When Dying Patients Want Unproven Drugs

A very interesting although long read, covering ethical questions and effective advocacy. I hope as many people as possible read it. The article, I think, evenhandedly discusses the often conflicting approaches of allowing easy access to the hope that a new drug can provide versus advocating for high quality research and ensuring that scarce government funding goes only to treatments that really help.

Some excerpts for people who can't tackle the article:

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.

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.

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.

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.’ ”

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.



Re Amylyx for ALS:
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.

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.


On the utility of placebo-controlled trials versus evidence from clinical use:
The accelerated-approval pathway is supposed to split the difference by making drugs available while confirmatory trials are pending. Once a drug is on the market, however, it can be difficult to recruit participants for placebo-controlled trials. (Why would anyone risk getting a sugar pill when she could get the real thing?) The remaining option—a process of trial and error—sounds more plausible in theory than it is in practice. Alison Bateman-House, a bioethicist at N.Y.U.’s medical school, raised the example of convalescent plasma, which was indiscriminately used to treat covid patients at the beginning of the pandemic. “People were, like, ‘Wow, ninety thousand people are using this, so we’ll get real-world data,’ but, as it turns out, we still have no idea,” she said.


"the total number of people in the U.S. who will ever get A.L.S.—maybe five years from now, maybe seventy years—is well over half a million people, and we owe them actions and policies and principled behavior that maximize the odds of getting a therapy that stops or prevents this disease. Part of this, for me, is the clarifying effect when you’re given a terminal diagnosis: How do I want to live the rest of my life? I try to live as best I can.” He was willing to articulate this argument only anonymously, because it left him vulnerable to nasty mobs on social media: “When you mention our obligations to people who don’t yet have A.L.S., you don’t always get a positive reception.”

“I have had friends who’ve died from A.L.S. over the years,” he told me. “I’ve long thought it’s the worst disease anyone can have. It is important for us as a field to be motivated by their desperation but not to take advantage of it.” He related a story from early in his career: “One patient’s family had gone to Florida to get a snake-venom extract that cost, like, forty thousand dollars, and they had sold their house in Philadelphia to pay for that. I found that so abhorrent.”

“We kept asking him, ‘How much is it going to cost? How much?’ ” He said that when Klee revealed the answer—a hundred and fifty-eight thousand dollars a year—“people were just flabbergasted. You did this for patients?”

She had been diagnosed as a thirty-two-year-old newlywed. (A psychiatrist she first saw thought that her balance issues were psychosomatic, and prescribed anti-anxiety medication.) She had participated in a trial for an investigational stem-cell treatment called NurOwn. “I had seven lumbar punctures with a fifty-fifty coin flip of getting a placebo, and I did it for the next generation,” she said. “If these drugs truly work, and the evidence is there, then let people have them! But do we want a bunch of subpar therapies where the data has been sliced and diced three different ways from Sunday? And do we want to pay a hundred and sixty thousand dollars a year for a therapy that has ‘eh’ benefit?”

The aids crisis also created the policy instruments to chart a middle path. Clinical trials could be made as inclusive as possible. Patients who cannot enroll in trials could have access, circumstances permitting, to investigational drugs through comprehensive expanded-access programs. Accelerated approvals could be subject to a tight timeline for confirmatory evidence, and there could be an enforcement mechanism for the rapid withdrawal of drugs that are not serving the sick. There is growing consensus on these points, but all are easier said than done. And no policy will ever fully resolve the tension between access and knowledge.

Collet told me a story about a patient who spoke at an F.D.A. meeting to describe a preternatural recovery. “He got up and talked about how before he took NurOwn he’d been having trouble walking, and then he ran around the conference-room table,” she said. “In the back of my mind, I thought, A.L.S. has its ways of having ups and downs, and it’s entirely possible that he was on the placebo. I suspect some of these miracle stories are the reason the company never unblinded the trial.” She added, “It’s easy for us to romanticize the H.I.V. history, but it wasn’t all demonstrations that got things done—it was a lot of hard work figuring out what the science could and couldn’t do. There’s a tendency in A.L.S. to say, ‘I am real-world evidence,’ but that’s not how it works.”