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The U.S. Food and Drug Administration (FDA) last month approved Nolvadex (tamoxifen citrate) for the "reduction in breast cancer incidence in high-risk women." The label does not allow the drug's sponsor, Zeneca Pharmaceuticals, to claim that the drug "prevents" breast cancer in high-risk populations, a claim requested by the company in the Supplemental New Drug Application (SNDA). However, in a move that benefitted the company, the FDA did not follow its advisory committee's recommendation that the drug be approved for the "short-term" reduction of the incidence of breast cancer.
"[The label] does not specifically say ‘short-term,’" Susan Honig, Medical Officer in the FDA Division of Oncology Drug Products, said. "We felt that it was more descriptive and helpful to list all of the factors that actually occurred in the study. That provided more information than just saying ‘short-term.’"
The FDA also expanded the tamoxifen label to include the reduction in the incidence of contralateral breast cancer. The FDA Oncologic Drugs Advisory Committee was not asked to comment on the contralateral indication, which was based in part on the results of the B-14 trial. That trial provided the intellectual justification for conducting the P-1 prevention trial. Both trials were conducted by the National Surgical Adjuvant Breast and Bowel Project.
In another change, the label now includes data that support five years of adjuvant therapy with tamoxifen for patients with breast cancer.
The October 29, 1998 approval of new indications had the appearance of a last-minute deal. Since Zeneca filed the SNDA for prevention of breast cancer on April 30, 1998, the six-month deadline imposed by law was running out. However, until the last moment, the agency and the sponsor were locked in negotiations over labeling, Zeneca officials said.
The most significant of the changes—the downgrading from "prevention" to "reduction of incidence"—occurred after ODAC, in its September 2, 1998 meeting, voted unanimously that the data from the Breast Cancer Prevention Trial (P-1), on which the Zeneca application was based, was insufficient to support the claim to prevention.
In the trial, women treated with tamoxifen had 44% fewer breast cancer cases than women on the placebo arm. However, ODAC members said the "prevention" indication could not be justified. Committee members said follow-up was insufficient and it was unclear which subsets of patients stood to benefit the most from tamoxifen.
The committee's decision was entirely unexpected by the company, NCI, and the investigators, sources said. ODAC had reviewed the breast cancer trial protocol on three occasions. The committee approved the concept in 1990, signed off on the protocol in 1991, and recommended protocol modifications in 1994. However, at the September 2nd session, ODAC voted 11-0 against approval of tamoxifen for prevention of breast cancer. Once the offending word was replaced with "short-term reduction of incidence," the committee recommended approval in a 9-0 vote, with two members abstaining.
A transcript of the ODAC attempt to translate the findings of the P-1 trial into the language of a drug package insert is available on the FDA web site, http://www.fda.gov/cder/news/tamoxifen/
After FDA approved the new indication for tamoxifen, Zeneca and the U.S. Department of Health and Human Services issued press releases that were consistent with the language of the label. However, the word "prevention" appeared throughout press coverage of the approval. Even when reporters understood the significance of the terminology, headline writers appeared to ignore them. The lead of the Reuters story said simply that tamoxifen was approved for preventing breast cancer in healthy women. High-risk was not mentioned until the fifth paragraph. The New York Times and Los Angeles Times similarly used "prevention" in the lead and the headline. The New York Times worked in the offending word by saying that tamoxifen could "help prevent or delay" the disease in high-risk women.
While oncologists and epidemiologists may be able to understand the subtle concepts in the tamoxifen label, women who will want to consider the drug and general practitioners who will prescribe it may have a harder time discerning a reasonable risk from one that is gratuitous.
Zeneca said it plans to distribute a breast cancer risk assessment model to health care professionals nationwide. The model—called the "Gail Model"—was developed by the NCI and used to determine eligibility for the P-1 trial. Now the NCI is adapting the model for broader use.
Early next year, the American Society of Clinical Oncology is expected to issue a "technology assessment" of tamoxifen and the Eli Lilly & Co. drug Evista (raloxifene hydrochloride). "No one has yet undertaken an independent assessment of the data to determine who would benefit most from these drugs," said Rowan Chlebowski, a medical oncologist from the University of California at Los Angeles Harbor Medical Center, Co-Chairman of the ASCO working group developing the recommendations. "Oncologists are seeing more and more healthy women who think they are at risk of breast cancer and want to do everything possible to prevent it," Chlebowski said. "But these drugs are not for everyone, and may in fact only be appropriate for a select group of women."
The assessment, which will attempt to define the risks and benefits of the two drugs, will be published in the society's Journal of Clinical Oncology. 
U.S. Senate Confirms Oncologist Henney as FDA Commissioner
Oncologist and administrator Jane Henney was confirmed by the U.S. Senate as commissioner of the FDA October 21, 1998. The Senate's action, in a voice vote on the last day of the legislative session, was taken after Senator Don Nickles (R-OK) removed his objections to Henney after receiving assurances from the White House about abortion policies, according to news reports. Henney was said to have promised that she would not seek a U.S. manufacturer for RU-486, the French abortifacient.
Henney has been Vice President for Health Sciences at the University of New Mexico since 1994. She replaces David Kessler, who resigned as FDA commissioner 18 months ago to become Dean of the Yale University Medical School. Michael Friedman has served as acting commissioner.
