Compassionate use allows very sick people to get access to treatments that might help Covid-19, but it?s not without problems

Eleven days after the first confirmed Covid-19 patient in the United States reported symptoms, he was treated with an experimental antiviral drug called remdesivir.

The 35-year-old man had recently returned to Washington from visiting family in Wuhan, China, where the virus originated. He was admitted to Providence Regional Medical Center in Everett, Washington, a few days after he developed a dry cough, fever, and ? just before admission ? nausea, according to a case report published March 5 in the New England Journal of Medicine. During the first five days of his hospital stay, the man was generally stable. But on the night of the fifth day, which was nine days after he first reported symptoms, an X-ray showed evidence of pneumonia in his left lung, which progressed to both lungs on the following day. His blood oxygen level dropped to 90 ? well below the 95-to-100 range that?s considered normal ? and he needed supplemental oxygen.

His downward spiral was similar to reports of Covid-19 patients in China who had died. His doctors decided to try an experimental therapy. They obtained remdesivir from the pharmaceutical company Gilead Sciences under a regulatory protocol known as compassionate use, which allows desperately ill people to try unapproved medicines outside of conventional clinical trials. The doctors gave the man the drug through an IV, and waited.

Since the early days of the AIDS pandemic in the 1980s, thousands of people with tough-to-treat illnesses who are out of options and don?t qualify for clinical trials have made similar requests to drug companies and regulatory agencies in last-ditch efforts to get a drug that might reduce their suffering or save their lives. Compassionate use is an important avenue during the ongoing coronavirus pandemic for some patients to get experimental medicines, as there are currently no available vaccines or drugs for treatment. Mayo Clinic just announced on May 5 a $26 million federal grant to support ?expanded access,? as compassionate use is also known, for a promising but unproven treatment called convalescent plasma to fight Covid-19. But as the history of compassionate use suggests, broadening use of the strategy is almost certain to raise risks and trigger ethical dilemmas that have long plagued the approach.

On its face, a compassionate use request may seem straightforward. Even though the drugs people request through compassionate use are not yet approved ? which means questions remain about their safety and effectiveness ? what harm would result from granting a dying person?s wish? Why not leap at the opportunity to save a life?

?It?s a theme of our health care system,? says Arthur Caplan, PhD, director of the division of medical ethics at NYU Langone Health. ?We may not be very good at prevention, but if you get sick, we love to try and rescue you. Morally, rescue is a very powerful force in American culture.?

But these requests can disrupt development of new medicines, and they pose daunting ethical challenges that have triggered fierce debates in boardrooms, among legislators and regulators, in scientific journals, and on social media. One case challenging denial of access to an experimental drug made it to the steps of the U.S. Supreme Court.

The long-shot quest to save one sick person?s life or a group of people?s lives with an experimental drug can delay or even undercut the development of medicines that could eventually help or save far more ?future? patients, say people who consider such requests. If outcomes are poor, drug companies worry it could jeopardize their future attempts at market approval. Heavy demand for compassionate use could threaten limited supplies of drugs intended for clinical trials.

?We may not be very good at prevention, but if you get sick, we love to try and rescue you. Morally, rescue is a very powerful force in American culture.?

There?s also the risk-benefit balance of giving people drugs that are not ready for prime time, rather than waiting to confirm a treatment is safe or figuring out the best dosing. Take, for example, a drug like hydroxychloroquine, which showed initial promise and was touted as a possible ?game changer? by President Donald Trump. It has since caused deaths, and though studies are underway, its effectiveness against Covid-19 is considered overblown. Hydroxychloroquine is approved for malaria and lupus and can be prescribed ?off-label? for Covid-19 without compassionate use. But as experience quickly showed, such unapproved use carries much the same risk as experimental medicines and raises ethical issues: A run on the drug left a short supply for patients who needed it for its approved uses.

?All the landmark cases keep showing this fundamental moral dilemma,? Caplan says. ?Do we have an obligation to get to safe and effective treatments for the largest number of people in the long run, and what do we owe the desperate individual in the short run??

