Expansion of ‘Right to Try’ legislation raises ethical, safety concerns

Early access to experimental drugs has historically been reserved for patients enrolled on clinical trials.

In 2009, the FDA revamped its 1980’s expanded access program, which allows terminally ill patients ineligible for clinical trials and for whom no alternative, approved therapies exist to ask pharmaceutical companies for access to an investigational drug in their pipeline. More than 1,500 patients received an experimental treatment through the FDA’s program in 2014.

Now, some legislatures are going a step further by adopting so-called “Right to Try” legislation, intended to give terminally ill patients comparable access to investigational drugs but removing the FDA from the process.

Since 2014, thirteen states have passed Right to Try laws, and legislators in 20 more states have plans to introduce similar legislation this year.

“When an individual has a life-threatening illness and a terrible cancer, there is a natural sympathy,” Ezekiel J. Emanuel, MD, PhD, professor of medical ethics and health policy in the Perelman School of Medicine at the University of Pennsylvania, told HemOnc Today. “These laws are based on the fact that a young person with a terminal cancer or illness often — and understandably — would probably try everything they can.”

However, concerns among those in the clinical community — who must authorize patients’ requests for investigational agents — may limit the extent to which patients access treatments through such legislation.

Without the FDA’s oversight, data from patients who use treatments obtained through Right to Try laws would essentially be lost knowledge. Further, pharmaceutical companies are not mandated to provide the drugs, nor cover their costs.

“Patients with terminal illness are the perfect cases for being exploited and exposed to high levels of uncertain risks with low chance of benefit,” Emanuel said. “Some people argue that these people would die anyway. Yes, but we all know that there are better and worse ways of death. Part of what doctors are committed to is making it a better death and not preying on people’s false hopes.”

HemOnc Today spoke with clinicians and medical ethicists about the momentum Right to Try laws have gained nationwide, the cost and safety concerns that accompany treatment with experimental agents, and the moral dilemmas this type of legislation may pose to pharmaceutical companies with investigational drugs in their pipelines, as well as to oncologists whose patients have few options left.

Laws in practice

Colorado’s state legislature unanimously passed the country’s first Right to Try bill.

The legislation states terminally ill patients “do not have the luxury of waiting until an investigational drug, biological product or investigational device receives final approval from the U.S. FDA” and that these patients “have a fundamental right to attempt to pursue the preservation of their own lives” by seeking investigational treatments.

Since early April, Arizona, Arkansas, Louisiana, Maine, Michigan, Mississippi, Missouri, Montana, South Dakota, Utah, Virginia and Wyoming have since passed similar measures.

The Goldwater Institute — a conservative and libertarian public policy think tank — has been a driving force behind the Right to Try movement and hopes to see similar legislation adopted in every state.

“From my personal perspective as a voter, I’m happy that people in public office want a better system to get compassionate use of drugs,” Charles F. Levenback, MD, professor in the department of gynecologic oncology and reproductive medicine at The University of Texas MD Anderson Cancer Center, said in an interview. “I’m glad people outside of health care in the legislative world are listening to the public and want to respond and do something useful.”

Cancer centers in states with Right to Try laws must prepare.

“There are a lot of issues not addressed in the bill that make the feasibility more challenging,” W. Thomas Purcell, MD, MBA, associate director for clinical services at the University of Colorado Cancer Center and executive medical director of oncology services at University of Colorado Hospital, told HemOnc Today. “If the drug is made available, who is going to administer it? Who is going to pay for any side effects related to the treatment? Are insurance companies going to cover any treatment-related complications? There are a lot of practical things that come into play with the introduction of the law, although the law doesn’t address any of those things.”

These concerns would need to be addressed after a pharmaceutical company grants access to a drug through a Right to Try law.

“People do not actually read the bills,” Alison Bateman-House, PhD, MPH, MA, Rudin postdoctoral fellow in the division of medical ethics at New York University Langone Medical Center, told HemOnc Today. “They think ‘Right to Try’ sounds fantastic and allows access to treat terminally ill patients. How could you not support that? For the most part, the response that we’ve seen is that these laws don’t do much, aside from giving people hope.”

