There is nothing like a touching anecdote to spur a politician into action. And those who want to try investigational drugs outside the FDA’s clinical trial process have touching anecdotes in spades. If I, or a loved one, had a terminal cancer, I’d probably be right there with them, telling my story and hoping to get my hands on an investigational drug, no matter how slim the chance for improvement it offered. But a less emotion-driven analysis of so-called “Right to Try” bills currently before several state legislatures reveals some sobering truths about the false promises behind these bills, promises which in some cases appear to be driven more by political ideology than genuine concern for patients.
“Right to Try” bills are pending before four state legislatures: Colorado, Louisiana, Arizona and Missouri. We’ll get to the details of these in a bit. Legislators in other states have expressed an interest in filing similar bills. On February 26th, a Missouri legislative committee “heard emotional debate from supporters of a bill that would allow makers of investigational drugs, biological products or devices to make them available to eligible terminal patients.” Among those testifying were the parents of a young girl with a brain tumor and the father, a physician, of a patient with metastatic colon cancer. These stories are hard to hear and make it hard to say no.
The Right to Try bill has been christened with another catchy name (Warning! Link to credulous media report!) – the Dallas Buyer’s Club bill after the terrific movie which just won Matthew McConaughey and Jared Leto Academy Awards for best actor and best supporting actor, and deservedly so. It depicts a macho, homophobic, HIV-infected cowboy (McConaughey) who saves the day battling the evil, bureaucratic FDA and the medical establishment. He skirts the law to bring life-saving drugs to AIDS patients at a time when AIDS was pretty much a death sentence. The plot even includes a delicensed American doctor who supplies the unapproved drugs from his Mexican clinic. And dietary supplements, of course. (You’d be tempted to suspect Stanislaw Burzynski, Hulda Clark and a naturopath co-authored the script.) But no matter its merits as a movie, it is just that, a movie. It is based on a true story but its interpretation of events has been called into question. (Orac also deconstructs the factual inaccuracies on Respectful Insolence today.) Nevertheless, it is a public relations boon to the Right to Try promoters, although, considering their decidedly right-leaning political inclinations, there has to be a certain amount of squeamishness in associating their cause with a movie featuring raunchy, sexually-explicit scenes, lots and lots of cussing, and a colorfully dressed trans-gender person (Leto) as its most sympathetic character.
Attempts to liberalize FDA’s expanded access
The genesis of these bills can be traced to another young cancer victim, 21-year-old Abigail Burroughs, who died of the disease in 2001. Abigail herself led a lobbying and media campaign to urge greater access to investigational drugs after one was recommended by her oncologist. After her death, her father formed the Abigail Alliance for Better Access to Developmental Drugs because they considered the FDA’s expanded access policy insufficient.
To help us better understand what the Alliance wanted, here’s a brief explanation from the FDA of how the extremely complicated process for a new drug approval works:
The first step for a company seeking approval to sell a new drug is to perform laboratory and animal tests to learn how the drug works and if it will be safe enough to be tested in humans. The company submits an Investigational New Drug Application (IND) for FDA’s review prior to testing in humans. The company performs a series of clinical trials in humans in three phases, which FDA monitors, to test if the drug is effective and safe. Next, the company sends its data from all these tests to FDA’s Center for Drug Evaluation and Research (CDER) in a New Drug Application (NDA). A team of CDER physicians, statisticians, toxicologists, pharmacologists, chemists and other scientists review the data and proposed labeling. If this review establishes that a drug’s benefits outweigh its known risks for its proposed use, the drug is approved for sale.
(New biologics and medical devices are regulated by the FDA in a somewhat different manner, but from now on we are going to focus on drugs because that appears to be the main target of the Alliance and other advocacy groups.)
