The Realities of “Right to Try”

Overlooking Expanded Access? 

On May 30, 2018, when President Trump signed the “Right to Try” legislation, he proclaimed (via Twitter), “With the ‘Right to Try’ [law] I am signing today, patients with life threatening illnesses will finally have access to experimental treatments that could improve or even cure their conditions.”⁵

He failed to acknowledge, though, that these patients already had a pathway to obtaining investigational drugs: the FDA’s expanded-access, or “compassionate-use,” program.⁶ Under this program, if a physician believes that a patient will benefit from an experimental treatment, he or she must request from the FDA a single-patient investigational new drug (IND) application for the therapy. Next, the drug’s manufacturer decides if it is “able and willing” to provide the product for expanded-access use.

According to the FDA, expanded access is appropriate when the following conditions are met: patients have a serious or life-threatening illness; there is a lack of comparable alternative therapy; the patient does not qualify for a clinical trial; the potential benefits outweigh the risks of treatment; and providing the investigational therapy would not interfere with investigational trials.⁶

“‘Right to Try’ legislation is designed to provide easier access to certain medications that would not otherwise be available to patients and to provide an extra level of protection for people who want to engage in that process,” according to Rafael Fonseca, MD, a visiting fellow at the Goldwater Institute and chair of the Department of Medicine at Mayo Clinic in Phoenix. (The views expressed by Dr. Fonseca and others quoted in the article are individual and do not necessarily represent those of their institutions.)

“Everyone agrees that clinical trials are the way to go for generating knowledge,” Dr. Fonseca said. “They provide options for patients and generate information about new medications as [trial sponsors] go through the process of drug development.”

However, he noted, “most patients are not on clinical trials or don’t qualify for them for a number of reasons.” For example, he explained, a patient with a hematologic malignancy might be a candidate for a monoclonal antibody but might be ineligible for a trial because of age or comorbidities. “By participating in ‘Right to Try,’ that person would derive the same potential benefit as someone enrolled in a phase II trial.”

On righttotry.org, a website funded by the Goldwater Institute, advocates of the “Right to Try” movement also argue that strict trial-eligibility criteria preclude most terminally ill patients from participating in trials, which they cite as one of the reasons “why we needed ‘Right to Try’ [laws].”⁷ Those who do gain access to experimental drugs through clinical trials, they continue, will lose access to the drug once the trial is completed.

Debunking the Myths About Compassionate Use 

Representatives from the Goldwater Institute claim that the FDA’s process for approving “promising treatments” is too lengthy but, according to Steven Joffe, MD, MPH, chief of the division of medical ethics at the University of Pennsylvania Perelman School of Medicine, this argument advances a false narrative that the FDA presents a barrier to patients accessing these investigational drugs.

This position was supported by results of a 2016 study that analyzed individual IND applications received and granted by the FDA’s Office of Hematology and Oncology Products (OHOP).⁸ Steven J. Lemery, MD, MHS, the OHOP’s lead medical officer, and colleagues reviewed 1,332 single-patient IND applications submitted to the FDA between January 2012 and December 2014, which covered more than 150 unique drugs for conditions like chronic myeloid leukemia, breast cancer, and acute lymphocytic leukemia.

The median review time for the 1,309 INDs with documented receipt and “proceed” dates was one day, and the mean review time for all requests was 2.2 days (ranges not provided). Three-quarters of INDs were reviewed within three days and all but 30 of the single-patient IND requests were granted within 14 days of receipt.

Requests that took longer to grant decisions had major issues with documentation, the authors noted. “OHOP’s review time and approval of nearly all cancer-related, single-patient expanded-access requests is consistent with FDA goals to facilitate expanded access,” the researchers concluded. “OHOP is continuing to work to improve this process and increase transparency to facilitate access for more patients.”

“By participating in ‘Right to Try’, [a patient who is ineligible for a clinical trial] would derive the same potential benefit as someone enrolled in a phase II trial.”

—RAFAEL FONSECA, MD

Recent efforts to streamline the expanded-access IND process include reducing procedural burdens by revising the application form. The new “Individual Patient Expanded Access Investigational New Drug Application – Form FDA 3926” is much shorter than the previous version and is designed specifically for these requests. New regulations also eliminate the previous requirement that a physician receive permission from all members of his or her institution’s internal review board (IRB) to treat a patient with an experimental drug; now, only one designated member of an IRB – such as the chair – needs to approve the request.⁹

In announcing these updates, the FDA also reported that, of the more than 1,000 expanded-access applications it receives each year, it authorizes about 99 percent.

Proponents of “Right to Try” legislation are still unsatisfied with the process, because it does not solve what they see as the essential problem of the expanded-access program: As righttotry.org advocates wrote, people should not have to ask the federal government permission to save their own lives.⁷

“‘Right to Try’ legislation does not provide anyone with a ‘right’ but gives a patient the ability to interact directly with the manufacturer,” Dr. Fonseca clarified. “It opens opportunities.”

