Demand Builds for Access to Experimental Drugs

Bruce E. Johnson, MD

Right-to-try (RTT) legislation, which allows dying patients to take investigational medications without approval from the FDA, is on a roll. Legislatures in 39 states have approved such laws in recent years, as has the US Senate, and bills are pending in all other states¹ and the US House of Representatives (FIGURE).

Figure. Status of Right to Try Legislation on State Level

The concept is far less popular, however, among academic researchers, learned societies, professional regulators, and other members of the medical establishment. Some objectors believe that RTT laws endanger patients. Others think the laws could hinder the FDA’s ability to weigh the harms and benefits of experimental drugs. Still others think that RTT laws are pointless bromides that leave the real obstacles to patient access fully intact.

There is, however, one aspect of RTT that generally wins the establishment’s support: the underlying goal. Organizations such as the American Society of Clinical Oncology (ASCO) and the American Cancer Society want to make it easier for people who have run out of approved treatments to receive promising new drugs that just might deliver a miracle.^2,3 They don’t say, however, that RTT laws provide the best means of maximizing patient participation, benefit, and safety.

“The question isn’t whether patients should have better access to investigational agents. It’s whether right-to-try laws are the best way to improve access— and we don’t think that they are,” said Bruce E. Johnson, MD, president of ASCO, who also heads clinical research efforts at Dana-Farber Cancer Institute in Boston, Massachusetts.

Researchers outside the FDA have no real way to evaluate the efficacy of the current system for granting terminal patients access to investigational medicines. The agency has procedures in place through its expanded access program, sometimes called “compassionate use,” for 3 categories⁴: individual patients; intermediate-size populations, defined as smaller than the typical cohort for an investigational new drug (IND) of 20 to 80 patients⁵ or for a treatment protocol; and widespread use through a treatment IND or protocol. The FDA does not disclose exactly how many patients participate in the program each year, and it does not publicize any information about disease response or adverse events.

The FDA reports that it receives about 1400 requests a year, about half of them for individual patients and half for groups. The agency also has reported that it approves more than 99% of all applications.⁶ Unfortunately, the FDA does not disclose the size of each group, so there’s no way to know if it grants expanded access to 4500 patients a year or several times that number.

Either way, the total number is certainly tiny compared with the number of Americans who die as a result of diseases each year. Cancer, the second most common cause of death in the United States after heart disease, is expected to kill more than 600,000 people in 2017, accounting for nearly 1 of every 4 deaths.⁷ Although the expanded access program is open to patients with any serious medical condition, the oncology field is particularly affected.

It is, of course, impossible to compare experimental drug usage across nations when there are no concrete American figures, but compassionate use programs in several other countries seem to have far higher participation rates. France, for example, has just over a fifth as many residents as the United States, but it provided 6000 dying patients with access to investigational medications in 2013.⁸ This suggests to some that the number of Americans who would want experimental treatments may greatly exceed the number who get them under the current system. Others explain the discrepancy, in part at least, by asserting that the United States now approves breakthrough treatments faster than many nations and thus has less need of compassionate use.

Aids Crisis Fueled Debate

“It’s pretty hard to argue that the FDA is a major obstacle to access right now—let alone the major obstacle—because they approve more than 99% of the requests,” Johnson said. “It is, therefore, difficult to see how patients would benefit from laws that take the FDA out of the loop, but it’s pretty easy to see how such laws might end up depriving regulators and the research community of valuable information about therapeutic effects and potential adverse events.”The use of experimental medications by ordinary patients is a relatively modern phenomenon. Patients didn’t have to wait very long for new drugs to reach the market until 1962, when Congress mandated that the FDA use clinical trials to evaluate the safety and efficacy of would-be medications—and the average drug development time shot up from 2.5 to 8 years.⁹ Demand for investigational treatments began rising shortly thereafter and spiked in the 1980s, when the AIDS crisis reached its highest point. The FDA responded in 1987 by creating the first version of the basic compassionate use system that exists today.⁹

Under current federal law, dying patients who have stopped responding to everything approved for the treatment of their condition have 2 main ways to access experimental medications: (1) enroll in a clinical trial or (2) apply for expanded access, which allows a doctor to administer an investigational drug to all patients in a similar therapeutic setting or to a single patient. The FDA has outlined 8 basic conditions that must be met to gain access (TABLE).¹⁰

Table. FDA Requirements for Expanded Access Uses¹⁰

Patients who wish to go the second route must work with a physician to find a promising experimental drug, convince that doctor to support a compassionate use application, petition the drug’s manufacturer for a supply, submit a formal application to the FDA, and— finally—ask an institutional review board (IRB) at the doctor’s practice or hospital for permission to use the therapy at that practice or hospital. Drugmakers typically give their products away, but patients who cannot independently finance the associated treatment costs must also secure monetary assistance from their insurer, which is not required to cover such costs, or some form of charity.

