Scrutiny of the FDA’s Accelerated Approval Processes Should Be a Wakeup Call; It’s Time for Employers to Advocate for Precision Medicine

Blake Long, Chief Medical Officer, and Hannah Mamuszka, Founder & CEO, Alva10

Over the last few months, the Food and Drug Administration’s accelerated approval of oncology drugs has come under increased scrutiny. Introduced in response to the HIV epidemic in 1992, accelerated approval is one of several regulatory pathways employed by the FDA to facilitate important advances in therapy. Now, criticism suggests that the FDA has compromised its regulatory role by allowing drugs approved through the accelerated approval process to remain on the market despite failing or not completing confirmatory trials to demonstrate clinical benefit. The FDA announced a meeting of the Oncologic Drugs Advisory Committee scheduled for April 27–29, 2021 to review the status of six indications (uses of a drug for treating a particular disease) granted accelerated approval. This follows recent withdrawal in four indications, all involving immune checkpoint inhibitors across several cancer types.

To put it simply, even by the FDA’s own standards, many drugs that are on the market today have so far failed to follow through with the clinical validation that would give an accurate sense of how effective and beneficial they truly are to patients with the diseases they are approved to treat.

The accelerated pathway allows the use of surrogate endpoints in trials on which approvals were based. These markers do not have a guaranteed relationship with real clinical outcomes and should be followed post-approval with confirmatory trials demonstrating true clinical benefits such as improved overall survival (OS) or quality of life. Of 93 oncology indications that received accelerated approvals over a 25-year period, a 2019 FDA analysis showed only 19 (20%) confirmed using a clinical benefit endpoint.[i] Yet, even though 80% did not confirm using a clinical endpoint, “since the inception of the accelerated approval program, only 6% of accelerated approvals for oncology indications have been withdrawn” [ii] — many occurring only recently.

In a recent study of 85 oncology indication approvals from 2006–2018 (53 of which were granted accelerated approval), 16% of the indications had response rates (cases where the cancerous tumor shrank in response to the drug) of less than 20%. The median complete response rate (tumor disappeared) was only 6%, and 74% had a complete response rate of less than 20%.[iii]

So, how do we do better? To diminish the criticism of the accelerated approval process, the FDA’s scheduled review this month should pursue a more meaningful use of biomarkers and companion diagnostics to identify and stratify patients — an approach that remains limited and is predominantly viewed as an optional guide today. Biomarkers assessed through diagnostic testing can be used to examine biological processes and gauge how one is likely to respond (or not respond) to a drug in order to develop targeted and highly effective treatment strategies. They hold the potential to enrich and strengthen clinical trials within the accelerated approval process to increase response rates; tighten the correlation between surrogate endpoints and clinical benefit; and improve the timeliness and power of confirmatory trials. This is not only true of cancer drugs, but also for treatments prescribed for infectious disease, autoimmune disease, cardiovascular disease, NASH, rare disease, and more.

But, despite this promise of biomarkers and the signs that a reckoning for the pharmaceutical industry may be looming, it offers little consolation for the patients that are affected today by a model in which patients (on average, more than 60%) are often prescribed a drug that won’t be effective for their condition — underscoring the need for a larger shift in our healthcare paradigm. Employers have an important role to play in flipping the traditional reimbursement model for patients that have suffered from being treated with the longstanding approach of “trial-and-error medicine” — a system in which the top 10 highest-grossing drugs in the U.S. today have an average efficacy rate of 36%.

Diagnostics are essential to:

• accurately diagnose and stage diseases;
• determine what drugs might be beneficial or what drugs could cause a severe adverse reaction;
• determine if a patient’s genetic profile makes them susceptible to certain diseases;
• and critically, determine if a patient is/isn’t going to respond to a particular drug or therapeutic intervention.

When diagnostics are applied correctly, this “Precision Medicine” can dramatically reduce healthcare costs and improve patient outcomes.

While health plans, carriers and insurance providers (payers) have historically been more apt to reimburse billions annually for drugs that may or may not work than to cover novel diagnostic testing that shifts age-old formulary practices, the overwhelming clinical and economic benefits of Precision Medicine require that employers advocate for diagnostics in order to optimize their own outcomes and pharmacy spending. Most insurance plans are not “one-size-fits-all;” 75% of employer-sponsored health plans are self-insured, which gives employers the power to customize offered benefits.

By advocating for coverage of diagnostics and working with health plans and carriers to incorporate the use of diagnostic tools that better determine which patients should/shouldn’t be on which therapies, employers can support better health outcomes for their employees; enable early diagnosis of diseases in more manageable stages; and reduce spending on ineffective therapies and unnecessary hospitalizations.

References

[i] Gyawali B, et al. Assessment of the clinical benefit of cancer drugs receiving accelerated approval. JAMA Intern Med. 2019;179(7):906–913.

[ii] FDA In Brief: FDA Oncologic Drugs Advisory Committee to review status of six indications granted accelerated approval https://www.fda.gov/news-events/fda-brief/fda-brief-fda-oncologic-drugs-advisory-committee-review-status-six-indications-granted-accelerated

[iii] Chen E, et al. An overview of cancer drugs approved by the US Food and Drug Administration based on the surrogate end point of response rate. JAMA Intern Med. 2019;179(7):915–921.