Those skeptical of Right to Try laws with whom HemOnc Today spoke all voiced the potential for instilling “false hope” as a major concern.

“These laws are built on false hope,” Emanuel said. “There are advocates who say every drug that has been granted expanded access have been winners and receive FDA approval, and that is nonsense. That is just not the way this is going to go.”

Although these laws specify manufacturers are not liable if toxicities occur, pharmaceutical companies may be reluctant to grant access to investigational agents due to concerns about bad publicity or fears that adverse events may threaten a drug’s chances for approval.

“The vast majority of drugs that come through the pipeline do not make it, either because they are too toxic or because they do not work,” Colin Begg, PhD, chairman and attending biostatistician in the department of epidemiology and biostatistics at Memorial Sloan Kettering Cancer Center, said in an interview. “You are starting with a pretty slim hope at the outset.”

Limited data exist on the safety and efficacy of a drug this early on in development.

“The purpose of a phase 1 trial is to obtain data on safety and maximum-tolerated-dose, but these laws are phrased in such a way that it appears that access to these drugs would be beneficial to patients,” Yoram T. Unguru, MD, MS, MA, pediatric hematologist/oncologist at the Herman and Walter Samuelson Children’s Hospital at Sinai Hospital in Baltimore and bioethicist at The Johns Hopkins Berman Institute of Bioethics, said in an interview. “This may be true, but often it is not.”

The risk for toxicity may be even greater in patients who meet requirements of Right to Try laws.

“These are people who are ineligible for clinical trials because they’re sicker, they’re older or their vital signs are too negative to qualify,” Bateman-House said. “If you are going to see a negative outcome, that’s where you would expect to see it.”

Cost also is a concern, as Right to Try legislation allows pharmaceutical companies to charge for a drug but does not require insurance companies to pay for it.

“If it is not covered by insurance, then this just reinforces that only the rich get these options,” Emanuel said. “If the insurance company pays, then the rest of us are paying for a situation where there is no knowledge gained and a low chance of success. We have to remember that the law affects everyone, not just individual patients who understandably are in a desperate situation.”

Outside clinical trials

Expanding patients’ access to investigational agents outside of clinical trials, without the FDA’s oversight, may threaten the structure of the research and approval process in the United States, Emanuel said.

“This is a classic case where what is good for the individual may not be what is good for society,” Emanuel said. “The laws may actually undermine the possibility of a drug working and slow down the process of approval. The best way of helping people is to get an effective drug to market quickly.”

In multiple cases, access to an experimental therapy has been expedited due to an early benefit observed in early studies that was not substantiated in subsequent research, Unguru said. One example was the use of autologous bone marrow transplantation in women with metastatic breast cancer, based on preliminary data published in 1995 in the Journal of Clinical Oncology.

“This completely backfired,” Unguru said. “In addition to being poorly designed, the study raises serious ethical concerns and, ultimately, people did much worse, including some who even died. This is why we go through the laborious, lengthy and, at times, seemingly maddening trial phases.”

Although physicians and drug companies are required to report data attained from patients treated through the FDA’s compassionate use program, Right to Try laws do not carry such stipulations.

Adverse events arising from agents obtained through Right to Try laws may discourage other patients from joining clinical trials for that drug, thereby slowing the approval process.

“Even though we want to rescue individuals, decisions — as much as they may appear to be for just one person — have ramifications for potentially huge numbers of people who are the population waiting for the drug,” Bateman-House said. “These patients may be deprived of a good opportunity.”

Eliminating the FDA from the equation may have many significant consequences.

“There is good reason we have the FDA,” Begg said. “The rigorous testing with scientific methods of drugs that come through the pipeline is absolutely essential. Without it, the market would be flooded with drugs that do not work. You would have a cupboard full of drugs that you would want to try, and you would have no idea which one to try because there would be no reliable evidence about the efficacy of any one of them.”

Right to Try laws may create a precedence for additional changes to drug R&D.

“If we go down this road, there might be a loosening of the standards of drug approval in the first place, and that would be bad for public health,” Begg said. “This movement may ultimately lead to situations where … drugs, in general, would no longer have to go through such rigorous testing to see if they work.”