In 2003, the Abigail Alliance and the Washington Legal Foundation filed a Citizen’s Petition with the FDA requesting that the Agency amend its IND regulations “to grant Initial Approval for promising drugs, biologics, and devices intended to treat life-threatening diseases with unmet needs,” and to seek “regulatory changes to permit expanded availability of developmental lifesaving drugs following phase 1 clinical trials and at all subsequent stages of the trial and review process.”
A Phase I Clinical Trial, which typically involves only a few patients, is designed to assess toxicity and dosing but does not establish either the safety or efficacy of a drug. While the trial may incidentally show some evidence of efficacy, that initial evidence is not always borne out in later phases. As our good friend Orac explained:
Phase I clinical trials represent the very first time a promising new substance is ever given to humans. The intent is not really therapeutic. Rather, it is to gather toxicity data and to determine the optimal dose. Basically, what is done is something called a dose escalation, where increasing doses are tried until toxicity is observed. The usual patients enrolled in these trials when done for cancer drugs have advanced disease that is incurable with present modalities. One reason for this is that in many cases it would be unethical to try such drugs out in patients who could expect to have a chance at long-term survival using conventional treatments, and that healthy volunteers would be unlikely to be willing to undergo the risk of toxicity from these very powerful drugs. Another reason is that sometimes we can see anti-tumor activity even in a phase I trial. However, it is not expected that antitumor activity will be observed, and not observing activity would not preclude moving on to a larger, randomized Phase II trial, in which the drug is tested against specific tumors.
The FDA denied the Petition and the Alliance sued the FDA in federal court claiming that terminally ill patients had a constitutional right to access as-yet-unapproved drugs. The U.S. District Court disagreed and the Alliance lost the case, but that decision was overturned by the U.S. Court of Appeals for the District of Columbia Circuit. A three-judge panel of the Court held that where there are no other FDA-approved treatment options, a terminally ill patient has a constitutionally-protected “fundamental right” to access investigational drugs This decision became the subject of some debate among legal scholars, especially on the right end of the political spectrum. They were torn between their distaste for federal regulation they regard as limiting personal freedoms and their distaste for courts finding constitutional rights not specifically enumerated in the Constitution itself, which is exactly what the Court of Appeals had done.
The FDA then requested a rehearing en banc, that is, before the full Court of Appeals. Here, the FDA was joined in seeking a reversal of the decision by several medical organizations, including the American Society of Clinical Oncologists. The Court’s en banc decision was 8-2 against the Alliance, a decisive victory for the FDA. The Alliance filed a petition for certiorari asking the U.S. Supreme Court to hear the case but the Supreme Court denied the petition. That does not mean the Supreme Court might not decide the issue in a future case, but for now the Court of Appeals decision stands.
Meanwhile, over in the U.S. Congress, Sen. Sam Brownback introduced Alliance-supported legislation allowing expanded access to investigational drugs not already available under the FDA’s rules, but it didn’t go anywhere. (It contained some disturbing provisions gutting placebo controls in clinical trials.) Later, Rep. Diane Watson introduced the Compassionate Access Act of 2010, but the bill never made it past the House Subcommittee on Health.
There are a number of good reasons to disagree with the position taken by the Alliance in its suit against the FDA and the two bills it supported, and we will get to some of the reasons to oppose expanded access in a minute. But before we move on to the Right to Try bills, I want to note the extent of access to investigational drugs at issue up to this point. The first Court of Appeals decision held that where there are no other treatment options, terminally ill patients have a fundamental right to access investigational drugs. And both Congressional bills retained some FDA oversight of the expanded access process.
A more radical approach
Enter the Goldwater Institute, an extremely conservative think tank which, beyond lambasting the Affordable Care Act, doesn’t seem to have any real interest in healthcare policy. The Institute is named for, and was founded “with the blessing of,” the late U.S. Sen. (and unsuccessful presidential candidate) Barry Goldwater. The Institute’s model statute, on which the current state “Right to Try” bills are based, doesn’t just liberalize FDA requirements for access to investigational drugs. It completely removes FDA from the picture. The model statute conveniently comes complete with pre-packaged legislative findings so a legislature doesn’t have to bother with making an independent determination of the wisdom of the Right to Try bill.
