Accelerated drug approvals present a mounting challenge to oncologists and raises concerns about cost effectiveness for health system finance leaders

In the past year, Americans have witnessed two extremes of the FDA’s accelerated approval process, exposing both profound strengths and worrisome weaknesses.

On one hand, the rush to review and distribute COVID-19 vaccines has been a shining example of the program functioning as intended — to meet an unmet need with highly promising drugs. On the other hand, the controversial approval of Aduhelm for Alzheimer’s patients has exposed the many shortcomings in the system, as a case in which desperation for treatments seems to outweigh proof of efficacy.

This enormous discrepancy may come as a surprise to the public — and it might not be self-evident to health system leaders who are focused on promoting cost effectiveness of health. However,  many in the oncology community are all too aware of the implications of the situation. Some fast-tracked cancer drugs have been game changers, some have flopped, and many others have landed in between. The fact that a cancer drug is available on the market via accelerated approval does not necessarily mean it is more effective than established, less-costly therapies. And that is a reality that not only oncologists but also finance leaders should understand.

Clinicians and their health system partners should be clear-eyed about the FDA’s drug approval process and thoroughly evaluate new therapies and indications before adding them to drug formularies and treatment plans. This need is especially crucial in the field of oncology, where drug prices are consistently among the highest on the market and access to the right treatment can make the difference between life and death.

Health system finance leaders also should be part of this process. Although it clearly is not appropriate for them to dictate treatment options, finance leaders should be well informed about drug treatment options and their associated costs and efficacy, and the availability of lower-cost alternatives that have the same efficacy. With such knowledge, they can engage in meaningful conversations with clinicians about which options truly help their organizations, and the nation overall, achieve better cost effectiveness of health.

3 crucial criteria for evaluating accelerated approvals

When analyzing the costs and benefits of a drug with an accelerated approval timeline, payers and providers should focus on three key questions.

1 Does this drug satisfy a truly unmet need? Part of the criteria for accelerated approvals is satisfying an unmet need. Pembrolizumab (Keytruda), for example, was a game-changer for the treatment of melanoma, dramatically increasing life expectancy to the point where many in the cancer community dared to use the word cure.

However, many oncology drugs are granted accelerated approvals despite doing no better than a drug that is already on the market for the same indication. An example is Trilaciclib (Cosela), which used to decrease the incidence of low blood counts from chemotherapy when given with two drugs for small cell lung cancer. Cosela was not shown to decrease the incidence of fevers that occur with low blood counts or to prevent hospitalizations. In short, it did not demonstrate meaningful benefits to patients above and beyond that provided by drugs already on the market (such as myeloid growth factors).

Of new cancer therapeutics brought to market between 2002 and 2014, 74% had an overlapping mechanism of action with others that had already been approved or were still in clinical development. This begs the question: If one drug is already available via accelerated approval for a particular indication, is a second drug that serves the same purpose meeting an unmet need? And given the incomplete data available for these fast-tracked therapies, how can an oncologist make an informed decision about which one to use?

2 How strong are the surrogate endpoints? Patients are concerned about the bottom line: Will a new therapy help them live longer or better lives? Yet the answer typically is not available when accelerated approvals are granted. Instead, drugs get the green light based on improvement in surrogate endpoints, which are measures that point to a possible overall survival advantage.

Two commonly used surrogate endpoints are:

• Progression-free survival — how long a patient lives before the disease progresses
• Response rate — percentage of patients whose cancer shrinks or disappears

Although using such surrogate endpoints makes logical sense, they unfortunately do a poor job of predicting overall survival or improvements in quality of life.

For example, a review of 36 drugs approved on the basis of progression-free survival or response rate found that 18 failed to improve overall survival, 13 had unknown survival effects roughly 4.5 years after approval and only five were shown to improve survival. Even when survival is increased, the gains are frequently modest. Across 72 consecutive approvals for solid tumors in the U.S., median overall survival increased by only 2.1 months, on average. These findings suggest that, unless a new fast-tracked drug addresses a truly unmet need, it’s best to rely on therapies with proven benefits to survival or quality of life.

