Note: This post appeared originally on 18 November 2011 at my Chemical & Engineering News CENtral Science blog, Terra Sigillata. I found the FDA document so useful that I wanted to reproduce the post here for our Take As Directed readers and for my students in the BIOG 5400 – Physiology and Pharmacology class at North Carolina Central University – yes, students, this is required reading!
As reported around the wires today, US FDA Commissioner Dr. Margaret A. Hamburg formally revoked the accelerated approval of the antiangiogenic drug Avastin (bevacizumab) for breast cancer treatment. Avastin is a humanized mouse antibody that binds and inactivates the vascular endothelial growth factor VEGF-A, a mediator of blood vessel growth. Andrew Pollack at The New York Times does a nice job condensing this episode for us.
The highlights are that Avastin was approved based on the surrogate endpoint of progression-free survival in metastatic breast cancer, meaning that it appeared to increase the time from treatment to return of the growth of cancer metastases. However, the true endpoint is long-term patient survival. There, subsequent studies showed that Avastin had no benefit.
Moreover, Avastin also use appears to increase the risk of hemorrhage and bowel perforation. These are potentially life-threatening side effects and are considered too great of a risk when no statistical benefit of survival or quality of life are apparent.
Of course, there are cases of individual patients who have benefited from Avastin and many questions remain for them. In the 69-page ruling made available today (PDF), Dr. Hamburg includes a well-articulated Q&A for patients and their caregivers. I doubt seriously that the full text of this section will be published in the mainstream media, although Pollack does provide the hyperlink.
I found this quite valuable as someone who cares about family and friends with breast cancer. But the text also provides an espeically close look at the rationale behind the US drug approval process. As this rich information is buried in a 69-page federal document, I wanted to provide this text here for ease of reading by those concerned about this ruling. This following statement is from US FDA Commissioner Dr. Margaret Hamburg. The full text is in the public domain and can be accessed here.
I. AN EXPLANATION FOR PATIENTS AND THOSE WHO SUPPORT THEM
This document, which lays out the basis for my decision, has several purposes. It is an explanation, for physicians, scientists, patients and the public in general, of the data available on the metastatic breast cancer indication for Avastin and of FDA’s evaluation of those data. It also describes how FDA has applied the law and its regulations in making the decision to withdraw the approval for that indication.
I know I speak on behalf of the many physicians that have been involved with this issue here at the Food and Drug Administration and elsewhere in saying that we encourage patients and those who support them, to ask hard questions and to demand explanations concerning the drugs that are recommended to treat serious illnesses. I will address here some of the questions that patients and their supporters may have about this decision.
Does the FDA decision mean that patients will not be able to use Avastin for the treatment of breast cancer?
The short answer to this question is “No.” FDA does not regulate the practice of medicine, and it is part of the practice of medicine for a physician to be able to prescribe a drug that is approved for one use (and Avastin continues to be approved for use in several cancers) for another, unapproved use. Thus, a physician can prescribe Avastin for the treatment of breast cancer if he or she chooses to do so, despite the withdrawal of approval for that use.
Does the FDA decision mean that patients will lose insurance coverage for the use of Avastin for the treatment of breast cancer?
This is a more complicated question. FDA’s decision have no direct effect on insurance coverage. At this point, the Centers fro Medicare and Medicaid Services (CMS) has said that it is continuing to reimburse for this use. While health insurance contacts with private providers obviously vary, it is our understanding that private insurers do cover the use of drugs for unapproved uses in those circumstances in which that use is considered appropriate medical practice. They may continue to reimburse for the use of Avastin for the breast cancer indication (use with paclitaxel), as many apparently now reimburse for the use of Avastin with anti-cancer drugs other than paclitaxel even though use in combination with other drugs has never been approved by FDA. To be very clear, FDA’s decisions on approval do not require any change in insurance coverage.
If I, as a patient, and my treating physician believe that Avastin is the right drug to treat my breast cancer, why shouldn’t FDA approve the drug for that use?
By law, FDA can only approve a drug for a particular use if there is credible, objective evidence that the drug is safe and effective for that use. This is, in effect, what FDA approval means: that the public and physicians can have confidence that claims made about a drug in its labeling have been carefully and impartially reviewed, and that they are supported by evidence. This requirement provides an essential protection to the public. When Congress first required FDA to being evaluating the effectiveness of drugs in 1962, it required sponsors of drugs that had been on the market without proof of their effectiveness through adequate and well-controlled clinical trials to perform those trials and submit the evidence to the FDA. Ultimately FDA found that many drugs that had been in common use prior to 1962, and that both doctors and patients had believed to be effective, were not shown by objective testing to be effective for the uses for which they were labeled.
