May 1, 2000-Overexposed
Bigger and faster drug launches are producing more immediate information about possible adverse effects and drug interactions The rapid uptake or pharmaceuticals with broad market appeal, driven by huge promotional programs such as direct-to-consumer advertising campaigns, are making some drugs vulnerable and exposing their manufacturers to risk. High-visibility products such as Rezulin and Propulsid, which have been associated with safety concerns, are being voluntarily withdrawn from the market. Some industry critics blame the regulatory process for the recent spate of product withdrawals.
"The problem is not the rapidity of the drug approval process as much as the rapidity of market acceptance," says Mara Goldstein, executive director, CIBC World Markets Corp., New York. "Seldane was on the market for seven years before there were enough adverse events to really cause the need to raise the red flag. Now the uptake of drugs is so much faster. Drugs are so much more affordable because of managed care and patients are more aware than ever before. Drug trials are more complex, they involve more patients and more data points, and more information is available than ever before. The Food and Drug Administration is approving drugs with more access to information than ever before." In the past three years, eight pharmaceutical products have been pulled from the market and two have been restricted to small-patient populations. Redux, Pondimin, Seldane, Duract, Posicor, Raxar, RotaShield, and Rezulin have been withdrawn from the market, either by the Food and Drug Administration or voluntarily by their marketer. Propulsid and Trovan have been restricted in their use. Six of these products, most of which had splashy launches, were approved in the past three years
"Eight recalls in the last three years, that's unprecedented," says Hemant K. Shah, president of HKS & Co. of Warren, N.J. The wave of product withdrawals has critics finding fault with the regulatory process, but the Food and Drug Administration disagrees. Regulators say recent product withdrawals do not signify that the drug pre-approval process is faulty. Instead, agency officials say withdrawals indicate that the post-marketing drug surveillance system is working.
The Food and Drug Administration's post-marketing adverse events reporting program, MedWatch, is designed to provide health professionals with a simplified way to report serious adverse events. Data collected by MedWatch can sometimes lead the agency to make labeling changes or add a boxed warning to a product's prescribing information. In addition, the agency can issue medical and safety alerts and call for a product's recall or withdrawal.
FDA officials defend the post-approval process, saying the smaller clinical trials conducted during the pre-approval process are not enough to bring to light a serious adverse event. "It is very difficult to indict the pre-approval system because it doesn't pick up on a serious adverse event - one that might occur in one in 50,000 people," Murray M. Lumpkin, M.D., deputy center director of the Center for Drug Evaluation and Research at the Food and Drug Administration told Med Ad News. "We have known all along that rare, serious, unexpected adverse events are not going to be picked up in the pre-approval process, and that is why we have our post-approval system."
According to Dr. Lumpkin, the clinical trial data presented with a new drug application allow the regulatory agency to identify adverse events that occur in one of 500 patients to 1,000 patients. This system has been the standard for the past 30 years. Dr. Lumpkin told Med Ad News that finding one adverse event in 50,000 patients would require gathering clinical trial data from 150,000 patients, which means pharmaceutical companies would need to spend up to 18 years conducting clinical trials for each drug.
According to the Pharmaceutical Research and Manufacturers Association, Washington, the average time for a product to move from discovery to approval is 12 years to 15 years. The average cost for developing one product is $ 500 million.
The latest medication to be withdrawn from the U.S. market is Rezulin, a treatment for type 2 diabetes. Approved in 1997, Rezulin was the first member of a class of drugs known as thiazolidinediones to reach the market. Rezulin was voluntarily withdrawn in March by its marketer Parke-Davis, the pharmaceutical division of Warner-Lambert Co. based in Morris Plains, N.J.
According to the Food and Drug Administration, severe liver toxicity has been associated with Rezulin since 1997. Parke-Davis jointly marketed Rezulin with Sankyo Parke Davis, a joint-venture company established by Warner-Lambert and Sankyo Co. During Rezulin's market life, Parke-Davis revised the drug's labeling several times and recommended that physicians closely monitor liver function in patients taking Rezulin. Allegedly, 63 deaths have been connected with the use of Rezulin. Rezulin generated about $ 600 million in sales in 1999. Before Rezulin's withdrawal, analysts at Salomon Smith Barney, New York, estimated that the product would have generated $ 400 million in 2000, $ 250 million in 2001, and $ 100 million in 2002.
Analysts at Merrill Lynch & Co., New York, say Rezulin's withdrawal will have a minimal effect on Warner-Lambert's earnings. Furthermore, analysts do not believe that this event will have any impact on the proposed merger of Warner-Lambert and Pfizer Inc., New York. Merrill Lynch is acting as a financial advisor to Pfizer in connection with the acquisition of Warner-Lambert. "Rezulin was a product that had sales of maybe $ 400 million and declining," Ms. Goldstein told Med Ad News. "Pfizer was able to withstand the withdrawal of Trovan, which was barreling toward $ 1 billion. So it is not a big deal."
Officials at Warner-Lambert still maintain that the benefits of treatment with Rezulin outweigh the risks associated with the product. The decision to withdraw Rezulin was made under the pressure of negative media reports and statements from citizen advocacy groups that company officials say were inaccurate and misleading.
"We felt that we were at a point where patients and physicians were really unable to make a well-informed decision," says Jason Ford, supervisor of media relations at Warner-Lambert.
