After the ACT UP occupation, Grossman writes, the F.D.A. “never really resumed business as usual.” In 1992, it introduced a pathway called “accelerated approval,” which could be granted to drugs that showed an impact on a biomarker associated with a given disease (H.I.V. viral load, for example), even if they hadn’t yet demonstrated a clear clinical benefit. The agency had also formalized its commitment to “expanded access,” a way for patients with serious or life-threatening diseases who had no other options to get investigational drugs. In 1997, Congress allowed the F.D.A. to approve drugs on the basis of a single trial, as long as the evidence was persuasive enough. The entire orientation of the agency changed. It was no longer chiefly protecting patients from drugs that might hurt; it was now trying to facilitate consumer access to drugs that might help.
Brian Wallach grew up in Washington, D.C., the grandson of the last U.S. Ambassador to Iran and the son of establishment lawyers. He served as a political director on the first Obama campaign, where he met his wife, Sandra Abrevaya, a communications director. He then got a job in the White House counsel’s office, and later served as a federal prosecutor in Chicago. In 2017, while he was working on a gun-trafficking case, his left hand started to cramp. He dropped his pen, then dropped it again. A few months later, on the same day that the couple brought their second daughter home from the hospital, he was given his diagnosis and told that he had perhaps six months to live. In March, I spoke with Wallach and Abrevaya, as they were preparing for a ski trip to Colorado. Wallach has curly graying hair and sensible blue-rimmed glasses. He spoke into a small marshmallow of a microphone, and wore around his neck a voice amplifier that resembles a camera, giving him the look of an unapologetic tourist. A varsity-style banner on his wall reads, “Joy is an act of resistance.” When he first told friends about his diagnosis, he said, he often found himself doing the consoling. “My family never knew if the vacations we were on would be the last,” he told me. “I’m someone who’s stubborn and optimistic, so it was my job to say, ‘This is awful, but we will find a way forward.’ ”
Wallach and Abrevaya founded I AM A.L.S. as a “patient-centric, patient-led” organization. One of his goals, as a proper Obama disciple, was to “change the narrative” around the disease. He and Abrevaya remember turning off a “60 Minutes” segment about A.L.S. because it was so depressing. “We knew this was not the whole story,” he told me. Researchers felt that the Ice Bucket Challenge had put them in a position to make great advances, but they needed influential allies. “The fuller story was one of hope, and the only question was when that hope would be realized,” Wallach said. He read every book he could about AIDS activism, and learned that only a “sustained advocacy presence” in D.C. could make A.L.S. a priority. The group hired a lobbying firm and helped form an A.L.S. congressional caucus, which worked to pass legislation that directs a hundred million dollars a year to research. Wallach hand-delivered an open letter to the F.D.A. inquiring after treatments that were “stuck in the pipeline.” In a short film circulated by the Obama Foundation, Abrevaya describes the couple as “back in campaign mode. We spend our date nights editing Web-site copy and coming up with awareness strategies.”
One of the ways I AM A.L.S. differentiated itself was its relentless pursuit of any treatment that seemed promising. Wallach told me that modest gains could add up: “When you’re dealing with a terminal illness, you piece together the therapies that keep people alive longer until more curative therapies come on the market.” The F.D.A. had made it clear that Amylyx was expected to complete another trial, but Wallach knew that the agency could approve the drug immediately. Scientific certainty was a luxury that only the healthy could afford. He and other patients were already buying a version of the product from compounding pharmacies, for about seven thousand dollars a year. “I will give credit to those drugs for me being here well past the point when I should have passed away,” he said. The A.L.S. Association, which some patients had criticized for failing to advocate more aggressively for other experimental medicines, launched an e-mail campaign. Members met with regulators, including the acting director of the F.D.A. “I saw on the campaign and in the White House how important it was for people in Congress to know who you are,” Wallach said. “When we announced my diagnosis, everyone reached out and said, ‘How can I help?’ ”
In late May of 2021, the A.L.S. Association convened an event called the We Can’t Wait Action Meeting. A patient named Troy Fields expressed frustration that a purported survival benefit of several months, in patients who live only a few years, had been described as “modest.” “For me, this could mean walking my daughter down the aisle at her wedding, or witnessing my grandson’s birth,” he said. Sandy Morris, a well-known A.L.S. activist, told a story about a friend, Cory, who had surveyed the community and determined that patients had a “sky-high acceptance” of the potential risks. “Cory died waiting,” she said. “I am here today to say that I am dying waiting.”
