HemOnc Today's PharmAnalysis
HemOnc Today's PharmAnalysis
Source/Disclosures
Disclosures: Cohen reports grant support to his institution from Celldex Therapeutics, Genocea Biosciences, Heat Biologics, Innate, Merck and Xencor for the conduct of clinical trials; and consultant fees from Alkermes, Cantargia, Genocea Biosciences, Heat Biologics and Innate. Schilsky reports serving on the board of directors for the FDA’s Reagan-Udall Foundation and research grants to ASCO in support of clinical trials from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Genentech, Merck and Pfizer. Bateman-House, Fernandez Lynch and Gonsalves report no relevant financial disclosures.
March 10, 2020
16 min read
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Right to Try: A ‘well-intentioned’ but ‘misguided’ law

Source/Disclosures
Disclosures: Cohen reports grant support to his institution from Celldex Therapeutics, Genocea Biosciences, Heat Biologics, Innate, Merck and Xencor for the conduct of clinical trials; and consultant fees from Alkermes, Cantargia, Genocea Biosciences, Heat Biologics and Innate. Schilsky reports serving on the board of directors for the FDA’s Reagan-Udall Foundation and research grants to ASCO in support of clinical trials from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Genentech, Merck and Pfizer. Bateman-House, Fernandez Lynch and Gonsalves report no relevant financial disclosures.
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The objective of the Right to Try Act seems beyond reproach — the law purports to provide a new avenue to treatment for patients with terminal illnesses after they have exhausted all other options and for whom no suitable clinical trial exists.

However, its striking similarity to the FDA’s Expanded Access Program has led some clinicians to view Right to Try as a politically motivated attempt to undermine and jettison the FDA.

Further, without the FDA program’s protections and oversight, Right to Try could be more harmful than helpful for patients, especially those of the vulnerable cancer population.

Although terminally ill patients might assume they have nothing to lose by trying an investigational treatment, this is not necessarily the case, according to Holly Fernandez Lynch, JD, MBE.
Although terminally ill patients might assume they have nothing to lose by trying an investigational treatment, this is not necessarily the case, according to Holly Fernandez Lynch, JD, MBE. “They could take a medication that could make them die faster or in a worse way,” she said. “They might be losing valuable time with their families, or they might be missing out on palliative options.”

Source: Hoag Levins.

“On its face, it seems as though Right to Try would streamline the process and make it easier for patients, but actually, the FDA approves almost all the requests for investigational treatments received through its longstanding Expanded Access pathway,” Holly Fernandez Lynch, JD, MBE, John Russell Dickson, MD, presidential assistant professor of medical ethics in the department of medical ethics and health policy at Perelman School of Medicine at University of Pennsylvania, told HemOnc Today. “But, unlike Right to Try, the FDA ensures safety issues are examined when a patient receives a treatment using Expanded Access.”

Because many terminally ill patients are living with cancer, oncologists are likely to face many Right-to-Try requests. As clinicians begin to encounter these requests, they may consider using this teachable moment to educate patients about reasonable expectations for any experimental therapy and seek to identify and discuss equally promising options.

“It all stems from the groundwork that’s been laid between the oncologist and the patient from the start in terms of the goals of treatment and the expectations for their outcomes,” Richard L. Schilsky, MD, FACP, FSCT, FASCO, chief medical officer and executive vice president of ASCO, told HemOnc Today. “I’ve always felt it was best to be direct with patients, but not direct to the point of removing all hope.”

Richard L. Schilsky, MD, FACP, FSCT, FASCO
Richard L. Schilsky

HemOnc Today spoke with experts about the differences and similarities between Right to Try and Expanded Access, the importance of not letting the programs undermine clinical trial enrollment, and how oncologists can approach conversations with their patients about accessing investigational drugs.

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An unclear picture

Right to Try — first introduced as state legislation, with similar laws in 41 states — was signed into federal law by President Donald J. Trump on May 30, 2018.

The concept of the law was generated by the Goldwater Institute, a “free-market public policy research and litigation organization” that promotes “limited government, economic freedom and individual liberty,” according to its website.

“Their whole mission is to get big government out of the way,” Fernandez Lynch said. “Right to Try is a test balloon, in the most sympathetic case.”

Critics have been trying to tear down Right to Try for years, Mike Brownfield, director of communications at the Goldwater Institute, said in a statement provided to HemOnc Today.

