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Sick kids, desperate parents, and the battle for experimental drugs

The complex world of compassionate use drugs and who gets access to them.

McNary, here with her oldest son, Austin, decided against fighting for compassionate use in his case. The shift came with her realization that “the world is bigger than my family.”

Joanne Rathe/Globe Staff

Pembroke mom Jenn McNary, here with her oldest son, Austin, decided against fighting for compassionate use in his case. The shift came with her realization that “the world is bigger than my family.”

Joanne Rathe/Globe Staff

McNary’s four children were born with a rare genetic disease. Her then 9-year-old son qualified for a trial of the drug eteplirsen, but her older son did not.

JENN MCNARY KNOWS ANGER. It has overcome her often, and with the ravaging might that only a mother knows when her child is dying. Except in her case, it’s not one son but two who face a death sentence.

At 34, McNary’s face still has the glow of youth, and it lights up when she talks about all four of her kids, although she knows she has given most of her life, her energy, and all of her fight to her two oldest. As McNary sits in the kitchen of her modest apartment in Pembroke, her eyes harden as she remembers the moment a few years back when she realized there was something worse than knowing both of her children would die — knowing there was something out there that could help them, but that only one of them could have.

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That something was an experimental drug, made by Sarepta Therapeutics, a company in Cambridge. The worlds of a young New England mom and the high-stakes multibillion-dollar biotech industry were about to collide in what seemed like anything but a fair fight.

AUSTIN AND MAX, AGES 16 AND 13, were born with a rare, cruel genetic disease called Duchenne muscular dystrophy. It robs children of their muscle function, so they lose the ability to walk, then move, until their breathing muscles and their hearts start to give out. Survival into adulthood is rare, and there is no cure.

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McNary’s younger son Max was 9 when he qualified for a small clinical trial of Sarepta’s drug, called eteplirsen, for boys with a certain mutation causing the disease. When the trial started, Max was having difficulty walking, as is typical for boys that age with Duchenne. But within 16 weeks of taking the medicine, McNary saw him begin to improve.

She was elated. Naturally, she immediately saw hope for Austin. At 12 and already in a wheelchair, he had not qualified for the Sarepta clinical trial. McNary assumed — naively, she now says — that she would just ask the company to provide the drug to Austin via a program known as “expanded access,” also commonly called “compassionate use.” The program was established by the Food and Drug Administration in the late 1980s, during the days of the AIDS epidemic, after HIV patients implored the agency for access to promising experimental drugs (though the agency made some therapies available as early as the 1970s).

Via compassionate use, patients who are deathly ill, have no other treatment alternative, and do not qualify for clinical trials are able to gain access to experimental drugs as long as the drug maker is willing to provide them and the FDA approves the request.

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Austin’s neurologist reached out to the company, requesting eteplirsen on a compassionate-use basis. But the company denied the request. The doctor tried again, and the company again said no. Then McNary saw Chris Garabedian, Sarepta’s CEO at the time, at a conference on Duchenne muscular dystrophy, and she had the chance to ask him, in person, the one question on her mind: Why couldn’t Austin get the drug?

Garabedian gave her more than one reason. The company, called AVI BioPharma then, was small and cash-strapped. It had barely enough drug supply for the 12 kids in the clinical trial, let alone compassionate use. Garabedian said it would not be fair to pick one child, even if it was the sibling of a child in the trial, to begin taking his drug.

That explanation didn’t satisfy McNary, at least not at the time. “I was furious,” she says. “How could he put a dollar amount on my kid’s life?”

She went home, ready to do anything in her power to get the drug for Austin. But as she pondered options that involved, as she put it, “raising a huge stink,” Austin asked her a question she would never forget. “He said, ‘I have some friends who are worse than I am. Are you going to get them on the drug too?’ ” McNary recalls.

Realizing that “the world is bigger than my family,” McNary shifted gears. “The conclusion that we came to was that compassionate use wasn’t going to work,” she says. “I thought: OK, new plan. Get drugs for everybody.”

JENN MCNARY JOINED FORCES with several highly vocal parents within the Duchenne community, putting pressure on the FDA to consider eteplirsen for what’s known as accelerated approval, a program that allows drugs to be approved based on scientific indications that a drug is working, pending confirmation from larger or longer studies.

