Anyone who has been reading this blog for the last three years or so knows that I’m not a fan of so-called “right-to-try” laws. Basically such laws, which have sprung up like kudzu since 2014 and now exist in 33 states, purport to allow terminally ill patients the “right to try” experimental therapeutics. Thus far, they have been sold to the public as giving terminally ill patients “one last shot” and touting how such laws could save lives. As a result, as I’ve grimly quipped on multiple occasions, to politicians opposing right-to-try laws is akin to opposing motherhood, apple pie, and the American flag; you just don’t do it and expect to be re-elected. It’s much easier just to go along than to explain to the voters, the vast majority of whom do not understand the drug approval process and therefore do not understand why right-to-try laws are harmful to the very patients their proponents purport to be helping and why they’re such an astonishingly bad idea, particularly as currently formulated. That would require going into the details (which I will do shortly). So at the state level, right-to-try advocates have basically won. Just shy of 2/3 of the states have passed such laws in a mere three years, and I wouldn’t be surprised if the remaining 17 states without a right-to-try law pass such laws within the next year or two.
All right-to-try laws thus far hew very closely to model legislation written and promoted by a libertarian think tank, the Goldwater Institute, with a few state-specific differences here and there, and share several key features. They also share one key shortcoming, and that’s federal law. States do not regulate drug approval in the U.S.; the federal government does, through the Food and Drug Administration (FDA). In general, the FDA has not supported right-to-try laws, but has liberalized expanded access programs (also sometimes called compassionate use) to make it easier for terminally ill patients to access experimental therapeutics outside of FDA-sanctioned clinical trials. Not surprisingly, I’ve as yet been unable to find a single compelling example of a patient who has been helped by access to an experimental therapeutic through a state right-to-try law, although I’ve found that cancer quack Stanislaw Burzynski has taken advantage of Texas’ right-to-try law to ply his quackery, just as I warned that he would three years ago. Basically, right-to-try laws are a solution looking for a problem or, as I like to call them, placebo legislation. They make lawmakers feel good, but they do nothing concrete to help actual patients. It’s also important to remember that the real purpose of right-to-try laws is not to help patients, but to neuter the FDA’s ability to regulate certain drugs, consistent with the source of this legislation. Passing state right-to-try laws is part of a strategy to build pressure to pass a federal right-to-try law and thus weaken the FDA:
@gorskon Yes but I'm afraid much more support now. Goldwater's playbook was get laws in at least 25 states & then claim mandate for fed law
— Alison Bateman-House (@ABatemanHouse) August 24, 2016
Thus far, proponents have failed not once, but twice, to pass a federal right-to-try law, once in the form of The Compassionate Freedom of Choice Act of 2014 and then again last year in the form of the The Trickett Wendler Right to Try Act of 2016, which fortunately failed to pass. Now they’re at it again.
If you can’t pass a right-to-try law, bury it in an omnibus bill
With the election of Donald Trump and both houses of Congress under the control of Republicans, a decidedly deregulatory mood has overtaken the government. Moreover, Vice President Mike Pence supports right-to-try laws, having signed one into law when he was Governor of Indiana. So you’d think that right-to-try would just pass, and then President Trump would sign it. Yes, The Trickett Wendler Right to Try Act has been reintroduced this session, but proponents apparently don’t want to wait that long. The Prescription Drug User Fee Act (PDUFA) is the law that allows the FDA to collect user fees from drug companies to fund the drug approval process. The current legislative authority for the PDUFA expires at the end of September and needs to be renewed before then. Right-to-try proponents thus see an opportunity to sneak a provision into the PDUFA renewal that would serve their ends as well as a federal right-to-try law:
And now, for the first time, federal legislation is gaining traction.
Congressional supporters may try to attach a measure — drafted with a unique and highly controversial restriction on the FDA — to the agency’s must-pass funding bill this year. The anti-regulatory mood dominating Washington is boosting these efforts.
More detail can be found in this account (behind a paywall, so I’ll quote a bit more liberally than usual):
The ‘Right to Try’ movement is gaining momentum at the federal level with support from both the Trump Administration and Republicans in Congress to enact legislation that would direct FDA not to interfere with existing state laws and allow terminally ill patients to access unapproved treatments.
The “Right to Try” movement now has the explicit backing of the White House and enactment of legislation to prevent FDA from interfering with state laws in that area may now be inevitable. Vice President Mike Pence met with right-to-try advocates Feb. 7. Pence is a backer of opening up broader access for compassionate use; as governor of Indiana, he signed state “Right to Try” legislation in law in 2015 and made statements during the Presidential campaign in support of such efforts. (Indiana is one of 33 states to enact legislation.) The official “readout” of Pence’s meeting makes clear that his support for the effort is now Administration policy.
