The U.S. now offers 43 different pathways for patients with serious or life-threatening diseases or conditions who want to try drugs under investigation, but not yet approved, by the FDA. This comprises one federal and 41 separate state “right to try” (RTT) laws, all passed in the last few years, as well as the FDA’s long-standing expanded access (EA) program. Unfortunately, instead of actually improving patient access, as promised, the addition of state and federal RTT laws has created a confusing, and sometimes contradictory, patchwork, introducing new legal issues for patients, physicians, and drug manufacturers.
(The FDA’s EA program works with the sponsor of an Investigational New Drug [IND] Application, which is not necessarily a drug manufacturer, but, for ease of reference, we’ll use the term “drug manufacturer” or “drug company” in this post.)
It was not always this way. Prior to the passage of the first “right to try” law in Colorado in 2014, access to investigational drugs, that is, drugs currently making their way through the FDA approval process but not yet on the market, was available (unless the patient was enrolled in a clinical trial) only through the FDA’s expanded access (sometimes called “compassionate use”) program, first established in the 1970s. Under EA, the FDA oversees the process of granting patient access to investigational drugs, although the final decision rests with the drug manufacturer. According to a recent statement from FDA Commissioner Dr. Robert Gottlieb, in the last five years, the FDA has authorized more than 9,000 applications for drugs, biologics and medical devices (the latter two are also available via EA), approximately 99% of all requests.
That is not to say the expanded access program is without its problems. Patients and physicians complained of lack of information, burdensome paperwork, and delays. Drug companies were worried about whether adverse events from use of investigational drugs they provided would be used against them in the drug approval process.
In response to these complaints, as well as a 2017 GAO report, the FDA stepped up its efforts to make expanded access more user friendly. The FDA issued guidance on EA to the drug industry in 2016 (updated in 2017). The agency also commissioned an independent report, the results of which were released in November of last year, that made further recommendations for improvement. Dr. Gottlieb has vowed to implement these as well. They include reducing the time physicians spend on paperwork to an estimated 45 minutes, more information on the FDA website, and expedited Institutional Review Board (IRB) consideration of EA requests.
Although the independent report found significant progress in reducing delays and satisfaction among stakeholders (patients, physicians, drug manufacturers) with the process, by that point the “right to try” train had already left the station. State “right to try” laws were specifically intended to remove FDA oversight of a patient’s request for and, if the request is granted by the drug manufacturer, receipt of, investigational drugs. Actually, “right to try” is a misnomer: Like the FDA’s EA program, all these laws guarantee is a “right to ask” a drug manufacturer for access to an investigational drug, a request the manufacturer is under no obligation to grant. This may be why the FDA uses the more modest term “expanded access” instead of the false promise implied in “right to try.”
As noted, 41 states have “right to try” laws with similar, though varying, requirements. In May of last year, Congress passed, and President Trump signed, a federal “right to try” law with provisions comparable to that of the states’ laws. An article in Health Affairs summed up the differences between the new federal law and the existing FDA EA program.
There are notable differences between the two pathways. RTT applies only to investigational drugs; EA includes all types of medical products. RTT requires drugs to have completed a Phase 1 (dosage-setting) trial, while EA can permit access to products in any stage of development. RTT provides liability protection to companies and everyone else involved in therapeutic attempt; EA does not. The biggest difference concerns oversight: in EA, the treating physician, drug company, FDA, and IRB work together to ensure that only patients who have no other treatment options receive access; that costs are appropriate; that informed consent is legally and ethically sound; and that the proposed treatment plan offers a favorable risk/benefit profile for the patient. Under RTT, only the treating physician and the drug company — neither of whom is a neutral party — provide oversight. In the best case, the physician and company can together plan an ethical protocol that offers the highest chance of benefit and the least risk to the patient. In the worst case, an unscrupulous physician and company can work together to sell useless, possibly risky, treatments to patients.
SBM’s managing editor and resident cancer expert, Dr. David Gorski, and our good friend Orac have blogged about the problems of “right to try” laws, and I have contributed a couple of posts myself. (You can find a list of SBM “right to try” posts here.) I’ll not repeat the many concerns both we and others, including physicians, ethicists and drug companies, have raised about these laws. Rather, this post will explore how a libertarian desire to cut the government out of the process may have backfired, driving patients, physicians, and especially drug manufacturers, back into the arms of the very agency they sought to eliminate: the FDA.
The “right-to-try” movement was fueled by the Goldwater Institute and the Koch brothers (at the suggestion of the CAM-friendly Cancer Treatment Centers of America) who were looking for a stick with which to poke the FDA in the eye and apparently not overly concerned with how the process would play out in actual practice. This is not to deny the sincere wishes of patients and their families for a reprieve from serious illness, their genuine frustration with the FDA, or their good faith in wanting to expedite access. Unfortunately, however, the Goldwater Institute’s prepackaged draft of a “right to try” bill is the one that got introduced in state legislatures, thereby providing a template that aligned more with their libertarian goals than a practical solution to the problem (or, more correctly, non-problem, as the FDA’s EA program already existed.)
Into this breach of forethought, the law of unintended consequences happily stepped. In their attempt to grease the wheels of access to investigational drugs, RTT has instead introduced new complications for all involved, ones that will potentially require years of litigation to resolve and most certainly have already given lawyers expert in the field of drug regulation scores of billable hours.
