The Ethics of Compassionate Care

Back in the late 1980s, when activists from Act Up were demonstrating in pharmaceuticals companies’ parking lots to demand greater access to experimental AIDS drugs, bioethicist Arthur L. Caplan, Ph.D., was chairman of amfAR, the American Foundation for AIDS Research, the arbiter of such requests. In May of this year, Professor Caplan was tapped by Johnson & Johnson to create a new panel that will decide which patients get early access to potentially life-saving medicines before they obtain regulatory approval, a process commonly known as compassionate use.

Known to nearly everyone as Art, Caplan is in some ways a surprising choice to head the panel, which is believed to the industry’s first. Large drug companies are typically tight-lipped, and Caplan is anything but. A professor at New York University, Caplan is easily the most-quoted bioethicist in the business; indeed he may be quoted more than all other bioethicists combined. His fame, or notoriety, depending on your point of view, has made him a controversial figure in his field, but he said it never entered the conversation with Johnson & Johnson.
“J&J already knew me. They asked, ‘What would you do if we said, how would you manage this differently?’ ” Caplan said. “I went back to my group at N.Y.U. and said, ‘What about instead of having a medical officer at the company decide what to do, what if we tried a panel with many different perspectives: patient advocacy, medicine, law?’ The panel would work anonymously, so you wouldn’t have social media chiming in, or people calling their politician.”

Amrit Ray, a physician and chief medical officer of Janssen Pharmaceutical Companies of Johnson & Johnson, said that Caplan’s high profile was not an issue for the company. “N.Y.U. has a long history of expertise and engagement in this area,” Ray said. “We chose to collaborate with N.Y.U. and Dr. Caplan because our assessment was they were uniquely qualified and at the forefront of ‘compassionate use’ thinking. Dr. Caplan will lead the group, but he has also elected that the panel will make the decisions and he will step in if it’s not possible to reach consensus among the members.”

Though the leaders of Act Up, the AIDS Coalition to Unleash Power, were often arrested, their ultimate success in gaining early access to new drugs inspired other patients with life-threatening illnesses to become activists. But from Act Up’s street actions, which included a demonstration that closed the Food and Drug Administration for a day in 1988, compassionate use campaigns grew ever more sophisticated. Today nearly every disease, some of them not remotely life-threatening, has an organized patient group seeking early access to new drugs, using every tool available, from professional public relations firms to slick social media pages.

A growing number of states passed so-called right-to-try laws allowing patients to try experimental drugs, but Caplan said these have been ineffectual. “I don’t like them because they give false hope,” he said. “They say, ‘You have a right,’ in spite of the F.D.A., in spite of drug companies or anything. What they really are is ‘right-to-beg’ laws. They also don’t give you any money, so if you need a baby sitter to travel to where a trial is, you don’t get that help. A lot of these drugs are biologic. They’re complicated to deliver, and you have to get them by infusion. The main thing I don’t like is the laws don’t do anything. They sound good, politicians like them. Normally if something is a right, then somebody has to do something. Nobody has a duty to do anything” under these laws, he said.

Besides, the F.D.A. grants nearly every request for early access, which typically means letting patients take a drug that is still somewhere in the three-phase process that leads to regulatory approval. Phase One trials, typically in a small group of patients, assess safety, establishing first that the drug does no harm or at least that its side effects are tolerable in the target population. Phase Two, among greater numbers of patients, at more than one site, attempts to prove that the new drug works by hitting predetermined end points such as reduced tumor size. Phase Three, among many more patients at multiple clinical settings, is intended to confirm safety and efficacy as well as the company’s ability to produce an adequate drug while meeting F.D.A. standards. Experimental drugs can fail at any stage.

So getting early access to new drugs is no panacea, yet desperate patients continue to ask for it. “I was around back in the AIDS days,” said Caplan, referring to his time at amfAR. “We got a lot of requests, and I approved a lot of them, as chair. I never saw one person get better. That is not the impression that is conveyed in things like the ‘Dallas Buyers Club’ movie. There were things that happened in terms of community that I think were good, but there’s this mythology that because of activism, certain people got better. I have seen one or two cases recently where someone got better because of an unapproved drug, but it’s rare.”

Because the F.D.A. has essentially passed the issue of early access off to the companies developing the drugs, biopharma executives are confronted with constant requests that they lack the time or the resources to evaluate properly, Caplan said. Investors urge them not to get involved, because honoring compassionate use requests, also known as expanded access, is costly and distracting. Small biotech firms, which often pioneer new types of therapy, often have no one on staff to manage the program. Yet the Twitter and Facebook onslaught is unrelenting.