The FDA has had mechanisms in place since at least 1962 that enable patients and their doctors to get access to experimental medicines. The procedures were expanded in response to the AIDS pandemic in the mid-1980s, when the tension between the need for new drugs and the needs of patients who needed the drugs came into sharp relief. Drug companies scrambled to develop new agents that could treat the disease, but they needed patients to test them in clinical trials that under conventional timelines to prove safety and efficacy would take several years to lead to an approved drug.

For people infected with HIV, the virus that causes AIDS, that timeline was unacceptable, Caplan says. They were dying by the thousands, and a drug-development process with a five-year time horizon would be of little help. Sick people generally were reluctant to sign up for a randomized trial anyway since it meant they could be assigned to the placebo arm instead of getting the drug.

These tensions helped fuel the rise of ACT UP and other patient advocacy groups, which staged scathing demonstrations against regulators, researchers, drug companies, and agencies like the National Institutes of Health (NIH) in a drive to ease access to potentially helpful drugs under investigation. Among the vilified was Anthony Fauci, MD, then early in his career as director of NIH?s National Institute of Allergy and Infectious Diseases.

As described in a recent New Yorker profile, Fauci eventually reached out to his critics and came to propose and champion a strategy known as parallel track. This system provided access to a drug in a single-arm (no control group) study that ran parallel with more conventional randomized studies necessary to get drugs approved. This approach helped establish expanded access as a way ?to let more people come into a trial-like study,? Caplan says.

Since then, requests from individual patients have influenced the evolution of compassionate use and raised broader questions around Americans? rights to experimental treatments. A young woman named Abigail Burroughs died of head and neck cancer in 2001 at age 21 after she was denied a chance to take a then-experimental drug called Erbitux that was being tested in clinical trials only for colon cancer.

Her father, Frank Burroughs, formed an advocacy group called the Abigail Alliance, which later sued the FDA, claiming his late daughter had a constitutional right to purchase experimental medicines that haven?t yet won regulatory approval. The alliance took the case all the way to the U.S. Supreme Court, which declined to hear an appeal of an appellate court ruling that denied a person has a legal right to access unapproved drugs. This let stand FDA regulations requiring robust evidence of safety and efficacy before allowing drugs on the market.

Even so, the case was an important driver of efforts led largely by conservative groups that have resulted in passage of so-called right-to-try laws in nearly every state and in the U.S. Congress. They?re intended to help people circumvent FDA rules in pursuit of access to experimental treatments. Caplan and other critics of right-to-try argue that the effect of the laws is negligible because, despite what people might think, the FDA isn?t the bottleneck in such cases; it approves some 99% of requests, which patients or their doctors must initiate with the companies developing the drugs. The laws don?t compel companies developing new agents to provide drugs in such cases. And drug companies aren?t always keen to grant the requests.

Take the case from 2014 of seven-year-old Josh Hardy, who had battled kidney cancer since infancy. He had just undergone a bone marrow transplant, which led to a life-threatening viral infection. His doctor asked a North Carolina company called Chimerix for compassionate use access to its experimental antiviral brincidofovir.

The company and its CEO, Kenneth Moch, said no. Chimerix had recently shuttered a compassionate use program that provided brincidofovir to more than 400 patients so it could focus its limited resources on studies that could lead to FDA approval. Moch worried that granting Josh?s request would ?torch the company? ? and the drug ? because it would overwhelm Chimerix?s capacity, with its 55 employees, to deal with a likely flood of additional requests that he felt ethically he would have to say yes to.

Growing interest in compassionate use ?sets the lengthy and complex process of developing new medicines for future patients in conflict with the immediate needs of current patients,? Moch says. ?This wasn?t about Josh. It was about many Joshes.?

That argument doesn?t resonate with a family of a dying child.In response, the family mounted a #SaveJosh campaign on Facebook and Twitter on a Thursday night, Moch recalls, that attracted national TV coverage over the weekend and triggered a deluge of emails and phone calls to the company in support of Josh.

