More than 140 possibilities for making a vaccine against Covid-19 are being studied around the world. The vast majority of them are still just concepts in a lab, but more than a dozen have been injected into humans, mostly in small-scale trials to make sure each formula is safe to receive. Three are headed toward large human trials this summer, and a surprise announcement on Monday revealed that China is allowing military use of one vaccine being developed there.
That pace, faster than any vaccine has ever been produced, is intended to satisfy the US federal government’s goal of delivering a safe and potent vaccine by January. But as developers race toward broad testing, they are about to crash into a complication: the patchwork nature of the pandemic across the United States.
In order to know whether a vaccine works as intended, you have to pick your test site with care: There has to be enough virus circulating there to create a reasonable chance that vaccinated trial participants will be exposed to it. But even though the United States’ case count keeps heading upward, with 2.68 million cases as of Tuesday, the pandemic isn’t uniformly distributed across the country.
What this means: During a trial, vaccine makers always face the possibility of finding out their formulas don’t work. But because of the pressure to achieve a vaccine as fast as possible, they now also run the risk of testing in a place that can’t give them a clear answer. If their chosen test site happens to be where incidence of Covid-19 is low, because the infection curve has been flattened or the virus has barely arrived, the trial may not give them the data they need, and they’ll have to pivot to new sites and risk additional delays.
Trial plans are competitive intelligence, and companies making Covid-19 vaccines aren’t discussing them. But vaccine experts not involved in the trials say the puzzle of accurately siting trials is a known risk. That is true for any vaccine research, but it’s especially important during the coronavirus pandemic because its spread across the country has not been uniform. (For an example, compare the case counts in Arizona and Florida with Montana and Maine.) Making this more challenging still: Aggressive but uneven efforts to suppress cases and deaths—an effort that’s good for public health, but not necessarily ideal for testing vaccines—have only increased its geographic patchiness.
“An important issue with vaccine clinical trials is that you’ve got to go to a place where there’s a high probability of infection—but with the pandemic ebbing and flowing, that can be a bit difficult to figure out,” says Alex John London, a professor and director of the Center for Ethics and Policy at Carnegie Mellon University. “For instance, in the United States, New York would have been a prime target a couple of months ago, but probably less so now, whereas Florida and Arizona might be better.”
But recalibrating to adjust to the ebb and flow of a novel virus requires a nimbleness that can be hard for pharmaceutical companies to achieve. It attests to the reality that everything being attempted to counter Covid-19 is happening faster than normal. (The multi-agency federal program that aims to deliver 300 million doses of an eventual vaccine by January even is called Operation Warp Speed.) Simply getting this far this fast is unusual: In the past, vaccines have taken years, sometimes decades, to go from first concept to delivery into arms (or noses, in the case of some flu vaccines).
A word about how clinical trials work. Candidate vaccines and potential drugs spend years progressing through lab studies, then animal studies, and then tests in humans. The current trials are able to move so fast because the National Institutes of Health is permitting vaccine-makers to skip or delay animal testing. Instead, vaccine-makers are taking their formulas straight into human testing, in three steps called phases.
Phase 1, usually done in fewer than a hundred volunteers, tests for the vaccine candidate’s safety and also tries to determine the right dose. Phase 2 expands the pool to several hundred people, continues to look for safety issues and side effects, and starts to examine whether the vaccine evokes an immune response. Phase 3 uses thousands of people—for the current vaccine trials, an estimated 20,000 to 30,000—who are divided between those getting the vaccine candidate and others getting a placebo, to determine whether the formula actually prevents a disease.
The Phase 3 trials are the stage in which location becomes crucial. If people in the unprotected placebo arm turn out not to have been exposed to the disease, something that would be determined by testing, that means the trial participants who received the vaccine will not have been exposed, either—and thus, that there has been no real test of whether the vaccine works or not.
Three vaccine candidates, by the company Moderna, the University of Oxford with the company AstraZeneca, and the companies Pfizer and BioNTech, have passed to Phase 2 and are scheduled to start broad Phase 3 tests this summer. Another 11 are in Phase 1 or, for speed, a combined Phase 1/2. In addition, on Monday the Chinese pharma company CanSino Biologics announced that it will begin giving its vaccine candidate to China’s military, effectively creating a giant Phase 3 trial.
But to conduct a Phase 3, you can’t just start passing out shots; running a trial requires substantial personnel and physical resources. “Ideally, you need a staff that is already focusing their primary research work on doing clinical trials of vaccines, laboratory capacity that is already doing this work, a surveillance system capable of detecting cases, and a good institutional review board,” says Walter Orenstein, a physician and associate director of the Emory Vaccine Center.
