Right-to-try legislation: time for a new paradigm?

RECENT passage through the House of Representatives in the United States of right-to-try legislation, which provides a pathway for access to experimental treatments for patients with terminal diseases or conditions, should be thoroughly supported here in Australia, as it represents not only compassion but an enlightened understanding of the complexity of drug regulation.

Those who steadfastly defend the status quo of Australian drug regulation are defending a system so lacking in a sophisticated understanding of complex processes that it has been justly derided as the “magic moment” system. The magic moment is the point of approval of the drug: the moment between pre- and post-licensing, when the drug goes from being used only in a tightly controlled, narrowly defined trial population to being used more widely in less well controlled settings by heterogeneous patient populations with confounding factors.

Currently, it is very difficult for anyone to access an unapproved drug outside of a clinical trial (and they might not even get the drug in the clinical trial if they are randomly allocated to the placebo arm) no matter how much evidence has accumulated regarding safety and efficacy. Then comes the magic moment, many years and many lives down the road, when the drug is approved for certain indications.

For patients with uncommon yet lethal diseases, there exists a large unmet need for new therapies.

And yes, this is personal. A friend of mine was in dire straits with chronic lymphocytic leukaemia (CLL) and needed venetoclax.

The New England Journal of Medicine (NEJM) published a trial of venetoclax plus rituximab versus standard therapy in CLL. There was a breathtaking difference in outcomes: the 2-year rates of progression-free survival were 85% versus 36% favouring venetoclax. We can argue whether the power calculations, the interim analysis and stopping rules were appropriate and whether the non-responders in the conventional treatment arm should have been crossed over (which they weren’t). However, the vast disequilibrium speaks for itself. Was this a surprise result? Given the statistics, it’s difficult to make a case that the profound superiority was not expected. The authors’ reference results from the respective treatments obtained from previous studies (here and here).

Indeed, the lead author was also the lead author involved with a previously published (yet overlapping) study, in which it was concluded:

“Implications of all available evidence: venetoclax administration in combination with rituximab is a tolerable and active combination for difficult-to-treat patients with relapsed or refractory [CLL]. The data indicate that minimal residual disease-negative complete remissions are now readily achievable in patients with relapsed [CLL].”

The added evidentiary benefit of a phase 3 randomised controlled trial is ultimately dependent on the pre-test likelihood, derived from data from all phases and all real-world use. To steadfastly refuse to acknowledge this axiom is to logically affirm Smith and Pell’s landmark satire in the BMJ, whereby they proved that parachutes should only be used in clinical trials until their safety and efficacy could be proven in a placebo-controlled trial. The added evidence from a placebo-controlled trial of parachutes would of course be negligible, but according to magic moment purists, there could be confounding effects and parachutes might not be effective after all.

All drugs and all situations are different. An expensive drug for which pre-phase 3 testing shows a 1% improvement in one subscale of dementia is a completely separate beast to a drug that melts away “incurable” tumours in young people.

My friend had all the data about venetoclax, as did my friend’s treating doctors. With these data, would my friend have rationally chosen years of conventional therapy over the metaphorical parachute?

The tragedy of the current system is that time prior to the magic moment, it’s not that we know nothing about a risk–benefit profile.

Many dedicated academics and organisations are advocating for more sophisticated ways to prevent the disequilibrium and inefficiencies of the current magic moment system. For example, Europe’s ADAPTSMART and the Massachusetts Institute of Technology’s NEWDIGS are designing Medicines Adaptive Pathways to Patients (MAPPs) which “seek to foster access to beneficial treatments for the right patient groups at the earliest appropriate time in the product life span in a sustainable fashion”.

Right-to-try legislation represents another departure from the rigidity of the magic moment. Right-to-try legislation doesn’t give a patient a right to access therapies in earlier stages of development, but it prevents regulators from prohibiting access if a company, a dying patient and their treating doctor want to try a therapy that has shown significant promise.

Many doctors have opposed right-to-try legislation. Prominent among the opposition was a recent article published in the NEJM, which argued that:

• dying patients lacked sufficient autonomy and therefore needed paternalistic protection from, for example, predatory biopharmaceutical companies. However, the article gave no acknowledgement of the overwhelming ethical critique of this position. Even desperate patients can autonomously decide to take on risks if that risk assessment is overall positive (for a devastating academic critique, see Halpin and colleagues’ view); and
• right-to-try legislation would deplete the pool of patients willing to be recruited for regulatory-required randomised controlled trials, without any acknowledgment of what this placebo aversion signifies in relation to breakthrough drugs.

And this is where the mantra used to defend the current system is so tragically excruciating, that the current system is needed to ensure the safety and effectiveness of new drugs.

Saliently, the adoption of penicillin for the treatment of syphilis in the 1940s did not proceed along the lines of today’s magic moment system. Therefore, would it have been okay to allocate one arm of a study of syphilis to combination arsenic and mercury therapy (known to be ineffective treatments) until more definitive, methodologically rigorous phase 3 studies of penicillin in the treatment of syphilis were available? From an ethical perspective, therefore, sometimes the current system is not too far removed from the infamous Tuskegee syphilis study.

Sometimes satire is the best way to make a point. Watch this Youtube excerpt from Blackadder, substitute a magic moment proponent for General Melchett and you will understand perfectly the need for a new more sophisticated paradigm.

Associate Professor Michael Keane is a specialist anaesthetist and part-time visiting medical officer at Monash Health, with research positions at Swinburne University and Monash University.

 

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