“They were wrong then. They’re still wrong,” he said. “Right to Try is working. Doctors are using the law to treat patients. Patients are using Right to Try to save their own lives. It’s time for the naysayers — and the media — to look at the actual results and how the law is giving new hope to terminally ill Americans.”

According to a policy report from the Goldwater Institute, the premise of Right to Try is that regulatory bodies should not be involved with doctor-patient decisions about best treatments for terminal illnesses. The FDA “often stands between patients and the treatments .... that may provide a cure,” the policy report states, and, as a result, “sadly, over half a million [patients with cancer] and thousands of patients with other terminal illnesses die each year as the bureaucratic wheels at the FDA slowly turn.”

However, this logic conflates the length of time it takes to bring a drug to market with the length of time it takes to get access to the drug via Expanded Access, according to Alison Bateman-House, MPH, PhD, assistant professor in the department of population health at NYU Grossman School of Medicine.

“The former takes years. The latter can take — in emergency situations — days and, by law, cannot take more than 30 days, at least with regard to the FDA part of the process,” she told HemOnc Today. “Of course, companies can be as slow as they want in deciding whether to grant access or not, but Right to Try focuses on FDA, not company, policies.”

To be eligible for Right to Try, a patient must have a life-threatening illness, have exhausted all treatment options and be unable to participate in a clinical trial of the requested drug, and provide written informed consent. According to the law, an investigational drug is eligible if it has completed a phase 1 trial and is in active development, has not been approved by the FDA for any use, and is the subject of an investigational new drug application filed with the FDA.

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It is not entirely clear how many patients have received drugs through the federal Right-to-Try pathway to date, due in part to poor reporting requirements, according to Fernandez Lynch.

She said pharmaceutical companies are expected to make annual reports of their Right-to-Try activities, but the FDA has not yet stipulated the content of these reports. Nonetheless, the statutory reporting obligation stands, she added.

News outlets have reported that at least one patient with amyotrophic lateral sclerosis, or ALS, has received the investigational drug NurOwn (BrainStorm Cell Therapeutics) through Right to Try, and seven patients have received Gliovac (ERC1671, Epitopoietic Research Corp.), an immunotherapy vaccine under evaluation for glioblastoma.

Conversely, in a study published in JAMA Network Open in 2018, Puthumana and colleagues identified 92 drugs and biologics with expanded access programs initiated between 1996 and 2017. Half of these drugs were used to treat cancer, and 90 (97.8%) went on to receive approval for the expanded access indication, which may be driven by the fact that many Expanded Access programs are initiated around the time the company submits a marketing application.

According to Schilsky, Right to Try may be a misnomer.

“What it really does is guarantee people the right to ask to try a drug,” he said. “In essence, Right to Try says that a patient with a life-threatening disease who has no other standard treatment option and who is not a candidate for participation in a clinical trial has the right to ask a drug company to make their drug available prior to marketing approval.

“The primary way in which Right to Try differs from the FDA’s Expanded Access program is by circumventing the role of the FDA in the process,” he added. “This is one of the reasons ASCO and many other organizations have objected to it, because we think that the inclusion of the FDA provides for a number of important patient protections.”

Right to Try vs. Expanded Access

Experts with whom HemOnc Today spoke all agreed with Schilsky that the primary difference between Right to Try and Expanded Access is the former’s exclusion of FDA oversight from its process.

Roger B. Cohen, MD
Roger B. Cohen

“I don’t think Right to Try creates any important opportunities for patients they don’t already have with Expanded Access,” Roger B. Cohen, MD, associate director of clinical research at Penn’s Abramson Cancer Center and professor of medicine at the Hospital of the University of Pennsylvania, told HemOnc Today. “The danger of Right to Try is that patients will, understandably, seek therapies that are not only unproven, but about which very little is known, such as their side effects or efficacy. Most people don’t realize that many, if not most, experimental drugs, however promising they may seem, don’t work well or don’t work at all once they are tested in humans.”

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With Expanded Access — also known as Compassionate Use — the patient and physician start by discussing the option of trying an investigational drug outside of a clinical trial setting, Fernandez Lynch said. They would then request the drug from the manufacturer, which would decide whether to provide the drug.

If the manufacturer agrees to provide the drug, the physician or the manufacturer would petition the FDA to authorize the use of the drug for the patient. An institutional review board (IRB) would review the request and informed consent documentation prior to authorization.

“Right to Try is similar in that the doctor and the patient go to the company, but if the company says yes, there is no need to do anything further,” Fernandez Lynch said. “They don’t have to go to the FDA or the IRB.”

