Physicians have an obligation to ensure that patients are not harmed during the process of treatment Image by iStock
Physicians have an obligation to ensure that patients are not harmed during the process of treatment. Image by iStock

Balancing ethics, risks of ‘right to try’


Legislators, regulators, and private industries can't seem to agree on compassionate use of experimental drugs in desperate, sometimes terminal patients. Internists are left to juggle an imminent need to help against their oath to do no harm.

A spate of controversial state laws and proposed federal legislation—spawned by some advocates' frustration with dying patients' access to experimental drugs—might pose logistical and ethical challenges for physicians in years to come.

More than three dozen state legislatures have enacted what's been dubbed “right-to-try” legislation from January 2014 through August 2017, according to the National Conference of State Legislatures. The Senate passed a federal bill along similar lines—albeit with some key differences—in August 2017.

The ongoing debate over the legislation rests on a dispute over how much patients facing life-threatening diseases are hampered in their access to experimental drugs outside of research studies. Supporters of the laws, initially largely led by the Phoenix-based Goldwater Institute, believe that terminal patients should have the opportunity to try drugs that have cleared a phase 1 study without FDA oversight.

“That decision, especially if you're dying and out of options, really ought to be something that's the patient's and not something that's left to the government,” said Christina Sandefur, an attorney and executive vice president at the institute.

Opponents, which include some physician and patient advocacy groups, say that the FDA already has a process to get patients these drugs, called expanded access, and worry that the new laws erode the FDA's ability to protect both terminally ill patients and future patients.

Meanwhile, the laws don't alter one of the most notable obstacles. Drug manufacturers can still refuse to provide the medication that a patient requests, said Richard L. Schilsky, MD, FACP, chief medical officer at the American Society of Clinical Oncology, which issued a critical position statement on access to experimental drugs in spring 2017.

Oncologists have enormous sympathy for patients in desperate medical straits, Dr. Schilsky said, and offer investigational options through research trials and the expanded access program. They also have an obligation to ensure that patients are not harmed in the process of treatment, he said.

“If you're a patient who is likely to die from your cancer,” he said, “you could die sooner or you could die in greater discomfort by taking an investigational drug that produces only side effects and no real opportunity for benefit.”

Heightened scrutiny

Amid the recent scrutiny, FDA officials have already implemented several measures to streamline requests for expanded access, otherwise known as compassionate use.

In 2016, the FDA reduced the paperwork that a physician must fill out for an expanded access request, with FDA officials estimating it should require less than an hour to complete. In fall 2017, FDA Commissioner Scott Gottlieb, MD, announced another change. Physicians making such a request now only need the approval of one key member of their facility's institutional review board, such as the chair, rather than the full board.

Even prior to these changes, though, the overwhelming majority of expanded access applications have been allowed to proceed, 99.7% of the nearly 11,000 received by FDA officials from January 2005 through December 2014, according to data published in November 2016 in Therapeutic Innovation & Regulatory Science. (Ms. Sandefur, of the Goldwater Institute, countered that it's unknown how many drug requests never reach the FDA because the process has been too time-consuming. She pointed to a Goldwater Institute report that cited 1,200 compassionate use applications approved by the FDA annually.) In roughly 10% of those cases, FDA officials recommend modifications to improve patient safety, such as changes in dosing or additional monitoring, Dr. Gottlieb said during his Oct. 3, 2017, testimony to a House subcommittee.

Various state laws and the federal legislation, particularly in earlier versions prior to Senate passage, undercut the FDA's safety-related oversight for patients able to obtain an experimental drug outside a research trial, said Alison Bateman-House, PhD, MPH, an assistant professor in the division of medical ethics at NYU Langone Health in New York City and one of the leading critics of right-to-try legislation. Initially, she said, the Senate bill (S.204) barred the FDA from using any clinical outcomes from experimental drugs used by right-to-try patients in evaluating the drugs' safety and efficacy.

The argument, Dr. Bateman-House said, is that drug manufacturers might be loath to provide these drugs to patients—most of whom are too sick to qualify for research studies—if they are fearful that an adverse outcome in one of these patients would negatively impact eventual FDA approval of the new drug. “Many people I talk to in the pharmaceutical world have that very fear,” she said. “Is it a fear based on fact? No.”

She pointed to the same 2016 study in Therapeutic Innovation & Regulatory Science, which identified only two instances across a 10-year span where an adverse event in the expanded access setting resulted in a clinical hold being put on an experimental drug by the FDA.

The final version of the Senate bill passed in August 2017 did cite a few exceptions regarding when clinical outcomes could be shared with federal officials. They included scenarios in which the manufacturer requests that the outcomes be shared and when it's determined that the information is “critical to determining the safety of the eligible investigational drug.”

The final Senate version sent to the House also stipulated that there would be no liability for the involved drug sponsor or manufacturer. Neither would there be any for the prescriber, with a few exceptions such as reckless or willful misconduct or gross negligence. The House has its own bill, HR. 2368, that was introduced on May 4, 2017, and was referred to a subcommittee in June.

Detailing in the federal legislation when and how any adverse events could be later used in the drug approval process will hopefully ease manufacturer worries about being penalized, Ms. Sandefur said. “The drug companies, whether it's justified or not, and I think it is justified, say that they're afraid that they could be the next one.”

Weighing relative risks

An opinion piece published in the Nov. 17, 2015, Annals of Internal Medicine, authored by Dr. Bateman-House and others, argued that allowing patients to bypass FDA officials to access these drugs could open the door “for the unscrupulous or inept to prey on desperately ill patients and their families.”