The switch in strategy was due in great part, McNary says, to having felt that the company was trying to listen and had reached out to her and other parents to explain its position. She was plenty upset when Sarepta denied compassionate use, she says, but Chris Garabedian “educated me,” she adds. “If he had ignored me, I probably would have gotten a lot angrier.”

When it comes to compassionate use, educating parents and patients hasn’t been the norm, and it’s been the industry’s biggest mistake. Patients with no time to lose have faced companies offering little support navigating the compassionate-use process — often because the companies themselves don’t know how to handle it. They “get surprised or even nervous” when press releases are posted with clinical trial results and patient requests start pouring in, says Henri Termeer, the former CEO of Cambridge-based Genzyme Corp. During his tenure at Genzyme, Termeer oversaw multiple compassionate-use requests for the company’s rare-disease drugs. “It doesn’t go away because you wish it to go away,” he says. “You have to be part of the solution.”

Compassionate use is developing into “a major issue for the industry to grapple with,” adds Garabedian, who left Sarepta in April. “With the therapeutics that we see emerging, many of them from the Boston-based companies, you will be able to see signals very early on in a patient or two, and then the entire community is going to say, ‘There is nothing else out there, we want this drug.’ ”

Indeed, compassionate-use requests to the FDA are exploding. In fiscal 2014 the agency received 1,882 compassionate-use requests, a 93 percent increase over the 977 requests in 2013, and the highest number since the agency started publishing these figures in 2010. The vast majority of the requests, 1,809, were filed by doctors on behalf of individual patients, and a little more than 1,000 of those were emergency requests filed when death is imminent — a huge increase over the 317 filed in 2013.

That’s not the total number of patient requests for compassionate use — those are just the petitions that the FDA sees. An unknown, presumably much higher number of requests never reach the FDA because the companies deny them first. The way the system works, doctors first petition a company for compassionate use, and only if a company agrees can the doctor file a request with the FDA. The chatter in industry meetings and boardrooms is that compassionate-use requests are going up, but that’s not the main concern.

There’s growing unrest with the realization that when a company denies a request, patient voices are getting louder. The power of the Internet and especially social media has allowed patients and their families to take their plea to the masses and, in some cases, see their story go viral.

“What began during the AIDS epidemic as social protest has evolved into social media protest,” biotechnology executive Kenneth Moch recently told the audience of the MassBio Patient Advocacy Summit. Cancer patients Andrea Sloan and Nick Auden, both lawyers, famously took their pleas for experimental drugs to Twitter, Facebook, YouTube, and Change.org, amassing the support of hundreds of thousands to challenge drug companies’ denials of their petitions.

KENNETH MOCH has been at the epicenter of one of those battles. His case was the stuff of movies, a fast-moving saga that featured one boy’s family begging for a drug, a CEO who would not budge, an aggressive patient advocate who masterfully choreographed a PR siege against the company, and legions of online supporters who elevated the family’s plight to deafening levels.

In early 2014, 7-year-old Josh Hardy developed an aggressive viral infection after a bone marrow transplant. The only approved drug sent him into kidney failure. An alternative drug was under development at Chimerix, the small biotechnology company in Durham, North Carolina, where Moch was CEO. Josh’s doctors pleaded with the company to release the drug, called CMX001, via compassionate use.

Chimerix had run a compassionate-use program of CMX001, and more than 400 patients had received the drug, including several, like Josh, with adenovirus infections. There were a few published case reports of patients with the same infection as Josh, and some showed patients getting better. But the program was shut down in 2012 — a “difficult decision,” according to the company, so it could focus its resources on getting CMX001 approved. Chimerix’s answer to Josh’s doctors was a polite but steadfast no.

By March 5, 2014, Josh’s doctors told his family he had about a week to live. With nothing to lose, his family took to social media. Thursday, March 6, 2014, marked the first post on the Facebook page of Josh’s mom, Aimee Hardy. “The drug company has refused to release the drug for compassionate care because they are trying to take it to market. Basically they are not going to save a child’s life for money,” her post stated.

She triggered an avalanche. The next day, employees and board members of Chimerix received hundreds of phone calls and e-mails in support of Josh, including a call from a US congressman, says Moch.

Joanne Rathe/Globe Staff

Grass-roots efforts to help parents acquire scarce and unproven drugs for their gravely ill children laid bare questions about fairness and equality of access.

