Many covid-19 patients are still receiving these drugs, which have only been tested to treat malaria, through a program known as “expanded access.” Their approval for covid-19 use could also be much quicker than many drugs, thanks to the Food and Drug Administration’s expedited review process. Both expanded access and expedited review were changes the FDA instituted in response to an earlier pandemic: the AIDS crisis. Covid-19 is not the same as HIV, which was much deadlier. Given how different the diseases are in both their mortality rates and transmission methods, the FDA may reach very different conclusions on whether to approve the malarial medicines — or other drugs — to treat covid-19. However, the agency is balancing similar concerns as to scientific integrity, patient safety and compassionate care today as it was in the 1980s.
In 1982, accounts surfaced of a mysterious and deadly new disease affecting gay men. Within five years, more than 4,000 Americans had perished from the virus, which weakened its victims’ immune systems. Infected people typically developed skin tumors, had difficulty breathing, suffered chronic diarrhea and wasted away from malnourishment. With limited treatment options, and only one approved drug more than half a decade into the epidemic, AIDS activists were enraged. They directed their fury at the government agency that held up medical testing through a morass of arcane regulations.
On Oct. 11, 1988, the group that would become the AIDS Coalition to Unleash Power (ACT UP) converged on the FDA in Rockville, Md. Holding signs that read “the FDA has blood on its hands,” protesters chanted “FDA, don’t delay, 52 will die today” as hundreds of scientists looked askance through the building’s windows. In nearby Bethesda, at the National Institutes of Health (NIH) campus, activists waved banners that read “Stop Killing Us!” and “NIH Wake Up!” One of those watching from his office above was Anthony S. Fauci, the director of the National Institute of Allergy and Infectious Diseases, who today is the scientist leading the government’s covid-19 response. In 1988, Fauci was the face of the federal government’s effort to combat AIDS.
The protesters demanded more drugs — and faster access to them. New medications go through three phases of testing. The first involves a small group to ensure the drug is safe. The second focuses on efficacy, using a larger sample of patients, while the third provides more evidence as to both safety and efficacy in an even larger population.
Protesters wanted people with AIDS to have immediate access to drugs that had made it through the first phase because these experimental medications were all that was available. The only alternative was to wait to die. Protesters also derided the idea that testing had to take years, particularly since other countries approved drugs in a fraction of that time. People with AIDS, who only had a few months to live, did not have the luxury of waiting.
Scientists worried about a conflict between drug access and scientific research. Unrestricted access to experimental treatments might hamper the ability to conduct trials, since patients had little incentive to enroll in a controlled study when they could have the medicine anyway. AIDS activists explained that existing policies actually undermined studies, since patients frequently bribed or lied their way onto studies and mixed drugs to reduce the risk associated with being on a placebo. Patients also mixed drugs in the hope of finding something that worked, which muddled the test results.
Most people with AIDS did not qualify for the clinical trials anyway because they were also taking medications to treat diseases that would be fatal to them because of their HIV status, like pneumonia.
To increase access to medication, ACT UP activists proposed a “parallel track” program, under which people with AIDS who were unwilling or unable to participate in clinical trials would receive free drugs that were undergoing Phase II clinical trials. The program expanded the FDA’s compassionate use policy, which allowed doctors to request experimental drugs undergoing Phase III trials for their patients suffering from life threatening diseases, where there were no satisfactory alternatives available. At the time, the request process took doctors so long that few even tried to get the FDA’s approval, which it granted on a case-by-case basis.
The parallel track, which supplemented the compassionate use exception, provided patients easier access to drugs at an earlier point in time. Fauci quickly endorsed the parallel track program, which ultimately proved that scientists’ concerns had been unfounded, as patients continued to enroll in clinical trials. The FDA has since streamlined compassionate use and combined it with the parallel track program under the heading of “expanded access.”
Activists also urged the FDA to complete their review more quickly through an expedited approval process. Drug testing took years, in part because of the standards that clinical trials had to meet. Where a drug claimed to reduce the likelihood of death from AIDS, companies were required to submit long-term studies that compared patients taking the drug with a control group.
Activists urged the FDA to use a “surrogate marker,” meaning a measure that correlated with the drug’s hoped-for-benefit, to evaluate a medication’s efficacy. For AIDS, that surrogate marker was the drug’s effect on T cells. HIV, the virus that causes AIDS, reduced T cells, which are white blood cells that fight infection. When T cell counts dropped below a certain level, a person was diagnosed with AIDS. Given that T cell depletion was the hallmark of AIDS, it was likely that a drug’s positive effect on the cell count would translate into improved patient outcomes, as patients would have stronger immune systems to fight off things like pneumonia.
The FDA was hesitant to approve drugs based on a surrogate marker because doing so introduced greater uncertainty about a drug’s effects. No one could be sure that the surrogate was an adequate stand-in for the medication’s ultimate goal. The drug might improve a patient’s T cell count, while not improving the person’s ultimate prognosis. Given that people with AIDS were unlikely to live long enough for the drugs to reach the market, activists insisted patients had the right to take a chance on medications that might help them.
To resolve the tension between scientific standards and compassion for patients, activists promoted a conditional approval plan. Under this framework, the FDA could revoke a drug’s license if later studies failed to prove it did what researchers claimed. In 1991, the FDA agreed to use T cell counts as a surrogate marker and conditionally licensed the first of several new AIDS treatments. The FDA now grants conditional approval pursuant to an accelerated approval program. The agency also designates certain drugs as “fast track,” which provides access to accelerated approval and priority review.
AIDS was a merciless and lethal disease until the FDA’s new programs made drugs easier to test and more widely available. These changes to FDA policy did not just change the course of the AIDS epidemic, but also will play a role in how covid-19 treatments are tested, and how quickly patients have access to them.
The anti-malaria medications in limited use are not the only treatment options for coronavirus. Remdesivir, the antiviral originally developed to treat Ebola, is being made available to patients by its manufacturer Gilead through the parallel track option, although studies so far are inconclusive.
Like HIV treatment options, the FDA has to balance rigorous scientific testing with the needs of patients. A drug’s side effects may tip the scales against accelerated approval, particularly since covid-19 is not nearly as deadly as AIDS. Thanks to the AIDS activists who pressed the agency to clear their red tape, however, the FDA has a process to evaluate those competing concerns, though that same mechanism assumes the agency will carefully weigh the data on the drugs’ effects.