Here are the main provisions, with a few comments (more of those later):
- The drug must have successfully completed Phase I clinical trials and still be involved in the clinical trial process. As we know, Phase I is designed to assess toxicity and dosing but not safety or effectiveness. And any evidence of either safety or effectiveness which appears at this point may not hold up in later phases of the process.
- To access the drug, the patient must have a “terminal illness,” defined broadly as “an advanced stage of a disease with an unfavorable prognosis and no known cure.”
- The patient, in consultation with “a physician” (no matter the physician’s lack of expertise in treating cancer or other terminal illnesses, or, for that matter, never having a previous relationship with the patient at all) has “considered” (not tried, “considered”) all other FDA-approved treatment options. There is no mention of how the drug is to be administered, how the dose is to be calibrated, or what follow-up must be provided.
- The patient has a prescription “or recommendation” for the drug and has given informed consent (or it has been given for him if he is a minor or mentally incapacitated).
- All of the above must be documented by the physician. Just “documented;” no medical rationale for the decision needed.
- The drug’s manufacturer can, but is not required to, make the drug available (although it can do so without an actual prescription) and can choose whether or not to charge the patient. “Drug manufacturer” is not defined; clinical trials do not necessarily involve a “manufacturer.”
- Insurance companies can, but don’t have to, cover the cost of the drug itself. Other costs of treatment with the drug are not addressed.
- The state medical board is prohibited from taking action against the physician “solely based on a medical professional’s recommendation, prescription or treatment with a the investigational drug.” “Solely based on” is not further defined.
- Any “official, employee, or agent of the State” who blocks access, or even attempts to block access, is guilty of a class-one misdemeanor punishable by up to 6 months in jail and a $2,500 fine.
In other words, extremely powerful drugs with no evidence of safety or efficacy would be removed from FDA jurisdiction once the cursory requirements of this legislation have been met. Disciplinary action against a physician would be thwarted, and perhaps denied altogether, possibly even in cases where the physician fell far below the standard of care. Yet physicians and manufacturers would remain subject to liability for injuries even if they comply with the act. No matter how devastating the effects of an unapproved drug might be, or how reasonable their actions might be, any state employee or official who takes action to block access could wind up in jail for 6 months and paying a $2,500 fine.
What could possibly go wrong? A lot, that’s what. Physicians with less-than-pristine intent could set up practices specializing in filling out the paperwork necessary for patient access. And what if, after careful evaluation, an ethical, competent physician has to refuse a patient’s desperate pleas to facilitate access? Patients could be deterred from participating in clinical trials, lured by the false “get-well-quick” promises of an unapproved and costly drug. And patients in the last months of their lives could be diverted from palliative care and a meaningful opportunity to spend time with loved ones by an experimental drug with terrible side effects that, in fact, kills rather than cures them. One could even envision a scenario where a patient who pushes aside other options in favor of an investigational drug ends up thereby disqualifying himself from a later clinical trial offering a real hope of improvement. What if child welfare authorities try to intervene in favor of a terminally ill child who is about to be treated with a horribly inappropriate drug? Will they go to jail?
The proposed statutory language is based on a Goldwater Institute “Policy Report,” with the superficially appealing title, “Everyone Deserves the Right to Try: Empowering the Terminally Ill to Take Control of Their Treatment.” It contains a number of dubious claims about expanded access, among them:
- Expansion of FDA authority in the 1960′s to require that a drug demonstrate efficacy was “drastic” and “unwarranted.”
- Polls purportedly showing medical specialists think the drug process is too slow, a broad assertion that says nothing about whether they would halt all FDA supervision for particular patients once a drug passed Phase I trials.
- “The major emphasis of Phase I testing is safety” and drugs that have passed Phase I have “passed basic safety testing.” This is a half-truth that could leave the uninformed with the impression that the FDA has decided at this early stage that a drug is actually safe.