The family was introduced to Richard Plotkin, a former litigation lawyer who heads the Max Cure Foundation, which he founded after his grandson was diagnosed with lymphoma. With the same relentless energy once deployed in the courtroom, Plotkin plunged headlong into the Hardy cause, directing its PR campaign. “Josh was akin to my grandson, and if Chimerix withheld the drug, Moch and Chimerix became my enemies,” Plotkin says.

Plotkin helped arrange interviews with CNN, Fox & Friends, and CBS. Aimee Hardy’s first major appearance was on a Sunday night with CNN’s Elizabeth Cohen. “The fact that they say that we can’t have it is absolutely infuriating to me,” she told CNN of Chimerix and CMX001.

Moch tried to explain why Chimerix denied Josh the medicine. Based on the hundreds of requests for compassionate use of CMX001 that Chimerix received the year before, Moch knew that granting Josh’s request would have meant hundreds more “Joshes” would come knocking at the company’s door, arguing they were as deserving of a chance, which the company didn’t have the resources to handle. As Moch explained to CNN: “If this were just one patient wanting this drug, then this would be a very different question. But it’s yes to all or no to all.”

Plotkin asked Erica Bailey, the social media expert at the Max Cure Foundation, to reach out to supporters. “I was up for 48 hours straight,” Bailey says. “I probably took a nap an hour here or there, but I was constantly communicating on Twitter and Facebook and getting updates.”

Within several days, the SaveJosh Facebook page had reached more than 1 million views, and #SaveJosh trended in the Twitter national top five. Social media posts and comments teemed with frustration. A lot of the anger was directed at Moch: “Your CEO is #heartless.” “There is no excuse not to save a life where you can when you can. No one should have the right to say no.” “Hey Mr. CEO, what if Josh was your baby? That would change your mind. Where is your humanity if you won’t save a child?”

One commenter on the SaveJosh Facebook page posted Moch’s home address and phone number. (Moch would receive death threats, deemed serious enough by the FBI that he and his wife had to spend five nights in a hotel under an assumed name, with armed protection.)

Not known to Josh’s supporters was that Chimerix had been working with the FDA to create a clinical trial through which Josh could get the drug. By Tuesday afternoon, five days after Hardy’s initial Facebook post and with the social media firestorm in full swing, CMX001 was on its way to Josh.

At the time, Moch couldn’t talk about the behind-the-scenes negotiations because of patient privacy rules. Chimerix, a public company, also had to be careful about making premature announcements. “The press and social media were demonizing and threatening me and Chimerix, and there was nothing we could publicly do or say to stop the body blows,” Moch recalls.

Late on Tuesday, March 11, the news broke, and quickly went viral, that Josh would get the drug. “We changed our entire tone. We changed our hashtag from #SaveJosh to #SavedJosh,” Bailey says. “It was political, it was romantic, it was social media wrapped up in a little bow.”

Shortly after taking the medicine, Josh started to improve. He went home a few weeks later and is today recovering at home. Moch was fired a few weeks after Josh got the drug.

THE HARDY SAGA laid bare questions about fairness and equality of access to a scarce resource in an era where social media can amplify the voices of some patients over others. “Should an experimental product be made available to an individual patient who is more vocal, more sophisticated in the use of media, more knowledgeable about the system, more adept at electronic searches?” wrote Arthur Caplan, director of the Division of Medical Ethics at the NYU Langone Medical Center, in a Health Affairs Blog piece titled “Rescue Me: The Challenge of Compassionate Use in the Social Media Era.”

According to Caplan, the Josh Hardy case was the trigger for the creation in early 2014 of the NYU Working Group on Compassionate Use and Pre-Approval Access, which is working with companies, regulators, and patient advocates to reform the compassionate-use process.

One of the advisers to the group is Richard Plotkin, the man who helped vilify Chimerix and Moch. In a fantastic turnaround, Plotkin now calls Moch a hero. Today the former enemies consider each other friends and have appeared at patient advocacy events recounting their experiences.

Plotkin speaks of having evolved in his understanding of the complexities of compassionate use, including the potential negative impact to the company if the drug had failed to save Josh. “In hindsight, I can now say that if I were CEO of Chimerix, I would have taken the same position as that taken by Ken Moch — not allowing my subjective emotions to control what was the more reasonable position, namely, not derail what Chimerix was doing to save hundreds, if not thousands, of Joshes’ lives.”

