From: Bruce Quinn <bruce@brucequinn.com>
Subject: Harvard's Jerry Avorn Advice for NCD Reform. Foley Hoag's Paul Kim Responds.
Below, I clip a new Washington Post op ed by Harvard's Jerry Avorn, arguing for major NCD process reform.
Below that, I clip a response by a former colleague (recently left Foley Hoag LLP) Paul T Kim.
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https://www.washingtonpost.com/opinions/2023/06/15/fda-conditional-approval-alzheimers-drug-leqembi/
New Alzheimer’s drug is a problem for FDA’s pass-fail approach
By Jerry Avorn
Jerry Avorn is a professor of medicine at Harvard Medical School and co-director of the Program on Regulation, Therapeutics and Law (PORTAL) at Brigham and Women’s Hospital in Boston.
The Food and Drug Administration is slated to soon give full approval to Leqembi, a new medicine for Alzheimer’s disease that offers only modest benefit, could pose worrisome risks and stands to cost the nation $2 billion to $5 billion per year. But the agency has an all-or-nothing problem. Even when evaluating a drug that’s minimally effective or could carry considerable risks, the FDA’s decision nearly always comes down to accept or reject.
Under this pass-fail system, a drug that the FDA disapproves remains mostly unavailable, except to subjects in research studies, while one that is approved can generally be prescribed to anyone. Certain risks may be described in the official product labeling, which few physicians read, or in educational risk management programs that are not designed to measure a drug’s effectiveness. But the decision is almost always a binary one that is ill-suited to the way science works — and to the needs of patients.
The Leqembi decision illustrates the problem. In clinical trials, the drug did not improve patients’ memory, but it slightly reduced their rate of cognitive decline — a small change that might be welcome to some patients but unnoticeable to many others and their families.
Yet the drug didn’t do nothing clinically, and that makes it nearly impossible for the FDA to disapprove.
The treatment requires ongoing intravenous infusions every two weeks, it can cause cerebral swelling and bleeding, and it will be priced at $26,500 a year, not including physician charges. This raises the question: How much minimal improvement in dementia is worth what level of patient burden and risk of complications?
Similar questions come up for other drugs to treat muscular dystrophy and ALS (amyotrophic lateral sclerosis). For these medicines, the FDA has granted “accelerated approval” based not on patients’ clinical improvement but merely on small changes in lab tests. After accelerated approval, drugmakers are asked to do follow-up studies to prove that their drugs actually help patients. But the government may allow many years to complete such studies, and they are often started late or done poorly, my research group has found.
The FDA faces enormous pressure from patients and their families — and from drug companies — to grant full approval to these drugs with thin credentials, and many others like them, including cancer treatments. But what happens if the medicines don’t fulfill their promise, or their side effects turn out to be worse than expected? It has proved difficult to get such products out of circulation. In 2011, a medication meant to prevent premature birth, Makena, was approved on an accelerated basis, but then was never clearly shown to work. Getting it off the market took until this past April.
Medicine has been dealing with tough benefit-risk trade-offs for well over a century.
The FDA’s simple all-or-none decision framework is a poor fit for this evolving scientific reality. The agency should instead create a new status for some drugs that is neither full approval nor outright rejection — a conditional approval that would allow a new drug with ambiguous credentials to be used only in a limited way until better evidence is collected. This would let doctors and patients learn how well it works in typical use outside of trials.
Then, in two or three years, the FDA could evaluate a richer portfolio of evidence to decide whether to make the drug available to all patients without restrictions. This would save tens of millions of dollars wasted on ineffective or unnecessarily risky drugs — and thousands of preventable adverse events.
The Medicare program has said it will create registries to track Leqembi use and outcomes. But it will not require that any untreated comparison patients be enrolled in these registries, rendering this approach nearly useless in measuring whether the slight reduction in decline that was seen in the drug’s single clinical trial is borne out in typical use.
A more nuanced approach to final approval could also influence the price of a new medicine, though cost is not the FDA’s direct responsibility. The Medicare and Medicaid programs are usually required to buy most FDA-approved drugs at whatever price the manufacturer sets, regardless of any questions about their relative value, efficacy or safety.
At an industry conference in Boston this month, FDA Commissioner Robert M. Califf admitted that companies that receive accelerated approval for their drugs often fail to complete the needed follow-up studies promptly to fully define their actual benefits and risks. He suggested that it might make sense for the prices of such drugs to be set lower until their true worth is better established.
Medical science is not an all-or-none, once-and-for-all endeavor: Knowledge evolves as evidence and experience accumulate, and that’s wonderful. But the FDA’s all-no or all-yes framework doesn’t fit the way our understanding of prescription drugs develops. For some drugs, the agency needs to become nonbinary to better reflect this reality.
PAUL T KIM ON LINKED IN
Jerry Avorn is an insightful scholar, but stumbles in this #washingtonpost op-ed on the pending #FDA review of Leqembi to treat Alzheimer’s disease.
Avorn wants to fundamentally alter FDA's "pass-fail" review of new drugs because it "is ill-suited to the way science works — and to the needs of patients," and that "FDA’s simple all-or-none decision framework is a poor fit for ... evolving scientific reality."
His solution? "The agency should instead create a new status for some drugs that is neither full approval nor outright rejection — a conditional approval that would allow a new drug with ambiguous credentials to be used only in a limited way until better evidence is collected."
This is a deceptively risky idea, one that—
• ignores how "conditional approval" would create unprecedented confusion -- changing a global "gold standard" into a "green? No, more like yellow?" standard;
• doesn’t recognize the enormous risks that off-label prescribing would swamp the "conditionally" in "conditionally approved" drugs - and that manufacturers would exploit the new pathway to market as a shortcut to a drug’s sale for more lucrative but unproven uses; and
• is highly dependent on labeling that Avorn says "few physicians read" (!) to ensure conditionally-approved drugs are "used only in a limited way".
Most surprising, Avorn never acknowledges the enormous flexibility FDA exercises regularly - and sometimes creatively - under current law to dictate the specifics - indeed, the minutiae - of approved uses, labeling, and other conditions for new drugs.
That creativity is why, using current authorities, FDA reviews drugs with astonishing efficiency - deciding on the latest, most novel and challenging medicines in six months or less! - and why the most important new drugs are approved here in the US before the rest of the world. "Conditional approval" promises little to improve that record, and may instead threaten to complicate regulatory pathways to market and patient access to new treatments.
Finally, I find it strange that Avorn dismisses the power of #CMS, private payers, and PBMs to control or restrict coverage, reimbursement and prescribing of new drugs. Rather than have Congress undertake risky major surgery to FDA’s statutory authorities, we should instead be scrutinizing how these entities play their own roles, fulfill their responsibilities, and exercise their contractual or statutory authorities to manage prescription drug utilization. PBM reform, anybody?
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