Ethics and the Limits of the Randomized Controlled Trial: Time to Enhance Access to Novel Therapies in Lethal Diseases?

Parts of this blog are drawn from ‘Improving access to medicines: empowering patients in the quest to improve treatment for rare lethal diseases’, a forthcoming paper  in the Journal of Medical Ethics

Jenn McNary witnesses the miracles that modern medicine can produce every day when she sees her son Max, once increasingly reliant on a wheelchair due to his Duchenne muscular dystrophy, now able to walk, run and jump, the progression of his deadly disease apparently halted due to his enrolment in a clinical trial of a new drug, Eteplirsen.

Tragically, she also witnesses the suffering of her son Austin, who has the same genetic condition, denied the drug as his disease progresses and left no longer able to leave his wheelchair unaided. Like most with Duchenne muscular dystrophy, he is expected to die in his early twenties.

Eteplirsen works by rewriting some of the genetic code that is linked to the disease. If Max’s improvement is repeated in other patients in the trial who are receiving the drug and not the placebo, it is likely that in a few years this treatment will be revolutionizing the prognosis for Duchenne sufferers and offering hope to many of the 1 in 3600 boys who are affected by the disease.

In the meantime, patients like Austin are denied treatment, on the grounds that the drugs have not been tested- in order to protect him from unknown side effects and complications, and to test its efficacy scientifically. Yet the alternative for Austin is continuing degenerative disease, and in a few years, death.

Les Halpin, founder of Access to Medicine, and himself a motor neuron disease sufferer has argued that for those with life threatening and rare illnesses, current drug approval procedures do not work. He argues in our forthcoming paper that “for such individuals, the “risk-return ratio” is different compared to patients with more benign conditions and drug regulations should be adapted to allow such people the opportunity to try out new combinations of drugs”. He has argued for greater use of new media to track patient progress, and cites the use of the website ‘Patients Like Me’ by MND patients to track their progress on lithium treatment.

In fact, unrestricted access to medicines may be technically no different to the current relaxed attitude to complementary therapies already used by a high percentage of patients. Nevertheless, there are of course significant challenges to creating a new research method that would be scientifically valid and avoid returning to unregulated , risky innovations that ultimately harm patients. Three physicians in this area suggest in our forthcoming paper in the Journal of Medical Ethics that one answer to the scientific challenges may be to create “data linkages which harness the power of the patient’s own observations to population based disease registries and hospital outcome data”. Given that for this group of patients, receiving a placebo and receiving the new drug may be a matter of life or death, there is a strong imperative to face these challenges head on.

No one would argue that randomized controlled trials should be replaced for all patients. They are the gold standard. However, the ethical landscape for patients facing an untreatable, lethal disease is very different from that of most patients. It is rational to take a small chance of survival when the alternative is certain death. Patients receiving a placebo in an RCT or denied access to a trial are in some cases foreseeably harmed. If a person like Les, or parents like Jenn decide, knowing all the available facts, that it is worth taking some unknown risk to try to improve, then provided they have the status quo (no treatment) as an option, the choice to take the unproven therapy is based on his assessment that the risks are worth the benefits. It is an example of gross hard paternalism to deny them this option. An offer is not coercive if the person has the status quo as an option. To choose to move from the status quo to accept the option on offer is to make a rational choice that it improves one’s lot. Not all drugs will produce benefits like those Max has apparently gained, but patients should be given the freedom to choose.

Knowledge is not the only or ultimate goal. Science should be sensitive to a variety of ethical considerations. Randomized clinical trials have been instrumental in identifying treatments that do more benefit than harm, in protecting patients and identifying cost-effective therapies. But today, science should be able to effectively evaluate the effects of novel interventions in rapidly fatal diseases without denying hope and a chance to people like Austin McNary.

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4 Responses to Ethics and the Limits of the Randomized Controlled Trial: Time to Enhance Access to Novel Therapies in Lethal Diseases?

  • Oli Rayner says:

    Very interesting. As a patient with a rare disease, I see a lot of problems/bottlenecks in the drug development process that result in patients going untreated when they could be treated. We leave a lot of therapeutic value on the table. The design of trials, regulatory processes and reimbursement issues all block access to good medicines and prevent Pharma developing in the first place. When you say patients are not being coerced if they have the status quo as an option, it gets to the heart of the matter. It also made me wonder whether we could in fact use those patients who do elect the status quo as the placebo group as part of clinical trials. We ought to be able to use technology in a smarter way to do remote monitoring of people in trials (active drug and placebo groups) and incorporate more “real world” data both to enrich trials, make it less disruptive to patients and enable much larger trials to be done. In cases of rare diseases where doing nothing may be doing arm, we may find using technology in this way delivers better quality trials, notwithstanding any loss of randomisation.

  • Oli Rayner says:

    Very interesting. As a patient with a rare disease, I see a lot of problems/bottlenecks in the drug development process that result in patients going untreated when they could be treated. We leave a lot of therapeutic value on the table. The design of trials, regulatory processes and reimbursement issues all block access to good medicines and prevent Pharma developing in the first place. When you say patients are not being coerced if they have the status quo as an option, it gets to the heart of the matter. It also made me wonder whether we could in fact use those patients who do elect the status quo as the placebo group as part of clinical trials. We ought to be able to use technology in a smarter way to do remote monitoring of people in trials (active drug and placebo groups) and incorporate more “real world” data both to enrich trials, make it less disruptive to patients and enable much larger trials to be done. In cases of rare diseases where doing nothing may be doing harm, we may find using technology in this way delivers better quality trials, notwithstanding any loss of randomisation.

    • Julian Savulescu says:

      Thanks Oli and thanks for the tweet. I agree. We could find alternatives to randomized controlled trials if we wanted to. There are huge problems with bias but the RCT is not a panacea for all.

      Case controlled trials is another possibility. I am not an expert on scientific method but it seems to me that if we can split atoms or peer into other galaxies, we should be able to evaluate the effectiveness of new drugs in a variety of ways, not only in one way.

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