Defining Meaningful Benefit: The Debate Continues in Bevacizumab’s Wake

A Conversation with Harold J. Burstein, MD, PhD

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The events surrounding the labeling of bevacizumab (Avastin) have been well covered since last November when the FDA withdrew the drug’s accelerated approval as a treatment for metastatic breast cancer. However, the controversy initiated a debate over the value of endpoints in clinical trials in advanced cancer that remains unresolved.

The ASCO Post recently spoke with  Harold J. Burstein, MD, PhD, Associate Professor of Medicine, Harvard Medical School, and a medical oncologist at Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, about some of the unsettled issues surrounding the bevacizumab story.

Adequate Endpoints

Did the bevacizumab trials and ensuing revocation of its indication in metastatic breast cancer give us a better understanding of endpoints that will help inform future trials?

The bevacizumab trials and subsequent analyses clearly underscored the concept that survival is a very important endpoint in cancer clinical trials. However, I do not believe that the bevacizumab issue resolved the important question that remains in breast cancer studies: What magnitude of benefit would be required (and in which specific line of therapy) to determine whether progression-free survival is an adequate endpoint in breast cancer?

Accelerated Approval

The accelerated approval system is seen, especially by the lay public, as a necessary vehicle to rapidly bring lifesaving drugs to patients. Has the system suffered a credibility crisis?

3.7.01_quote-burstein.jpgNo, in fact, I think the credibility of the accelerated approval system will be strengthened by the controversy surrounding the bevacizumab issue, largely because of comments that arose from a comprehensive 2009 Government Accountability Office (GAO) report that addressed the value of the accelerated approval program.1 One recommendation was that the FDA Commissioner should clarify the conditions under which the agency would exercise its authority to expedite the withdrawal of drugs that are approved based on surrogate endpoints under the accelerated approval process, if sponsors either fail to complete required confirmatory studies with due diligence, or if studies are completed but fail to demonstrate the clinical effectiveness of the drugs.

Bevacizumab is an example of what this GAO mandate was striving to accomplish. The subsequent confirmatory trials—AVADO and RIBBON-1—did not demonstrate a benefit on par with the original E2100 study. In response, FDA applied its authority and revoked the approval, which is what the GAO report encouraged.

So, I think the bevacizumab episode actually gives more backbone to the requirements that follow an accelerated approval, which strengthens the whole scientific and drug regulatory process.

Associated Guidelines and Coverage

Has the guideline system used for coverage decisions been challenged by FDA’s revocation?

The data that have emerged in the years following the original bevacizumab trial have eroded the sense that this drug is a major advancement in the treatment of breast cancer. In response to those data, my understanding is that the utilization of bevacizumab for breast cancer has sharply declined. That response by clinicians across the country has more to do with the data than the FDA decision, because this usage trend was beginning before the agency took the formal action to withdraw the drug’s indication.

It is also likely that anytime there is uncertainty about a drug’s coverage status, the utilization of that treatment will decline. Moreover, whether third-party payers will continue to support use of a drug that has specifically had approval withdrawn by the FDA remains to be seen.

The Cost Issue

Although the regulatory bodies do not use cost as an instrument in their decision-making, is it realistic to believe that given the untenable rise in health-care expenditures that cost can be left out of the equation?

Current law prevents cost from being a consideration in the FDA approval process or for Medicare and Medicaid coverage decisions. Approval and coverage is based solely on a drug’s safety and efficacy. Other countries, by mandate, do include cost analyses in their drug regulatory decision-making procedure.

Everyone wants newer, better treatments for cancer. Innovation is expensive, and companies that invest in research and development to promote innovation that brings important new drugs to patients deserve the appropriate rewards of the marketplace. However, we as a medical community do not ask rigorously enough what cancer drugs should cost and what clinical return they should deliver for that cost. Throughout the medical system, there is a sense that we are going to have to start looking at how health-care dollars are being spent relative to cost and benefit.

The discussion about bevacizumab in breast cancer highlighted the fact that we do not have a solid enough process in the medical community for evaluating a drug before it goes to market.

Closing Thoughts

As a breast cancer specialist, do you have any last thoughts on what we’ve learned from the bevacizumab experience?

There is still tremendous innovation in the field of breast cancer, and the good news is that there are many exciting drugs in the pipeline. We have a growing understanding of tumor biology, and we are still going to see progress in breast cancer in spite of the controversy surrounding bevacizumab.

But it is important to note that the final word on bevacizumab isn’t out yet. Results from studies in the adjuvant setting and more research in the metastatic setting are yet to be seen.

At the same time, I think the bevacizumab experience emphasizes some real challenges for regulators, researchers, and clinicians to identify the most important endpoints for clinical trials. Also, how much data are required for decision-making, and what clinical benefits should we insist upon from a regulator’s perspective, taking into consideration the clinical and patient perspectives, which add another layer of value to the process. And last, as a community, what cost should we bear relative to the clinical benefits of the treatments we provide to society.

The bevacizumab debate poses all these questions but fails to answer all but one: Is bevacizumab going to be part of current breast cancer treatment? The answer seems to be no.

As we move forward into an era when more drugs become available for more types of cancers, we will face more of these difficult questions, not fewer. Over the past decades, we have seen tremendous success in breast cancer survival rates, and the best is yet to come. ■

Disclosure: Dr. Burstein reported no potential conflicts of interest.


1. U.S. Government Accountability Office: New drug approval: FDA needs to enhance its oversight of drugs approved on the basis of surrogate endpoints. September 2009. Available at Accessed March 12, 2012.