Industry’s dilemma

The fact that manufacturers are not liable if a drug obtained through Right to Try fails or causes significant harm may allow pharmaceutical companies to benefit from such legislation, Unguru said.

“The way the laws are written, pharmaceutical companies are under no commitment to release these drugs, but should patients be able to access them, there is almost no consequence in the event of a bad outcome,” Unguru said. “Bypassing the current regulatory system means that some drugs that may not be safe or ready for widespread use essentially get a ‘free pass.’ Some pharmaceutical companies might see such laws as a way to test their drugs in a way they typically would not be able to without being held accountable.”

This would pose significant safety issues to society.

“It is hard to argue that individual patients who are dying and want access to a drug should not get it,” Begg said. “But the concern I have is that the ability of drug companies to market drugs that have not been properly tested is not in the interest of the public.”

Yet, for the most part, pharmaceutical companies have been reluctant to release their drugs through such programs.

“After they have spent years and millions of dollars developing a drug, to have it potentially fall by the wayside because of a negative outcome in a compassionate use case would be a huge loss,” Bateman-House said.

The Pharmaceutical Research and Manufacturers of America (PhRMA) has voiced its concern about Right to Try laws.

“We have serious concerns with any approach to make investigational medicines available that seeks to bypass the oversight of the FDA and clinical trial process, which is not in the best interest of patients and public health,” Sascha Haverfield, PhD, PhRMA’s vice president of scientific and regulatory affairs, told HemOnc Today. “The clinical trial process is the primary mechanism by which patients may participate in the drug development process and receive access to unapproved investigations medicines. Successful completion of the clinical trial process is necessary to demonstrate that an investigational medicine is safe and effective, which is required to obtain FDA approval, so that companies may make the medicine available to a broader patient population when clinically appropriate.”

In the past, public pressure has forced pharmaceutical companies to grant access under compassionate use.

Last year, Chimerix denied Josh Hardy — a then 7-year-old boy who developed an adenovirus infection after undergoing a bone marrow transplant for rhabdoid tumor of the kidney — access to the experimental antiviral drug brincidofovir (CMX001). After a social media firestorm — which included death threats to the company’s leadership — Chimerix commenced an open-label phase 3 trial so Hardy could enroll and receive treatment.

“This became publicized, and everyone assumed that if Josh Hardy got brincidofovir he would survive,” Bateman-House said. “He did get brincidofovir, and he did survive. Thomas Duncan, the man who died of Ebola in Texas, got the same drug and died. Chimerix is a small drug company and brincidofovir is its only drug in development, and its stock took a nosedive after Duncan’s death. If it were not for the fact that phase 3 trials were already close to completion, this could have killed the company. If Josh Hardy had died, that could have killed the company.”

In late 2013, BioMarin Pharmaceutical denied Andrea Sloan expanded access to talazoparib (BMN 673), an oral PARP inhibitor, for her recurrent ovarian cancer. Levenback, Sloan’s oncologist, thought the drug might help her because she carried a BRCA mutation, she had exhausted all other options and she was ineligible for clinical trials. The public attention Sloan’s case received prompted another company, which wished to remain anonymous, to provide her with a similar drug.

“Although we got a PARP inhibitor from a different company, there was negotiation and back and forth, delays with paperwork, and a delay for treating my patient,” Levenback said. “Her prognosis was terrible, and I cannot say that she died because of the delay. She died because she had a bad cancer. But it was disappointing to me that BioMarin could just say, ‘We don’t believe in compassionate use.’ There was a reasonable rationale for treatment, and it just did not make sense to me.”

These cases occurred when patients sought treatment through the FDA’s program, and access through Right to Try laws may be even more perilous for industry, Unguru said.

“It can go either way — you’re damned if you do and you’re damned if you don’t,” Unguru said. “If you release the drug and it does badly, then you’re going to get bad press. If you don’t release it, then you risk being vilified.”

The physician’s role

Physicians also may face a dilemma when their patient has exhausted all treatment options yet wants to pursue experimental treatment through Right to Try laws.

“If you do not think it is going to work, how do you break the news to a patient?” Bateman-House said. “You do not want to destroy their last hope, but what do you do to support the patient?”

