One of my favorite shows right now is True Detective, an HBO show in which two cops pursue a serial killer over the course of over 16 years. Starring Woody Harrelson and Matthew McConaughey, it’s an amazingly creepy show, and McConaughey is amazing at playing his character, Rustin Cohle. I’m sad that the show will be ending this week.
Unfortunately, as much as I like Matthew McConaughey as an actor, he is in part responsible for re-inspiring a movement that has the potential to do profound harm to patients and cancer research. That’s because his other big role over the last year has been in an Oscar-nominated movie, Dallas Buyers Club, where he plays Ron Woodroof, an early AIDS patient who in the 1980s smuggled unapproved pharmaceutical drugs into Texas when he thought he found them effective at alleviating his symptoms, distributing them to fellow sufferers by establishing the “Dallas Buyers Club” while battling the FDA. I haven’t seen the movie, and I really don’t want to, given that, from everything I’ve heard about it, it’s basically the story of a “brave maverick” who bucks the FDA, complete with all the tropes about uncaring bureaucrats who don’t care if these brave patientd die. That might not be so bad if it weren’t also riddled with inaccuracies and misinterpretations of the AIDS crisis in the 1980s. Worse, the real Woodruff rejected the one truly promising drug at the time, AZT as hopelessly toxic and instead smuggled drugs like Peptide T, which never panned out. Basically, what Woodruff appears to have smuggled as part of his activities for the “Dallas Buyers Club” was a mixture of useless supplements, experimental drugs that panned out, and a handful of experimental drugs that showed promise. Meanwhile, the movie portrays the FDA as the implacable enemy of theses sorts of activities, jackbooted thugs not unlike the stereotype promoted by “health freedom” quacks who don’t like the FDA preventing them from selling their quackery. As far as I can tell without actually seeing the movie is that the overall message is a typical uplifting story of an underdog who fights the power and in doing so finds redemption.
Of course, Dallas Buyers Club is just a movie, no matter how good a movie it might be and how much Matthew McConaughey might have deserved an Oscar for his performance. Unfortunately, it appears that legislators in several states seem to think that it should serve as a template for health policy. This public policy, which is extremely bad policy being considered and promoted in four different states, comes in the form of laws known as “right to try” laws. Basically, “right to try” laws grant terminally ill patients the right to have access to experimental therapies. According to these laws, the drugs need only have passed phase I trials. Now, remember, phase I trials do not demonstrate efficacy. They are only designed to test for safety and toxicity, determine the maximum tolerated dose, and provide an estimate for the dose to use in real clinical trials. The concept of “right to try” bills is highly popular, because if you don’t know a lot about medicine and how clinical trials work it sounds like a good idea What could be the possible harm, after all? A lot, it turns out, but I’ll get to that in a moment. First, let’s take a look at the rationale for Arizona’s “right to try” law, which is being promoted by the Goldwater Institute:
Arizona legislators are poised to green-light legislation in committee Thursday that would pave the way for terminally ill patients to access experimental drugs not yet cleared for market. Known as the “Right to Try” Act, similar bills are currently being considered by lawmakers in Colorado, Louisiana and Missouri, and legislators in California and Massachusetts have expressed interest.
Designed by the Goldwater Institute, the Right to Try Act would enable terminally ill patients who have exhausted all of their available treatment options to access experimental drugs that have been deemed safe but whose efficacy has yet to be determined. Under the current system, even after an investigational drug has passed the Food and Drug Administration’s Phase I (the testing phase during which safety is established), it can take an additional six or more years for the drug to be approved for market–even if clinical trials are yielding promising results.
And while many patients facing terminal illness attempt to get into those clinical trials, the vast majority cannot, because they are too far along in their illnesses or because of other factors. 40% of cancer patients pursue admission into clinical trials, but only 3% succeed. Last year, more than 500,000 Americans died from cancer alone.
According to Christina Corieri, a health care policy analyst at the Goldwater Institute, the tragedy is that many of the drugs terminal patients can’t access today will be saving the lives of future patients just a few years from now.
