The subjects wanted to get out of the clinical trial Luft is helping oversee of an experimental vaccine made by another company, Novavax.
They wanted to be “unblinded'' and find out if they had received a placebo in the Novavax study, and, if so, try to get the Pfizer and Moderna vaccines, which have already been proved to be about 95 percent effective at preventing coronavirus infections.
“The number who have been calling me has been significant, and the numbers are increasing,'' Luft, an infectious-disease expert at Stony Brook University Hospital, said in an interview. Fresh recruits also have begun to dry up, he said: “As we are doing our recruitment, all of a sudden the people over 65 became less interested.''
States have responded to the confusing, uneven and slow rollout of coronavirus vaccine by expanding eligibility for the shots ahead of schedule, quickly moving from the goal of immunizing front-line medical workers and long-term care residents into much broader populations of millions of elderly people.
But the moves have instantly made it more difficult to recruit and retain test subjects for clinical trials of vaccines that have yet to win emergency authorization.
The most immediately impacted vaccine trial in the United States involves Novavax, which on Dec. 28 set out to recruit 30,000 people for a major domestic trial, including 25 percent in the crucial over-65 category who are at the greatest risk for serious covid-19 disease.
Two-thirds of the test subjects in the Novavax study are getting the experimental vaccine, and one-third get the placebo, in the type of double-blind clinical trial that is considered the gold standard for testing whether drugs and vaccines work. But without recruiting and keeping a robust cohort of elderly subjects in the trial, the value of the data generated by the trial will be diminished.
“We hope Novavax vaccine will not be derailed by the fact that subjects in the trial would leave the trial to get access to a known vaccine,” Moncef Slaoui, the chief scientific adviser to Operation Warp Speed, said last week at a JP Morgan conference. Novavax and the Food and Drug Administration, which oversees trials, say they remain hopeful the Novavax study can achieve full recruitment.
It is the latest in a series of challenges for Novavax, a Maryland biotechnology company that in July received $1.6 billion in federal taxpayer money via Operation Warp Speed development and manufacturing contracts. Earlier in the year it received nearly $400 million from the Coalition for Epidemic Preparedness Innovations (CEPI), a Norway-based nonprofit that supports global vaccine development.
The infusions of public and nonprofit money have dramatically boosted the prospects of a company that has never had a marketed product in its three-decade history. Its stock price began 2020 trading below $4 per share; it was worth $127.43 on Friday. But the company’s predictions last summer that it would produce 100 million doses by the end of 2020 and early 2021 proved overly optimistic.
The Novavax effort was crippled by manufacturing-related time lags that pushed its Phase 3 trial launch date from the fall into late December — a delay that has now put the company in its current bind over the trial.
Novavax did not have its own manufacturing facility, so it was forced to use contract manufacturers to make its vaccine for trials and eventually commercial operations.
The company said Operation Warp Speed last year kicked it out of its first contract manufacturer in Baltimore, Emergent, which made its early batches of vaccine for small-scale trials, and shifted it to a second manufacturer, Fujifilm, which is making the vaccine at plants in North Carolina and Texas.
The Novavax project was taken out of the Emergent facility to make way for manufacturing for Johnson & Johnson’s experimental vaccine, said Gregory Glenn, Novavax’s president of research and development. Slaoui also wanted Novavax to prove it could produce commercial-scale batches of 2,000 liters at a time in FujiFilm’s facilities, before it launched its Phase 3 trial, Glenn said.
The reason behind the switch and details about the delays have not been previously reported.
The changes pushed the pivotal trial so long into the competition among drug companies that the ability to recruit subjects is disappearing, Glenn said.
“The window is closing on the ability to conduct a randomized trial,'' he said.
Asked to respond, Operation Warp Speed did not directly address the Novavax issues.
Novavax said it had 9,000 subjects as of last week toward its goal of 30,000 and intended to persevere. If it does not recruit enough people over 65 in the United States, it will ask the Food and Drug Administration to consider data from that age group from a smaller trial in the United Kingdom that is fully enrolled, Glenn said. Data from those trials is expected soon.
“If there is some reason we can’t complete the trial, we do have a large, 15,000-person placebo controlled trial from the U.K., and there is every reason to think the FDA would accept that,'' Glenn said. He said 27 percent of the people in that trial were over 65 years old.
The FDA is hopeful there will still be a few months left to push through trials with full participation, but it is willing to look at foreign trial data, said a senior agency official who spoke on the condition of anonymity to discuss internal deliberations.
“We have no problem with accepting data from foreign trials, provided they are conducted under good clinical practices,'' the official said. “We’re in a place here where we’re going to do our best with the data we have because we are in the middle of a pandemic.
