This article is based on a commentary in the American Journal of Bioethics.
With the roll out of Obamacare we should pause to appreciate not only the lethal inefficiency of bureaucratic control of such a complicated system as health care, but how unethical and even brutal it can be when people’s lives are determined by the whims of ideologically-charged committees of experts. And there is no more tragic example than that of the regulatory system for approving new and lifesaving medicines. Indeed in terms of bioethics and basic morality this is the Tuskegee syphilis experiment of our time.
There is a continuous stream of cases reported in the media of desperate people trying to access medicines which have demonstrated promise. Yet organizations such as the National Coalition for Cancer Survivorship (NCCS) actively campaign to stop such people accessing the only hope they have to stay alive, all under the false premise that “properly conducted” trials need to be performed. The basic, inescapable form of this argument is that ‘this panel has decided that you have been chosen to be sacrificed so that others can (maybe) live.’ Many brave Senators and Congressmen and women have risked scorn from the established academic-scientific complex for daring to challenge Big Academe’s slavish, pompous, unsophisticated and pseudo-religious-like adherence to ‘evidence-based medicine.’ We should applaud these law-makers, because they actually support a far more convincing and sophisticated understanding of the issue than the NCCS and their ilk.
Over the years, Courts have rejected attempts to frame access to lifesaving medicines as a constitutional right, most notably in the case of the Abigail Alliance. Regardless of whether one agrees with the judicial reasoning of the Courts, a new push needs to be made, based on the lack of benefit of the clinical trial ritual. Courts have generally considered a balance of interests rather than an absolute rejection of constitutional protections of access to life-saving medicines, but as evidence-based medicine is increasingly coming under scrutiny, courts need to update their balancing equation.
Constitutional protections aside, it is essential to develop a more moral, ethical, and efficient system for approving all new potentially lifesaving medicines: a system, I argue, based on free-market principles in which all clinical and preclinical information is evaluated at each step by patients, physicians, researchers, regulators, and third-party-payers.
Who should benefit from new drugs and how this benefit is distributed across different current and future patients is intimately involved with one of the main arguments against a more free-floating approach to drug regulation, as summarized in an analysis of the landmark Abigail Alliance case: “Expanded access may reduce clinical trial enrollment, which in turn will slow the completion of the clinical trials needed for approval. If potential subjects had the choice to either enroll in a clinical trial with a placebo control and a 50 percent chance of obtaining treatment or enter an expanded access program knowing that they would receive access to the unapproved therapy, few would choose to enroll in clinical trials”
As reported in the Lancet, the argument that “Allowing access to treatments outside the clinical trial setting slows the general availability of some drugs by as much as a year by reducing the number of people in trials … When possible, people would choose the route that ensures they will receive the therapy being tested instead of risking the chance they will be assigned to the placebo arm of a trial” was supported by groups such as the National Coalition for Cancer Survivorship when opposing more liberal access to new medicines in the Abigail Alliance case.
The circular nature of this argument can be understood by reference to a classic scene from the cartoon “South Park.” The character Stan’s suitability to join a group of extreme animal liberationists was determined by the otherwise random reaction of a goat. In other words, if you establish a system based on superstitious nonsense, then in order to comply you have to undergo the ritual. In this regard, innocent people are being sacrificed because the likes of NCCP have been indoctrinated to worship the FDA’s goat.
Smith and Pell’s landmark 2003 critique of evidence-based medicine in the British Journal of Medicine (when they satirically demonstrated the lack of appropriate evidence for the efficacy of parachutes) is particularly relevant to this argument. They pondered, whether “we continue our quest for the holy grail of exclusively evidence based interventions and preclude parachute use outside the context of a properly conducted trial. The dependency we have created in our population may make recruitment of the unenlightened masses to such a trial difficult. If so, we feel assured that those who advocate evidence based medicine and criticize use of interventions that lack an evidence base will not hesitate to demonstrate their commitment by volunteering for a double blind, randomized, placebo controlled, crossover trial.”
As a community we have willfully ignored the obvious about people’s reluctance to enroll in a study and risk being allocated to the placebo arm. All the innumerable market signals of efficacy and side effects from all the preclinical and clinical studies would, at each and every stage, be part of the entire mix as individuals, physicians, researchers, institutions, regulators, and funders make optimal decisions around the margin. Any deviation from the margin would be rapidly corrected. This method of market signaling is established in economics.
Indeed, the lack of participants who would be willing to chance being randomized to a placebo arm is a significant signal. This may prompt regulatory approval for limited use prior to exhaustive randomized controlled trials (RCTs). Future patients would then weigh the lack of an exhaustive RCT against the drugs’ efficacy and side effects in what are termed pre-Phase III trials. The system would be self-correcting. If there was clinical uptake of a newly approved treatment that subsequently proved to be disappointing, this would create market signals to patients and clinicians. This new information would make patients less confident and potentially amenable to an RCT.
While pretest probability is a clinical and statistical axiom, it is flagrantly ignored by regulators. In this regard there is a potential for an enormous generational disequilibrium to exist between patients. For example, there may be a new cancer drug or vaccine with incredible promise in different phases of testing. Current patients may have an inordinate desire for the drug. But they may be sacrificed in order for exhaustive RCTs to be performed so that future patients may receive only a relatively small degree of extra surety that the drug is effective.
Without a comprehensive RCT (and ironically even with such an RCT) it is possible that after widespread use the new drug might be found to be not so effective. Prospectively, the likelihood of this would be dependent on the pretest probability determined with all information at hand. And yes, in this instance, future patients may be inconvenienced. However, why insist that the lives of current patients be sacrificed for the (often false) comfort of future patients to have marginally more information regarding their treatment? Why not turn it around and say, sorry, but future patients will have to accept some degree less certainty in their treatments for the benefit of current patients. Some may argue that the sacrifice of a few now will benefit large numbers in the future. Only a free-market approach will see an overall minimization of those competing interests as the system forms an equilibrium. Remember that even if a new drug is “proven” to be effective, when background treatments change and alternatives arise, the new drug might not be more effective in the new context. At each and every stage clinicians and patients weigh up all the updated knowledge.
Furthermore, the risk-benefit calculation of any intervention is dependent on the circumstances of the individual not just the profile of a new drug per se. And this also involves willingness to be part of a controlled trial. If you are 80 and have had a good life and an intervention is likely to extend life by only a few years, or you are unconvinced by the efficacy, you may willingly enroll in a trial. If you are young and desperate for five extra years you may want to access the unproven drug. It is conceded that this would select out skeptical patients to RCTs and thus bias the results. But life is complicated and the knowledge of that bias would be weighed when reviewing the results of the trial.
As a society, why do we actively intervene against the voluntary donation of potentially lifesaving medicines to autonomous, informed patients who desperately want them? What we are saying is this; sorry, you have been selected to die for the greater good and future benefit of others. The form of this argument must be openly discussed; if accepted, it would be breathtaking in its expansive scope. And for what? A system of trial-driven regulation of medicine that is hopelessly unsophisticated, almost ritualistic, lacking any acknowledgment of the complexity of weighing evidence that occurs across all other disciplines, which treats the pretest probability of the effectiveness of all drugs the same, doesn’t even pass the laugh test (as exemplified by Smith and Pell) and allows disequilibriums of demand and supply that would not be tolerated in any other social context.
If nothing else, this issue gives a stark reminder of the superiority of the market as a means of protecting the individual. On this issue, the market wins hands down over the liberal regulatory state in the morality stakes.