“The sickest Americans don’t have the luxury of time to wait for these drugs to come to market through the traditional process,” said Corieri. “The Right to Try Act puts the decision about whether to try an experimental treatment back where it belongs: in the hands of patients and their doctors.”
This is, of course, partially true. There is always an inherent conflict between wanting to push for faster approval of drugs in order to treat patients who are dying and the need for rigorous testing to assure safety. Patients and their families ask, “What’s the harm?” while advocates like Corieri sell their policy with the assumption that experimental drugs are highly likely to help these patients, or at least not so unlikely as not to be worth trying. Here’s the problem. Just because a drug has passed phase I trials does not mean that it is effective. It does, however, frequently mean that the drugs have significant side effects. Indeed, determining those adverse events is part of the entire reason that we do clinical trials in the first place.
The Arizona law is the template for laws that are metastasizing to other states, such as Colorado; so I’ll look at it. The text of the law is available online. The major provisions of the law include a definition of the eligible patients that includes:
1. “ELIGIBLE PATIENT” MEANS A PERSON WHO MEETS ALL OF THE FOLLOWING:
(a) HAS A TERMINAL ILLNESS.
(b) HAS CONSIDERED ALL OTHER TREATMENT OPTIONS CURRENTLY APPROVED BY THE UNITED STATES FOOD AND DRUG ADMINISTRATION.
(c) HAS RECEIVED A PRESCRIPTION OR RECOMMENDATION FROM THE PERSON’S PHYSICIAN FOR AN INVESTIGATIONAL DRUG, BIOLOGICAL PRODUCT OR DEVICE.
(d) HAS GIVEN WRITTEN INFORMED CONSENT FOR THE USE OF THE INVESTIGATIONAL DRUG, BIOLOGICAL PRODUCT OR DEVICE OR, IF THE PATIENT IS A MINOR OR LACKS THE MENTAL CAPACITY TO PROVIDE INFORMED CONSENT, A PARENT OR LEGAL GUARDIAN HAS GIVEN WRITTEN INFORMED CONSENT ON THE PATIENT’S BEHALF.
(e) HAS DOCUMENTATION FROM THE PERSON’S PHYSICIAN THAT THE PERSON HAS MET THE REQUIREMENTS OF THIS PARAGRAPH.
The bill defines an “investigational” drug as a drug that’s passed phase I trials but has not yet been FDA-approved. The law doesn’t require manufacturers of an investigational drug to make it available, but basically allows them to do so if they so choose. Worse, it doesn’t require that the manufacturer provide the drug for free, as it must to patients undergoing clinical trials in order to achieve FDA approval:
A. A MANUFACTURER OF AN INVESTIGATIONAL DRUG, BIOLOGICAL PRODUCT OR DEVICE MAY MAKE AVAILABLE THE MANUFACTURER’S INVESTIGATIONAL DRUG, BIOLOGICAL PRODUCT OR DEVICE TO ELIGIBLE PATIENTS PURSUANT TO THIS ARTICLE. THIS ARTICLE DOES NOT REQUIRE THAT A MANUFACTURER MAKE AVAILABLE AN INVESTIGATIONAL DRUG, BIOLOGICAL PRODUCT OR DEVICE TO AN ELIGIBLE PATIENT.
B. A MANUFACTURER MAY:
1. PROVIDE AN INVESTIGATIONAL DRUG, BIOLOGICAL PRODUCT OR DEVICE TO AN ELIGIBLE PATIENT WITHOUT RECEIVING COMPENSATION.
2. REQUIRE AN ELIGIBLE PATIENT TO PAY THE COSTS OF OR ASSOCIATED WITH THE MANUFACTURE OF THE INVESTIGATIONAL DRUG, BIOLOGICAL PRODUCT OR DEVICE.
C. THIS ARTICLE DOES NOT REQUIRE A HEALTH CARE INSURER TO PROVIDE COVERAGE FOR THE COST OF ANY INVESTIGATIONAL DRUG, BIOLOGICAL PRODUCT OR DEVICE. A HEALTH CARE INSURER MAY PROVIDE COVERAGE FOR AN INVESTIGATIONAL DRUG, BIOLOGICAL PRODUCT OR DEVICE.