First, unlike the FDA’s regulations and guidance governing the EA process, there is no regulatory infrastructure spelling out just how patients and physicians should go about accessing investigational drugs or how drug companies should respond. Normally, an agency under whose jurisdiction a particular matter falls would flesh out new legislation impacting the agency’s remit with informal guidance and formal regulations. Basic stuff like forms, established procedures, eligibility guidelines, explanation of terms left undefined in the law (like “informed consent”) and phone numbers to call if you need help are usually within the purview of the regulatory agencies.
It looked as if the FDA was setting about fulfilling its traditional regulatory role when Dr. Gottlieb announced last year that the FDA might need to draft guidance and regulations to implement the new federal RTT law. This drew a swift rebuke from Sen. Ron Johnson (R-Wis.), the principal sponsor of the law, who told the FDA to butt out of the process. This, in turn, prompted another FDA official to tell those inquiring about RTT to go ask the drug manufacturer if they have questions about eligibility.
That advice has now been memorialized on the FDA’s website, which devotes one page to RTT:
If you are interested in Right to Try, you should discuss this pathway with your licensed physician. Companies who develop and make drugs and biologics, also known as sponsors, can provide information about whether their drug/biologic is considered an eligible investigational drug under Right to Try and if they are able to provide the drug/biologic under the Right to Try Act.
In other words, good luck with that!
Disturbingly, this also means that it is not at all clear who will go after the bad actors when things go south for patients who choose the RTT route.
In any event, this is not a role drug companies, who worked to maintain the FDA’s oversight when Congress was debating RTT, particularly relish. As Dr. Robert Cardiff, former FDA Commissioner and now at Duke Health, pointed out,
For the traditional pharma and biotech companies, the last thing they want is chaos. The requirements for good evidence protect them from charlatans . . .
Ironically, this desire to avoid uncertainty about the RTT process has led some companies to direct persons who inquire about access via the RTT law right back to the FDA’s EA program.
Another snafu is that the RTT laws, in supposedly streamlining access to investigational drugs, added liability protections for drug companies as a deal-sweetener. They also removed “obstacles” like patient protections, such as IRB oversight. What proponents failed to consider, however, is that drug companies can, and do, add their own liability protections contractually when access is sought via the FDA’s EA program. In other words, liability protection may not be the big attraction for drug companies RTT fans thought it might be. Likewise, one law firm is suggesting drug companies consider adding their own IRB requirement, or some other form of institutional review process, contractually before granting access via RTT, even though RTT doesn’t require it. What RTT laws were supposed to take away in the interest of speed, the drug companies may simply add back in on their own via contract.
Finally, and this is a big one:
the tremendous uncertainty surrounding the governing law when federal “right to try” overlays a state “right to try” statute.
To figure this out, drug companies are going to have to (or, actually their lawyers are going to have to) take a deep dive into the Supremacy Clause of the U.S. Constitution because, with 41 state and one federal RTT law on the books, it is not at all clear which provisions of which law apply in any given situation. This is such a big issue one law firm is suggesting that, even the with touted advantages of RTT over EA for manufacturers – less government oversight, protection from liability, and limits on the use of adverse events in determining drug approval – this complexity may tip the scales favor of using EA.
I’ll try to keep this as simple as possible. The Supremacy Clause makes federal law “the Supreme Law of the Land”. Where state law stands in obstacle to federal law, federal law prevails. This is why everyone, including me, thought the state RTT laws would not survive a court challenge, because they are in direct conflict with the FDA’s exclusive jurisdiction over new drug approval. Drug companies could just ignore the state RTT laws because of their obvious conflict with federal law.
The new federal RTT law, however, has thrown a monkey wrench into the system. The federal law does not specifically preempt the state RTT laws, so the question becomes whether a particular state’s law and the new federal RTT law conflict. If so, the federal law preempts state law and state requirements can be ignored. If not, and there are good arguments that, with at least some provisions (such as informed consent) this is the case, then the manufacturer must comply with both state and federal requirements. As a practical matter, in each state, a drug manufacturer is likely to encounter both provisions that conflict and those that do not, thereby having to meet all federal requirements as well as some state mandates, but not others.
Mind you, there are no certainties in the drug manufacturer’s choices of which provisions to comply with and which it can ignore, leaving itself open to a court challenge to its decisions. Or, the company could decide to seek a declaratory judgment and leave it up to a court to make the choices on its behalf. Either way, it is an added, and considerable, expense a manufacturer would not face with the FDA’s EA program.
Thus, as these lawyers point out,
The ironic result for those who advocated “right to try” as a means of simplifying and expediting access may be that stakeholders operating under the federal “right to try” framework may now have to navigate two layers of regulations – one federal and the other state — with the latter consisting of a national patchwork of state-by-state variations.
I’ll add another complexity to this conundrum: Suppose the patient lives in State A and plans to ingest the drug she hopes to access via RTT there; her physician, who will dispense the drug, is just across the state line in State B; the drug manufacturer is in State C. Which state’s RTT law applies? That’s a decision the patient, physician, and drug company have to make even before getting into the preemption question.
Why bother with all of this when a manufacturer can simply choose, as a matter of policy, not to consider RTT requests, directing patients instead to the already familiar FDA expanded access program?
So, congratulations Goldwater Institute and the Messrs. Koch. Your effort to undermine the FDA looks like it backfired because drug manufacturers (at least the ethical ones) simply don’t want to deal with many problems raised by “right to try” and prefer the FDA after all.
Note: I will be on a trip and happily out of internet range when this post goes up. I’ll try to answer any questions or concerns raised in the comments when I return next week.