She added although the federal law does not require review by an IRB, some state Right to Try laws have this requirement, and at least one for-profit IRB has reported receiving a small number of Right-to-Try requests.

“So, there may be other patients who have accessed drugs through Right to Try that haven’t yet been reported in the media,” she said. “Overall, though, it’s fair to say that the numbers remain very low — definitely not reaching the ‘hundreds of thousands’ Trump claimed would gain access under the law.”

Proponents of Right to Try have suggested that eliminating the FDA from the process saves time and avoids unnecessary bureaucracy.

However, FDA approves nearly all Expanded Access requests within days, requiring changes in about 10% of cases for patient protection. Thus, many opponents consider Right to Try to be redundant at best, and potentially dangerous at worst.

In addition to examining safety issues, the FDA also reviews the treatment plan to maximize likelihood of success, Bateman-House said.

“For example, they may adjust the proposed dosage, on account of information they have that allows them to better predict what dose of the drug may be useful,” she said.

Gregg Gonsalves, PhD
Gregg Gonsalves

Right to Try, meanwhile, leaves patients without legal recourse in the event of treatment-related complications, according to Gregg Gonsalves, PhD, assistant professor of epidemiology and adjunct professor of law at Yale Law School, and co-director of the Collaboration of the Global Health Justice Partnership and Collaboration for Research Integrity and Transparency.

“The legislation indemnifies companies from any harm that may come from these drugs and, more importantly, it is part of a plan to neutralize the FDA in the long term,” Gonsalves told HemOnc Today. “The endgame of Right to Try is to push FDA to the sidelines in terms of decision-making about new drugs, with the idea that the market can figure these things out and doctors and patients can rely on their own experience to judge the effectiveness of new medicines. The point is, they can’t. We don’t need a ‘Yelp’ for drugs; we need rigorous clinical trials.”

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Right to Try also includes a clause exempting clinicians and hospitals from liability related to treatment. This provision may appeal to oncologists who might otherwise be hesitant to offer investigational drugs to their patients.

“Right to Try has a provision that says if something terrible happens, nobody — the doctor, pharmacist or the drug company — can get sued by that patient or their heirs,” Bateman-House said. “So, one could argue that we need Right to Try so physicians can provide these options for patients without the risk for a lawsuit. I don’t think that’s a reasonable response, though, because in the entire lifetime of Expanded Access, there have been no such suits.”

Further, whereas Right to Try is limited to situations in which a patient faces a life-threatening condition, Expanded Access also is available to patients with serious chronic diseases. Additionally, a drug must have gone through phase 1 trials to be obtained through Right to Try.

“Right to Try is limited to products that have been through phase 1 and are in active development moving into phase 2, at least,” Fernandez Lynch said. “Expanded Access is available at any point in clinical development; it does not have to be past phase 1.”

Notably, both Right to Try and Expanded Access require the manufacturer’s approval of the drug request, Schilsky said.

“At the end of the day, it’s up to the company whether they want to offer premarket access to any of their drugs,” he said.

First, clinical trials

When discussing a Right-to-Try request with a patient, oncologists should first rule out any other available, standard-of-care treatments that might be appropriate, Schilsky said. If none is available, he said the patient and physician should discuss the possibility of clinical trial eligibility.

“That discussion has to occur, because if there is a clinical trial the patient can qualify for, that is usually a far better option,” he said. “If not, there should be a discussion about the drug the patient is interested in and about the available evidence regarding its efficacy in treating any kind of cancer.”

Fernandez Lynch said clinical trials not only give eligible participants potential access to investigational drugs, they also achieve the long-term goal of advancing the development of these drugs.

“The purpose of clinical trials is not to treat patients, it is to gather information for future patients,” she said. “But, trials also are the best way for current patients to gain access to investigational products. These patients might get access to something they want to try, but it’s also good for the community of patients, because we’re gaining data that will help us move progress along.

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“FDA has to make sure that allowing patients access to these drugs outside of a trial is not going to derail the clinical development of the product,” she added. “If it’s going to take too much of a company’s resources or if it’s going to mean that they can’t enroll their clinical trials, the answer is no. That’s because the best way to get these drugs in the hands of the most patients is to get them approved for marketing.”

Cohen said over the past year, he has had three instances of patients mentioning Right to Try. He said he generally approaches the topic by educating patients about the law and redirecting them to either clinical trials or Expanded Access.