“I thought, you’ve got to tamp that down,” said Caplan. “Social media is not fair. People with means have an advantage. People who are photogenic have an advantage. You’re not going to see some 60-year-old alcoholic in one of these appeals. By having a committee trying to wrestle with anonymized requests, we’re ahead of the game already.”

Johnson & Johnson had previously reached out to Caplan for advice on a drug for ovarian cancer that was already approved and on the market, but in short supply due to a manufacturing problem. “They were short, and they asked for my advice,” he said. “I said, ‘You can’t take the drug away from people who already have it, to give it to new people.’ I also said we ought to do all we can to get the drug back from people who have already died. We were literally taking the drug out of medicine cabinets. It extended life for a month or three.”

Caplan is not a physician; he has a Ph.D. in the history and philosophy of science from Columbia University. But he said he was attracted to the medical field due to a childhood experience with polio. “As a 6-year-old in the hospital, I watched how kids were treated,” he said. “I was paralyzed for a time, I had to go through rehabilitation for years, so I had this early contact with the health care system, and even as a little kid it raised questions in my mind. Then when I was hanging around Columbia Medical School, way back in the early ’80s, I kept seeing all these issues, like newborn preemie babies—how do we keep them alive? But I went off and got a philosophy degree and never returned to medicine, much to the continuing dismay of my 91- and 94-year-old parents. Once I got into bioethics, I really liked it. There’s a new issue every day, and sometimes I think it can really make a solid difference.”
Examples where Caplan’s direct involvement in public policy has made a difference are many. He helped found the National Marrow Donor Program, which created the policy of required request in cadaver organ donation adopted throughout the U.S. He helped create the system for distributing organs, and worked with then-Sen. Al Gore to develop the National Organ Transplant Act, which included rules governing living organ donation. He has also contributed to legislation and regulation in many other areas of health care.

Caplan secured the first government apology, in 1991, for the infamous Tuskegee experiments, in which black patients with syphilis were left untreated—to test the progress of the disease—without their knowledge. He also worked with William Seidelman, M.D., and others to secure an apology in 2012 from the German Medical Association for the role of German physicians in the Holocaust.

In 2000, after the death of a teenage patient during a gene therapy trial at the University of Pennsylvania, Caplan and several researchers involved in the trial were sued by the patient’s family, who claimed the patient had not been informed of the risks. Caplan, who had provided ethical commentary, was later dropped from the case. But he has also clashed with his bioethicist peers on various topics, including a study on informing parents of potential risks to premature babies in 2013. Public Citizen, an advocacy group, criticized the study as well as Caplan’s written defense of it, saying he was not adequately informed.

But Caplan is unapologetic, noting that his opinion had appeared in the New England Journal of Medicine, a peer-reviewed journal. “I mean, that’s about as good an endorsement as you’re going to get,” he told the New York Times.

Nor is Caplan shy about politics. He is the author or editor of 32 books, but his layperson’s guide to bioethics, “Smart Mice, Not-So-Smart People” (2008), has been cast by some critics as a transparently anti-Republican screed. And indeed, Caplan pulled few punches, highlighting conservative hypocrisy on matters medical and ethical, from stem cell research to right-to-die laws. “Rather than shackle American scientists, the U.S. should encourage cloning research,” he wrote. “Myths should not be the basis for public policy where cures hang in the balance.”

And he has no doubt that the foes of science will be quick to tag his new effort with their favorite sobriquet: death panel. “Absolutely yes, I do think critics will latch onto that,” Caplan said. “But it’s a misunderstanding. I would say it’s a panel that’s going to try to find a fair solution. As with donor organ distribution, this is about finding the best way to allocate a scarce resource. It’s great to theorize, but sometimes you have to sit down and do it: try to design something that is fair.”

For J&J, the creation of the panel is about bringing together internationally recognized medical experts to bring a thoughtful approach to complex decisions, said Ray. “For us at J&J, the collaboration with N.Y.U. comes at a time when innovation in science offers great potential for patients. That presents a need for compassionate use processes that are fair and patient-centric,” he said. “That really is the driving force.”

Johnson & Johnson is beginning the panel with just one drug to consider, but Ray said he hopes the effort will broaden to other therapies and to other drug companies. There is no exclusivity to J&J’s contract with Caplan, who is not being paid. “This is new. This is innovative. This is taking a big step for patients, and we want to be very responsible, so we are beginning with one drug; but if this is successful, the hope is this will be extended across J&J’s drugs and devices,” he said. “The intent is that we will look at all of our assets and make the decision on what the right time is depending on what we learn from the pilot.”