Pence’s meeting builds on statements made by President Trump before a Jan. 31 meeting with pharmaceutical CEOs, where he talked about the need to “change a lot of rules” in drug regulation. (Also see “Trump Promises Changes To ‘A Lot Of Rules’ At US FDA” – Pink Sheet, 31 Jan, 2017.) “One thing that’s always disturbed me is we come up with a new drug for a patient who is terminal, and the FDA says we can’t have this drug used on the patient. But the patient within four weeks will be dead,” President Trump said. “They say ‘well we still can’t approve the drug and we don’t know if the drug works or if it doesn’t work but we can’t approve the drug because we don’t want to hurt the patient.’ But the patient is not going to live more than four weeks.”
This is a fallacious argument frequently used by right-to-try advocates. Basically patients with only four weeks to live are highly unlikely to be helped by pretty much anything, experimental or otherwise. However, they can be harmed. Right-to-try proponents often ask, “What’s the harm?” or “How can it get worse?” It can. A terminally ill patient could lose those four weeks with his family or could suffer far more than he would have otherwise with palliative care. Be that as it may, it’s clear that right-to-try backers, having thus far been unable to use state right-to-try statutes to force the FDA to grant access to experimental therapeutics and failed to pass a federal law, are going to try to sneak a right-to-try provision into the bill that will fund much of the FDA’s operations for the next four years.
To understand why this move is such a threat to patients, let’s briefly review what state right-to-try laws claim to do (which is a lot) and actually do (almost nothing) and then review the federal right-to-try bill that’s been re-introduced.
State right-to-try laws: Harmful placebo legislation addressing a nonexistent problem
I mentioned before that all the state right-to-try laws hew pretty tightly to an approved model legislation template originally published by the Goldwater Institute. Such legislation includes several major shared features. First is the requirement that the disease the patient has be terminal, usually defined as having a life expectancy of less than six months, although the model legislation is more vague, requiring an “advanced disease,” defined as “progressive disease or medical or surgical condition that entails significant functional impairment, that is not considered by a treating physician to be reversible even with administration of current federal drug administration approved and available treatments, and that, without life-sustaining procedures, will soon result in death.” Various states define this condition in somewhat different ways, but you get the idea.
One of the most problematic passages, if not the most problematic passage, is the one where the term “investigational drug, biologic product, or device” is defined:
“Investigational drug, biological product, or device” means a drug, biological product, or device that has successfully completed phase 1 of a clinical trial but has not yet been approved for general use by the United States food and drug administration and remains under investigation in a United States food and drug administration-approved clinical trial.
Every right-to-try bill or law I’ve read uses minor variations of the above definition. Anyone who knows anything about drug development knows that having completed a phase 1 trial is a dangerously low bar to clear to allow more widespread use of a drug. Basically phase 1 trials are small trials, usually consisting of less than 30 subjects, that look for major toxicities and adverse events. That is not enough to determine safety, nor is it intended to. Phase I trials are designed primarily to identify major side effects and to use a process known as dose escalation to determine what is commonly referred to as the “maximum tolerated dose.” It is utterly impossible for such a small clinical trial to determine the safety of a drug. Phase II and Phase III trials are needed to confirm safety. Think of phase I trials as a screening test looking for the most obvious toxicities, with phase II and III studies confirming them. Indeed, even phase III trials can’t always adequately demonstrate that a drug is safe; it’s not uncommon for less common adverse effects not to show up until post-marketing surveillance, when much larger numbers of patients receive the drug. Moreover, only 5% of all cancer drugs that enter clinical testing are ultimately approved for patient use. Among drugs tested in phase II trials, only 30% go on to phase 3. I like to point to the cautionary example of amonifide for treating breast cancer. The drug made it through phase I trials, but serious life-threatening hematologic toxicity emerged during phase II trials.
Right-to-try laws limit who can access them by wealth. The reason is that all of them have a provision that says that health insurance companies do not have to pay for such treatment. They can pay if they so desire, but what’s the likelihood of an insurance company paying for an experimental treatment? However, nearly all right-to-try laws also say that the company providing the experimental therapeutic under right-to-try can charge the patient for it. (One notable exception, as I learned a year ago, is Texas, where the right-to-try law bars charging the patient.) A terminally ill patient could easily go bankrupt before he died paying for drugs accessed through right-to-try laws, and many couldn’t access experimental therapeutics through such laws in any event because they simply don’t have the money or the fundraising wherewithal to do so.