“We’re not going to cut corners, but we’re not going to stand on ceremony … It’s not like we’re going to sit there and make rules to make it difficult to use foreign data.''
Specialists in clinical trials said the case of Novavax highlights the predicament in trying to develop a roster of multiple vaccines simultaneously to battle a global pandemic. In the United States and the world, multiple vaccines will need to be deployed to reach the immunization levels needed to reach herd immunity, which is estimated to be upward of 70 percent of the population.
The first two vaccines to win emergency authorization from the FDA, Pfizer and Moderna, were made with novel mRNA technology that allowed the shots to be engineered extremely rapidly. Their rapid development, testing and authorization in December make it difficult to recruit and complete trials by competitors later in the pipeline, according to experts in clinical trials.
“The future of large-scale trials [for coronavirus vaccines] is in doubt,'' said Arthur Caplan, a medical ethicist and clinical trial specialist at the New York University Langone medical center. “The more vaccines appear with either emergency approval, expanded criteria or plain licensing, there’s no way that people are going to sign up for trials with placebo controls.''
Alternatives to placebo-controlled trials are “non-inferiority'' trials, or comparative trials that pit an investigational vaccine or drug up against an existing product. With the high degree of efficacy of the Moderna and Pfizer vaccines, it could be difficult to prove other vaccines are equal or better at immunizing against the coronavirus. But because Moderna and Pfizer require ultracold handling, and there is such a shortage of vaccines generally, there is intense demand for a competing vaccine that can be more easily distributed.
“Given that we need more vaccines on the market, the number of doses and storage requirements all matter. It may not just be about efficacy, it may be about those things,'' said Walid Gellad, director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh.
The FDA official said a number of factors would have to be considered in non-inferiority trials.
“Obviously to do a non-inferiority trial with a vaccine that has 95 percent efficacy is very challenging and it really will depend on the specific vaccine,'' the official said. Mitigating factors for a vaccine that is less effective could be a one-shot regimen, fewer side effects or easier shipping and handling, the official said.
Caplan said the problems with recruitment are bound to increase attention on the potential of “challenge trials,'' in which subjects are given a vaccine and then intentionally exposed to the virus to see if the vaccine works.
Challenge trials are the subject of ethical controversy and would also be unlikely to be tried in older patients who are most at risk of developing severe disease or dying from covid.
Sanofi, which partnered with GlaxoSmithKline to develop a vaccine, also experienced significant setbacks in early-stage clinical trials. It has opted to compare its vaccine candidate with another previously authorized vaccine (which has not been disclosed) in a mid-stage trial in February as well as a subsequent large Phase 3 trial in the second quarter.
Investigators are required to permit subjects to exit clinical trials once proven vaccines hit the market.
Johnson & Johnson said it had fully enrolled its Phase 3 placebo-controlled trial in December. It would not comment for this story.
AstraZeneca said it is nearing complete enrollment of its U.S. trial.
“Regarding unblinding, as vaccines receive emergency use authorization or approval, and participants in the AZD1222 trial are eligible to receive them, we have provided guidance to site investigators and trial participants so they can discuss the options that are available to them,'' AstraZeneca spokesman Brendan McEvoy said in an email.
While Johnson & Johnson and AstraZeneca wrapped up enrollment of their placebo-controlled trials, and Sanofi’s delays are so severe it opted for its non-inferiority trial, Novavax appears to have been caught in the middle — with a placebo-controlled trial that risks falling short.
What Novavax really needs is more test subjects like Maureen Reininger, 65, a retired New York transit system supervisor and analyst who lives in the Long Island suburb of South Hempstead. Reininger was in charge of recovering cash and MetroCards from the booths in subway stations beneath Lower Manhattan after the 9/11 terrorist attacks, and she breathed toxic dust that she said has contributed to chronic sinus problems.
Yet despite New York’s moves last week that made her eligible for the proven vaccines, she said she wants to continue in the Novavax trial, not knowing if she received the vaccine candidate or the placebo. The reason she joined the trial in the first place was altruism, and a sense of contributing to the quest for vaccines, rather than her own possible early access to a shot, she said.
“I just wanted to be of assistance, to be helpful to our fellow humans,'' she said. Reininger added that she is still taking precautions that will protect her if she received the placebo.
“I’m basically not going anywhere outside of my home, and when I do go out, when I go to the supermarket, and I’m in and out, and the mask is on, and I wear gloves,'' she said. “When I do go into areas where there are other people, I physically will remove myself, even when I have my mask.''
Reininger acknowledged one factor that makes her different from many other people over 65 who want faster access to a vaccine: She does not have grandchildren.
“That would change things,'' she said.
Carolyn Y. Johnson contributed to this report.