FDA Letter February 27, 2008
February 27, 2008
Dr. Andrew Von Eschenbach
Commissioner
Food and Drug Administration
Bldg. PKLN, Mail Stop HF-1
Rockville, MD 20857
Dr. Richard Pazdur
Director, Division of Oncologic Drugs
Food and Drug Administration, HFD-150
5600 Fishers Lane
Rockville, MD 20852
RE: Avastin and the lowered standard for approval of cancer drugs
Breast Cancer Action (BCA), along with several other breast cancer organizations, have already expressed to the FDA our grave concerns about the marketing of Avastin for metastatic breast cancer. The decision made by the FDA last Friday, February 22, 2008, allowing this label for Avastin has vast and disturbing implications not only for patients who will receive this drug, but for future cancer patients treated with other therapies. I write on behalf of BCA’s international constituency to urge you to reconsider the standards that have emerged as determinative for cancer drug approval, which became clear with the Avastin decision.
What the standards should be
In light of the number of drugs now available to treat breast cancer, BCA has long maintained that any new drug approved for treatment should meet at least one of the following standards:
• Extend the life of the patient, i.e., improve overall survival (OS), and/or
• Improve the patient’s quality of life, and/or
• Cost less than therapies already available
Standards short of these put the interests of drug companies before those of patients and undermine the FDA’s mission. The FDA’s decision on Avastin reflects that the agency’s standards are dangerously different from these.
PFS and “Direct Clinical Benefit”
Much of the discussion about Avastin for breast cancer has focused on whether progression free survival (PFS), absent evidence of improved quality of life or overall survival (OS), should justify approval. This is an important issue, and many people believe, as BCA does, that by accepting this standard in the case of Avastin the FDA has lowered the bar on the approval of cancer drugs. While Dr. Pazdur states the position, articulated in the New York Times on Saturday, February 23, that overall survival is still favored by the agency, the FDA’s actions on Avastin, Tykerb and Ixempra belie that position.
Many people involved in drug approval issues understand that there is a great risk of bias in the reporting of PFS results in the absence of standardization of assessment schedules for evaluating time to progression (Panegeas, KS et al., When You Look Matters: The Effect of Assessment Schedule on Progression Free Survival,” J Natl Cancer Inst 2007: 99: 428-32). Eliminating this risk is critically important if drugs are to be approved on the basis of PFS efficacy.
BCA does not disagree that PFS may sometimes be a useful standard for cancer drug approval. But it is only a useful standard if PFS can be objectively measured and if it correlates with either OS or with an improved quality of life for breast cancer patients. As you know, in the case of Avastin, neither has been shown in the E-2100 trial. By approving the marketing of Avastin for metastatic breast cancer under these facts, the FDA has made PFS a standard for drug approval, a standard that is open to enormous subjectivity.
By focusing -- as the FDA in fact has in the Avastin case -- on “direct clinical benefit” as a possible measure for cancer drug approval, the possibilities of bias inherent in the PFS measure are compounded. As difficult as it is to clearly define parameters for PFS, it is that much more difficult to define “clinical benefit” in a way that is not subject to intense subjective variation. The further that drug approval standards move from objective measures of drug efficacy, the more difficult it will become to know whether drugs are effective in a way that is truly meaningful for patients with metastatic disease.
As important as the PFS issue is, there are other ways in which the FDA’s decision in the Avastin case highlights a decline in standards at the FDA regarding cancer drug approval that will ultimately harm patients – the very people that the FDA is supposed to protect.
How many trials?
It used to be the case that the FDA required more than one study showing that a drug’s benefits outweigh its risks before approving the marketing of a drug. While the Avastin situation is not the first time that the FDA has violated this practice, it is an egregious one because it comes under circumstances that indicate that the FDA is also now willing to accept trial results that do not meet the FDA’s important and strong standards for drug evaluation.
Trial rigor
Before the Avastin decision, a drug could not be approved for marketing unless it had been subjected to a drug registration trial with standards set by the FDA. This standard is higher than the standard for classical clinical trials, largely because routine clinical trials often do not reveal the true side effects of drugs or are done in populations that are likely to result in overstated benefit.
By making the Avastin decision on the basis of an NCI-sponsored clinical trial (E-2100) rather than a trial designed for drug registration, the FDA has made it highly likely that other drug companies will be able to argue successfully in seeking drug approval that the agency’s drug registration standards do not have to be met. Instead, industry-sponsored clinical trials will become the standard for assessing drugs.
Industry Influence at the FDA
BCA is deeply concerned by the fact that most of the funding for FDA drug review comes from the drug industry. We believe that this fact gives inordinate influence to the regulated industry, an influence that is compounded by the amount of private access that drug company representatives have to agency decision-makers.
As long as the FDA’s drug review funding comes from industry, the leadership of the agency must do everything in its power to avoid even the appearance of undue influence by the regulated industry. Yet, in the case of Avastin, the agency appears to have been influenced by data from Genentech’s AVADO trial that has yet to be made public and that was not even mentioned during the ODAC’s December 2007 consideration of the company’s application for Avastin.
Cost
BCA understands that the FDA has no legal authority to consider the cost of drugs in deciding whether to allow them to be marketed. Nonetheless, it is impossible to live in American society without realizing the impact of drug costs on the accessibility of new therapies and the viability of the health care system. The staggering annual $100,000 cost of Avastin far exceeds the cost of other breast cancer therapies, and will certainly not be the sole cost incurred by patients who take the drug. After all, the FDA Avastin approval is for the use of the drug in combination with paclitaxel. While Genentech relies on its patient assistance program for this drug, focusing on patients with household incomes less than $100,000, and capping the cost for these patients at $55,000 a year, the fact is that the median household income in the United States is $48,000.
The FDA’s mission statement states in pertinent part: “The FDA is also responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable” (emphasis added). To achieve this mission, cost will have to be considered, particularly of emerging biotech therapies whose manufacturers are engaged in “social value” pricing.
Breast Cancer Action is committed to seeing public health put before private profits, and the needs of patients put before the profit margins of drug manufacturers. The need for more effective and less toxic treatments cannot be met at the expense of having an FDA that fails to put the public’s interests first. We call on the FDA leadership and the leaders of the cancer research community to work with the cancer community to re-establish standards for drug approval that protect the public’s health.
Sincerely,
Barbara A. Brenner
Executive Director