In Michigan, the requirement is particularly suspect in that it requires “written informed consent” for using the experimental drug that attests that the “patient understands that he or she is liable for all expenses consequent to the use of the investigational drug, biological product, or device and that this liability extends to the patient’s estate, unless a contract between the patient and the manufacturer of the drug, biological product, or device states otherwise.” This puts the patient on the hook for any expenses or debt that he incurs using experimental treatments, but also seems custom-made for drug companies, to make sure that they get their money for experimental therapies administered under “right-to-try,” no matter what. Basically, they can go after a deceased patient’s estate, something that will frequently be necessary because patients eligible for “right-to-try” by definition have a terminal illness, and the vast majority of even the most promising drugs will, at the very best, prolong their life, not save it. It goes beyond that, though. If a patient uses a right-to-try drug and suffers complications, these laws basically state that the insurance company doesn’t have to pay for care resulting from that complication, and all such laws state that patients undergoing right-to-try therapies lose their coverage for hospice.
Right-to-try laws are patient-hostile in other ways, too, as Jann Bellamy and I have described many times. The most egregious example of which is how they strip patient protections away from patients who access them. One way to see this is by comparing what happens when a patient accesses an experimental therapeutic under the FDA expanded access program to what happens when another patient accesses one under a right-to-try law. Under FDA expanded access, patients retain full protections under federal and state laws. They can sue for malpractice if there is any, and their care is still monitored by an institutional review board (IRB), with any adverse events recorded and considered by the FDA. Moreover, the FDA approves nearly all such requests (99%). In contrast, under right-to-try, there is no IRB oversight. It’s all between the company and the patient.
Right-to-try laws also limit what patients can do in the event of malpractice or negligence. All of them immunize physicians advising or administering right-to-try medications against malpractice suits or actions against their medical license by the state medical board for doing so. All of them contain provisions broadly immunizing companies providing experimental therapeutics under right-to-try from liability. All of them contain provisions stating that state employees can’t interfere with a patient seeking right-to-try, which could be interpreted to mean that a doctor at an academic medical center at a state university couldn’t counsel a patient not to seek right-to-try without running afoul of the law. As Jann notes, even if state authorities believe, for example, that an elderly person is being exploited for financial gain by a physician, presumably this provision would prohibit their acting.
As you can see, these state laws are potentially very harmful, but they’re easy to demagogue. Anyone supporting them can easily paint himself as the champion of terminally ill patients with no hope left, while those of us who oppose such laws have the difficult task of explaining clinical trials and how these laws harm patients. Indeed, when right-to-try came to Michigan, I was endlessly frustrated by how pretty much none of our major medical schools or cancer centers would speak out. Flacks from the Goldwater Institute, complete with patients with compelling stories, were there in abundance, though.
I called state right-to-try placebo legislation because it basically does nothing while making everyone feel better. That’s why federal legislation is in the works.
Two of the biggest hurdles to actually utilizing state right-to-try laws include the authority of the FDA, which preempts state laws, and the fact that the FDA has thus far taken a dim view of companies using experimental therapeutics outside the auspices of an FDA-sanctioned clinical trial or under its expanded access program. Enter federal right-to-try bills. The most recent ones are S. 204: Trickett Wendler Right to Try Act of 2017, introduced into the Senate by Ron Johnson (R-WI) and H.R. 878: Right to Try Act of 2017, introduced by Rep. Andy Biggs (R-AZ). Both are basically the same as the bill introduced last year. They both have two main provisions:
Notwithstanding any other provision of law, no liability shall lie against a producer, manufacturer, distributor, prescriber, dispenser, possessor, or user of an experimental drug, biological product, or device for the production, manufacture, distribution, prescribing, dispensing, possession, or use of an experimental drug, biological product, or device that is in compliance with subsection (a).
(2)No use of outcomes
Notwithstanding any other provision of law, the outcome of any production, manufacture, distribution, prescribing, dispensing, possession, or use of an experimental drug, biological product, or device that was done in compliance with subsection (a) shall not be used by a Federal agency reviewing the experimental drug, biological product, or device to delay or otherwise adversely impact review or approval of such experimental drug, biological product, or device.
