Raising the Bar: Rethinking the Accelerated Drug Approval Process

A Conversation With Bishal Gyawali, MD, PhD

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Our growing knowledge of the molecular and genomic drivers of cancer has translated into a robust pipeline of promising anticancer agents. However, bringing new drugs from the lab to the patient with cancer can be frustratingly slow. To that end, the accelerated approval system was created by the U.S. Food and Drug Administration (FDA) to allow expedited access to life-saving drugs and fulfill an unmet medical need. In theory, it balances early access to therapies and the need for robust evidence generation. However, despite its intentions, the accelerated approval process is not without flaw. 

To shed light on this and other related issues, The ASCO Post spoke with Bishal Gyawali, MD, PhD, Associate Professor in Medical Oncology and Public Health Sciences and scientist in the Division of Cancer Care and Epidemiology, at Queen’s University, Kingston, Canada.

Bishal Gyawali, MD, PhD

Bishal Gyawali, MD, PhD

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Please tell us a bit about your work and research interests.

Much of my inquiry and research centers on global oncology and the attending issues surrounding the delivery of cost-effective and equitable cancer care. I’m originally from Nepal, and I maintain affiliations with Nepalese institutions, where I serve as a visiting scientist and/or professor. As a medical oncologist, I see patients with gastrointestinal malignancies, genitourinary malignancies, and breast cancer. And my academic interests focus on international policy issues, including clinical trial designs and regulation of cancer drugs that affect how cancer services are delivered, in both high-income and low- to middle-income countries.

Surrogate Endpoints

You coauthored several pieces in the literature examining the use of surrogate endpoints in the FDA’s accelerated drug approval process. Please describe these research efforts and your findings.

First, it’s important to put this issue into context. Patients with cancer need timely access to drugs that meaningfully improve how they feel, function, or survive. However, measuring clinical endpoints such as improvement in overall survival can take time, and patients may be willing to tolerate uncertainty about such benefits in exchange for early access to promising cancer drugs, particularly for cancers that lack other treatment options. 

The FDA’s accelerated approval pathway covers this very important clinical situation in that it allows drugs to be approved early on the basis of improvement in surrogate outcomes that are reasonably likely to translate to clinical benefit. This approval is conditional, with a mandate that drugs are tested in a postapproval confirmatory trial to substantiate the presumed clinical benefit, in the absence of which approval will be withdrawn.

The most widely known example of this occurred with bevacizumab, which was granted accelerated approval for the treatment of metastatic breast cancer in 2007 based on improvements in progression-free survival in a randomized clinical trial. When subsequent confirmatory trials failed to demonstrate a benefit in overall survival but did demonstrate an increase in toxic effects, the FDA revoked approval for this indication in 2011.

It’s important to note that I’m a big supporter of the FDA’s commitment to bring cancer drugs to the clinic as rapidly as possible, given the history of very long lag periods between discovery and approval. To that end, I have collaborated with colleagues to look at how the accelerated approval system based on surrogate endpoints functions in real-world oncology outcomes. In theory, it’s an excellent pathway to expedite the drug approval process. However, what we found and published in multiple papers was that, in most cases, the postapproval confirmatory trials that are supposed to verify the drug’s efficacy are not done in a timely fashion—in fact, they often take several years before releasing their results. Moreover, when the mandated confirmatory trials were eventually conducted, they used surrogate endpoints such as progression-free-survival, which was simply a repetition of the original endpoint.

More concerning was the fact that even when confirmatory trials failed to show a benefit, we have seen instances where the FDA convenes an advisory committee to decide whether to rescind the drug’s indication. In many cases we looked at, the committee has voted to continue the drug’s market approval, despite the drug having failed the confirmatory trial. And in recent years, we have seen an uptick of cases in which the FDA gives full approval based on surrogate endpoints without having to undergo further evaluation in confirmatory trials.

Please describe a surrogate endpoint that is commonly used in this process.

Response rate is a commonly used surrogate endpoint, but it does not actually give an accurate prediction of outcome. For example, if you take a cohort of 100 patients with cancer and identify how many of those patients had their tumors reduced in size by 30% or more, you come up with the response rate. This is evaluated largely by a radiographic measurement, which in itself is not exact and does not directly correlate with overall survival or symptom relief. 

In other words, a surrogate endpoint does not measure the clinical benefit of primary interest in itself but rather is expected to predict that clinical benefit. Further, there are no hard-and-fast standards defining exactly what percentage of tumor shrinkage or how many trial participants are needed to define a positive response rate.

When the FDA gives full approval upfront based on a surrogate endpoint such as response rate, there are no other data available to determine exactly how a particular drug is performing in clinics across the country or, for that matter, on the international stage. By doing this, we inadvertently lower the bar for approval, which increases the number of drugs in our armamentarium, but it also allows too many drugs with uncertain benefit onto the market.

