In spring 2008, Kelly Shanahan of South Lake Tahoe, California, was diagnosed with stage II breast cancer. She underwent a mastectomy and chemotherapy. In November 2013, she learned her cancer had metastasized.
Shanahan’s cancer has been kept stable thanks to the aromatase inhibitor Aromasin (exemestane). Still, she knows her cancer will eventually grow again. Trying to stay one step ahead, the 57-year-old already has talked to her doctor about her next treatment, which is a commercially available therapy. One day, she expects she will need an experimental treatment.
The primary way to access experimental treatments is through a clinical trial. But as a metastatic breast cancer patient who has been on numerous therapies, Shanahan fears she may not be eligible to participate in a trial. She is hoping the Right to Try Act, signed by President Donald Trump on May 30, will give patients like her more streamlined access to treatments outside of clinical trials.
Right to Try gives patients with life-threatening diseases who have exhausted approved treatments and are unable to participate in clinical trials access to therapies that have not been approved by the U.S. Food and Drug Administration (FDA). The drugs, biologics or devices must be proven safe in phase I clinical trials and be undergoing additional clinical trials, the law states.
Opponents of the Right to Try Act note that Americans already have a pathway to experimental drugs through the FDA’s expanded access program, also referred to as compassionate use. But Right to Try’s path has been touted by supporters as a more direct route for access because it cuts out FDA oversight and paperwork. Critics of the new law say the FDA doesn’t pose a barrier to access in the first place.
“I think the fundamental problem here is that there has been a narrative set up around access to unapproved therapies that the FDA is a roadblock, and we know that the FDA approves over 99 percent of the requests it receives and it typically does so very rapidly,” says Mark Fleury, who is principal of policy development and emerging science at the American Cancer Society Cancer Action Network in Washington, D.C. Fleury notes that emergency requests for expanded access are typically approved by the FDA over the phone within a day, while non-emergency requests take a few days.
“Most of the times when a cancer patient is seeking access to an unapproved drug and they don’t get it, it’s because the drug sponsor is unable or unwilling to provide it,” Fleury says. “Removing the FDA from the process does not do anything at all to address the primary reason why folks are declined.”
Alison Bateman-House, a medical ethicist at NYU Langone Health in New York City, has studied expanded access as the chairperson of the NYU Langone Health Working Group on Compassionate Use and Pre-Approval Access.
“If you look at the obstacles, the FDA is not one. It approves everything and it approves it quickly,” says Bateman-House, who says she believes the law will not improve patient access and could harm patients. She is not alone in this assertion. Prior to the law being passed, 38 organizations, including the American Cancer Society Cancer Action Network, American Lung Association, Susan G. Komen, American Society of Clinical Oncology, and Oncology Nursing Society, expressed concerns in a letter written in opposition to two similar versions of the Right to Try legislation.
When patients request therapies through the expanded access program, the FDA may suggest modifications, including adjustments to dosing, increases to safety monitoring or changes to informed consent forms. The FDA makes such modifications in about 10 percent of the expanded access requests, Fleury says.
“You have to understand that with these unapproved drugs, little is known about them, and the drug sponsor and the FDA are those who know the most,” says Fleury. Phase I clinical oncology trials—the prerequisite for expanded access—are the first trials in people and include between 15 and 30 people. The purpose of a phase I trial is to determine safe dosages in people and the best administration routes for a drug, and to make observations about the drug’s effects on the body and cancer, according to the National Cancer Institute. Phase II trials evaluate the effectiveness of the drug for a specific type of cancer.
Fleury points out that two-thirds of drugs that are distributed through expanded access do not ever go on to receive FDA approval. “There is a broad assumption that every unapproved drug is a curative breakthrough drug,” Fleury says. In fact, most drugs do not receive FDA approval because they are not shown to be effective or safe, he says.
Another concern stems from questions surrounding informed consent from patients. Right to Try does stipulate that patients need to provide written informed consent to their treating physician. However, expanded access requires that physicians submit the therapeutic protocol to an Institutional Review Board (IRB), which is the same process required before treating patients through a clinical trial.
IRBs are groups of experts who review research protocols for hospitals and research facilities to make sure protocols, including obtaining a patient’s written consent, are in place so that patients understand the risks of treatments and the nature of the research. (In emergency cases with expanded access, the prescribing physician can receive FDA permission to start treatment without IRB approval, but needs to notify the IRB within five days of treatment. In addition, to expedite all requests, the FDA will accept approval from an IRB representative rather than needing full board approval.)
“With an unapproved therapy, if it were given in a clinical trial, it would be subject to informed consent and third-party review, so there is this construct that protects patients from being taken advantage of,” says Fleury. “What Right to Try does is strip all of those protections away and doesn’t even provide the same level of oversight and protection as research does.”