These provisions are pretty self-explanatory. These bills would prevent federal lawsuits against drug or device manufacturers, dispensers, users, or physicians prescribing or administering right-to-try. The more pernicious part of the bill is the second provision, which would explicitly bar the FDA from considering any adverse events that occur in patients using right-to-try laws in its decision whether to approve or reject an application for approval to market. This clause is clearly intended to address the concern of drug and device manufacturers that if they provide an experimental therapeutic to a patient under right-to-try and the patient suffers complications due to the treatment, the approval of its product might well be jeopardized. This, of course, is not an unreasonable concern on the part of manufacturers, given that it can easily cost $1 billion to bring a drug or device to market, and by the time the product has passed phase I clinical trials a great deal of that cost has already been invested in development. However, this clause goes way too far. Basically, it says that even if a patient death is clearly due to use of an experimental drug under right-to-try, that death should not be considered by the FDA in deciding whether to approve the drug. Think of it this way. Let’s say dozens of patients die from using an experimental drug under right-to-try. This bill, if passed, would bar the FDA from even considering those deaths during its deliberations regarding whether to approve the drug for marketing or not. This is not a good thing for patients.
Basically, the Trickett Wendler Right to Try Act of 2017 would not help terminally patients. It would endanger them. Proponents often ask, “What does a terminally ill patient have to lose?” The answers are simple. They can lose money, perhaps their life savings, given that accessing right-to-try could easily cost tens or hundreds of thousands of dollars. That’s because, when you come right down to it, “right to try” is a misnomer. It’s really “right to buy.” If you’re terminally ill and don’t have the money or the means to raise it, right-to-try will not help you. Worse, thanks to right-to-try, terminally ill patients can lose some of their precious quality time remaining with their loved ones if they suffer complications that place them in a hospital or prematurely kill them.
The New York University School of Medicine Working Group on Compassionate Use and Pre-Approval Process has published an excellent bullet-point summary of the problems with right-to-try, as well as policy suggestions going forward.
Right-to-try against patients
As I wrote this, I contemplated a simple question: Which federal action is worse? Would passing the Trickett Wendler Right To Try Act of 2017 be worse, or would sneaking a right-to-try provision into the must-pass PDUFA be worse? The answer is not obvious. Trickett Wendler would prevent the FDA from considering outcomes in patients undergoing right-to-try treatments in its approval deliberations, which would have the potential to be disastrous, particularly if right-to-try usage of experimental therapeutics becomes more widespread. Meanwhile adding right-to-try to the bill that funds the FDA, in essence baking-in a ban on interfering with patients seeking experimental therapeutics under state right-to-try has the potential to cause a lot of harm, because state right-to-try bills do not prevent the FDA from considering outcomes of patients accessing experimental therapeutics. At least, I don’t think it does but can’t be sure. The specific language of the right-to-try provision of PDUFA hasn’t been revealed yet. If that language contains a Trickett Wendler-like ban on the FDA using outcomes from right-to-try patients in its considerations of drug approval, then the PDUFA approach will be equally, if not more, harmful. Basically, both the PDUFA and Trickett Wendler bills are plenty bad.
As has been the case since 2014, I remain frustrated by the relative lack of pushback by the medical community against such ill-advised right-to-try bills and efforts. I’m not the only one. Beth E. Roxland, senior adviser on law, ethics, and policy at NYU Langone Medical School agrees:
Roxland, the NYU ethicist, is watching, dismayed, as the right-to-try bills sweep the country.
“What I see is, unfortunately, very little pushback in terms of what the downsides could be,” she said. “If anything, it’s just picking up steam.”
Roxland said she has spoken to medical industry leaders and policymakers who support the rights of patients to seek potentially lifesaving treatments, but who feel the right-to-try laws, as written, will ultimately harm patients. She said these leaders are frequently reluctant to to [sic] express nuanced objections in the face of more emotionally charged arguments. “It’s hard to argue against when it’s framed as the terminally ill having the right to save their lives,” she said. “How do you argue against that?”
This could be one reason why the FDA and major trade groups, including the American Medical Association and the Pharmaceutical Research and Manufacturers of America, have taken no public stance on the legislation.
Roxland’s experience mirrors my own. Everyone in academia or pharma with whom I’ve ever discussed right-to-try thinks these laws are a horrible idea that will harm patients, but no one wants to be the one to speak out, for the reasons listed by Roxland above or, as I put it, because they don’t want to be perceived as yanking a dying patient’s last hope away. Of course, that’s not what we’re doing, but that’s what right-to-try advocates have successfully portrayed us as doing.
For instance, it wasn’t until earlier this month that the largest oncology professional society, the American Society of Clinical Oncology (ASCO) finally—finally!—came out forcefully against right-to-try. In a statement, ASCO noted:
As the leading medical society for physicians involved in cancer treatment and research, the American Society of Clinical Oncology (ASCO) supports access to investigational drugs outside of clinical trials when there are adequate patient protections in place. However, ASCO is concerned that existing and proposed RTT laws do not adequately protect patients, do little to facilitate patient access to such therapies, and potentially interfere with recent reforms that are already streamlining patients’ access to investigational agents.
