There is ongoing discussion in the medical community and among politicians about when and whether terminally ill patients can receive access to medicines not approved by regulators. With the support of the "right to try" movement, 37 states—and recently, the U.S. Senate—have passed laws aimed at providing easier access to experimental treatments that have undergone only the most rudimentary human testing.
The "right to try" website, operated by the libertarian Goldwater Institute, seeks to allow "terminally ill Americans to try medicines that have passed Phase 1 of the FDA approval process and remain in clinical trials but are not yet on pharmacy shelves. . . [and] expands access to potentially life-saving treatments years before patients would normally be able to access them."
But there's the rub: About three-quarters of drugs that pass Phase 1 will ultimately fail to be approved and never be accessible on the grounds of safety or lack of efficacy. And of those that do ultimately gain approval, the use (and therefore, the patient population) for which the FDA approves them will often be very different from the expectations during Phase 1 testing. An example is the infamous drug thalidomide, which had catastrophic side effects when tested and used as a sedative and to treat anxiety in the 1950s, but in recent years has been resurrected as a valuable treatment for patients with newly diagnosed multiple myeloma, a blood cancer, and for the skin lesions of leprosy.
The right to try unapproved drugs has the potential to be compassionate and sound public policy, but the devil is in the details. The most worrisome detail is that most—perhaps all—of the proposals, including the one recently passed by the U.S. Senate, would enable patients to request the drugs after only the most meager safety testing. But safety should be a concern even for terminally ill patients.
The FDA's Phase 1 testing, often the first time a new drug has been administered to humans, amounts to practically no testing at all. Those trials are performed for a short time on a very small number of subjects, usually only a few dozen (paid) healthy volunteers, who may not provide a good representation of how the drug will affect terminal patients. Those studies are intended to determine what doses of the drug are tolerated (in healthy volunteers) without obvious adverse effects, such as sudden death, seizures, or severe toxicity to organs like the liver or kidneys. Phase 1 trials are not designed to determine efficacy. Testing for efficacy begins in Phase 2, when the drug is administered to volunteers who suffer from the disease or symptom for which the drug is intended. If the results of Phase 2 are promising, the drug moves into still larger Phase 3 trials, the most extensive, expensive, and definitive part of drug development.
The phases of drug development, though sometimes onerous and costly, serve an important purpose. They prevent potentially harmful drugs from reaching the market. When I was a medical student at the University of California, San Diego, we would often admit patients who, out of desperation, had traveled to Mexico's "miracle cure" clinics, where unapproved drugs were available for a price. But these clinics would fleece—and often kill—terminal patients by administering unproven treatments. These patients would then be admitted to our university hospital with sepsis and multiple-organ failure.
Some people might say that terminal patients should be allowed to access these drugs because things cannot possibly get worse for a patient who is dying anyway. But that's a myth. They can get worse. Adverse reactions can make the last days or weeks far more miserable if the drug causes a stroke, liver or kidney failure, anaphylactic shock, neuralgia, or the agonizing Stevens-Johnson syndrome, a reaction to certain drugs marked by an excruciatingly painful rash that spreads and blisters. An example of an unexpected side-effect comes via the drug Viberzi, which was approved two years ago to treat inflammatory bowel disease. It was only just discovered that administration of the drug to patients who do not have a gallbladder can cause a serious and painful condition called pancreatitis. And that was a drug that had undergone extensive pre-approval testing (through Phase 3) on more than 2,600 patients during the pivotal clinical trials.
When I wrote an article for the Wall Street Journal about this topic, I pointed out that patients have the "right to make choices based on their own judgments about risk and benefit." But I added that "society also has a role in preventing desperation-driven coercion of patients and their exposure to unacceptable risks." One reader responded with a letter to the editor arguing that "society most certainly does not have a role in telling terminally ill patients that it knows better about analyzing risks and benefits and denying them choice." Another commenter offered: "If a patient is terminal and legally competent, why should disapproval by you, or society, or fear of liability (which should be able to be neutralized) rob that patient of a humane, possibly life-extending option?"
These comments raise legitimate issues but ignore an important fact: Society frequently intervenes to protect consumers from risks considered unreasonable—for example, by not affording them the freedom to experience the exhilaration of riding a motorcycle without a helmet. And in the pharmaceutical realm, the government polices drugs bought via the internet from certain offshore pharmacies known to pose a significant risk because their products are often counterfeit, contaminated, or otherwise substandard.
There is significant opposition in the medical community to a "right to try". As the Washington Post reported in its coverage of the just-passed Senate bill: "Alison Bateman-House, an assistant professor of medical ethics at NYU Langone Medical Center, called the bill 'inherently deceptive' because it simply says patients can ask drug companies for the treatments. Companies often are reluctant to provide unapproved products for a variety of reasons, and the FDA has an efficient system to handle requests for experimental drugs," she said.
In parallel with the legislative initiatives, federal regulators seem committed to making right to try work. From 2010 to 2015, the FDA approved more than 99% of applications for such "compassionate use" applications, and since then has worked to simplify the process. According to FDA Associate Commissioner Peter Lurie in congressional testimony last year: "Emergency requests are usually granted immediately over the phone and non-emergencies are processed in a median of four days. The treating physician is then responsible for obtaining informed consent from the patient and approval from an ethics committee before administering the drug."
Right to try is, in theory, a compassionate concept, but it needs thought and refinement based on an understanding of the drug-approval process and of physicians' commitment to primum non nocere—first, do no harm. Thus, to invoke the right to try, there needs to be some actual evidence of efficacy, beyond just speculation derived from computer simulations, cell culture, or animal experiments. An appropriate minimum threshold might be at least one Phase 2 trial—in which the drug has been administered to patients with the disease or symptom it is intended for, once it is marketed—whose results provide a reasonable expectation of effectiveness. And, of course, the manufacturer of the medicine (most often a drug company, but sometimes a university research laboratory) should have to provide a statement to patients that conveys the uncertainty about the likelihood of a positive response and of the known and possible side effects.
We need to prevent well-intended treatments from being worse than the disease. As one of my medical school professors admonished us, there is a difference between a patient living longer and interventions that make him so miserable that it just seems like longer.