"I am deeply honored to have been confirmed by the Senate to serve as the next commissioner of the Food and Drug Administration," Henney said in a statement. "FDA has a long, proud tradition of promoting and protecting the health and safety of all Americans, and I look forward to assuming its leadership.
"The discussions I have had with many members of the Senate over the past several weeks have reaffirmed my belief that the FDA serves as a non-partisan arbiter of public policy, with decisions that are grounded in science and the law," Henney said. "As I have made clear in prior statements, my priority as commissioner will be to implement the FDA Modernization Act and to strengthen the agency's scientific base to ensure the best science guides the critical decisions that need to be made."
NCI Outlines Need for $3.873 Billion to Seize Cancer Research Opportunities
The U.S. National Cancer Institute says it needs a budget of $3.873 billion for fiscal year 2000 to sustain its research programs, seize extraordinary opportunities in cancer research, and translate those findings into practical applications. The funding request is $946 million above the $2.927 billion FY1999 appropriation approved by Congress.
The NCI submitted its annual "Bypass Budget" request to the White House on October 23, 1998, just two days after President Clinton signed a spending bill that gave the NCI the largest increase in its history. "Our ability to act on the new initiatives that we have spent the last few years articulating, through an enormous amount of effort by hundreds of advisors, is certainly made much more possible by the fact that the NCI received the largest increase that we've ever received, a 15.1% increase," NCI Director Richard Klausner said. "It's an enormous measure of expectation, and a vote of confidence, that we actually have a program that we can articulate and defend," Klausner said at a meeting of an advisory group of cancer patient advocates. "It's important that we come back next year to Congress and be very clear about what we've done."
The $385 million increase amounted to about half of the increase the Institute requested in last year's Bypass Budget, Klausner said.
The new Bypass Budget requests $2.99 billion as a "core" amount to sustain the Institute's research programs, plus $189.5 million to "seize extraordinary opportunities to further progress," and $693.5 million to "create and sustain mechanisms that will enable us to meet the challenge of rapidly translating our findings from the laboratory into practical applications."
The National Cancer Act of 1971 requires the NCI director to send a document each fall directly to the President outlining the Institute's professional judgment of the funding needs in cancer research. Because the document skips over the usual review levels at NIH and the Department of Health and Human Services, it is referred to as the "Bypass Budget."
Copies of the FY2000 Bypass Budget, "The Nation's Investment in Cancer Research," may be ordered by fax at 301-330-7968, by e-mail at cisocc{at}nih.gov, or by phone at 800-4-CANCER. Previous Bypass Budgets may be viewed online at http://www.nci.nih.gov by clicking on "What's New."
FDA Approves Camptosar for Metastatic Colorectal Cancer
Pharmacia & Upjohn Inc. of Bridgewater, NJ, said it has received full U.S. FDA approval for its colorectal cancer treatment Camptosar (irinotecan hydrochloride). Camptosar is indicated for second-line therapy for refractory metastatic colorectal cancer.
In June 1996, Camptosar received an accelerated approval for metastatic cancer of the colon or rectum that has recurred or progressed after standard therapy with fluorouracil. Since data from phase III trails were not available, marketing authorization was granted under regulations designed to accelerate approval of new drugs for serious or life-threatening illnesses.
The FDA decision to grant full approval was based on the results of two international phase III trials that demonstrate Camptosar significantly increases survival in patients with metastatic colorectal cancer who develop recurrent or progressive cancer despite first-line therapy with 5-FU, the company said. Survival was the primary efficacy measurement in these trials, and secondary measurements included the European Organisation of Research and Treatment of Cancer (EORTC) Qualify of Life Questionnaire and measures of clinical benefit.
One phase III trial in patients who failed first-line therapy with 5-FU compared Camptosar (350 mg/m2 once every three weeks) and best supportive care with best supportive care alone in 279 patients. On average, patients receiving Camptosar lived significantly longer, 9.2 months, compared with 6.5 months for patients receiving best supportive care alone, representing a median survival increase of 41%. The trial also demonstrated that Camptosar improves certain aspects of quality of life, as measured by the function and symptom scales of the EORTC Quality of Life Questionnaire.
The second phase III trial compared Camptosar (350 mg/m2 once every three weeks) to 5-FU in patients with metastatic colorectal cancer whose disease had recurred or progressed despite standard first-line therapy with 5-FU. On average, survival of patients treated with Camptosar was 10.8 months compared with 8.5 months for patients receiving 5-FU, representing a median survival increase of 27%. The difference in survival was also statistically significant.
The results of the EORTC Quality of Life Questionnaire did not indicate a statistically significant difference between Camptosar and 5-FU, the company said.
Camptosar is associated with both early (during or shortly after infusion) and late (more than 24 hours after infusion) forms of diarrhea, that may be severe. Early diarrhea may be accompanied by symptoms such as sweating, flushing and abdominal cramping, and may be treated with atropine. Late diarrhea can be prolonged, life threatening, and should be treated promptly with loperamide.
In the two phase III trials, the most clinically significant adverse events were diarrhea (84%), alopecia (72%), nausea (70%), vomiting (62%), cholinergic symptoms (47%), and neutropenia (30%). In these studies, 8% of patients receiving Camptosar discontinued treatment due to adverse events.
Pharmacia & Upjohn markets Camptosar in the U.S., Canada, Latin America, New Zealand and Australia. Rhône-Poulenc Rorer markets it in Europe, the Middle East, Africa, and South East Asia. It is marketed by Yakult Honsha Co. Ltd. in Japan.
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