Wallach called for a congressional hearing, and his wish was swiftly granted. At the hearing, Representative Anna Eshoo referred specifically to Amylyx’s drug as she interrogated an F.D.A. official about agency sluggishness, a rare congressional endorsement of an investigational treatment. Representative Jan Schakowsky, who beforehand had met with Wallach, a constituent, thanks to Abrevaya’s connections, told a story about a friend with A.L.S. who had chosen assisted suicide. “If I sound upset—because my constituents are here—I have been getting calls from their friends all over the country, who are begging for a bit of hope,” she said. Wallach, in his testimony, noted that thousands of patients were watching. “Some of them have waited and postponed their decision for suicide to see this hearing,” he said. “When you are diagnosed with A.L.S., you are told you have two to five years to live. So if this won’t be on the market for four years, every single A.L.S. patient, including us, will be dead.” Two months later, the F.D.A. reversed its position, and invited Amylyx to submit its application.
Contemporary patient advocacy might owe its energy and ambition to AIDS activists, but the radical theatricality of the eighties and nineties—wrapping Jesse Helms’s home in a giant condom, scattering victims’ ashes on the White House lawn—has largely given way to a shrewd professionalism. The A.L.S. Association’s office, in Rosslyn, Virginia, could be confused with the glossy sanctuary of a midsize lobbying firm. When I visited, in March, Calaneet Balas, the C.E.O., told me that the group’s goal is “making A.L.S. livable”—an objective that means different things to different people. What we now call A.L.S. might ultimately be understood to encompass several different diseases. For ten per cent of patients, the disease is linked to known genetic mutations. For the remaining cases, environmental and behavioral factors are presumably relevant. There are unexplained clusters, for example, in Ohio and Michigan, and veterans are more than twice as likely to contract the disease. At the A.L.S. Association’s urging, the V.A. has designated the disease as connected to military service, which has unlocked additional benefits. Before Amylyx’s drug, the Association hadn’t involved itself in an approval process—not that it had many opportunities to do so. But the group was invested in this drug, both literally—it stood to make a return of a million dollars on its original grant, which it planned to dedicate to future research—and symbolically: approval would pleasingly close the loop on the Ice Bucket Challenge. Still, Thakur, the chief mission officer, told me that the organization was ultimately convinced by the evidence: “We don’t want to be confused with a group that’s not scientific.”
AIDS advocacy—which drafted on previous movements—helped adapt the health-care system to the desires of patients. Today, they are consulted at every stage of the drug-development and approval process: they help shape funding strategies at the National Institutes of Health and contribute to technical debates over trial design, study criteria, and the relevance of particular metrics to their own experiences. As an F.D.A. representative put it, patients come to the table with their own Ph.D.—“personal history of disease.” Patient-advocacy organizations have flourished, and some have been extremely fortunate in their strategic decisions: the Cystic Fibrosis Foundation funded research into drugs that have proved nothing short of magical for some patients, transforming a death sentence into a manageable condition.
Investments in basic research, however, are generally long-term bets, and people with terminal diagnoses are understandably impatient. They have come to see drug-approval decisions as their moments of maximum leverage. As Grossman put it to me, advisory-committee meetings, in which outside experts advise the F.D.A. on particularly vexing cases, “used to be snorefests, just a group of green-eyeshade people sitting around running numbers. Now, depending on the drug, they’ve turned into fora for public advocacy.” Many patient-advocacy groups are lushly funded: last year, the Alzheimer’s Association’s revenue was about half a billion dollars. A study in The New England Journal of Medicine found that at least eighty-three per cent of the largest groups receive money from pharmaceutical companies. “H.I.V. activism was a true grassroots movement, not one funded by drug companies,” Daniel Carpenter, the author of “Reputation and Power,” a colossal history of the F.D.A., told me. “I don’t want to say everything since then has been astroturfed. But companies do learn the lesson of ‘Oh, that’s how you get a drug through the F.D.A.’ ”
Groups that are wealthier and better coördinated have significant advantages: breast-cancer advocacy organizations have been particularly potent, and Carpenter has shown that they enjoy much faster approval times than groups dedicated to prostate cancer, which is similarly prevalent, or to lung cancer, which is deadlier. In 2002, lung-cancer patients coalesced in support of Iressa, a drug that faced considerable F.D.A. doubt; the drug was approved, and is still prescribed to a subset of patients. In 2016, parents of children with Duchenne muscular dystrophy pressured the F.D.A. to green-light a drug that had been studied in a single uncontrolled trial of only twelve boys. Hundreds of supporters flocked to an F.D.A. committee meeting, including several children in wheelchairs, and the approval camp prevailed.
It wasn’t until recently that the role of advocacy groups provoked public scrutiny. In June, 2021, the F.D.A. announced the accelerated approval of Aduhelm, the first new treatment for Alzheimer’s in eighteen years. Aduhelm reduced levels of amyloid plaques in the brain, a biomarker that tracks with cognitive decline. But the drug seemed to do little, if anything, to arrest or reverse the course of the disease. It also carried the risk of serious adverse effects, including brain bleeding. Nevertheless, many enrollees felt sure that their progression had been slowed. The Alzheimer’s Association—which had collected about half a million dollars that year from the drug’s sponsor, Biogen—exhorted its members to plead the drug’s case. (The Association’s C.E.O. at the time said that its actions were not affected by pharmaceutical funding.) An F.D.A. advisory committee voted against the drug’s approval, but the committee was overruled by the F.D.A.
