Who gets to decide who receives experimental medical treatments?

Jessica Hamzelou, MIT Technology Review, August 10, 2023

Max was only a toddler when his parents noticed there was “something different” about the way he moved. He was slower than other kids his age, and he struggled to jump. He couldn’t run.

Blood tests suggested he might have a genetic disease— one that affected a key muscle protein. Max’s dad, Tao Wang, a researcher for a climate philanthropy organization, says he and his wife were initially in denial. It took them a few months to take Max for the genetic test that confirmed their fears: he had Duchenne muscular dystrophy.

Duchenne is a rare disease that tends to affect young boys. It’s progressive—those affected lose muscle function as they get older. There is no cure. Many people with the disorder require wheelchairs well before they reach their 20s. Most do not survive beyond their 30s.

Max’s diagnosis hit Wang and his wife “like a tornado,” he says. But eventually one of his doctors mentioned a clinical trial that he was eligible for. The trial was for an experimental gene therapy designed to replace the missing muscle protein with a shortened, engineered version that might help slow his decline or even reverse it. Enrolling Max in the trial was a no-brainer for Wang. “We were willing to try anything that could change the course [of the disease] and give us some hope,” he says.

That was more than two years ago. Today, Max is an active eight-year-old, says Wang. He runs, jumps, climbs stairs without difficulty, and even enjoys hiking. “He’s a totally different kid,” says Wang.

The gene therapy he received was recently considered for accelerated approval by the US Food and Drug Administration. Such approvals, reserved for therapies targeting serious conditions that lack existing treatments, require less clinical trial data than standard approvals.

While the process can work well, it doesn’t always. And in this case, the data is not particularly compelling. The drug failed a randomized clinical trial—it was found to be no better than a placebo.

Still, many affected by Duchenne are clamoring for access to the treatment. At an FDA advisory committee meeting in May set up to evaluate its merits, multiple parents of children with Duchenne pleaded with the organization to approve the drug immediately—months before the results of another clinical trial were due. On June 22, the FDA granted conditional approval for the drug for four- and five-year-old boys.

Between 2009 and 2022, 48 cancer drugs received accelerated approval to treat 66 conditions—and 15 of those approvals have since been withdrawn.

This drug isn’t the only one to have been approved on weak evidence. There has been a trend toward lowering the bar for new medicines, and it is becoming easier for people to access treatments that might not help them—and could harm them. Anecdotes appear to be overpowering evidence in decisions on drug approval. As a result, we’re ending up with some drugs that don’t work.


Expanding access

There’s a difficult balance to be reached between protecting people from the unknown effects of a new treatment and enabling access to something potentially life-saving. Trying an experimental drug could cure a person’s disease. It could also end up making no difference, or even doing harm. And if companies struggle to get funding following a bad outcome, it could delay progress in an entire research field—perhaps slowing future drug approvals.

In the US, most experimental treatments are accessed through the FDA. Starting in the 1960s and ’70s, drug manufacturers had to prove to the agency that their products actually worked, and that the benefits of taking them would outweigh any risks. “That really closed the door on patients’ being able to access drugs on a speculative basis,” says Christopher Robertson, a specialist in health law at Boston University.

It makes sense to set a high bar of evidence for new medicines. But the way you weigh risks and benefits can change when you receive a devastating diagnosis. And it wasn’t long before people with terminal illnesses started asking for access to unapproved, experimental drugs.


Today, there are lots of ways people might access experimental drugs on an individual basis. Perhaps the most obvious way is by taking part in a clinical trial. Early-stage trials typically offer low doses to healthy volunteers to make sure new drugs are safe before they are offered to people with the condition the drugs are ultimately meant to treat. Some trials are “open label,” where everyone knows who is getting what. The gold standard is trials that are randomized, placebo controlled, and blinded: some volunteers get the drug, some get the placebo, and no one—not even the doctors administering the drugs—knows who is getting what until after the results have been collected. These are the kinds of studies you need to do to tell if a drug is really going to help people.

But clinical trials aren’t an option for everyone who might want to try an unproven treatment. Trials tend to have strict criteria about who is eligible depending on their age and health status, for example. Geography and timing matter, too—a person who wants to try a certain drug might live too far from where the trial is being conducted, or might have missed the enrollment window.

Instead, such people can apply to the FDA under the organization’s expanded access program, also known as “compassionate use.” The FDA approves almost all such requests. It then comes down to the drug manufacturer to decide whether to sell the person the drug at cost (it is not allowed to make a profit), offer it for free, or deny the request altogether.

Another option is to make a request under the Right to Try Act. The law, passed in 2018, establishes a new route for people with life-threatening conditions to access experimental drugs—one that bypasses the FDA. Its introduction was viewed by many as a political stunt, given that the FDA has rarely been the barrier to getting hold of such medicines. Under Right to Try, companies still have the choice of whether or not to provide the drug to a patient.