Two Roads Diverged 

The major difference between expanded access and programs advanced by the “Right to Try” legislation is the level of oversight: The FDA’s program incorporates the agency’s review of experimental drugs, while “Right to Try” laws eliminate it.

Because the FDA is responsible for weighing the risks and benefits of an investigational agent and, in some cases, advising on dosage or administration, “the expanded-access program provides patients a level of protection that ‘Right to Try’ [laws] cannot offer,” according to Alison Bateman-House, PhD, MPH, of the division of medical ethics at NYU Langone Health in New York City.

Although some health-care experts and policy makers have compared “Right to Try” legislation to access to a phase II clinical trial, these comparisons hold little weight with critics.

“A clinical trial offers oversight from investigators, the institution, the IRB, and the FDA,” Dr. Joffe said. “Through the clinical-trial experience, we also learn about a drug’s safety and potential efficacy. Science advances.”

These contributions are unlikely to happen under the “Right to Try” Act, Dr. Joffe said.

The federal legislation states that the government may not “use a clinical outcome associated with the use of an eligible investigational drug … to delay or adversely affect the [FDA’s] review or approval of such drug.” However, exceptions are noted, including if “the use of such clinical outcome is critical to determining the safety of the eligible investigational drug” or the manufacturer “requests use of such outcomes.”¹

This language likely was included to assuage manufacturers concerned about the impact of expanded-access treatment, which takes place outside of a defined and controlled clinical trial, on their drug’s regulatory review. (Note: In 2017, the agency updated its guidance document, stating that adverse reactions need to be reported “only if there is evidence to suggest a causal relationship between the drug and the adverse event.”⁹)

“The fact that we can’t use any information from patient experience with the “Right to Try” pathway to inform decisions about regulatory approval is a problem,” Dr. Joffe stressed. “If there are reports of adverse events associated with patients taking investigational drugs, the FDA is almost precluded from using that information.”

The FDA’s expanded-access program is a good alternative, but it lacks widespread awareness, Dr. Bateman- House said. “It is an issue of education. I’ve talked to doctors who frequently have no idea that the system even exists.”

The expanded-access program also has been a victim of disinformation campaigns that paint it as difficult and overly time-consuming.

“If you ask people who study expanded access, the place where patients encounter obstacles to these drugs is at the point of manufacturer’s involvement,” Dr. Bateman-House said. “There are numerous reasons a company would not be inclined to give access to investigational drugs, and ‘Right to Try’ legislation changes nothing about that, except now there is a blanket liability statement [for manufacturers].”

However, Bart Scott, MD, associate member of the Fred Hutchinson Cancer Research Center in Seattle, and member of the ASH Committee on Government Affairs, disagreed.

“From a physician’s perspective, it can be a nightmare to request access [to investigational drugs] using the expanded-access program,” said Dr. Scott. “It requires weeks of work. This is not something that can be completed in a day, so I am glad we have this new avenue available.”

The Realities of Implementation

Most people would likely agree that the goal of “Right to Try” legislation – giving patients easier access to a drug that they might be given under expanded access – is a noble one. So, why are some doctors concerned about the prospect of implementing it?

“The reason that the hematology/oncology community hasn’t bought into ‘Right to Try’ legislation whole hog is because it is unclear how we are going to actualize those goals, given some of the vagueness of the legislation,” said Mikkael Sekeres, MD, MS, director of the Leukemia Program and vice-chair of clinical research at Cleveland Clinic Taussig Cancer Institute and editor-inchief of ASH Clinical News.

Dr. Sekeres is leading the effort on implementing “Right to Try” requests at Cleveland Clinic, where managing expanded-access requests has proved timeconsuming. He estimates that it takes one research coordinator a full workweek to get everything in place to apply for a drug through the FDA’s program. “Most of that time is not spent interacting with the FDA,” he explained, adding that “the FDA is quick to make a decision. Most of the time is spent in writing a protocol and an informed-consent document.”

“I don’t know why any company that is committed to gathering evidence to support a claim of efficacy … would go the ‘Right to Try’ route.”

—STEVEN JOFFE, MD, MPH

Like any patient participating in a clinical trial, patients requesting access to drugs through the FDA’s program must provide informed consent consistent with federal requirements. While the text of the Right to Try Act of 2017 states that eligible patients must provide the “treating physician written informed consent regarding the eligible investigational drug,” it offers little guidance as to the content of this consent form.¹

“In the typical FDA procedures for informed consent, physicians are required to describe the potential risks and benefits, alternatives to the investigational drug, and more,” Dr. Bateman-House said. “All that is removed with ‘Right to Try’ [legislation]. There are no standards about what these documents need to say.”

For therapies administered through the ”Right to Try” pathway, it also is unclear who will explain to patients that they may be responsible for the costs of the drug, its administration, and any costs incurred as a result of the investigational treatment.

According to Dr. Sekeres, many insurance companies will typically pay for the “usual care” associated with clinical-trial treatment, but it is unclear whether insurance companies will pay for treatment accessed under “Right to Try” legislation.

