From Our 2004 Archives

Unsafe Drugs - Who Is Responsible?

The drug Vioxx (rofecoxib) was approved in 1999 by the FDA. This year, after being on the market for more than 5 years, the maker of Vioxx, Merck, voluntarily withdrew it because the drug appeared to be associated with an increased risk of strokes and heart attacks. How could the whole process of drug approval in the US have gone so awry? Who is responsible? Major fingerpointing has started and a US Senate investigation is underway. Heads are surely going to roll over the Vioxx issue but the question is whose?

Traditionally, most research and development in medicine were done with federal funds under the auspices of academic institutions that prided themselves on being independent and objective. Truth and honor was the aspired code. Then, as funding sources changed, academic institutions and individual researchers developed increasing financial ties to commercial companies. This raises concerns as to who can now serve as an objective overseer and critic of the pharmaceutical industry.

The journal Lancet has just published the results from a cumulative meta-analysis which show that the unacceptable cardiovascular risks of Vioxx were evident as early as 2000 -- a full 4 years before the drug was finally withdrawn from the market by its manufacturer Merck. The Lancet editorial goes on to say that "...this points to astonishing failures in Merck's internal systems of post-marketing surveillance, as well as to lethal weaknesses to the US Food and Drug Administration's regulatory oversight."

Her Comment: It seems that the FDA views the pharmaceutical industry as its client -- one that need to be encouraged and nourished. This makes it virtually impossible for the FDA to also regulate and discipline the drug companies. The bottom line is -- to whom does the FDA ultimately owe its allegiance? The drug industry or to the drug consumer? I don't see how the FDA can continue to have it both ways.

His Comment: The FDA is on the hot seat and, in my opinion, that is right where it deserves to be. Americans have a reasonable right to expect the FDA to protect them from undue harm from drugs from the pharmaceutical industry.

In the past the FDA has had similar problems. For example, in the 1960s the drug thalidomide was on the market in many countries but not yet in the US. The FDA narrowly averted approving thalidomide. Only the efforts of Dr. Helen Taussig, a pioneering pediatric cardiologist at Hopkins, saved the day. She had personally seen children with severe limb malformations from thalidomide in Europe.

Barbara K. Hecht, Ph.D.
Frederick Hecht, M.D.
Medical Editors, MedicineNet.com

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FDA, Drug Industry Under Fire on Safety

By Amanda Gardner
HealthDay Reporter

THURSDAY, Nov. 18 (HealthDayNews) -- U.S. Food and Drug Administration officials defended their record on drug safety Thursday in the face of attacks from both inside and outside the agency.

Drug giants also found themselves with their feet held to the fire during a Senate Finance Committee hearing.

Dr. David Graham, an FDA reviewer who initially recommended the arthritis drug Vioxx be taken off the market, told committee members that the blockbuster medication may have caused up to 160,000 heart attacks and strokes, or 1 percent of the entire state of Florida.

"I would argue that the FDA, as currently configured, is incapable of protecting America against another Vioxx," the Associated Press quoted Graham as saying. "We are virtually defenseless."

The drug's maker, Merck & Co., voluntarily withdrew Vioxx in late September after its own studies found an unacceptable cardiovascular risk. The FDA did not force the recall.

Sen. Jeff Bingaman (D-N.M.) pointed to the FDA's own inner workings as the culprit. "The culture within the FDA, being one where the pharmaceutical industry -- which the FDA is supposed to regulate -- is seen by the FDA as its client instead," he said.

Dr. Sandra Kweder, director of the Office of New Drugs at the FDA's Center for Drug Evaluation and Research, spoke up for her agency. The "FDA worked actively and vigorously with Merck to inform public health professionals of what was known regarding cardiovascular risk with Vioxx, and to pursue further definitive investigations to better define and quantify this risk," she said. "Indeed, the recent study findings disclosed by Merck, leading to its decision to voluntarily withdraw Vioxx from the marketplace, resulted from FDA's vigilance in requiring these long-term outcome trials to address our concerns."

The drug has had a somewhat checkered history. The FDA approved Vioxx in May 1999. In 2002, labeling changes were required to highlight an increased risk in cardiovascular events, especially at the higher, 50-milligram dose.

Raymond Gilmartin, Merck's chairman and CEO, said the company "puts patients first," according to prepared testimony. He told the panel that Merck had conducted many studies on Vioxx both before and after its approval, and the research had found the results at best safe and at worst contradictory. He said he was surprised by the results of the study that led to its withdrawal. "Merck believed wholeheartedly in Vioxx," he said. "In fact, my wife was a user of Vioxx until the day we withdrew it."

Graham was the lead author on one study, which involved almost 1.4 million Kaiser Permanente patients. According to the AP, the study found high doses of Vioxx tripled the risk of heart attacks and sudden cardiac death.

Graham also testified that at least five other drugs are on the market today should be looked at seriously to see whether they should remain there, the AP reported. He cited the acne drug Accutane,made by Hoffmann-La Roche Inc. (Roche); the weight-loss drug Meridia, made by Abbott Labs; the anti-cholesterol drug Crestor, made by AstraZeneca; the pain reliever Bextra, made by Pfizer Pharmaceuticals; and the asthma drug Serevent, made by GlaxoSmithKline.

According to the AP, Graham has testified that his bosses pressured him to downplay his Vioxx conclusions. A statement issued Wednesday by Dr. Lester Crawford, acting commissioner of the FDA, said that "the project officer voluntarily chose to revise his conclusions, and he did so, in his own words, 'without compromising my deeply held convictions.'"

According to Crawford, that "project manager," assumed to be Graham, did not submit a draft report requested by his superiors until after Vioxx had been voluntarily withdrawn from pharmacy shelves. "Senior drug experts in [the] FDA did not have this report or the underlying data prior to that time," Crawford said. Crawford also alleged that Graham had submitted his findings to The Lancet without going through the "long-established peer-review and clearance process established for scientific papers submitted by FDA scientists."

Both Crawford and Kweder emphasized that additional steps are being undertaken by the FDA to strengthen its mission to protect the public's health. This included a "five-step plan to strengthen its drug safety program," Kweder pointed out, and three guidances designed to "assist pharmaceutical firms in identifying and assessing potential safety risks not only before a drug reaches the market but also after a drug is already on the market."

SOURCES: Nov. 18, 2004, Senate Finance Committee testimony of Sandra Kweder, M.D., deputy director, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration; statement from Lester Crawford, D.V.M., Ph.D., acting commissioner, U.S. Food and Drug Administration; Senate Finance Committee statement, Raymond Gilmartin, chairman and CEO, Merck & Co., Inc.; Associated Press

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