The U.S. House Energy & Commerce Committee held a hearing this week on the so-called “Right to Try” legislation, and the discussion made clear three things in the debate over whether to allow patients broader access to unapproved therapies: first, Americans’ distrust of experts extends to the very regulatory agency that is charged with ensuring that we are helped, and not harmed, by food and medicines; second, a plausibly good idea can be ruined by overreach and a dysfunctional legislative process; and third, even on technical health policy issues our current political environment leads us to often react reflexively and emotionally, rather than thoughtfully.
After Vietnam, Watergate, Iraq, assorted FBI/CIA/NSA abuses of domestic civil liberties and near daily examples of mere incompetence, the question deserves to be asked: do Americans still believe that their government is capable of doing anything right?
Many say no. And this sentiment may be why a libertarian think tank known as the Goldwater Institute has been able to leverage broad principles of patient autonomy to drive passage in 37 states and the United States Senate of an ill defined proposal that will allow sick patients unfettered access to medicines not yet shown to work. This initiative is threatening to return us to the standard prevailing prior to enactment of the 1962 Kefauver amendments to the Food, Drug & Cosmetic Act that required manufacturers to show effectiveness.
But is this a problem only for the patient in question, or is there a broader impact on public health? It’s superficially tempting to regard this as the noble enablement of deathly sick patients and their caregivers, but by loosening the standards under which drugs will be made available in our society, we reduce the incentives for companies to conduct rigorous, adequately powered studies that meet or exceed predetermined clinical endpoints. We also will reduce the incentives for patients to agree to participate in the very same trials. When that reaches a critical point, we will begin to lose the promise of new medicines that actually do what they are intended to do.
The FDA may not always make the “correct” decision in balancing the risks and rewards of new therapies, but surely we can agree to rely on good science as a predicate to drug approval? By allowing significantly broader access to unapproved drugs, we risk weakening our approval mechanisms and increasing the costs of healthcare.
One interesting example of the problems that result from abandoning efficacy requirements concerns the Eli Lilly drug solanezumab in development to treat Alzheimer’s Disease. As reported in the New England Journal of Medicine on May 4, on the basis of early clinical studies the drug appeared to help those suffering from mild dementia but a definitive Phase 3 trial required by the FDA showed that it did not work. The authors make the case against loosening agency approval standards in an effort to speed medicines to market, but consider the millions in Medicare reimbursement dollars that would have been wasted for an apparently ineffective treatment; the very same concerns over prescribing on the basis of limited data are raised in the context of Right to Try.
Even leading cancer care advocates are squeamish about loosening the current expanded access standards without adding safeguards. Dr. Ellen Sigel, Chair of the Friends of Cancer Research, recalled that her late sister, who had exhausted all treatment options at the time, decided to try an experimental bone marrow transplant procedure; tragically, this resulted in her swift death and studies later concluded that the procedure was less efficacious and more risky than previously thought. Sigel believes more needs to be done to ensure that the proper incentives exist to spur innovation, but criticized the draft legislation as it would make worse existing problems in transparency and patient informed consent.
There is an impression fostered by the nature of faceless bureaucracies that the FDA’s current policies and practices are insensitive to the desperation of terminally ill patients and their families for a chance to extend their lives when approved therapies have proven to be fruitless. But this too, is unfair. In fact, at the Subcommittee hearing John Dicken, Director of Healthcare with the Government Accountability Office (GAO), cited a July 2017 GAO report that found the FDA approved 99 percent of the almost 5,800 compassionate use requests made between 2012 and 2015.
FDA Commissioner Dr. Scott Gottlieb noted that new industry guidance has streamlined the process so that all applications are reviewed by the agency within 24 hours, and going forward a single member of an institutional review board (IRB) may respond favorably to the prescribing physician’s request to secure early access. Gottlieb emphasized that about 10% of all requests are modified by the FDA to address concerns related to patient safety that may be known to agency doctors and scientists but not to the public. It is worth mentioning that only about 30% of drugs accessed through compassionate use are approved by the FDA.
So why do we need a Federal Right to Try law? Proponents contend that the state laws are limited in impact, and even with the FDA’s improved expanded access program procedures, the process remains cumbersome such that many who suffer from “life threatening diseases” die needlessly. Admittedly, that is a lot of folks. In fact, if you include only those Americans suffering from the top three diseases (e.g., diabetes, heart disease, cancer) that may be “life threatening”, you have about 60 million people. This would seem to allow virtually anyone suffering from a severe, chronic illness early access to unapproved drugs.
While acknowledging that President Trump generally supports broader access to unapproved therapies, Gottlieb proposed that the House modify the Senate version in several critical respects. The suggested amendments include defining the eligible population more narrowly to include only those who are fighting “terminal” diseases and are at a stage of disease progression in which there is a reasonable likelihood that death will occur within a matter of months, and allowing the FDA to enforce its existing rules that prohibit false or misleading advertising and promotional claims.
House E&C Committee Chair Greg Walden then took it upon himself to let Commissioner Gottlieb know that, while his ideas may have merit, any House amendments to the version passed by the Senate in August would kill the proposal as a modified bill would not likely be taken up by the Senate.
Interestingly, the pharmaceutical industry has not been terribly engaged on this issue. It may be that they have other, more threatening policy issues to address, such as pricing. But it also may be that the industry is underestimating the capacity for mischief that could be caused by this bill in the years to come. Consider that this will up the ante for companies with drugs in development to allow for accelerated and expanded release long before adequate data has been obtained; intense pressure can build around promising therapies, often on small research stage firms without the funds and staff to manage patient relations. If things go badly for the patient, only certain claims will be excluded under the draft legislation and state product liability laws could lead to judgments against companies. Further, the FDA will have limited ability to bring enforcement actions in light of Congressional intent to support broadened access.
There is an international aspect to this issue as well. Since 1990, the United States and other developed countries have recognized that drug development is a global endeavor, and that science must be preeminent in decision making. The guidelines adopted by the International Council for Harmonisation of Technical Requirements of Pharmaceuticals (ICH) are predicated on scientifically sound standards of quality, safety AND efficacy. The widespread use of unapproved drugs contemplated by Right to Try will effectively neuter efficacy requirements, and undermine the position of the United States as the world’s leading biopharmaceutical innovator nation.
You cannot listen to ALS advocate and Air Force Lt. Commander Matthew Bellina, who testified in support of the legislation, and not be moved by his circumstances. “Often times the greater good is to put the trial over the rights of the individuals. This however is not a one-size-fits-all situation. The processes for all trials and drugs are unique and must be treated that way,” he said. But if every situation is regarded as unique, we will have abandoned the very scientific process that is designed to sort thousands of individual circumstances into measurable, predictable outcomes.
Similarly, we need to balance the unfettered exercise of individual freedom against the potential consequences for the larger patient community. A well intentioned, but poorly written, bill can make us all feel good for a time, and yet harm or even kill those who dare to sample unapproved early stage compounds. At the same time, we may unintentionally undermine the prospect of subsequent access by millions to a drug that actually has been subjected to rigorous testing. It’s not a wise trade off.
In the end, this can be seen as yet another example of our predilection in the Trump era to place instincts and sloppy thinking ahead of science and real world data. Andrew Sullivan’s provocative essay on American tribalism in New York magazine contains an apt quote from George Orwell in making the case that policymakers increasingly are inclined to embrace feelings and eschew sound logical argument: Even if one does not deny that the crime has happened, even if one knows that it is exactly the same crime as one has condemned in some other case … still one cannot feel that it is wrong.