Accelerated Approval Pathway: What Gives?

Oncologist Chadi Nabhan offers a look under the hood at the FDA's accelerated approval pathway.

It is my pleasure to introduce this piece by my friend Dr. Chadi Nabhan.

Current FDA rules allow drugs for life threatening illnesses to come to market based on preliminary data that they might help. Companies then are tasked to prove that these hopes are reality with confirmatory studies. If negative, the drugs should come off the US market. This is called Accelerated approval.

The messy reality is that many drugs are pushed through this pathway even when there are many other treatments already on the market. When confirmatory trials are negative, the FDA often fails in its duty to pul the drugs. The net effect is that many products stay on the market for years, earning companies billions, without knowing in Americans benefit. Chadi talks about these tensions in a fascinating piece.

Vinay Prasad MD MPH

Accelerated Approval Pathway: What Gives?

By Chadi Nabhan, MD, MBA

Access to innovative cancer therapies is essential to improve the outcomes of the nearly 2 million cancer patients diagnosed each year.

The Food and Drug Administration (FDA) instituted the Accelerated Approval Program to allow earlier access to drugs that treat serious medical conditions including cancer.1

The approved drugs must fulfill an unmet medical need and could be approved based on surrogate endpoints, which are markers hypothesized to predict clinical benefit, but by themselves do not measure such benefit.

Clinical trials include many surrogate endpoints, but the most commonly used ones in oncology are response rates (based on radiographic measurements) and progression-free survival (PFS). Trialists use surrogate endpoints to shorten the time required to receive the FDA approval, and therefore expedite access to life-saving therapies.

Once a drug is approved based on the Accelerated Pathway, manufacturers are required to conduct confirmatory studies, known as post-marketing trials. If the confirmatory trial shows conclusively that the drug provides a clinical benefit, then the FDA grants traditional regulatory approval of said drug. If the confirmatory trial fails to show a clinical benefit, the FDA could mandate, by law, removing the drug from the market. Such withdrawal, however, is not always imposed. It is happening more commonly now. The recent withdrawal of Blenrep for myeloma by GSK is an example.

But this lack of general enforcement can be problematic especially to patients receiving these therapies.

First, the design and timeline of confirmatory trials are agreed upon between the manufacturer and the FDA in advance. Confirmatory trials that fail their primary endpoints is a likely indication that the drug may not be effective, especially since these confirmatory trials were designed to show the implied benefit.

In a perspective written by the FDA, the authors reviewed 10 approvals, whereby marketing authorization continued long after trial failure.2 The authors of this piece argued that failing confirmatory trials does not always imply the therapy has failed, and they argued that continued conversations with manufacturers might be needed to understand reasons for failure and to potentially find a subgroup of patients that might benefit.

Second, withdrawing drugs that fail in confirmatory studies protect patients from receiving ineffective or potentially harmful drugs. There is an inherent suggestion that confirmatory trials might illustrate the benefit demonstrated in earlier studies that were conducted to garner the approval via the accelerated pathway. This assumption presumes that potential harm to patients is minimal. But, if the confirmatory trial fails its endpoint and does not show benefit, the possible harm to patients cannot be ignored and can be substantial.

This harm can be in the form of physical adverse events and/or financial toxicity. Once a drug fails confirmatory trials, one cannot assume conclusively that the benefit/harm balance favors patients, and the absence of any benefit, patients might only be harmed when receiving a drug with severe adverse events.

Third, drugs approved via the accelerated pathway generate substantial revenue until confirmatory trials are complete. The FDA can grant manufacturers years to conduct and complete post-marketing trials, during which period manufacturers generate substantial revenue from sales of these drugs. There are no financial penalties imposed on manufacturers once their drugs fail confirmatory trials, and in fact in many circumstances, sales of these drugs can continue if not withdrawn voluntarily or by FDA mandates.

As an example, pembrolizumab was granted accelerated approval by the FDA for small cell lung cancer in June 2019, but that was withdrawn on 3/2/2021. In 2020, total revenue from global sales for all indications exceeded $14 billion (based on publicly available information and regulatory filings). While no exact information is available on total revenue for sales from the withdrawn indication, we can safely assume, it wasn’t negligible.

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There are ways to refine the Accelerated Pathway to assure that patients remain in the center of these approvals and that decisions are made with patients’ well-being and benefit as the core principle.

If a manufacturer acknowledges that it does not have confirmation that its compound is effective based on an FDA-mandated confirmatory study, this acknowledgement could be mirrored by some form of a price discount. As healthcare costs soar and as cancer care represents the lion share of these costs, one can envision a system whereby a company prices its drug at a substantially discounted price until confirmatory data are available.

If the confirmatory trial is positive and patients’ benefit is assured, the drug would then revert to 100% of the price on the market. The percent discounts can be negotiated based upon an agreed-criteria between the FDA and the manufacturer. This discounted price is fair because the accelerated pathway does not assume the compound will gain full approval. It assumes that there are limitations to the original study — perhaps the study used a questionable surrogate endpoints or studied the drug in a limited patient population. So, it’s only fair to the patients, payers, health care system and society at large to acknowledge this limitation by virtue of lower cost to the system.

Another plausible scenario would allow manufacturers to price their drugs as they see fit, which is the current system, but to demand a refund (percent of sales of said drug for the approved indication) if the drug is found ineffective and the confirmatory trial fails. The percent refund can be negotiated.

Conclusion:

The accelerated pathway is essential for patients and innovation if its original rules are followed properly. When the accelerated pathway is followed based on the rules it was enacted upon, patients stand to benefit.

The FDA has occasionally failed to enforce its own rules, specifically that a drug be pulled from the market if a manufacturer does not fulfill the confirmatory component of the trial.3

Allowing these drugs to remain on the market indefinitely is akin to dangling hope for vulnerable patients, and these decisions should be revisited.

@chainabhan

References

1.     https://www.fda.gov/drugs/information-health-care-professionals-drugs/accelerated-approval-program accessed 12/7/2021

2.     Beaver JA and Pazdur R. “Dangling” accelerated approvals in oncology. NEJM; 2021, May 6; 384 (18); e68.

3.     Zettler M and Nabhan C. Fulfillment of post-marketing requirements to the FDA for therapies granted oncology indications between 2011 and 2016. JAMA Oncol; 2018; 4(7): 993-994

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