That Monday, the FDA came to his aid with a proposal that the company mount a 20-patient single-arm clinical trial to study the drug against the virus attacking Josh. It was launched Tuesday ?without any paperwork,? Moch recalls. Josh would be patient number one. Within 120 hours of the launch of the social media effort, the drug was in an airplane en route to Josh?s hospital.

Three weeks later, Josh?s body was essentially free of the infection; soon thereafter, he was able to go home. But the victory ultimately was short-lived. A couple years later, Josh died of cancer at age 10. Despite the apparent benefit to Josh, brincidofovir some six years later is still in development at Chimerix. Clinical trials haven?t yet yielded evidence necessary to support approval.

The Hardy case illustrates another ethical conundrum with compassionate use. The family was able to put enormous pressure on the company with its savvy use of social media, underscoring long-standing concerns that the process is skewed toward well-connected people who know how to work the system. In some cases, Caplan says, well-connected patients or family members call a U.S. senator, who calls a CEO to say a constituent would like access to a company?s drug. Working with Johnson & Johnson, Caplan developed a Compassionate Use Advisory Committee in which individual requests are anonymized so committee members reviewing them are blinded to who the applicants are. Other companies have adopted the approach. ?It was a deep concern of mine that people at least have a fair shot,? Caplan says, ?that we?re not just responding to the richest or the famous or the people who had PR contacts.?

A pandemic such as the spread of Covid-19 clearly changes the risk-benefit conversation for drug companies and regulatory agencies. With millions of cases worldwide and tens of thousands of deaths, there?s a clear argument for creating easier access to potentially helpful treatments. With so many people seeking treatment, companies may see an advantage to granting such requests. But the risks remain substantial. Gilead drew some criticism for providing the drug to 1,800 patients via expanded access when early encouraging data were reported out of concern that the reports were misleading without a control group to compare outcomes. But Giliead also supported rigorous studies and in any event, the bet for remdesivir appears to be paying off ? so far.

The first man treated with the drug at Providence Regional Medical Center stabilized the day after his treatment began. His blood oxygen increased to 94 to 96, he was taken off supplemental oxygen, his lungs began to clear, and his appetite improved. Four days after he received his first dose of remdesivir, all of his symptoms had resolved, ?with the exception of his cough, which [was] decreasing in severity,? the case report says. He was still hospitalized then; the case report doesn?t provide further detail of his status.

Did remdesivir help this patient, or did he get better on his own? It?s impossible to say based on a single patient?s experience. But his outcome seems consistent with the results from a recent positive trial. On April 29, Fauci announced that an NIH-sponsored placebo controlled trial showed that remdesivir ?has a clear-cut, significant positive effect in diminishing the time to recovery? for people with Covid-19. ?It was proven that a drug can block the virus,? he said. Though results haven?t yet been published, the FDA on May 1 issued an emergency use authorization that allows doctors to treat people with severe Covid-19 with remdesivir until the pandemic is over. Whether the drug is eventually approved for marketing will depend on the results of additional trials.

Researchers are racing to try scores of other potential treatments against the virus and other complications arising from the body?s response to the infection. These include plasma from recovered patients in an effort to spur production of antibodies against the virus and a host of existing drugs and other experimental agents that might have activity against the novel coronavirus.

Compassionate use is likely to play a major role in how these patients get access to the therapies as efforts to test them are launched. The convalescent plasma program led by Mayo Clinic, announced less than a month ago, involves more than 2,000 hospitals and 4,000 physicians. They have enrolled 10,000 patients, 5,000 of whom have already been infused with the treatment, according to Mayo. The $26 million grant came from the Biomedical Advanced Research and Development Authority (BARDA) at the U.S. Department of Health and Human Services. BARDA has become a major funder of vaccine and drug research against Covid-19.

Compassionate use is ?a very fast way in a pandemic to get initial information about the potential for your experimental medicine,? Moch says. ?It?s not a substitute for clinical trials. We need to make sure people understand that.?