of the National Institutes of Health’s Trials Network explained to the news agency.
Velocity’s chief executive, meanwhile, deflected the unwanted attention by pointing to cultural barriers beyond his company’s control. “If there’s a problem with recruiting minorities, and there is, you can’t fix that overnight,” said the CEO. Getting the needed number of Black, Latino and Native volunteers is, he said, “notoriously difficult.”
Needles to say, it would not have been difficult had the vaccine been provided to the WHO network spanning 190 countries.
Unlike the Solidarity vaccine trial, the WHO’s Solidarity therapeutics trial did not require the consent and participation of the originator companies. And so, for six months beginning in February 2020, the WHO conducted randomized global mortality trials to test four antiviral drugs being repurposed as investigational COVID treatments: Remdesivir, Hydroxychloroquine, Lopinavir (used in combination with Ritonavir) and Interferon-β1a.
Only one of the four drugs was under patent: remdesivir. While the WHO conducted its trial, the drug grew to become Gilead’s second biggest seller, netting nearly $1 billion in revenues as a treatment to slow the progression and reduce the mortality of acute COVID-19. The publication of the WHO trial data was a blow to the future of these profits. Appearing in the NEJM just as Gilead was putting the final touches on remdesivir’s relaunch as the branded drug Veklury, the WHO data showed much weaker activity against COVID than the private trial data being touted by the company. That private trial data, meanwhile, came under scrutiny for a number of red flags, which some observers believed merited rejection by the FDA. Dr. Peter B. Bach, the director of the Center for Health Policy and Outcomes at Memorial Sloan Kettering Cancer Center, told the New York Times, “This is an extremely weak set of trials to support an approval for an antiviral.”
Gilead, for its part, responded to the WHO Solidarity trial results with a same-day press release that attacked the merits of the independent, six-month global trial. “The emerging [WHO] data,” the company stated, “appear inconsistent with more robust evidence from multiple randomized, controlled studies published in peer-reviewed journals validating the clinical benefit of Veklury®.”
Of the trials cited by the company, Gilead paid for two of three.