Applications can fail at every step, but anecdotes from both publications and interviews suggest that nearly all failures occur early, when the patients are trying to secure cooperation from doctors and drugmakers. The FDA, again, approves the overwhelming majority of applications, and IRBs appear to do likewise.

Alison Bateman-House, PhD, MPH, MA, an assistant professor in the Department of Medical Ethics at New York University Langone Health in New York City, has spent several years studying this topic and said in an interview with OncologyLive^® that she never heard of a rejection. Some doctors, on the other hand, clearly refuse to support at least some compassionate use applications, while some drug companies seem to decline them most of the time and the rest, at least some of the time. However, data are very sparse. Published papers don’t even try to estimate approval rates.¹¹

Strengths of FDA Review Process

Even when patients gain approval at each step, the process takes time that some people do not have. Researchers have yet to quantify the number of patients who die before final approvals grant them access to a potentially useful drug, but there are published accounts of patients who died before their applications succeeded or before a drug had a chance to help them.¹²RTT laws take a very simple approach to making the process faster and easier: Remove the FDA from it entirely. Opponents object to this idea on 2 grounds. First, they say, the FDA is not much of a barrier. It not only approves 99% of all applications but also does so quickly once paperwork is received. Urgent applications, sometimes made by phone, are reviewed in just a few hours, and nonurgent applications typically are reviewed in 4 days or less. The FDA does not charge anyone for a review.

Second, RTT opponents say, the FDA review does provide concrete and significant benefits to patients. The FDA has less information about any particular drug than the company that makes it, but it has far more information than any single company about the range of drugs in a particular class, because it sees data from every trial, including data that drug companies do not share publicly. Therefore the FDA sometimes knows that a drug is likely to be toxic above a particular dose before its manufacturer realizes it.

Additionally, the FDA applies this information when considering compassionate use applications. The agency may not reject more than a tiny fraction of applications, but it does suggest changes in the prospective dose size or timing or in the wording of patient consent forms in about 11% of all cases.¹³

“There’s an understandable tendency among patients, politicians, and the general public alike to think there’s no point in taking extra time and effort to reduce side effects when you’re dealing with people who don’t have long to live,” said Bateman-House.

Argument for Right to Try Laws

“Everyone thinks, ‘It can’t get worse. They’re already dying of cancer.’ But, in reality, it can get worse—it can get much worse. Dying of cancer is terrible, but it’s far worse to lose your last days, weeks, or months to a medication that hastens your death or to exchange the manageable pain of cancer with the agony of having your cells decompose while you’re still alive, as has happened. These are real risks, which is why even dying patients should think carefully about trying unproven medications and why the FDA should have a role in reviewing these cases.”Libertarians have sought to roll back the FDA’s ability to regulate the purchase and sale of medications since the modern agency began operations in 1930, but the movement that has made RTT the law in 38 states (in Hawaii, a bill passed but was vetoed by the governor) is quite recent. The movement began less than 4 years ago in the Phoenix offices of a Libertarian nonprofit organization called the Goldwater Institute, which drafted the sample legislation that is the basis for most RTT laws and remains a major force behind the movement. The model legislation, which is less than 4 pages long, allows patients with advanced, progressive, life-threatening disease who have run out of other therapeutic options to directly ask a drug manufacturer for an experimental medicine based on a physician’s recommendation and their own consent.¹⁴

Goldwater officials concede that the FDA’s tweaks may sometimes improve treatment regimens for some patients, but they think the agency has no business standing between dying patients and potential cures. Their first objection is philosophical: Terminally ill patients, working in conjunction with medical specialists in good standing, should be free to make their own decisions without asking permission from regulators in Washington. Their second objection is practical: The FDA might approve the overwhelming number of applications in just a few days, but the onerous amount of paperwork required greatly reduces the number of applications.

“The application process, which can amount to 100 hours of paperwork and administration for a single patient, makes it virtually impossible for a physician to apply,” said Naomi Lopez Bauman, Goldwater’s director of healthcare policy.

“If it were possible to fill out the paperwork in 45 minutes, which is what the FDA currently estimates, many more doctors would be willing to use compassionate use, but the current system is so burdensome that scant few are able to devote that amount of time to a single patient.

“The process is similar to filling out your taxes,” she said. “While it may take a couple of hours to complete the written application, many more hours are spent gathering and analyzing documents, requesting employer records, and retrieving bank statements.”