3 What was the quality of the trial?  Providers and payers also should keep in mind the interests of the entities conducting the trials upon which accelerated approvals are based: A pharmaceutical company’s primary goal is to get drugs approved and to market, which can influence the design and quality of the studies.

Given that so many accelerated approvals are based on Phase 1 and Phase 2 trials conducted by the manufacturer of the drug in question, health systems, health plans and clinicians should closely review the following details:

• Control arms: In many trials, a new drug is compared with an outdated or rarely used therapy that is less relevant rather than with current therapies physicians are actively using.
• Patient subgroups: Patients selected for a clinical trial often are not representative of the target patient population. They tend to be younger, wealthier and healthier than the individuals in the general population with the same disease. Some drugs work less effectively in older or minority populations, who may not have been included in the trial.
• Location: Standards of care vary from country to country. A clinical trial conducted outside of the U.S. may not be relevant to the way patients are treated here.

If the answers to these question raise valid concerns about the appropriateness of implementing the new drug, oncologists and health systems may have legitimate reasons for not adding it to their formularies and treatment plans.

The greater challenge posed by accelerated approvals

The sheer volume of drugs on the market — and for cancer treatment in particular — presents a significant challenge to clinicians and health systems: It is impossible for any individual to keep track of every new development, rigorously evaluate the quality of science behind each new therapy, subject that new therapy to cost/benefit analyses and develop the best possible treatment plan for each patient.

The intent here is not to disparage the FDA’s accelerated approval process. It can be a valuable tool for bringing groundbreaking new drugs to the patients who need them. However, on the flip side, particularly in the area of oncology, it also can muddy the waters for health systems working to deliver optimal treatment to patients as cost-effectively as possible. Moreover, there are few studies available that evaluate the comparative effectiveness of those accelerated options with meaningful endpoints (improved survival or quality of life).

The problem is that through its accelerated approvals process, the FDA is releasing too many oncology drugs that have dubious benefits and too few drugs that offer the clear advantages of the COVID-19 vaccines. Restoring the faith of physicians and patients in this process will require more rigorous clinical trials, more meaningful measures of efficacy and a focus on meeting truly unmet needs. Yet these changes also will be less likely to happen without the strong support and advocacy of health system leaders.

In the meantime, oncologists and healthcare financial managers should cast a more skeptical eye on new drugs emerging from the pipeline before deciding whether to include them in formularies and treatment plans.  

About the accelerated approvals process: Unanswered questions

The FDA introduced the accelerated approvals process in 1992 in response to the AIDS epidemic. Its objective is to bring drugs more quickly to market that “provide a meaningful advantage over available therapies” and that satisfy an unmet need. Along these lines, the FDA’s emergency authorization of COVID-19 vaccines enabled the U.S. to better protect large numbers of people from the risks of severe illness and death, as well as slow the spread of the novel coronavirus and its more contagious variants.

In the case of Aduhelm, the controversial drug that received FDA approval in June for treating Alzheimer’s patients, an advisory committee of independent experts recommended that the FDA not approve the drug. In clinical trials, the drug had not performed better than a placebo at delaying progression of Alzheimer’s.

Aduhelm was approved based on evidence that it reduces buildup of amyloid brain plaques, a marker of Alzheimer’s. Yet the hypothesis that these plaques cause the disease has been losing credence. The FDA even acknowledged a lack of evidence that the drug would benefit Alzheimer’s patients. But it was still granted an accelerated approval and is currently on the market for a price of $28,200 per year.

When the FDA approves a drug on an accelerated timeline, the manufacturer is required to conduct follow-up trials to “confirm the anticipated clinical benefit.” Yet these studies are not always completed, and to date the FDA has not strictly enforced the requirement. According to one 2017 analysis published in the New England Journal of Medicine, just 54% of the required follow-up studies were completed within five to six years after the commitment was made, and 20% were never even started.

The growing use of accelerated approvals has significant financial implications for health systems. Rather than giving pharmaceutical companies an incentive to complete follow-up trials by limiting the price points at which they can market fast-tracked drugs, the current regulatory framework allows drug makers to charge full price as soon as they hit the market, even though the drugs may not yet have been proven effective. As a result, providers and payers may be paying inflated prices for drugs that don’t actually improve patients’ survival or quality of life.