“Patients understandably don’t know, in most cases, how to interpret the scientific literature or the descriptions of science in the lay press,” he said. “I emphasize that we are not withholding wonderful, amazing drugs from our patients. In academia and in private practice, we all have our ear to the ground and have a fairly accurate sense of where there is positive buzz about a given therapy and where there is not.”

Navigational tools

As access to investigational treatment has gained attention, new programs are streamlining the process, perhaps further reducing the need for Right to Try.

For instance, FDA’s Oncology Center for Excellence has introduced a new pilot program to facilitate access to investigational drugs.

Introduced last June, the FDA describes Project Facilitate as “a single point of contact where FDA oncology staff will help physicians treating patients with cancer through the process to submit an Expanded Access request for an individual patient, including follow-up of patient outcomes.”

“Project Facilitate makes it a whole lot easier for doctors who navigate this process, because they can call the center, get their input on the drug their patient seeks to use, and they will help complete the necessary paperwork,” Schilsky said. “They will help you find an IRB if you don’t have one, and they put you in touch with the drug company if you don’t know who to reach out to. It really is a concierge service to make it as simple as possible for doctors to navigate this process.”

Additionally, the FDA’s Reagan-Udall Foundation offers an Expanded Access Navigator online, providing patients and clinicians with a directory of pharmaceutical companies that offer Expanded Access programs. The site also offers information to aid patients in making informed decisions about the risks and benefits of investigational treatments.

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“It includes the companies’ policies and their contact information,” Schilsky said. “It is a one-stop shop for doctors and patients.”

Schilsky said it is important for patients to keep in mind that their oncologists are unlikely to have experience with investigational treatments, and therefore can benefit from the guidance the FDA offers.

“Almost by definition, an investigational drug is something the clinician will have no experience using, because it isn’t yet on the market,” Schilsky said. “So, the doctor needs some guidance about the right dosage to use, the possible side effects and strategies to mitigate those side effects. They can get that guidance from the FDA, because the FDA has a ton of information about the drug. With Right to Try, the clinician is flying by the seat of their pants.”

‘Grasp at hope’

Conversations about Right to Try are likely to be sensitive, because they often draw upon a patient’s urgent need to see a “silver lining” in an investigational treatment.

Schilsky said this is an area where oncologists need to show empathy and compassion.

“Patients need to understand that typically at this point in their illness, we’re not talking about a treatment that still has the potential for cure,” he said. “We’re talking about the possibility that there is some drug that is not FDA approved that might offer some modest prolongation of their survival. Of course, patients grasp at hope that the cure is still out there somewhere, if only they can get that drug.”

Gonsalves, who was diagnosed with HIV shortly before the advent of protease inhibitors, said he can relate to the fear and devastation patients experience upon learning of a terminal diagnosis.

“My cousin died [of HIV] a few months before I was diagnosed, while I was taking care of him,” he said. “All I could see was myself in his shoes. I understand firsthand how terrifying it is for someone to walk into a doctor’s office and learn they have a disease with no cure or effective treatment.”

Often, Gonsalves said, this fear compels patients to pursue investigational treatments without considering their efficacy or potential risks. He said it is very difficult to discuss realistic expectations with patients who are, understandably, in this heightened emotional state.

“It’s very hard to push back against hope and fear with facts and evidence,” he said. “A doctor faced with a patient excited about a new treatment would find it difficult to say, ‘The study you just brought me on this drug only has seven patients, and it was an uncontrolled phase 1 safety study. We don’t know if this drug really works or has side effects that might shorten your life.’”

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Gonsalves said in his early days as an HIV activist, he railed against the FDA for delaying access to investigational drugs, but eventually he began to see things differently.

“In the early days of the epidemic, we shouted that the FDA was killing us. But as soon as we started getting more involved in research and development, we realized it wasn’t that simple,” he said. “The early drugs we were banging our fists on the table for — like didanosine and zalcitabine — weren’t very useful at all on their own, or even in combination. We realized knowing the evidence about the effectiveness of new drugs is just as important as access. Maybe access and answers should go hand in hand.”

Although terminally ill patients might assume they have nothing to lose by trying an investigational treatment, this is not necessarily the case, Fernandez Lynch said, because the unknown effects of the drugs can worsen outcomes of even those with poor prognoses.

“Many patients, especially those who are desperately ill, will think, ‘I’ll try anything,’” she said. “But, they still have something to lose. They could take a medication that could make them die faster or in a worse way. There also is the concern that if a patient is continuing to try everything under the sun, they might be losing valuable time with their families, or they might be missing out on palliative options.”