Patients will receive the treatment free if their request is approved, which is common in compassionate use. But they may have to cover doctors’ fees and other related costs out of pocket. Insurance companies often do not cover such costs for experimental drugs.

The volume of requests is not a burden for a company J&J’s size, but the nature of the requests, which usually come from desperate patients who have exhausted all other remedies, makes them particularly difficult, said Ray. “When I think of these requests that we face from patients, their families and physicians, at a personal level, every single request is one of the most difficult decision I face as a physician. I give every one my full attention. These are heart-wrenching requests, and everyone that tries to help with them finds themselves challenged.”

Patients seeking early access to experimental drugs may have been excluded from clinical trials because they did not meet criteria of the trial design, or the trial was closed after a sufficient cohort was enrolled. Some patients do not wish to enter a clinical trial for fear that they will be placed in a control group, which receives a placebo rather than the drug that is being tested. Many do not understand how clinical trials work. Indeed, even as some patients demand access to new drugs, many biopharma companies struggle to enroll adequate numbers of patients in their clinical trials.

The problem is particularly acute for cancer patients. “Only roughly 3 percent of all cancer patients in the United States ever agree to join a trial,” Stan Collender wrote in an op-ed piece in the New York Times on June 19. Collender, an executive vice president at MSLGROUP, a global communications agency, has a rare and aggressive skin cancer for which there is no approved treatment. A colleague, upon hearing that Collender was taking part in a clinical trial, said he would rather not be treated than be used as a “lab rat.”

“I am not a lab rat,” Collender wrote. “What I am is a patient who needs and is receiving treatment.”

One development that may aid clinical trial enrollment and compassionate use alike is the emergence of so-called precision medicine, which applies new diagnostic tools to identify in advance those patients who are most likely to benefit from a given drug. Precision medicine allows doctors to prescribe appropriate and optimal therapies based on a patient’s genetic makeup or other molecular or cellular analysis, commonly known as biomarkers.

The era of precision medicine began with Genentech’s breast cancer drug Herceptin, which was approved by the F.D.A. in 1998. Herceptin only works in 20 percent to 30 percent of breast cancer patients. Ordinarily a drug that did not work in more than 70 percent of patients would have failed to win marketing approval, but because researchers at Dako, a Danish diagnostics company, were able to devise an accompanying assay that showed elevated levels of a protein called HER2 in those patients who did respond, Genentech was able to get Herceptin approved for that smaller group. Because many cancers are caused by genetic mutations, oncology has been the most fertile early ground for precision medicine, but it is applicable to other kinds of diseases as well.

“There is this revolution in treatment, with more precision,” Caplan said. “If you’ve got a drug that attacks a certain biomarker, I’m dying and I have that biomarker, then there is more of a rationale than 20 years ago, when we were shooting cannons off at targets all over the place. It makes more sense.”

Yet the fact remains that while precision medicine may remove some level of uncertainty, drugs in clinical trials are unproven, so there is always the risk of raising false hopes. Adequate disclosure is critical, said Ray. “Whenever patients are in that very difficult situation, with no treatment option available, they are always seeking hope,” he said. “The intent is never to give patients false hope. Whenever patients enter any preapproval avenue, there is the recognition that these are medicines under study. When a patient enters a clinical trial, there is an understanding that this is an experiment. That’s what informed consent is all about. In the expanded access program, the same principle applies, that these are medicines under study.”

While the F.D.A. hears its share of criticism, from patient advocates and pharmaceutical executives alike, Caplan said the agency has been very accommodating of compassionate use requests. “They’re even more receptive than they were years ago,” he said. “The F.D.A. today has tried to speed up its application process; you can do it in 45 minutes. They have approved 99 percent. The one percent is due to error, or because something else is already approved. If a person dies when taking the unapproved drug, they don’t hold that against the drug. I don’t think they’re the roadblock, but the right-to-try people do. I don’t think that’s true at all.”

The F.D.A. approved 1,873 requests in fiscal 2014 from companies to grant expanded access, up 85 percent from the 2010 fiscal year, when it approved 1,014 requests.

Caplan said there is a growing recognition that patients have a right to try new drugs. “As much as I don’t like right-to-try laws, they have shown that American people want some resources devoted to experiment,” he said. “There is a notion that the desperately ill deserve a shot, even if it’s a long shot. We rescue hikers off mountaintops; we scour the seas for missing boats. This fits into that moral universe. If you’re desperate, you deserve a chance, even if all we’re throwing you is a stick.”