When a patient is denied access through one of these pathways, it can make headlines. “It’s almost always the same story,” says Alison Bateman-House, an ethicist who researches access to investigational medical products at New York University’s Grossman School of Medicine. In this story, someone is fighting for access to a drug and being denied it by “cold and heartless” pharma or the FDA, she says. The story is always about “patients valiantly struggling for something that would undoubtedly help them if they could just get to it.”

But in reality, things aren’t quite so simple. When companies decide not to offer someone a drug, you can’t really blame them for making that decision, says Bateman-House. After all, the people making such requests are usually incredibly ill. If someone were to die after taking that drug, not only would it look bad, but it could also put off investors from funding further development. “If you have a case in the media where somebody gets compassionate use and then something bad happens to them, investors run away,” says Bateman-House. “It’s a business risk.”

FDA approval of a drug means it can be sold and prescribed—crucially, it’s no longer experimental. Which is why many see approval as the best way to get hold of a promising new treatment.

As part of a standard approval process, which should take 10 months or less, the FDA will ask to see clinical trial evidence that the drug is both safe and effective. Collecting this kind of evidence can be a long and expensive process. But there are shortcuts for desperate situations, such as the outbreak of covid-19 or rare and fatal diseases—and for serious diseases with few treatment options, like Duchenne.

Anecdotes vs. evidence 

Max accessed his drug through a clinical trial. The treatment, then called SRP-9001, was developed by the pharmaceutical company Sarepta and is designed to replace dystrophin, the protein missing in children with Duchenne muscular dystrophy. The protein is thought to protect muscle cells from damage when the muscles contract. Without it, muscles become damaged and start to degenerate.

The dystrophin protein has a huge genetic sequence—it’s too long for the entire thing to fit into a virus, the usual means of delivering new genetic material into a person’s body. So the team at Sarepta designed a shorter version, which they call micro-dystrophin. The code for the protein is delivered by means of a single intravenous infusion.

The company planned to develop the therapy to treat patients with Duchenne who could still walk. And it had a way to potentially fast-track the approval process.

Usually, before a drug can be approved, it will go through several clinical trials. But accelerated approval offers a shortcut for companies that can show that their drug is desperately needed, safe, and supported by compelling preliminary evidence.

For this kind of approval, drug companies don’t need to show that a treatment has improved anyone’s health—they just need to show improvement in some biomarker related to the disease (in Sarepta’s case, the levels of the micro-dystrophin protein in people’s muscle).

There’s an important proviso: the company must promise to continue studying the drug, and to provide “confirmatory trial evidence.”

This process can work well. But in recent years, it has been a “disaster,” says Diana Zuckerman, president of the National Center for Health Research, a nonprofit that assesses research on health issues. Zuckerman believes the bar of evidence for accelerated approval has been dropping. 

Many drugs approved via this process are later found ineffective. Some have even been shown to leave people worse off. For example, between 2009 and 2022, 48 cancer drugs received accelerated approval to treat 66 conditions—and 15 of those approvals have since been withdrawn.

Melfulfen was one of these. The drug was granted accelerated approval for multiple myeloma in February 2021. Just five months later, the FDA issued an alert following the release of trial results suggesting that people taking the drug had a higher risk of death. In October 2021, the company that made the drug announced it was to be taken off the market.

There are other examples. Take Makena, a treatment meant to reduce the risk of preterm birth. The drug was granted accelerated approval in 2011 on the basis of results from a small trial. Larger, later studies suggested it didn’t work after all. Earlier this year, the FDA withdrew approval for the drug. But it had already been prescribed to hundreds of thousands of people—nearly 310,000 women were given the drug between 2011 and 2020 alone.

And then there’s Aduhelm. The drug was developed as a treatment for Alzheimer’s disease. When trial data was presented to an FDA advisory committee, 10 of 11 panel members voted against approval. The 11th was uncertain. There was no convincing evidence that the drug slowed cognitive decline, the majority of the members found. “There was not any real evidence that this drug was going to help patients,” says Zuckerman.

Despite that, the FDA gave Aduhelm accelerated approval in 2021. The drug went on the market at a price of $56,000 a year. Three of the committee members resigned in response to the FDA’s approval. And in April 2022, the Centers for Medicare & Medicaid Services announced that Medicare would only cover treatment that was administered as part of a clinical trial. The case demonstrates that accelerated approval is no guarantee a drug will become easier to access.

The other important issue is cost. Before a drug is approved, people might be able to get it through expanded access—usually for free. But once the drug is approved, many people who want it will have to pay. And new treatments—especially gene therapies—don’t tend to be cheap. We’re talking hundreds of thousands, or even millions, of dollars. “No patient or families should have to pay for a drug that’s not proven to work,” says Zuckerman.