The patient first must meet many requirements before pursuing this option.

“If a patient comes in with a suggestion for an agent, we first must assess their performance status and rationale for treatment with that drug,” Levenback said. “The patient has to be well-informed and the risks have to be acceptable to them. They’d have to frequently advocate for themselves within these unwieldy systems. Getting a novel agent carries unknown risks and to extend survival you may be shortening it.”

Right to Try legislation stipulates that patients be well-informed of these risks.

“The onus is on us as physicians to make sure that we do a good job explaining the science, that the individual drug may or may not benefit the patient, and in the case of the Right to Try laws, that there is limited data,” Unguru said. “In the absence of adequate testing, it is unclear how to weigh the risks, and how patients can truly provide fully informed consent. We need to make sure what we are doing is best for the patient because sometimes we can cause more harm than good.”

Compassionate use discussions may carry as much weight as end-of-life discussions.

“I’ve heard ethicists say physicians may go in the direction of compassionate use to avoid the difficult conversation about mortality and the limits of what we can provide,” Levenback said. “All of compassionate use is predicated on the physician’s responsibility to be candid about the purpose of treatment — palliative vs. curative — and setting the patient’s expectations correctly.”

After these discussions, few patients may actually decide to pursue this option.

“In most circumstances, there is a high chance that the drug is not going to make any difference,” Levenback said. “Not only that, but there are social, spiritual and financial costs that are going to be borne by the patient. The number of patients who will actually want to go through with this is going to be modest.”

Room for improvement

Although the FDA accepts 99.5% of expanded access requests it receives, many had considered the process burdensome and inefficient.

“The system was so unwieldy that there were a lot of disincentives for physicians to suggest a compassionate use mechanism to patients,” Levenback said. “There are a lot of people who need to be involved — the individual provider, the provider’s health care system, the FDA, the drug company, a third-party payer, the patient themselves, oversight from lawyers — and it is not what doctors are used to when they write an order.”

In February, the FDA released a new draft guidance document on applying for expanded access.

The revised form would reduce the application process for physicians from 100 hours to 45 minutes, according to the FDA.

“This is progress, but some of the unwieldiness is not in a domain of any single entity or group — it’s everywhere,” Levenback said. “Providers, health care systems, insurance companies, drug companies and patients are all players in this. These changes certainly may alleviate some of the problems, but they are not going to alleviate all of them.”

Additional opportunities for change may exist within the clinical trial structure.

“From inception to delivery, it can take years for an effective drug to reach market,” Unguru said. “If you are a patient who is dying, you don’t have years. I understand why the current system is set up the way it is, but it does not give patients who are dying the ability to necessarily gain access to what may be a positive drug. The current clinical trial system is rigid, and there’s little room for flexibility.”

Trials designed in 2:1 or 3:1 ratios may help increase access to the agent, Unguru said.

An opportunity also may exist to improve education on the benefit of the clinical trial process.

“If you ask the average person how drugs get from the lab to an actual person, they probably do not fully appreciate all of the steps involved,” Unguru said. “Doctors may also confuse the goals of research with treatment, the so-called ‘therapeutic misconception.’ Such thinking may cause the doctor, and in turn his or her patient, to believe that the goal of a particular early-phase drug is for benefit, when in reality it is not. Physicians need to be specific about the purpose of research trials and carefully communicate to allow their patients to fully comprehend, so they may offer an informed choice.”

Options that exist outside of clinical trials are unlikely to improve the situation, Emanuel said.

“Society gains from a clinical trial because even if the drug doesn’t work, we gain that knowledge,” he said. “When there is no social benefit, and a low chance of success, it’s not clear that the cost ought to be socialized to everyone else. That means the well-off get their benefits and the rest of us don’t.”

Still, expedited access to effective drugs should be a motivation for change.

“All stakeholders — patients, physicians, biopharmaceutical companies, academia and FDA — must come together to identify ways to improve the existing federal expanded access program and modernize the clinical trial, drug development and FDA review process by harnessing the 21st century science to accelerate the availability of new medicines for patients who need them,” Haverfield said.