In fact, the most widely misunderstood learning from the Chimerix saga was that, in the end, it was a victory for the traditional clinical trial path toward approval. The flurry of celebratory headlines implied that Chimerix had reversed its position in giving the drug to Josh. But that’s not true. Chimerix never caved. It did not provide the drug via compassionate use. What saved Josh Hardy was Chimerix and the FDA moving faster to create a clinical trial, of which Josh was the first patient. More than 100 patients have been enrolled, and early results seem encouraging.

Thus, one warrior mom and an army of advocates helped expedite the creation of a study that might very well help get CMX001 approved. Multiple lives have been saved through the new study, and with a greater purpose, because the information gleaned would have been lost had the patients received the drug via compassionate use.

THIS IS WHERE THE STORIES of Chimerix and Sarepta and the lives of Jenn McNary and Aimee Hardy intersect in a crucial way. They are examples of extremely vocal families pushing the FDA to pay attention. Even if CMX001 saved Josh Hardy and McNary thinks eteplirsen is helping her sons, the only way to know for sure if the drugs are efficacious is to do the proper studies. In the eteplirsen case, following patient pressure, the agency allowed the creation of a more flexible clinical trial in which McNary’s son Austin and several other boys who are no longer able to walk were enrolled. In both cases, the result has been to enhance and possibly expedite the approval process by enrolling patients into new trials, opening the treatment door to those whose only prior option was to ask for compassionate use.

“Patients have demanded and have taken a place at the table,” says Richard Moscicki, deputy center director for science operations at FDA’s Center for Drug Evaluation and Research. “So we recognize that, and we are committed to trying to figure out how to incorporate that into our own internal thinking.”

Compassionate use has been a hot topic for the agency, as patient frustration with the current system seems to have reached a tipping point. While it’s true the FDA grants 99 percent of the compassionate-use requests it gets, patients have complained that the application process itself is too cumbersome, involving forms that the typical doctor, working on behalf of a desperate patient, would find difficult to navigate. “We’re talking hours and hours and hours of work” by doctors, nurses, and other hospital staff, says Charles Levenback, an oncologist in Houston at MD Anderson Cancer Center. Levenback was Andrea Sloan’s main physician during her high-profile campaign to obtain an experimental cancer drug from a company called BioMarin.

It is this mounting sense of frustration with the FDA that has triggered the proliferation of so-called “Right to Try” laws. Now passed in 21 states and under consideration in many others, the laws allow terminally ill patients who have exhausted all treatment options, including clinical trials, to directly obtain from companies — and without needing the FDA’s consent — unapproved drugs that have advanced past phase I testing, which evaluates safety in a small number of people.

The impact of these laws remains to be seen. They don’t force companies to make their drugs available, and it’s hard to envision manufacturers willing to bypass the authority of the very agency that eventually approves their products.

But the laws have been a major wake-up call for the agency. In February, the FDA announced the creation of a single form to be filled out for compassionate-use requests, which should take about 45 minutes to complete.

WE ALL SHARE THE INSTINCT to rescue those in need. That’s what makes it so hard to grasp that an act that seems so benign — at the very least it offers hope, at its best it saves a life — could have negative consequences for the patients themselves and, even worse, for others.

There is a subconscious bias to believe, especially when a loved one is dying, that experimental drugs are miracle cures. “When we talk about experimental treatments, the doctor is frequently talking about a response rate, not a cure, but the patient is hearing cure,” says Charles Levenback.

In reality, very few of the phase I and II drugs in companies’ pipelines are likely to help patients, and could even cause harm from unknown side effects. In cancer, most drugs in phase I never make it to the market, and a significant percentage of those that make it to phase III, the larger studies used to determine a drug’s efficacy, still fail. In other therapeutic areas, like Alzheimer’s, the track record is, sadly, still worse.

Even some of the drugs showing early promise and that are fast-tracked for approval by the FDA end up failing.

Pressure from parents like Jenn McNary did lead to a more flexible clinical trial for eteplirsen. McNary’s wheelchair-bound son Austin, like his brother Max, is now getting the drug.

Joanne Rathe/Globe Staff

Pressure from parents like Jenn McNary did lead to a more flexible clinical trial for eteplirsen. McNary’s wheelchair-bound son Austin, like his brother Max, is now getting the drug.

Meanwhile, there is an ever-growing tsunami of information, with results from clinical trials constantly posted in press releases and on websites, where the slightest indication of hope takes on a new meaning in the hands of the desperately ill. There is little doubt among experts that, as the flow of information expands, so will requests for compassionate use.