Dr. Bateman-House, in the Annals piece and during subsequent congressional testimony, also noted that some of the states' right-to-try laws strip other protections away from patients. During her Oct. 3, 2017, testimony to the House Energy & Commerce Committee's Subcommittee on Health, Dr. Bateman-House said that in 19 of the 37 state laws enacted by that point, patients getting an investigational drug through right to try could lose their hospice coverage. In six states, patients may be denied coverage for home health care assistance.

The proliferation of right-to-try legislation might create treatment challenges for doctors as well, said Tom Bledsoe, MD, FACP, chair of ACP's Ethics, Professionalism and Human Rights Committee. (The American College of Physicians has not issued a policy statement on right-to-try laws.) Dr. Bledsoe, who was speaking personally and not in his committee role, said that “Sometimes what the patient wants, science, and the professional ethics and values are not all in alignment.”

As one example, he said, what if a patient wanted to try an operation that the physician thought would kill him or her? “Probably no one would require a surgeon to do an operation under that kind of setting,” said Dr. Bledsoe, a general internist and clinical associate professor of medicine at Brown University's Warren Alpert Medical School in Providence, R.I.

Ms. Sandefur didn't disagree with the physician's role in gauging risk-benefit. “That's why the doctor is part of the equation,” she said. It makes a lot more sense, she said, to have the doctor “use his or her own medical judgment to make those decisions” regarding requesting a drug directly from a manufacturer without getting federal officials involved.

During the related testimony in recent years, proponents on both sides have reflected the desperate straits under which experimental treatments are even considered.

Speaking before the Oct. 3, 2017, House subcommittee hearing, Ellen Sigal, PhD, chair of the nonprofit organization Friends of Cancer Research, described her sister's fight against metastatic breast cancer and decision some two decades ago to try an experimental bone marrow transplant. Ms. Sigal said the treatment's side effects were “swift and violent.” Her sister died two days later.

But Juran Cook, a registered nurse in Wisconsin who testified in support of the state law there, said that patients facing death should be free to make direct appeals to the drug manufacturer. (This is permitted under expanded access, Dr. Bateman-House said. The drug company will tell the patient to have his or her physician contact the company to discuss access.) She and her husband, Mitch, closely followed drug research after he was diagnosed at age 55 with amyotrophic lateral sclerosis. Some studies that seemed promising only wanted to enroll patients within a year of diagnosis, Ms. Cook said, and her husband had passed that point.

It was Mitch Cook, who died in 2016 at age 58, who first noticed and supported the emergence of right-to-try laws, his wife recalled. “He said, ‘I'm dying. I have very limited time. If there's something out there I want to try and I know the risks, I don't understand why the government says, no, I can't try it.’”

Advising patients

While subspecialist physicians might be more likely to be asked about right-to-try laws, ASCO's Dr. Schilsky anticipates that primary care doctors also might field patient queries on the behalf of severely ill loved ones. “It's going to put the burden on the primary care physician to both understand what these laws do and do not permit, and then provide some educational guidance to the patient,” he said.

Doctors should make sure that patients understand that many drugs, after clearing a phase 1 study, don't ultimately prove to be effective, Dr. Schilsky said. Also, he said, patients should be alerted that “After phase 1, we don't always fully understand either the correct dosage or the side effects of the drugs.”

Moreover, there are potential financial concerns, Dr. Schilsky said. Even if the drug manufacturer provides the drug, a patient's insurance may not be willing to pay for the costs of administering it, any related monitoring for side effects, or treatment of complications that arise, he said.

Depending upon the circumstances involved, if a patient wants to appeal directly to the manufacturer for an experimental drug, “It may be a very ethically defensible position for the physician to say, ‘I can't help you with that [application] project,’” Dr. Bledsoe said. “Personally, I have a strong civil libertarian streak. But I also feel like as a profession, we do have responsibilities for the welfare of our patients.”

One hurdle—determining whether a manufacturer will even offer a drug outside of a research trial—has become easier in recent years, Dr. Schilsky said.

The 21st Century Cures Act, signed into law in 2016, requires manufacturers studying drugs for serious conditions to post their policies about whether the drug is available under expanded access and related information, such as a point of contact, he said.

“Most of the pharma companies now have a reasonably identifiable place on their website where someone can put in a query about expanded access programs and there is generally a commitment that they'll receive a response within 24 hours,” Dr. Schilsky said.

In addition, the Reagan-Udall Foundation is developing an expanded access navigator tool to educate patients about the steps involved and to help them locate drug manufacturers' policies. The online tool is being test-driven with cancer drugs, said Dr. Schilsky, who is a board member of the nonprofit organization created by Congress to assist the FDA.

It's unknown how often state right-to-try laws have been used, as the Goldwater Institute doesn't collect the data, Ms. Sandefur said. Few doctors have been willing to talk publicly about using the laws, she said. Among some of the reasons are that a federal law hasn't been passed with related liability protections, and some physicians who want to conduct their own research studies worry about running afoul of FDA officials in some way, she said.

She added, “There is nothing in the right- to-try laws or federal bill that undermines FDA approval authority. In fact, right to try works in tandem with the FDA approval process.”

Dr. Bateman-House, however, said that she's become so outspoken about right-to-try legislation because she's concerned about weakening federal officials' oversight role. “I think that the FDA is really a national treasure in terms of protecting patients, protecting consumers,” she said. “The laws that we have saying that we want to be convinced of safety and efficacy through a rigorous process—they came about because of tragedies. They weren't just ‘magic-ed up’ out of thin air. It's been an ongoing evolution to create a system that works.”