And, to top it all off, the law prohibits the state medical board (or any other state regulatory board) from going after the license of any physician or health care practitioner who recommends and/or administers such investigational agents to patients while making any state official or employee who attempts to block access of an eligible investigational drug to an eligible terminally ill patient potentially guilty of a class 1 misdemeanor. If the bill passes both chambers in Arizona, it would next go to the voters in November. My guess is that if the bill makes it onto the ballot this fall, it will likely pass. I can picture the ads now. They’ll feature cute, terminally ill children and brave adults battling fatal diseases invoking their right to choose what goes into their body and begging voters to “give them a chance to live” and asking, “What’s the harm?” Against such images it will be hard for science-based medicine to prevail.
Currently, similar laws are wending their ways through the legislatures of multiple states, including Colorado (of course!), Missouri (where legislators recently listened to emotional testimony and the bill is sponsored by a legislator, Jim Neely, whose daughter suffers from stage IV colon cancer), and Louisiana, while states as disparate as Utah, Oklahoma, Massachusetts, and California are showing early interest in such laws. The draft laws under consideration are basically all based on the Goldwater Institute’s template (indeed, the Arizona law is almost verbatim the same), which is based on this policy report available on the Goldwater Institute’s website, deceptively entitled Everyone Deserves the Right to Try: Empowering the Terminally Ill to Take Control of their Treatment.
The report itself is loaded with emotionally charged language about the FDA and terminally ill patients and highly dubious statements. For example, it’s hard not to notice that every experimental drug is apparently “potentially life-saving,” at least the ones that made it through phase I trials. There’s so much loaded language, coupled with so many dubious assertions, that I can only hit the “high” points, such as they are. For instance, the Goldwater Institute bemoans the expansion of FDA authority in the 1960s by the Kefauver-Harris Amendments that required that the FDA not just to demonstrate safety but efficacy as well. This expansion of FDA power was in reaction to the thalidomide debacle, leading the Goldwater Institute to make the rather bizarre (OK, very bizarre) argument that because the issue with thalidomide was a safety problem, not an efficacy problem and because thalidomide was never approved in the US (mainly due to the FDA, let’s not forget), the expansion of FDA power in response to the thalidomide debacle was “unwarranted”?
Another highly dubious argument follows:
Phase I involves administering the investigational drug to a small group of 20 to 80 volunteers to test for toxicity and immediately observable side effects.30 The major emphasis of Phase I testing is safety. Over 60 percent of investigational drugs in Phase I testing are deemed safe enough to move on to Phase II.
Seriously? Phase I trials can be as few as 20 patients. 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, and even the Goldwater Institute inadvertently undermines its own argument. Note how the report says that over 60% of investigational drugs pass phase I testing and are determined to be “safe enough to move on to phase II.” That’s the standard: No unexpected major adverse events and a side effect profile that isn’t grossly more unsafe than the disease itself. Phase II and Phase III trials are needed to confirm safety. That’s why the premature diffusion of unapproved drugs has the potential to increase morbidity from adverse events and even hasten death. One example is amonifide for treating breast cancer. The drug made it through phase I trials, but serious life-threatening hematologic toxicity emerged during phase II trials.
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 III.
The Goldwater Institute also doesn’t like the current expanded access programs, not because it doesn’t like expanded access programs, obviously. (After all, what are “right to try” laws other than much more liberal expanded access programs?) No, what the Goldwater Institute doesn’t like is the current system because of all those nasty regulations. Under current law, the Food and Drug Administration Modernization Act (FDAMA) of 1997, single patient INDs (we’re discussed these before in the context of Stanislaw Burzynski patients), which are basically compassionate use exemptions, can only be granted if:
- The patient’s physician determines the patient has no comparable or satisfactory alternative therapy;
- the FDA determines there is sufficient evidence of safety and effectiveness to support the use of the investigational drug;
- the FDA determines that provision of the investigational drug will not interfere with the initiation, conduct, or completion of clinical investigations to support marketing approval; and
- the sponsor or clinical investigator submits information sufficient to satisfy the IND requirements.