Comparing the existing system for expanded access to right-to-try laws, ASCO finds many problems:
ASCO is concerned that most RTT laws, while well intentioned, are not an effective mechanism for improving access to investigational drugs for terminally ill patients and may cause unintended harms, for the following reasons:
- Right-to-try laws do not include an enforcement mechanism to provide access, since they do not require or compel drug manufacturers to provide investigational products. As such, these laws do not remove a frequent barrier to access.
- These laws place no legal obligations on insurers to pay for the routine care costs associated with delivery of treatment – unlike coverage requirements that do exist for patients who participate in clinical trials. As a result, RTT laws establish no new rights or protections for patients.
- Independent review of the potential safety and efficacy of investigational drugs is important for patient safety. Under the expanded access program, the FDA conducts a prompt review of the available data and makes an independent assessment on behalf of the patient. Such review is bypassed in RTT laws.
Moreover, these laws as currently envisioned and enacted will interfere with already- streamlined and effective protocols, potentially putting patients at high risk for unclear benefit. Specifically, these measures will:
- Jeopardize insurance coverage for the cost of patient care associated with the use of investigational drugs, particularly in the case of complications caused by these drugs;
- Circumvent the government’s responsibility to monitor and protect the safety of patients seeking access to investigational products; and
- Fail to provide adequate transparency, in part due to a lack of reporting requirements, on how patients respond to investigational drugs under a right-to-try scenario.
In addition to their lack of patient protections, RTT laws do not mitigate the delays that can occur during the expanded access application process. For example, regardless of whether under RTT or the FDA process, applicants must determine a sponsor’s willingness to provide the investigational drug. Providers and patients consistently report difficulty locating information about drug manufacturer contacts for such requests, significant delays in response and even denial of the request altogether.
Sound familiar? This is exactly what I’ve been saying for three years now, along with every other opponent of right-to-try who actually spoke up. ASCO goes on to describe strategies by which expanded access programs can be strengthened and patients provided more access to experimental therapeutics, complete with current protections. Unfortunately, ASCO is a day late and a dollar short. Actually, it’s three years late. The time for oncology professional associations to speak up was in 2014, as the first right-to-try bills were wending their ways through state legislatures, not now. Then, ASCO might have influenced the debate in a positive way. Now, it’s almost certainly too late.
All along, too few people have been willing to point out that right-to-try is not about helping patients. Consider the source of right-to-try, after all. Rather, it’s about this:
But the increased momentum is raising alarms, with opponents saying that such laws largely offer false hope. That’s because many drug companies are reluctant to provide medications outside of clinical trials — and why critics insist that the FDA is not the problem. In 2016, they note, the agency revamped its “expanded access” program to speed unapproved drugs to patients who have no alternatives and can’t get into clinical trials. The FDA approves almost all such requests, the data shows.
“A lot of this is smoke and mirrors for some other agenda,” said Andrew McFadyen, executive director of the Toronto-based Isaac Foundation, which assists U.S. and Canadian patients seeking access to medications. “A weaker FDA is what they are after.”
Exactly. Kudos to Mr. McFadyen for stating the obvious. Right-to-try is a strategy by libertarians to neuter the FDA, as could be seen rather plainly during the Ebola scare, when libertarians openly argued that the FDA was “killing patients” and that right-to-try was the answer.
I’ve pointed out before how the entire justification for “right to try” laws rests on a misperception that there are “miracle drugs” out there that we will have to wait years for because the FDA is too slow to approve them. Not only is this a myth (the FDA is actually pretty fast at approving new drug applications compared to, for example, its European counterpart), but if there really were such a “miracle drug” that was amazingly effective compared to anything we have now, a large randomized phase III trial would not be necessary to detect its efficacy. Indeed, its efficacy could show up in even a small phase I trial or, at the latest, in phase II trials, and, under previous policy and even more so under the 21st Century Cures Act, the FDA can consider that evidence in approving a drug. There would be examples of clinical trial subjects demonstrating amazing tumor shrinkage or even outright cures. In reality, we don’t see these things in phase I trials, because there are no miracle drugs, at least not yet. (The closest to a “miracle drug” I can think of is Gleevec, and drugs like Gleevec are rare.)
“Right to try” laws rest on a fantasy, and it’s a fantasy of false hope. Indeed, these bills serve an ideological purpose rooted in libertarian politics, free market fundamentalism that claims that deregulation is the cure for everything, and the desire to weaken the FDA that flows from such beliefs. Unfortunately, because stakeholders in medicine who recognized this were too timid to speak up, it is probably too late to stop some form of a federal “right-to-try” bill or provision from becoming law. Let that be a lesson to us.