- The report speaks of patients “battling an immediate life-threatening illness” who “lack other treatment options.” Yet neither of these situations is required before their legislation would allow access to investigational drugs. The report also makes the hyperbolic claim that the FDA’s regulations “impair health” or “cause death.”
- Drugs that have cleared Phase I are continually referred to as “potentially life-saving,” an assertion partially refuted by their own statistics. They note that 30% of drugs make it from Phase Two (which tests efficacy) to Phase Three. And that is for any drug demonstrating efficacy for any purpose, not just those designed to treat terminal illnesses.
- The report claims that “risk to an individual patient outside the clinical trial is no greater than the risk the FDA is permitting patients inside the trial to take.” Likewise, the report claims that informed consent will be an adequate protection because it is the same informed consent used in the clinical trials. Hardly. Clinical trial participants are carefully chosen based on certain eligibility requirements, and are closely monitored. If at any time it becomes apparent that further testing (for a particular participant or for all of them) is inappropriate, the FDA can pull the plug. An Institutional Review Board must sign off on the informed consent. None of these safety measures apply to patients allowed access by this legislation. There’s not even a requirement that administration of the drug be supervised or that the patient be followed at all.
There are other insufficiencies in the “Policy Report,” but we’ll leave it at that. In fact, the whole idea is so poorly thought out and so ill-considered the science-based community is really piling it on this week, with SBM’s own cancer expert weighing in, as well as our pal Orac.
We’ve already touched on some of the legal complications-in-waiting that might appear if the Goldwater Institute’s bill is passed. Indeed, the enthusiasts backing Right to Try bills in their states have had to clean up some of the more obvious drafting oversights. All states tightened the definition of terminal illness. Arizona excludes primary care physicians from the definition of physician. Missouri excluded controlled substances and Colorado added some protection against liability for manufacturers.
Political theater at taxpayer expense
But I’ve saved the biggest legal complication for last. Right to Try laws, as proposed here, are either wholly unconstitutional or at least unconstitutional in the majority of possible applications. That is because the FDA has exclusive jurisdiction over the regulation of drugs via Congress’s constitutional authority to regulate interstate commerce and state laws that impinge on that exclusivity are pre-empted. Federal drug laws regulate not only the approval process for new drugs, but also the misbranding and adulteration of drugs, both of which could come into play with the provision of an unapproved drug to a patient. It might be possible to envision a scenario where a manufacturer could have an operation that is so devoid of any interstate commerce it would fall outside the FDA’s jurisdiction. That would be extremely difficult to do although, according to David Gorksi, that is exactly what Stanislaw Burzynski did early in his career, before he started the (never completed) FDA approval process.
But here’s another hurdle: the drug must have passed a Phase I Clinical trial and still be involved in the clinical trial process. Colorado specifies that this must be an FDA-approved clinical trial; the other versions do not. However, they strongly imply that we are talking about an FDA drug approval process here by reference to the drug’s not yet having received the agency’s approval. Once the FDA-drug approval process is underway, the manufacturer is by definition under FDA jurisdiction. (Is there even such a thing as a non-FDA drug-approval, clinical trial process?) The FDA is certain to take a dim view of a manufacturer with a drug still in clinical trials going off and distributing that same drug to patients outside the trial process.
Could the FDA expanded access program use some more expanding? Perhaps. Could the FDA drug approval process as a whole be improved? Most definitely, and the place to start is adequate funding by Congress. But all the Right to Try legislation does is engender false hopes that access to “potentially life-saving drugs” is just around the corner. Of course, the Goldwater Institute won’t be paying for the ensuing litigation over the constitutionality of state right to try laws. That burden will fall doubly on the taxpayers, as both state and federal resources will be consumed. But it can benefit nicely from the political theater that allows it to pose as a champion of state rights and individual freedom defending a bill it most certainly knows cannot survive constitutional scrutiny.