- the sponsor of the investigational drug must also be willing to supply the drug to the patient.
If all of these conditions are met, then the treating physician or drug sponsor submits an IND application, a proposed treatment plan, and a commitment to obtain informed consent from the patient and permission from the Institutional Review Board (IRB). No one denies that the process could be more streamlined. The report lists some of the burdens of the IND process and bemoans the FDA’s veto power over single patient INDs. Here’s what’s particularly disturbing about what the Goldwater Institute advocates, though, is its attack on the FDA’s requirement for a full IRB review of single patient IND applications as being a bad thing that keeps patients from accessing drugs. The language sounds as though it could have been written by Stanislaw Burzynski himself. Particularly Orwellian is the part of the report that demands that legislators must “act to protect patients.” I don’t know about you, but I’m not sure how, basically, stripping all restrictions on letting patients have access to drugs that have passed only phase I trials “protects patients,” but then I’m not a libertarian.
The Goldwater Institute justifies its proposal through still more dubious assertions. For instance, the report starts out with patient anecdotes in which patients with terminal cancers exhausted all conventional therapies and then applied for experimental therapies, which they either couldn’t get or had to wait too long to get. In each case, the stories are told in such a way as to suggest that “if only” these patients had had access to experimental drugs sooner they might have survived. This is, of course, nonsense. All these patients had stage IV cancer. Barring the incredibly unlikely possibility that an experimental drug is a miracle cure for advanced cancer even better than Gleevec for chronic myelogenous leukemia or than what the quacks claim in Tijuana for their treatments, these unfortunate patients would have died anyway. True, if the drug were effective, they might have gotten a few more weeks or months, but they would have died. Using such stories is nothing more than tugging at the reader’s heartstrings. It is not a good scientific argument.
Actually, there isn’t a single good scientific argument in the entire report. There’s a survey of orthopedic surgeons cited in which a majority of them have said they thought that the slow FDA approval process had hurt patients. This is well nigh meaningless for a discussion like this one because (1) most orthopedic surgeons don’t take care of cancer patients (orthopedic oncology is a subspecialty, and, fortunately, orthopedic malignancies are rare) and (2) orthopedic surgeons are much bigger into medical devices than drugs. Moreover this survey is bundled in a table with other with results of other surveys that range from 1995 to 2007. Finally, the reference cited is from the Competitive Enterprise Institute, a free market “non-profit public policy organization dedicated to advancing the principles of limited government, free enterprise, and individual liberty.” I will admit that I’m a bit disappointed that between 68% and 73% of physicians would support a proposal to change FDA law so that unapproved drugs or medical devices could be made available to physicians as long as they carried a warning label about their unapproved status.
Wow. Talk about a boon to pharmaceutical companies! Why bother with those pesky and expensive phase II and phase III trials if you could market your drugs direct to doctors to use on patients after phase I trials instead?
Now, given how bad an idea this law is, here’s the funny thing: It almost certainly won’t do what it is designed to do. The reason is simple. It’s nothing but state laws, and the FDA controls drug approval. Arizona can say as much as it wants that patients can get any investigational drug they want, but it’s meaningless as long as the FDA says that you have to have a single-patient IND approved for patients to have access to an investigational agent outside the auspices of a clinical trial being undertaken to win approval for the drug, what the state says is meaningless. Because the FDA exercises a lot of its power through the federal government’s power to regulate interstate commerce, perhaps the only way I can imagine for a state to get around this would be if the pharmaceutical company is in the same state as the patient. If the company ships an investigational drug across state lines in violation of federal law, it’s screwed. Of course, even this might not be enough, because a lot of states have a “mini-FDA” act, which bans the use of drugs that haven’t been FDA-approved. Indeed, the only reason Stanislaw Burzynski managed to get away with administering antineoplastons to patients early in his career is because at the time Texas didn’t have a mini-FDA act, and Burzynski was very careful never to ship antineoplastons across state lines.