Another Right to Try-type law has recently been introduced at the national level. The Andrea Sloan Compassionate Use Reform and Enhancement (CURE) Act would mandate that the manufacturer of any drug granted a breakthrough, fast track or qualified infectious disease product designation from the FDA make publicly available its corporate expanded access policy for that drug.

“It’s extraordinarily frustrating to know that there is a medication that might fit a patient’s set of circumstances with medical and scientific reasoning, yet there is no access to it,” Levenback said. “It is going to take some people who are willing to walk across their narrow self-interests and put the patient first and answer the question, ‘Can we go through all of the issues that surround the different parties to achieve the goal of getting more novel drugs to people who might benefit?’ If you ask drug companies, insurance companies and providers, everyone would agree to that. The problem is, in spite of that, we have the system we have.” – by Alexandra Todak

References:

Access to Treatments for Terminally Ill Patients. Colorado Bill. Available at: www.statebillinfo.com/bills/bills/14/1281_enr.pdf. Accessed March 16, 2015.

Bezwoda WR, et al. J Clin Oncol. 1995;13:2483-2489.

Lurie P. A big step to help the patients most in need. FDA Voice. Available at: blogs.fda.gov/fdavoice/index.php/2015/02/a-big-step-to-help-the-patients-most-in-need. Accessed March 27, 2015.

For more information:

Alison Bateman-House, PhD, MPH, MA, can be reached at NYU Langone Medical Center, Translational Research Building, 227 E. 30th St., New York, NY 10016; email: alison.bateman-house@nyumc.org.

Colin Begg, PhD, can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: beggc@mskcc.org.

Ezekiel J. Emanuel, MD, PhD, can be reached at Perelman School of Medicine, University of Pennsylvania, 122 College Hall, Philadelphia, PA 19104; email: vp-global@upenn.edu.

Sascha Haverfield, PhD, can be reached at PhRMA Headquarters, 950 F St., NW Suite 300, Washington, DC 20004.

Charles F. Levenback, MD, can be reached at The University of Texas MD Anderson Cancer Center, 1155 Hermann Pressler Drive, P.O. Box 301439, Unit 1362, Houston, TX 77230-1439.; email: clevenba@mdanderson.org.

W. Thomas Purcell, MD, MBA, can be reached at University of Colorado School of Medicine, Division of Medical Oncology, 12801 E. 17th Ave., Mail Stop 8117, Research 1 South, Aurora, CO 80045; email: tom.purcell@ucdenver.edu.

Yoram T. Unguru, MD, MS, MA, can be reached at The Children’s Hospital at Sinai, Division of Pediatric Hematology/Oncology, 2401 W. Belvedere Ave., Baltimore, MD 21215; email: yunguru@lifebridgehealth.org.

Disclosure: Bateman-House, Begg, Emanuel, Haverfield, Levenback, Purcell and Unguru report no relevant financial disclosures.

Do the changes to the FDA’s compassionate use program eliminate the need for ‘Right to Try’ laws?

Yes. Patients are best served through the FDA’s program.

It is easy to understand the motivation behind the emerging state “Right to Try” laws. Any of us, faced with an incurable illness and no proven options, would want to be able to consider treatment with a promising — if unproven — new drug that might improve survival or relieve suffering. Many advocates of Right to Try laws understand and support the rigorous clinical trial process that is required to test the safety and efficacy of new drugs, and the need for FDA review and approval, before a drug becomes widely available. They tend to argue that, in cases of terminal illness, there is no justifiable basis for the state interfering with an individual’s ability to seek an unproven therapy, even one that might hasten death or lead to unexpected toxicity.

However, the question is not whether promotion of access to promising drugs for patients with terminal disease is justified, but how this can best be accomplished. The same imperative that drives Right to Try laws underlies the FDA’s compassionate use program. The primary difference is that access to experimental drugs through compassionate use programs is regulated in the interest of both the patient and society. Physicians must seek FDA approval before a manufacturer provides the unproven drug, and the rationale for use of the drug, absence of alternatives, informed consent and review by an independent institutional review board must be documented. In addition, toxicities and outcomes after administration must be reported. This process promotes responsible practice of evidence-based medicine — even as the evidence evolves — and provides a chance for monitoring, both of the specific intervention and of the use of experimental therapy more generally. Although the process can be burdensome, the FDA has recently streamlined the application to allow for completion in less than 45 minutes and still allows for rapid approval of emergency access by phone when this is clinically justified.

