The War Against the Boys … and Accelerated Approval

Price controls are a blunt tool. Drug regulations are nuanced. ICER (the Institute for Clinical and Economic Review) is an insensitive instrument designed to advance payor priorities. The FDA is an organization whose mission is to prioritize patient needs. It’s a battle between patients and profits. This is the blunt dynamic driving the recent debate over innovative medical technologies reviewed through the FDA’s Accelerated Approval pathway.

According to the National Organization for Rare Diseases (NORD), accelerated approval “is a complicated and nuanced pathway with a long and important history, but accelerated approval does not alter US Food and Drug Administration’s (FDA) gold standard of substantial evidence of safety and effectiveness.”

Scientific debate is good. Slanted use of facts is not. Whether it’s misrepresentation of therapeutic outcomes data for cancer patients or cost-effectiveness analyses that ignore patient input, the fear and ferocity with which the anti-Accelerated Approval crowd is fighting the advance of 21^st century healthcare technologies only serve to underscore its venality and fealty to an outdated status quo. Per ICER’s founder Steven Pearson, rare disease therapies place an “undue burden … on others for the sake of a few.”

The most recent example of this battle for the heart and soul of medical and regulatory innovation is a drug to treat Duchenne muscular dystrophy (DMD), Elevidys. In May 2023 an FDA advisory committee voted (8-6) that the benefits of the treatment outweighed the risks. After this meeting Dr. Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research (CBER), said that his review team will take the recommendation and “do something that we have to do every day at FDA. … We have to manage through the uncertainty here.”  In June the agency approved Elevidys via the Accelerated Approval pathway.

The issue under debate now, is whether the agency should grant Elevidys full approval, expand its labeled indications, chose to maintain the status quo, or take the drug off the market. Battle lines are being drawn.

A recent JAMA commentary by ICER’s chief medical officer, Dr. David Rind, argues that, since Elevidys failed to meet its primary endpoint in two randomized trials, the cost of the treatment ($3.2 million), “is an enormous price tag …” But what he ignores is something the FDA cannot – the totality of evidence, particularly the acceptance of real-world evidence from Phase IV studies.

As Dr. Janet Woodcock (FDA’s recently retired Principal Deputy Commissioner) commented during an earlier debate over another treatment for DMD, “Failing to approve a drug that actually works in devastating diseases—these consequences are extreme.”  

As with many issues, where you stand often depends on where you sit. ICER, representing the voice of payors, argues that the juice (successful patient outcomes) isn’t worth the squeeze (the cost). Indeed, ICER claimed a medicine to reduce anemia-related chronic kidney disease wasn’t cost-effective “because more people will live longer, more people will be at risk of needing care for end-organ damage, increasing the cost of keeping people alive.”

The FDA’s job is a lot harder – to focus on the science and the perspectives of patients and their families. It’s important to note that the opinions of the patient community are not monolithic. Another crucial variable is the message this debate (and the forthcoming FDA decision) will have on the appetite for future investment in DMD research and development – and for the future of the FDA’s Accelerated Approval program.

Elevidys doesn’t represent a free pass for bad science. Several therapies that did not hit statistical benchmarks of benefit in randomized trials have become first in class treatments or part of a standard of care regimen because of actual clinical benefit. That includes Galafold for Fabry Disease and Danyelza for neuroblastoma. 

The FDA is rightly supplementing its scrupulous review process with 21^st century regulatory science, appropriate compassion, and respect for patients. By balancing the need for speed, accuracy and improved public health, the agency has taken the next step toward a 21st century, entrepreneurial regulatory system and positioned itself as an innovation accelerator.

CBER director Marks and his dedicated product review staff face the same set of daunting challenges that accelerated approval provoked nearly 50 years ago when the FDA granted full approval to the first HIV drug (AZT) -- even as it missed it statistical endpoint. 

Elyvidis is part of a new generation of therapies that will generate proven benefits but often yield inconclusive clinical trial results. It is gene therapy with a controversial surrogate endpoint (microdystrophin levels), a patient community that wants hope but insists on data transparency, and outside pressure driven by cost-containment and the denizens of regulatory conventionality. 

The FDA mustn’t allow itself to be bullied by payors, politicians, pundits, or ill-informed academics. Most importantly, the FDA mustn’t be inappropriately restrained by the shackles of the status quo.

In the prescient words of Laurence Peters, “Bureaucracy defends the status quo long past the time when the quo has lost its status.”