This lowering of standards for new drug approvals is not a new issue. In fact, in 2014, the ASCO Cancer Research Committee challenged researchers and patients to raise the bar on expectations from novel therapies to significantly advance cancer care. So, we need to continue to press forward and make substantive changes to the system.

Global Oncology

How does the accelerated approval process affect global oncology?

We have found that up to one-third of oncology drugs that received accelerated approval for which primary endpoints were never borne out on mandatory confirmatory trials still remain on the market. Because most of the world’s low- and middle-income countries do not have established regulatory agencies, they rely on the FDA to evaluate the effectiveness of new cancer drugs. And once a drug is approved by the FDA’s accelerated approval process, it can be marketed in low- and middle-income countries, even though the drug is under conditional approval back in the United States.

It’s important to note that many of these countries with challenged delivery systems rely on the U.S. oncology system for guidance. Oncologists in resource-challenged areas around the world want to keep up with their counterparts in the United States, which can lead to an increased use of expensive drugs that have not undergone confirmatory trials or that have been rescinded in the United States but can still be marketed in other countries. Although the FDA enforces voluntary withdrawals in the U.S. market, the same rule does not apply outside of the United States, so it is not surprising that industry does not voluntarily withdraw drug approvals from the global market. Patients in poorer countries around the world are already disadvantaged by their lack of access to effective cancer drugs, and they do not need to be further hindered by being offered cancer drugs that cost dearly but are so marginal that they have already been withdrawn elsewhere. 

How can we improve the current system?

Bringing awareness to this issue is the first step. Then all stakeholders can reevaluate the accelerated drug approval process and change the system to ensure that only drugs with proven benefit are brought to the market. My colleagues and I have come up with a couple of suggestions to help the process. 

First, the confirmatory trial should be underway at the time the FDA grants a new cancer drug accelerated approval, which would prevent the present lag time that can take several years to complete. Second, confirmatory trials should use clinical endpoints and not repeat the same surrogate endpoints that were used for accelerated approval. Third, when a drug fails to reach its endpoint on a confirmatory trial, its indication should be rescinded without the need for an expert committee discussion on the fate of the approval. Finally, the cost of cancer drugs should be tied to the strength of evidence and the magnitude of clinical benefit. Currently, drugs that are approved on the basis of response rates alone and showing marginal benefits cost even more than drugs that have proven survival gains. 

Health Equity

You are serving as a member of ASCO’s Health Equity and Outcomes Committee for the 2021–2024 term. Please tell us about that and how your work in the financial toxicities of cancer treatment and evidence-based oncology fits into the larger discussion of global oncology.

Yes, I recently joined the ASCO Health Equity and Outcomes Committee, which is a great privilege and an opportunity to help improve our cancer care delivery system on the global stage—an area of research that I am passionate about. Our work indicates that increasing cancer drug prices present global challenges to treatment access and cancer outcomes, and there is a substantial variability in drug pricing across countries. Not surprisingly, low- or middle-income countries are more heavily impacted, with limited patient access to newer cancer treatments and financial toxicity seen across cancer types and health-care systems. But, people often think that when we talk about financial toxicity, we are focusing on resource-challenged countries only, when, in fact, we have noted pockets of populations within high-income countries such as the United States and Canada that also suffer from inequities and financial toxicity as severe as observed in low- or middle-income countries.

We have done a good job in defining the cause and scope of financial toxicity, which is a necessary first step. But, we now need to move from identifying the problem to implementing solutions. For instance, value-based pricing of oncology drugs may incentivize the development of higher-value medicines and eliminate excess spending on drugs that yield little benefit. Generics and biosimilars in oncology can also improve affordability and patient access, offering reductions in drug spending while maintaining patient benefit. 

We as oncologists can promote value-based care by following evidence-based clinical guidelines that avoid low-value treatments. Moreover, researchers can engage in research that critically explores optimal cancer drug dosing, schedules, and treatment duration and defines patient populations most likely to benefit from specific drugs. I’m very hopeful that ASCO’s lead on this critical issue will help create a more equitable delivery system for all of our patients with cancer.

Closing Thoughts

Please share any final thoughts on the current state of oncology and what changes you would like to see.

Despite the challenges that I’ve spoken about, I want to emphasize that over the past few decades, the oncology community as a whole has greatly advanced the clinical care of patients with cancer. And, as our knowledge of the molecular and genetic drivers of cancer increases, we will see greater advances in the future. That said, it is up to us to demand that our clinical trial system uses methods and endpoints that can make us confident that the treatment we are offering to our patients will help them live longer and/or better lives and that our policy actions ensure that effective drugs are available to patients globally, irrespective of where they live and how much money they have. We owe that to our patients with cancer. 

DISCLOSURE: Dr. Gyawali receives salary support from Ontario Institute for Cancer Research funded by the government of Ontario. His global oncology work is supported through a Conquer Cancer Foundation Global Oncology Young Investigator Award. He has received consulting fees from Vivio Health.