Even more pertinent, drug companies need their drugs to be FDA approved to recoup their investment in drug development and make a profit, because without FDA approval they can’t sell the drug. The Arizona “right to try” law requires that the “investigational drug” (1) have passed phase I trials and (2) still be in the clinical trial process. There’s only one reason for a drug to be still in clinical trials after phase I trials, and that’s because the drug company still wants FDA approval for its drug; i.e., that it hasn’t abandoned development. That means the investigational drug is still under FDA regulation. A single patient IND would still be required. Pharmaceutical companies providing drugs to patients in “right to try” states without proper INDs would be violating FDA regulations and would thus endanger their chances of ultimate FDA approval. In other words, these “right to try” laws are nothing but feel-good placebos. They have no real effect because reputable pharmaceutical companies will not cross the FDA by providing an investigational drug to patients without a proper IND. That means that they only companies that might take advantage of “right to try” laws would be disreputable companies like Stanislaw Burzynski’s institute. Like Burzynski, “right to try” laws offer nothing to cancer patients but false hope. In fact, I’m hard-pressed to think of anyone whom these laws would benefit other than Burzynski, which makes me wonder if his minions have anything to do with promoting them.
Worse, making essentially untested drugs more widely available, as these “right to try” laws propose to do will be far more likely to harm the individual patient than to help him. Advocates of these bills ask, “What’s the harm?” I’ll tell you: If there’s anything worse than dying of a terminal illness. It’s dying of a terminal illness and suffering unnecessary complications or pain for no benefit and having to pay for the medications causing the complications yourself. Remember, these laws allow the pharmaceutical companies to charge for their investigational medications. They don’t all necessarily require the company to provide the drug for free, as current law does in the case of single patient INDs. For example, as discussed before, the Arizona law doesn’t require drug companies to provide the investigational agent for free; the Colorado bill is being amended to have that requirement by its cosponsor Janak Joshi.
Worse, Dallas Buyers Club-style “right to try” laws risk undermining our entire clinical trial enterprise, which is a major part of the scientific basis for evidence-based medicine. After all, if early stage experimental drugs were made widely available outside of clinical trials and taken for a wide variety of cancers, the signal-to-noise ratio would become very low. It would become very difficult to tell which drugs were working and for which cancers (and which were not), particularly since it would be reasonable to expect that such a policy would result in enrollments in clinical trials plummeting. And what would be the potential payoff for the shredding of patient protections proposed in these bills, even if the FDA didn’t put the kibosh on widely providing experimental drugs early in clinical testing (and, make no mistake, only having passed a phase I trial is early in clinical testing)? Very little at best, if even any at all. In reality, the likelihood of saving the lives of even a handful cancer patients by giving them access to early-stage investigational agents is quite low and hard to justify on a moral and practical basis, given the high likelihood of potential harm or premature death to so many other patients through the damage or destruction of a system that has been built up at such cost over several decades.
The entire justification for “right to try” laws also seems to rest 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. However, 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. There’d 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 (if there ever will be). Dallas Buyers Club-style “right to try” bills rest on a fantasy, and it’s a fantasy of false hope. Indeed, these bills serve an ideological purpose rooted in libertarian politics far more than they serve patients. It’s not coincidental that virtually the only sign of opposition to the Missouri “right to try” bill was from lobbyists representing the hospice community, who warned lawmakers that such legislation raises false hopes for patients when further treatment is likely futile.
These bills seem new, but they’re just the latest wrinkle on an old story. We’ve been down this road before. For example, the Abigail Alliance has been lobbying for similar “right to try” laws for a decade now. Libertarians love these bad ideas because, you know, the market cures all. So does the press because of the human interest stories coupled with the “little guy” battling the FDA. Even though expanded access programs could definitely use some tweaking, never forget that the reason the laws we have exist is to protect the public against drugs that don’t work or are too toxic and, just as importantly, from companies that would sell such drugs with no evidence of efficacy or safety and from “investigators” like Stanislaw Burzynski.
And Dallas Buyers Club is just a movie, nothing more. It might be a really great movie (given its Oscar nominations and McConaughey’s winning Best Actor, it almost certainly is), but it’s a terrible model for health policy and highly unlikely to help patients with terminal diseases.
ADDENDUM: Jann Bellamy has written about “right to try” laws from a legal perspective.