The other product to be withdrawn from the market this year is Propulsid, marketed by Janssen Pharmaceutica Inc., Titusville, N.J., a subsidiary of Johnson & Johnson. Propulsid is indicated for severe nighttime heartburn experienced by adult patients with gastroesophageal reflux disease. After several labeling changes, in March Janssen decided to stop marketing the product in the United States. Patients who meet specific clinical eligibility requirements still will be able to obtain Propulsid under a limited-access program. According to the Food and Drug Administration, use of Propulsid has been associated with 341 reports of heart rhythm abnormalities, including 80 reports of deaths. Most of these adverse events occurred in patients who were taking other medications or suffering from underlying conditions known to increase risk of cardiac arrhythmia. Propulsid had undergone its fifth labeling change in January in an attempt to ensure that the product was being prescribed safely and appropriately. Despite label warnings, Janssen officials say some inappropriate use continued in the United States, which led to the product's withdrawal. Propulsid generated 1999 sales of $ 975 million.
Enrollment in the limited-access program for Propulsid is expected to begin in May. Janssen officials say to assure that Propulsid is available to appropriate patients during the transition, distribution will continue until July 14 and the product will remain in pharmacies until mid-August.
Lawyers representing patients who took Rezulin have filed the first nationwide class action against Warner-Lambert Co., Morris Plains, N.J., the product's manufacturer The class action was filed in the U.S. District Court, District of New Jersey. The complaint was filed on behalf of all individuals who took Rezulin from March 1, 1997, through March 22, 2000.
According to allegations listed in the complaint, Warner-Lambert knowingly concealed material facts about the safety and efficacy of Rezulin from the Food and Drug Administration. The complaint alleges that the company engaged in deceptive and misleading practices, including with-holding information from consumers and physicians about the adverse event reports confirming severe liver damage and the numerous deaths associated with the drug. The complaint also alleges that Warner-Lambert continued to say Rezulin had side effects comparable to a placebo even though clinical trial data indicated that patients who had received the drug developed liver problems four times as often as those who had received a placebo. In addition to the class action, lawyers also are filing complaints on behalf of individual patients.
Warner-Lambert marketed Rezulin through its pharmaceutical division, Parke-Davis. The product was indicated to improve glycemic control in patients with type 2 diabetes. Warner-Lambert officials will not comment on the specifics of the litigation. Company officials say their conduct, with respect to the development and marketing of Rezulin, was in strict accordance with Food and Drug Administration regulations and the company's commitment to patient health and safety.
"Any adverse events in connection with the use of a prescription pharmaceutical is a very unfortunate occurrence, and we acknowledge that some patients have experienced adverse events while taking Rezulin," Warner-Lambert officials say. "However, the company adequately warned about risks associated with the product and we intend to vigorously defend any lawsuits filed against Warner-Lambert relating to the use of Rezulin."
Filling The Void
Days after the voluntary U.S. withdrawal of the diabetes agent Rezulin by Parke-Davis, marketers for the leading competitor Avandia launched a consumer advertising campaign targeted to Rezulin users. SmithKline Beecham and Bristol-Myers Squibb Co., Avandia's joint marketers, took out full-page ads in The Wall Street Journal and other national newspapers to promote Avandia as a safer alternative to Rezulin. Avandia and Rezulin belong to the same class of drugs, known as thiazolidinedione, which sensitize a patient's body to its own insulin. Rezulin was removed from the market after postmarketing data linked the product with liver toxicity. Officials at the Food and Drug Administration say Rezulin poses an unacceptable risk now that safer alternatives in the same class of drugs are available.
Officials at Warner-Lambert Co., Morris Plains, N.J., refute claims that Avandia and another member of the thiazolidinedione class, Actos, are proven to be safer than Rezulin. Warner-Lambert is the parent company of Parke-Davis, marketer of Rezulin. "Any suggestion that the two recently approved drugs in the same chemical class as Rezulin are safer is incorrect," Warner-Lambert officials state.
Officials at SmithKline Beecham, Philadelphia, and Bristol-Myers Squibb, Princeton, N.J., say the post-marketing data and clinical trial data for Avandia support the safety and efficacy claims. More than 700,000 patients have taken Avandia in the United States and more than 2 million prescriptions have been written. (See related story in the March 2000 issue of Med Ad News.) In addition to the newspaper ads, SmithKline Beecham and Bristol-Myers Squibb have been supplying physicians with samples of Avandia to give to former Rezulin patients.
Officials at SmithKline Beecham say since Rezulin's withdrawal there has been a tremendous spike in the number of visits to avandia.com, the Avandia Website. Telephone calls to the 1-800-AVANDIA help line have doubled and requests for membership to Avandia's consumer program "I Can" have increased 25%. Avandia is indicated as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. In addition, Avandia is indicated in combination with metformin. Bristol-Myers Squibb markets metformin under the brand name Glucophage.
Bristol-Myers Squibb marketers have taken out full-page newspaper ads for Glucophage to reach Rezulin patients, using the same headline as the Avandia ad: "Attention Rezulin Users." For the time being, officials at Eli Lilly & Co. and Takeda Pharmaceuticals America Inc., joint marketers of Actos, have decided not to run a consumer advertising campaign targeted to Rezulin patients.
"Our main focus now is on helping physicians and patients transition to an alternative thiazolidinedione therapy," a spokesperson for Takeda told Med Ad News. "We would consider an advertising campaign if we felt that it would help assuage concerns stemming from the removal of Rezulin, but we are going to determine that as things unfold."
Takeda, Lincolnshire, Ill., and Lilly, Indianapolis, are actively assisting physicians in changing patients' therapy. The companies are increasing the number of professional samples of Actos supplied to physicians. By providing the additional samples, the companies want to enable physicians to provide Actos to patients who can no longer use Rezulin but need to continue using an agent to reduce insulin resistance.
Marketers of Actos say their product is better situated to step in for Rezulin than Avandia is. "In 1999, 40% of Rezulin patients were using an insulin combination therapy and 43% were using a sulfonylurea combination therapy," a Takeda spokesperson says. "Actos currently is the only FDA-approved product for use with both of those agents. Avandia is not."
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