The drug was put on the market at a cost of fifty-six thousand dollars a year. Three members of the committee resigned, among them Aaron Kesselheim, a professor at Harvard Medical School, who declared the ruling perhaps “the worst approval decision that the F.D.A. has made that I can remember.” Kesselheim saw it as part of a long war of attrition. “In recent years, under steady pressure from the pharmaceutical industry and the patient groups it funds, the F.D.A. has progressively lowered its standards,” he wrote. (Biogen stands by the drug, and maintains that it satisfied the requirements for accelerated approval.) Some patients felt as though they’d been sold a bill of goods; a retired neurologist in the early stages of the disease told the Times that he found the Alzheimer’s Association’s campaign “shocking and irresponsible.” But perhaps no one was as crestfallen as A.L.S. advocates, who lamented only that the F.D.A. had not yet shown them the same generosity.
In March, 2022, the F.D.A. gathered an advisory committee to discuss Amylyx’s application. Members would be asked to vote on whether the results so far “establish a conclusion” that the drug is “effective.” Agency officials, in their briefing documents, were polite, respectful, and unequivocal: the answer, as far as they were concerned, was no. One of the members of the committee was Caleb Alexander, a soft-spoken pharmacoepidemiologist at Johns Hopkins, who spoke with me from a sabbatical in Munich. He told me he wished that the evidence had been more persuasive. “Too bad but I suppose this is why one has advisory committees,” he wrote in his notes.
As the agency saw it, there were a number of problems with the trial. Recruits had been told that they might experience gastrointestinal side effects, so they could have guessed if they were getting the real thing or a placebo—a salient issue for a trial that relied on self-reported measures. Trickier still were potential “baseline imbalances,” especially during the trial’s extension: those who switched from the placebo to the drug were, on average, healthier than those who had dropped out along the way, which might have exaggerated the ostensible effects. Some outcomes were also compared with “external” controls—that is, data from patients in previous decades, when the general standard of care was lower. Most important, the F.D.A. had proposed one method of statistical analysis, but Amylyx had elected to use an alternative. When the F.D.A. subjected the data to its own test, the results were no longer statistically significant. (Administrators defended their analysis, and argued that the other apparent issues were either negligible or addressed.) Alexander told me, “It was like fourth down in football, where you have to bring out the measurement tape to see if you got a first down or not.”
The agency was reluctant to accept the apparent five-month survival benefit, which it regarded as the result of a statistical fishing expedition. Alexander told me, “I was mindful of the old Texas sharpshooter fallacy—you shoot holes in a barn and draw bull’s-eyes around those holes.” The agency did not rule out the possibility that the drug might do something. But the standard for approval is not “promising”; it is “substantial evidence of effectiveness.” Cudkowicz said, “In the end, we just didn’t know who was right. This was a really small study that was never designed to do what it was being asked to do.”
The patients, for their part, seemed unable to believe that this discussion was happening at all. They felt as though they were being buried alive by the disease while the F.D.A. was making a fuss about confidence intervals and P values. Wallach told me that the agency’s position had been pushed primarily by its biostatistician—the last defender of a retrograde regime that sought “one-hundred-per-cent certainty that a drug works.” Patients recruited by the advocacy groups told agonizing stories. When Jeff Derby was diagnosed, in 2018, his neurologists told him to get his affairs in order and to eat whatever he wanted. He believed that his presence at the meeting was due to Amylyx’s drug. “I have seen six A.L.S. patients in my social circle over the past two years pass away without it, and yet their timeline was similar to mine,” he said. He asked committee members to imagine having a loved one with A.L.S.: “Even if it is only six and a half months, would you not want that for them?” Sandy Morris, the patient activist who had commanded the room during the We Can’t Wait meeting, now spoke mostly through her daughter. “My apologies for my compromised voice,” she said on her own, at the end. “Maybe if I had been allowed to take AMX0035 you would be able to hear me more clearly.”
Alexander told me, “Those clips from the meeting are very compelling. But they’re not talking about the scientific merits at hand. Some of the patients just assume the five-month purported benefit is real. Didn’t they realize just how large the probability was that the drug won’t work? That this might not be a one-per-cent chance it won’t work but a good chance?” As Jonathan Glass, an Emory University researcher and physician with three decades of experience treating A.L.S. patients, told me, “What are we selling to patients? Are we selling hope? Is that what we should be selling? Or are we selling things that we know really work?”