There also is risk for financial harm, according to Bateman-House.

“Under both Expanded Access and Right to Try, the patient may have to pay for the investigational drug and may have to pay for the related clinical care (hospital stay, lab work, etc) because some insurance companies do not pay for anything dealing with experimental products,” she said.

Fernandez Lynch emphasized that oncologists can use Right-to-Try requests as an opportunity to discuss other potential pathways for gaining access to unapproved drugs. She said because patients often do not know the difference between Right to Try and Expanded Access, it is the oncologist’s responsibility to clarify the difference.

“Patients don’t really care how they are getting access,” she said. “They just want access. They may have seen Trump on TV talking about Right to Try, and so they come into the office asking about it. They might not have any idea that Expanded Access even exists. It’s part of the physician’s responsibility to make patients aware that they might still be able to get access to what they want, but with additional protections.”

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‘Opposite of obstructionist’

Given the similar opportunities and increased protections offered by Expanded Access, some clinicians view the perceived need for Right to Try in terms of a simple question: “Why?”

“I have been racking my brain trying to figure out why a company would go for Right to Try over Expanded Access, and I have only come up with three possibilities,” Bateman-House said. “Number one, the company doesn’t know what the difference is or why one is preferable to the other; two, they have a vested interest in showing that Right to Try can work; or three, they are trying to escape the regulatory oversight of pricing.”

Expanded Access permits pharmaceutical companies to charge only the direct costs of making the drug available, but prohibits them from making a profit, Bateman-House said. Although Right to Try has the same rule, it may not be enforced in the absence of FDA oversight.

“With Expanded Access, the FDA is making sure companies are charging patients in good faith for their costs; the FDA is involved in looking at the purchase price and the documentation from the company to justify the purchase price,” she said. “There is no such third-party oversight in Right to Try. They take the company’s word for it.”

Cohen said he cannot think of a circumstance under which he would encourage a patient to pursue Right to Try.

“Right to Try is a well-intentioned but ultimately misguided response to a misperception about the drug approval processes within a federal agency that is, in fact, the envy of the world,” he said. “In oncology, at least, the FDA is the very opposite of obstructionist.” – by Jennifer Byrne

Click here to read the POINTCOUNTER, “Do examples of achieving remission with a drug obtained via Right to Try justify the law’s existence?”

References:

Corieri C. Everyone deserves the right to try: Empowering the terminally ill to take control of their treatment. The Goldwater Institute Policy Statement No. 266; Feb. 11, 2014. Available at: goldwaterinstitute.org/wp-content/uploads/cms_page_media/2015/1/28/Right%20To%20Try.pdf. Accessed Feb. 5, 2020.

Puthumana J, et al. JAMA Netw Open. 2018;doi:10.1001/jamanetworkopen.2018.0283.

For more information:

Alison Bateman-House, MPH, PhD, can be reached at 27 E. 30th St., 7th Floor, #723, New York, NY 10016; email: alison.bateman-house@nyulangone.org.

Roger B. Cohen, MD, can be reached at Perelman Center for Advanced Medicine West Pavilion, 2nd Floor, 3400 Civic Center Blvd., Philadelphia, PA 19104; email: roger.cohen@uphs.upenn.edu.

Holly Fernandez Lynch, JD, MBE, can be reached at Perelman School of Medicine at the University of Pennsylvania, 423 Guardian Drive, Blockley Hall, Philadelphia, PA 19104; email: lynchhf@pennmedicine.upenn.edu.

Gregg Gonsalves, PhD, can be reached at 350 George St., Ste. 3rd Floor, New Haven, CT 06511; email: gregg.gonsalves@yale.edu.

Richard L. Schilsky, MD, FACP, FSCT, FASCO, can be reached at American Society of Clinical Oncology, 2318 Mill Road, Suite 800, Alexandria, VA 22314. email: richard.schilsky@asco.org.

Disclosures: Cohen reports grant support to his institution from Celldex Therapeutics, Genocea Biosciences, Heat Biologics, Innate, Merck and Xencor for the conduct of clinical trials; and consultant fees from Alkermes, Cantargia, Genocea Biosciences, Heat Biologics and Innate. Schilsky reports serving on the board of directors for the FDA’s Reagan-Udall Foundation and research grants to ASCO in support of clinical trials from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Genentech, Merck and Pfizer. Bateman-House, Fernandez Lynch and Gonsalves report no relevant financial disclosures.