There are many reasons why patients and physicians believe in drugs, whether based on personal experience or on their own evaluation of evidence. Over the years FDA’s decisions with respect to particular drugs have often been questioned by those who preferred to rely on their own eliefs. In some cases, the disputes involved differing evaluations of carefully done clinical trials. In others, there was little or no scientific data to support those strongly held beliefs.
Ultimately, my responsibility, and the agency’s responsibility, is to put aside any preconceived beliefs that I, or patients or physicians may hold, and take a hard look at the objective evidence. We may hope, as CDER scientists did when they granted the initial accelerated approval of Avastin for the breast cancer indication, that the additional studies conducted to support continued approval of a drug that has shown promise in an initial trial will confirm the effectiveness of the drug. But if the evidence does not show that, FDA cannot, and should not, continue to approve it.
Since FDA had already announced its decision to withdraw approval of Avastin for the breast cancer indication, did Avastin receive a fair hearing?
As explained elsewhere in this decision, FDA has taken advantage of the way our agency is structured to assure that the hearing was fair. Within our agency, CDER is generally responsible for decision with respect to the approval of this type of drug. That Center granted the accelerated approval of Avastin for the breast cancer indication in the first place, and then, based on new data, it made the determination that that approval needed to be withdrawn. I, as Commissioner, am not normally involved in drug approval decisions, and I was not involved in either the decision to approve this indication or CDER’s initial decision to withdraw approval. When Genentech objected to the CDER decision to withdraw approval, it exercised its right to seek a hearing on that decision.
In conducting the hearing, FDA decided to utilize something called the “separation of functions” to protect the independence of the Commissioner’s decision and make the process transparent. Under separation of functions, I as Commissioner (and those assisting me on this issue, such as Dr. Midthun, the Director of FDA’s Center for Biologics Evaluation and Research who served as presiding officer at the hearing) communicated with CDER about the subject of this hearing only as part of the formal hearing record, in exactly the same way that we communicated with Genentech. CDER presented its views as a party in the hearing, as did Genentech. As the applicant, Genentech was a motivated, knowledgeable, and well represented proponent of its view. Both CDER and Genentech presented evidence at the hearing and challenged each others’ presentations. In addition, members of the public submitted comments to the docket and testified at the hearing. That created the record that led to my own decision as Commissioner. I did not know, until review of that record and discussion of the issues with Dr. Midthun, how I would decide the issue presented. I have now made that decision based on the evidence.
How can FDA make a different decision than was made by the regulatory authorities in Europe?
It is true that the European Medicines Agency has continued to approve Avastin for use with paclitaxel in the treatment of metastatic breast cancer, though the United Kingdom’s National Institute for Health and Clinical Excellence (NICE) has not recommended Avastin’s use with taxanes as a first-line treatment for people with metastatic breast cancer. The regulatory standard for different government agencies may vary somewhat, and of course decision makers are different in different places. I can only apply the United States standards to the evidence that has been provided to FDA. That is what I have done with this decision.
Is it possible that Avastin might be approved, once again, for the treatment of certain patients suffering from metastatic breast cancer?
Genentech has said that it will consider conducting a further adequate and well-controlled clinical trial that would be designed to show that the use of Avastin with paclitaxel would be safe and effective for patients, or for some subset of patients. If such a trail were completed and showed clar benefit for this use, such as increased overall survival, better quality of life, or even a substantial increase in “progressional free survival” of the type seen with the E2100 study that formed the basis for the initial accelerated approval, a new approval could be granted. In addition, Genentech has said that it would consider including in such a trial a mechanism to determine whether certain patients (those with high plasma levels of Vascular Endothelial Growth Factor-A (VEGF-A) would benefit most from the use of Avastin. If such a therapeutic relationship could be demonstrated, that might represent a basis for Avastin to be approved for use by certain patients.
Ultimately, if Genentech does go forward with the new clinical trial that it has discussed, that will lead to more scientific evidence on the question of whether or not Avastin might provide a benefit for some patients in the treatment of metastatic breast cancer. At this stage, however, based on the evidence currently available, I have concluded that continued accelerated approval of Avastin for this use is not justified.
Hamburg, Margaret A. DECISION OF THE COMMISSIONER: Proposal to Withdraw Approval for the Breast Cancer Indication for AVASTIN (Bevacizumab). Department of Health and Human Services, Food and Drug Administration, Docket No. FDA-2010-N-0621. 18 November 2011. http://www.fda.gov/downloads/NewsEvents/Newsroom/UCM280546.pdf – last accessed 18 November 2011.