Shanahan, who spent 25 years as an obstetrician/gynecologist and is no longer able to practice medicine due to neuropathy from her treatment, thinks patients and their doctors should be able to weigh the risks and benefits of treatments on their own. “I’m a strong believer in patient autonomy,” she says. “I think we ought to be able to decide for ourselves, and that’s one of the reasons for this legislation. I think the arguments against Right to Try are somewhat paternalistic.”
Further, Shanahan sees the Right to Try Act as a step to less paperwork. “The thing I like about the Right to Try is it removes the [FDA] application process. I was a doctor for 25 years. Trying to get doctors to do stuff that they aren’t getting paid for is challenging, so I think that may help,” she says. “The fact that you don’t have to have IRB approval helps with people like me who see a community oncologist,” Shanahan adds. A community oncologist is in private practice and is not affiliated with a hospital or academic or medical teaching institute. These doctors typically do not have access to an IRB—though they can hire an independent IRB consultant.
Incentives for Companies
Still, the companies making the drugs ultimately are the ones who approve or turn down patients’ requests. Right to Try “doesn’t solve the overarching problem, and the overarching problem is getting the drug companies to supply the drug,” says Shanahan. “The FDA can’t compel drug companies and Right to Try doesn’t compel drug companies. I still think that is going to be where the roadblocks are.”
Drug companies are not required to disclose how many requests they receive for experimental access—though the FDA keeps track of the requests for expanded access that they receive and approve. Companies may deny a request for experimental use because they believe the drug’s potential risks outweigh the benefits. Companies may also have a limited supply of the drug or lack the resources to provide an experimental drug outside of the clinical trial. They may also worry about liability or be concerned that granting expanded access may detract from clinical trial participation.
A provision within the Right to Try Act releases the sponsor company, prescriber, dispenser and other entities from liability and stipulates that outcomes cannot be used to delay or adversely affect the review or approval of a drug. However, the FDA notes that adverse outcomes in patients receiving therapy via expanded access rarely ever affect FDA review to begin with.
There is also cost to consider. Under expanded access for individuals, federal regulations indicate that drug companies can only charge for their direct costs in making and providing the drug to the patient. Right to Try, on the other hand, specifically stipulates an exemption from this requirement. Proponents of Right to Try hope that by releasing requirements that limit what pharmaceutical companies can charge, the law will encourage companies to provide the drugs. This could also place a greater financial burden on patients, Shanahan notes, since these experimental drugs are not covered by insurance. In addition, insurance companies may deny coverage for care associated with administering the experimental treatments.
One potential upside of this national discussion, says Bateman-House, is that people with life-threatening diseases are now more aware that they have a way to ask for experimental treatments outside of a clinical trial—even if they may not fully understand that they have had that option all along.
“The sort of amazing thing in talking with people over the years … is that so many people had no idea that they had a route by which to get investigational drugs,” says Bateman-House, who believes educating people about the existing expanded use program and addressing other issues with the program would have benefited more patients.
Shanahan sees Right to Try as an additional way to get access to experimental treatment. If she did not qualify for a clinical trial, she says she would pursue the Right to Try and expanded access programs at the same time. She would choose the option that monitors the most outcomes, in hopes her experiences with the treatment might advance knowledge of breast cancer. “If I can help somebody else, I’m going to do that,” she says, noting that the Right to Try Act could have been stronger if it had a mechanism to gather more standardized data on patients who are traditionally not included in clinical research.
As it stands, the Right to Try Act stipulates drug companies provide annual summaries, including doses supplied, number of patients treated and adverse effects, to the Health and Human Services (HHS) secretary. The secretary has the option of reporting that outcomes data to the appropriate director within the FDA, which is an agency of HHS, if he or she believes the outcomes are relevant to safety. Under expanded access, physicians or companies must provide written treatment summaries, including outcomes, to the FDA when the treatment is over.
“Ultimately, we want to learn about these drugs,” says Fleury, referring to the FDA and its drug approval process. “The only way we are going to know if they work or not is if we get feedback about the outcomes.” Under Right to Try, Fleury says, those outcomes are less likely to be available.
Even though Shanahan supports Right to Try, she says that the FDA likely provides a more centralized mechanism for recording and tracking patient outcomes. Neither Right to Try nor the existing FDA mechanism for expanded access is ideal, she adds.
“In a perfect world, we wouldn’t be discussing this because [all patients would] be enrolled in clinical trials and have access to experimental drugs,” Shanahan says. “Information would be gathered. It would be freely shared, and everyone would benefit from this knowledge. It would all be entered into an international database where anyone who was a researcher could gather that data and look at it with different eyes.
“That’s the perfect world. Unfortunately, that’s not the world we live in.”
June 15, 2018