Until now, the industry dealt with this challenge in an ad hoc, haphazard way that has left many patients feeling confused and ignored. Some companies have compassionate use programs but don’t advertise them; others don’t have the programs at all and do not intend to. There isn’t a directory where patients can easily find this type of information — it’s not something companies systematically put on their websites.

Increasing transparency would be a major step forward in making the process more patient-friendly. The 21st Century Cures Act, overwhelmingly passed by the US House on July 10, has a provision that would require manufacturers to make publicly available their policies on compassionate use, including the posting of contact information for patients desiring to make requests.

For Henri Termeer, the former Genzyme CEO, transparency is the only way to deal with this growing challenge. “We create the dilemma by making something available that is enormously desirable. So we need to give guidance, the best possible guidance we can give, to clarify how this works.”

There are reasons companies are reluctant to adopt compassionate use programs. They can cost millions to establish. While the programs’ intentions are noble, a dollar spent underwriting the compassionate use of a drug is a dollar diverted from developing the drug for future patients — a choice favoring one individual over others.

Companies also assume significant risks, many of which the public is unaware of, with expanded access programs. The FDA wants to be informed of all serious side effects thought to be linked to a drug provided via compassionate use. On the other hand, any hints that the drug works are not taken into account during review.

This makes sense, since efficacy needs to be measured carefully in clinical trials. Still, it’s hard to imagine any other industry where a manufacturer is willing (or pressured) to release a prototype in an uncontrolled setting, knowing that its regulators are closely watching for instances where that product causes harm.

If major side effects surface via compassionate use, it’s much harder to understand why the side effects occurred, since these patients tend to be much sicker. And this can mean trouble with the FDA.

That’s what happened last year to Los Angeles-based oncology drug company CytRx Corp. after the death of a patient who had obtained the company’s cancer drug via compassionate use. The FDA ordered all of the company’s clinical trials of the drug to be stopped. The hold, which only meant new patients could not be enrolled, lasted two months.

Patient advocates complain that all too often the industry hides behind this fear of surprise side effects as a reason for not wanting to establish more compassionate-use programs. While the impact of a clinical-trial hold can’t be underestimated for a company, such holds do seem to be extremely rare. A preliminary look at some 5,000 compassionate-use cases has only produced two examples where side effects led to some FDA action, says Richard Moscicki. The flip side of that, he says, is that compassionate use can help flag promising drugs at his agency. “I can tell you that in the short two years that I have been here I have actually seen a compassionate-use case really turn the review division around in its thinking, seeing evidence that a drug really was having value.”

Austin plays chess while receiving an IV earlier this year.

Joanne Rathe/Globe Staff

Austin plays chess while receiving an IV earlier this year.

THE GOALS OF COMPASSIONATE USE are mostly incompatible with those of drug development. So perhaps the enterprise would function better overseen by an independent third party.

That’s the experiment being done by pharmaceutical giant Johnson & Johnson, which in May embarked on a novel partnership with NYU’s Arthur Caplan. He will lead an independent panel of 10 experts (to include doctors, bioethicists, and patient representatives) that will review the compassionate-use requests that Johnson & Johnson receives.

There’s increasing recognition that a mechanism to take the economic burden off companies, especially smaller ones, could greatly motivate the creation of more programs. “You’ve got to put money aside to pay for the access,” Caplan says. “Society needs to decide if they want to put money into this.”

Many questions remain open for discussion, and most defy a single, simple answer. Should phase I drugs even be considered for compassionate use, given that so little is known about their safety and efficacy? Where should society draw the line when defining a disease as “life threatening” for the purpose of qualifying for compassionate use? Should children be given special consideration for these programs because they rarely qualify for clinical trials?

A solution that caters to the sickest patients while doing what’s best for the general public will no doubt prove elusive. There are no better words than those of a mother to capture this predicament. When Aimee Hardy was asked what she would say to Kenneth Moch if she saw him today, this was her answer: “I would tell him that I hope and pray that his family and himself are doing very well, and again I am sorry the situation had to be so public and difficult. But I would do it all over again if I had to. Josh is not just any Josh. He is my Josh.”

Sylvia Pagan Westphal, who has a Ph.D. in genetics from Harvard Medical School, is a health care writer who has contributed to the Globe’s opinion pages. Send comments to magazine@globe.com.
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