“The decision to try a non–FDA-approved drug lies between a physician and patient,” a representative from UnitedHealthcare told ASH Clinical News in a statement. “We provide access to thousands of medications through our pharmacy programs and support participation in qualified clinical trials to help individuals get the proven treatments needed to support their care.”

Untangling State and Federal Laws 

Another aspect of implementation that Cleveland Clinic and other hospitals may struggle with is navigating differences between “Right to Try” legislation written at the state level and that written at the federal level, Dr. Sekeres said. For example, “Right to Try” legislation in Ohio (which became the 33rd state to adopt its own law, H.B. 290, in 2017) is 32 pages and includes more specific requirements on informed consent than the comparatively slim four-page federal document.¹⁰

“My understanding is that, in the past, we did not have to follow state legislation, but now that the federal law is in place, hospitals have to determine which guidelines to follow,” Dr. Sekeres said.

Holly Fernandez Lynch, JD, MBE, the John Russell Dickson, MD Presidential Assistant Professor of Medical Ethics and Health Policy at Perelman, agreed that the issue is quite complicated.

In the U.S. system of federalism, all the power not granted to the federal government is reserved to the states, she explained, but in areas where the federal government has authority, it preempts state law.

“In general, if the federal government has total authority over an area, states are precluded from regulating it – this is called ‘field preemption,’” Ms. Lynch said. “Sometimes, though, federal regulation is treated as the ‘floor’ rather than the ‘ceiling,’ meaning that states are free to regulate in the same space, as long as what they require does not conflict with federal law.”

If state lawmakers enact a law that conflicts with federal statutes, “it would be preempted as a matter of ‘conflict preemption.’ In this case, states can impose more stringent requirements than federal law, but not less.”

In the case of “Right to Try” laws initially passed by states in attempting to circumvent the FDA, state law would have been preempted by federal law. If any patient received an unapproved therapy under a state “Right to Try” law, state laws were in direct conflict with FDA requirements, Ms. Lynch explained.

The passage of the Right to Try Act of 2017 complicates matters further. Ms. Lynch laid out two scenarios: In one, the federal and state laws might not conflict, and there would be no issue. In the other, the federal “Right to Try” law could create “field preemption,” when Congress, without expressly declaring that state laws are preempted, legislates as to “occupy” the entire field of an issue.

In the first scenario, state “Right to Try” laws could be allowed to stand if they are more restrictive than what the federal law requires (for example, stricter eligibility criteria or more detailed informed-consent requirements) or if they cover different areas not touched by the federal law (for example, how accessing an investigational drug affects patient’s eligibility for insurance coverage or hospice).

“Ultimately, it is unclear how to view the state ‘Right to Try’ laws,” Ms. Lynch said, “and the question of preemption will likely need to be resolved by the courts.”

Until then, she offered the following advice for physicians unclear about the federal and state laws: If they want to provide access through the “Right to Try” pathway, compliance with federal law is most important.

“Better yet is not to provide access through the ‘Right to Try’ pathway at all because it is dangerous for patients,” she added. “Expanded access should be the preferred approach.”

The Buck Stops Here 

Regardless of the approach a patient and physician choose, decisions about accessing investigational drugs rest with the pharmaceutical companies.

“I don’t know why any company that is committed to gathering evidence to support a claim of efficacy, that knows it can use the expanded-access pathway, and that works collaboratively with the FDA would go the ‘Right to Try’ route,” Dr. Joffe said. “I do not see any positive benefit.”

Companies that choose to grant access to their experimental drugs through the “Right to Try”’ pathway will be required to provide the FDA with annual summaries that include “the number of doses supplied, the number of patients treated, the uses for which the drug was made available, and any known serious adverse events,” according to the law.

Whether those stipulations will discourage manufacturers from granting requests – especially when their drugs will be administered in a less-controlled and less-regulated setting (compared with a clinical trial) – is yet to be seen.

Dr. Fonseca argued that the adverse event– reporting requirement might make financial sense for manufacturers. “If a company sees a product it is developing causes heart failure in 50 percent of patients, for example, the company is not going to invest hundreds of millions of dollars in phase II and III clinical trials,” he said. “That information is important to everyone, including manufacturers.”

Summing up the ongoing controversy over “Right to Try” legislation, Dr. Sekeres said that it comes down to a matter of opinion: Some physicians believe in granting patients off-label or early access to therapies, and others do not.

“Treatment decisions should be collaborative between a doctor and patient,” Dr. Sekeres said. “As a licensed medical professional, though, I can’t ethically give a drug to a patient for whom the harm outweighs the benefit to him or her, even if the patient believes otherwise. All I can do is recommend that the patient see another doctor.”

Still, Dr. Scott pointed out that people faced with this decision generally are not healthy patients seeking treatment for benign conditions.

“These patients are facing life-threatening illness with no other options,” he said. “When you are in a position of having no treatment options available to you, you are willing to take more of a risk on a treatment with a potential benefit, because the alternative is dying from your disease.” —By Leah Lawrence