Such arguments have resonated with elected officials across the country. RTT laws have typically passed through legislative chambers with overwhelming bipartisan support. The most recent state to pass such a law, Pennsylvania, did so with unanimous votes in both the state’s House of Representatives and its Senate.¹⁵ The US Senate also passed its RTT bill with unanimous consent.¹⁶

Movement Prompts Change

The strength of this support may stem in part from the fact that state RTT laws are largely symbolic gestures supporting patient rights. No researcher or journalist has ever found a significant number of doctors and drug makers working to provide investigational drugs to dying patients without first getting the FDA’s approval. Just 1 doctor, Ebrahim Delpassand, MD, has used Texas’ RTT law to give an investigational treatment to about 100 patients with terminal cancer even though the FDA denied his request.¹⁷ If other doctors and patients are using state RTT laws, they are either very rare or very discreet.Nevertheless, even if hardly anyone uses them, state RTT laws have already had a profound effect on compassionate use policy in the United States. The Goldwater Institute’s efforts got the entire medical establishment to think about a relatively obscure corner of medicine and find a need for change. That growing consensus has spurred the FDA to streamline the compassionate use process several times in the past several years.

The most heralded change may have come in February 2015, when the agency unveiled the “45-minute” compassionate use application culled from a far longer application that took—even in the FDA’s estimation—100 hours to fill out. Doctors who want expanded access for a class of patients must use the old form, but they don’t have to complete all sections.¹⁸ This year, the FDA tried to further ease the application process by streamlining institutional review. Commissioner Scott Gottlieb, MD, announced that, rather than requiring full IRB approval for compassionate use cases, doctors seeking permission to use investigational drugs at a given hospital simply needed approval from the IRB chair or “another appropriate person.”¹⁹

These reforms do not mean the establishment is on board with RTT, however. The fact that RTT laws make truly discreet cases of compassionate use a genuine possibility ranks among opponents’ top concerns.

Compassionate use cases generate information about both the safety and efficacy of investigational medications, vital information that could be lost if drugmakers are not required to report responses to the FDA. Such concerns led to the revision of the Senate’s RTT bill, which originally forbade the FDA from penalizing candidate drugs because of adverse events among compassionate use patients but ended up mandating that the receive and use evidence of both benefits and harm.

Potential Harms of Right-to-Try Laws

Drugmakers, moreover, have not seemed enthusiastic about cutting the FDA out of loop. To the contrary, the Pharmaceutical Research and Manufacturers of America, an industry organization that represents most large drug makers, has been distinctly cool to the entire RTT movement. The organization has said state legislation is “unlikely to add any meaningful new approaches that can optimize the federal expanded access program”²⁰ and expressed concern about any federal RTT legislation that would jeopardize the current trial process.Why might RTT jeopardize the trial process? In theory, making it very easy for dying patients to access investigational medications on grounds of compassionate use could discourage them from participating in clinical trials. Why take a 50% chance of receiving either placebo or the existing standard of care when you can apply for compassionate use and guarantee yourself access to the newer medication?

That’s not the only plausible way that a massive expansion in compassionate use could reduce trial participation. “The current trial process is predicated on the fact that trials are about the only way to gain access to experimental medications. It’s pretty easy to imagine how a massive expansion in compassionate use could undermine that system,” said Y. Tony Yang, ScD, LLM, MPH, an associate professor in the Department of Health Administration and Policy at George Mason University in Fairfax, Virginia.

“For example, very sick patients often suffer serious adverse events from medications that are well tolerated by healthier patients, so if you have a dramatic increase in compassionate use, you’re going to have many reports of serious adverse events. Will those reports dissuade patients from participating in trials of seemingly dangerous medications? It certainly seems possible.”

It surprises many observers that drugmakers agree to supply their medications to patients who request compassionate use. Current regulations forbid them from selling investigational medications for a profit, so there’s no money to be made. What’s more, because compassionate use patients tend to be sicker than trial patients, they are more likely to suffer adverse events and less likely to respond to a drug, so compassionate use seems more likely to generate negative safety and efficacy data than standard trials.

The other surprise in the RTT debate is that nearly everyone, regardless of whether they support or oppose RTT, believes that dying patients should have easier access to investigational drugs than they do now.

“We simply have no idea whether compassionate use tends to help or hurt patients. The overwhelming majority of medications that begin phase II trials never win approval, so it’s almost certain the overwhelming majority of compassionate users get no benefit. But it could be worse than that. It may be that 90% of them are significantly harmed. We just don’t know, and yet nearly everyone, myself included, think we should make it easier for patients to access these medications,” said Bateman-House.

“It’s just an area where moral intuition trumps all else,” she said. “Most of us believe that dying people should be given wide latitude to try anything that may help them survive, even if it’s risky. But that doesn’t mean we have to throw out an FDA program that has helped, not harmed, patients, and make compassionate use anything goes.”

References

1. Right to try in your state. Right to Try website. righttotry.org/in-your-state/. Updated 2017. Accessed December 19, 2017.
2. ASCO releases position statement on access to investigational drugs [press release]. Alexandria, VA: ASCO; April 4, 2017. asco.org/about-asco/press-center/news-releases/asco-releases-position-statement-access-investigational-drugs. Accessed December 19, 2017.
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5. Investigational New Drug Application, 21eCFR, §312.20-312.48 (2017).
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