As with the compassionate use program, Right to Try laws do not mandate that a drug will be made available by the manufacturer. They also cannot eliminate the time required for a responsible physician to carefully review the risks and alternatives to use of an unproven therapy with their patient — including the option of symptom-directed care alone — or the need to seek access to a drug that is not commercially available from the manufacturer. Thus, these laws change little in a practical sense. In fact, it is possible that such laws will paradoxically decrease access if few manufacturers decide to make experimental drugs available outside of an FDA regulated pathway. It is far from clear that passage of state Right to Try laws will result in more patients gaining access to experimental therapy or in patients gaining quicker access. At best, Right to Try laws may simply remove the regulation and oversight of the treatment of patients who are among the sickest in society with drugs that are not yet proven safe or effective.

The Right to Try movement plays a constructive role in bringing attention to the efficiency of the drug approval process and to the regulatory burdens of compassionate use. There have been changes to both as a result of public pressure, including the FDA’s accelerated approval program, and the ongoing efforts to streamline the compassionate use process for physicians and industry. We can best serve the legitimate interest of patients in access to experimental drugs and promote the public interest in regulation of medical practice and drug development through the FDA’s compassionate use program.

 

Jeffrey M. Peppercorn, MD, MPH, is a medical oncologist specializing in breast cancer at Massachusetts General Hospital. He can be reached at Massachusetts General Hospital, Hematology/Oncology, 55 Fruit St., Boston, MA 02114-2696; email: jpeppercorn@mgh.harvard.edu. Disclosure: Peppercorn reports no relevant financial disclosures.

No. “Right to Try” Laws are necessary to bring the decision-making process back to patients and their doctors on the local level.

Right to Try laws bring potential medication to terminally ill patients, and they provide one last opportunity for patients to attempt to control what happens in their health care. Traditionally, medical regulation and decisions are reserved for the local level, and that’s what Right to Try laws do. The FDA — an organization that has resisted any change for 40 to 50 years — is now trying to revamp some of its procedures to grant greater access. However, the changes to its expanded access program only amended the physician’s application process. In one day, the process was reduced from 100-plus hours to 45 minutes, which really begs the questions, “Why was it 100 hours to begin with? How many people have been lost in the years without this change?”

With that being said, we are very happy that changes have been made and that they recognize there is an issue. But, these changes are not going to speed up the process to the extent that is necessary. This is only one prong of the application process. There still is significant data and paperwork that manufacturers need to do, and there still is a long review process. If the FDA has any questions, which it often does, the process starts over. Once the request is through the FDA review process, it has to go back to an institutional review board at the location where the drug would be administered for review. These changes are a great first step; however, states still need to pass Right to Try laws.

Many pharmaceutical companies agree to provide medications through the FDA’s expanded access program, so Right to Try laws provide a quicker avenue to do so. In reality, many of the medications patients will seek out are in use, developed and manufactured in America, and they are showing significant promise and efficacy in clinical trials and in use in other parts of the world. It is a travesty that Americans can’t access medications that are invented, developed and manufactured in America, but which might already be used in Europe.

It is likely the overwhelming legislative and public support for Right to Try laws played a factor in the FDA reviewing and changing its program so quickly. Overall, the FDA drug approval process is becoming outdated in a lot of aspects. Medical advancements and technology have moved toward more individualized medications and genomic testing to try and design things for specific people, which by definition no longer fits the FDA clinical trial approval process. The FDA needs to adapt with the advancements. Companies, hospitals and doctors are used to how things are, and Right to Try is an idea that could be called revolutionary, but once everyone analyzes it and figures out how it works, it’s going to be extremely beneficial.

 

Kurt Altman is the national policy adviser and general counsel for Goldwater Institute. He can be reached at Goldwater Institute, 500 E. Coronado Road, Phoenix, AZ 85004; email: kaltman@goldwaterinstitute.org. Disclosure: Altman reports no relevant financial disclosures.