Frequently, those resources reside in a place called a vaccine treatment and evaluation unit, or VTEU, a division within a research university or medical center that receives NIH funding to be a kind of rapid-response unit for testing vaccines. (Emory’s Woodruff Health Science Center houses a VTEU, and is part of the Moderna vaccine’s Phase 2. Orenstein is not involved in that study.) The National Institute of Allergy and Infectious Diseases created the VTEUs in 1962 out of the recognition that recruiting and managing volunteers and arranging lab studies and processing trial results were specialized skills that any one university or company might need infrequently, but that the nation would need access to at all times. That they exist speaks to the amount of infrastructure that is needed to run Phase 3 trials at all, let alone ones that may need to pivot if disease incidence in a location isn’t what developers forecast.
Derek Lowe, a drug-development chemist and author of the long-running blog In the Pipeline, has been forecasting that companies might face difficulty. “The logistics of setting up a Phase 2 or 3 trial are not exactly instantaneous, so it’s not like you can say, ‘Okay, we’re going to test in this one spot,’ (when) the one spot keeps jumping around,” he says. “These are going to have to be—and they probably were always going to be—large multicenter efforts, all across the country or in different countries simultaneously. That’s a bigger, more expensive way to do it. But some of these areas are going to turn out not to be too fruitful by the time you’ve got the trial underway, whereas others will.”
The challenge of choosing where to put a trial inevitably gets you to the ethics that underlie conducting it. In the United States, Covid-19 has hit hardest in disadvantaged communities: among racial minorities, the elderly, and people who live in multi-family housing or operate public transit, among others. Going where the disease is occurring thus poses the possibility of taking advantage of people who are already vulnerable, for the benefit of those who are not.
That’s even more true for trials outside the United States. The first wave of Covid-19 is now washing across low- and middle-income countries; the disease has established itself in South America and cases are rising across Africa. In fact, both Brazil and South Africa are already test sites for the Oxford-Astra Zeneca vaccine.
But there’s a long, ugly history of people in economically-developing countries being exploited by companies from industrialized nations that are seeking to test new drugs and procedures. In 2008, the Dutch nonprofit Centre for Research on Multinational Corporations documented more than 20 trials in which participants were harmed by the drugs they were receiving, or experienced serious side effects, or never received enough information to allow them to give real consent. (The novel and movie The Constant Gardener are inspired by one of them, a trial of a novel Pfizer antibiotic in Nigeria in 1996. Pfizer was sued in the United States and Nigeria over aspects of the drug trial, and settled in 2011.)
Even when participants aren’t directly harmed by a drug or vaccine trial, simply siting the trial in a developing country can invoke uncomfortable questions about power and inducement. The medical monitoring that is part of trial logistics might represent better healthcare than is normally available; cash compensation for participating might represent more money than a local resident could normally earn. As a result, “There are long-standing research ethics questions around conducting research in resource-limited countries,” says Karen J. Maschke, a research scholar at The Hastings Center, a bioethics research institute, who has written about how the race for a Covid-19 vaccine may undermine standards for both ethics and evidence.
The most sensitive question in offshoring trials may be what price drug companies affix to the finished product, and whether that places a new vaccine out of reach of health systems in developing-world countries whose participation made the vaccine possible. That raises further, complex questions of whether the appropriate response is simply to drop or subsidize the price, or whether companies should compensate countries with permanent improvements, from funding clinic construction to helping a country build up lab capacity and personnel.
There are already internationally agreed ethical guidelines, written by the Council For International Organizations of Medical Sciences, that call for negotiating post-trial access to the fruits of human-subject research. London, who participated in a recent rewrite of them, worries that—being guidelines—they don’t go far enough to protect the rights of developing-world trial participants, particularly for something as eagerly awaited as a Covid-19 vaccine. That may be especially true if the situation developers fear for the US—patchy viral incidence rendering a trial not useful—occurs in an international site as well.
“We’ve already seen that different countries have tried to get exclusive access to the vaccine,” London says. “I think that, before we know whose vaccine is the winner, there needs to be international agreements saying that if you host a study and the vaccine that is deployed there turns out not to work, you should get priority for access to a vaccine that does show efficacy—if one does.”
But it’s already well-understood that, at least at first, there won’t be enough doses of effective vaccine to go around. That means companies and governments in industrialized countries would have to agree to give up some portion of a commodity that everyone is jockeying for. Which means, in turn, that achieving a Covid-19 vaccine won’t only be a challenge to the expertise of global science. It will be a test of commitment to global equity, as well.
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