What about SRP-9001? On May 12, the FDA held an advisory committee meeting to assess whether the data supported accelerated approval. During the nine-hour virtual meeting, scientists, doctors, statisticians, ethicists, and patient advocates presented the data collected so far, and shared their opinions.

Sarepta had results from three clinical trials of the drug in boys with Duchenne. Only one of the three—involving 41 volunteers aged four to seven—was randomized, blinded, and placebo controlled.

Scientists will tell you that’s the only study you can draw conclusions from. And unfortunately, that trial did not go particularly well—by the end of 48 weeks, the children who got the drug were not doing any better than those who got a placebo.

But videos presented by parents whose children had taken the drug told a different story.


But the difference is not statistically significant for the results the trial was designed to collect. And there are some safety concerns. While most of the boys developed only “mild” side effects, like vomiting, nausea, and fever, a few experienced more serious, although temporary, problems. There were a total of nine serious complications among the 85 volunteers. One boy had heart inflammation. Another developed an immune disease that damages muscle fibers.

On top of all that, as things currently stand, receiving one gene therapy limits future gene therapy options. That’s because the virus used to deliver the therapy causes the body to mount an immune response. Many gene therapies rely on a type called adeno-associated virus, or AAV. If a more effective gene therapy that uses the same virus comes along in the coming years, those who have taken this drug won’t be able to take the newer treatment.

Despite all this, the committee voted 8–6 in favor of granting the drug an accelerated approval. Many committee members highlighted the impact of the stories and videos shared by parents like Brent Furbee.

“Now, I don’t know whether those boys got placebo or whether they got the drug, but I suspect that they got the drug,” a neurologist named Anthony Amato told the audience.

“Those videos, anecdotal as they are … are substantial evidence of effectiveness,” said committee member Donald B. Kohn, a stem-cell biologist.

The drugs don’t work?

Powerful as they are, individual experiences are just that. “If you look at the evidentiary hierarchy, anecdote is considered the lowest level of evidence,” says Bateman-House. “It’s certainly nowhere near clinical-trial-level evidence.”

This is not the way we should be approving drugs, says Zuckerman. And it’s not the first time Sarepta has had a drug approved on the basis of weak evidence, either. 

The company has already received FDA approval to sell three other drugs for Duchenne, all of them designed to skip over faulty exons—bits of DNA that code for a protein. Such drugs should allow cells to make a longer form of a protein that more closely resembles dystrophin.

The first of these “exon-skipping” drugs, Exondys 51, was granted accelerated approval in 2016—despite the fact that the clinical trial was not placebo controlled and included only 12 boys. “I’ve never seen anything like it,” says Zuckerman. She points out that the study was far too small to be able to prove the drug worked. In her view, 2016 was “a turning point” for FDA approvals based on low-quality evidence—“It was so extreme,” she says.


But for many in the scientific community, that data still needs to be confirmed. “The clinical benefit still has not been confirmed for any of the four,” Mike Singer, a clinical reviewer in the FDA’s Office of Therapeutic Products, told the advisory committee in May.

“All of them are wanted by the families, but none of them have ever been proven to work,” says Zuckerman.  


Selling hope

On June 22, just over a month after the committee meeting, the FDA approved SRP-9001, now called Elevidys. It will cost $3.2 million for the one-off treatment, before any potential discounts. For the time being, the approval is restricted to four- and five-year-olds. It was granted with a reminder to the company to complete the ongoing trials and report back on the results.


Doctors may end up agreeing that a drug—even one that is unlikely to work—is better than nothing. “In the American psyche, that is the approach that [doctors and] patients are pushed toward,” says Holly Fernandez Lynch, a bioethicist at the University of Pennsylvania. “We have all this language that you’re ‘fighting against the disease,’ and that you should try everything.”

“I can’t tell you how many FDA advisory committee meetings I’ve been to where the public-comment patients are saying something like ‘This is giving me hope,’” says Zuckerman. “Sometimes hope helps people do better. It certainly helps them feel better. And we all want hope. But in medicine, isn’t it better to have hope based on evidence rather than hope based on hype?”

A desperate decision

A drug approved on weak data might offer nothing more than false hope at a high price, Zuckerman says: “It is not fair for patients and their families to [potentially] have to go into bankruptcy for a drug that isn’t even proven to work.” 

The best way for people to access experimental treatments is still through clinical trials, says Bateman-House. Robertson, the health law expert, agrees, and adds that trials should be “bigger, faster, and more inclusive.” If a drug looks as if it’s working, perhaps companies could allow more volunteers to join the trial, for example.

Their reasoning is that people affected by devastating diseases should be protected from ineffective and possibly harmful treatments—even if they want them. Review boards assess how ethical clinical trials are before signing off on them. Participants can’t be charged for drugs they take in clinical trials. And they are carefully monitored by medical professionals during their participation.

That doesn’t mean people who are desperate for treatments are incapable of making good decisions. “They are stuck with bad choices,” says Fernandez Lynch.

To read the entire article, see here