Los Angeles Times, Mar. 28, 2004

Drug firms stalled on strokes

Bayer memo: Delay implementation of FDA recommendation

Tracy Patton had just arrived at a community theater rehearsal in August 2000 when she felt such a searing explosion in the back of her head that it knocked her to her knees.

At the hospital in Louisville, Ky., doctors said Patton, then 37, had suffered a catastrophic stroke, and they predicted she wouldn't survive the night.

Patton defied the odds. But nearly four years later, she is so overwhelmed by simple tasks that she must post a "personal hygiene checklist" in her bathroom to remind herself to brush her teeth and flush the toilet.

At 15, Tricia Newenham was full of promise when she suffered her stroke in October 2000 while hanging out in her bedroom with a cousin. A Down East Mainer from a family of woodsmen and lobstermen, she had been named her middle school's student of the year and was on track to become the first Newenham to attend college.

She spent a month in a coma, and emerged blind and profoundly mentally impaired. When reminiscing about her former self, about her prom dates and nights at the movies, she dissolves into inconsolable sobbing, condemned to remember just enough of what her life was like then to understand how much less it is now.

Only hours before these devastating strokes, each victim had washed down a seemingly innocuous over-the-counter cold medicine, one of billions of doses consumed annually nationwide.

The medicines contained phenylpropanolamine, or PPA, the active ingredient in scores of popular non-prescription decongestants and diet aids until November 2000, when the Food and Drug Administration declared PPA unsafe and asked drug companies to stop selling it.

By then, the drug industry had spent more than two decades fending off growing evidence of a possible link between PPA and hemorrhagic stroke. But Patton and Newenham were among hundreds of PPA consumers who suffered attacks after a landmark study - sponsored by the drug industry itself - concluded in October 1999 that the use of PPA was associated with an increased risk of that deadliest form of stroke.

Recently obtained internal company documents show that rather than alerting the public, drug makers launched a yearlong campaign to keep the results quiet and stall government regulation.

By the time the FDA acted, 13 months and hundreds of strokes later, the companies had reformulated their brand names with little interruption in sales. The market for PPA has been estimated at $500 million to $1 billion annually.

In the interim, Americans continued to purchase PPA products right off the shelf and assume they were safe.

"It never even dawned on us," said Tim A. Bybee, Newenham's stepfather, speaking of the Triaminic product Tricia took shortly before her stroke. "It was in the store. Everyone uses it. It must be all right."

The Times reviewed thousands of pages of documents produced through discovery in PPA lawsuits and obtained from the FDA through a Freedom of Information Act request.

The documents demonstrate that the pharmaceutical industry consistently challenged any notion that PPA could be dangerous and dismissed evidence to the contrary. They also show that the manufacturers assured the public that PPA was safe even as some FDA scientists and industry officials were raising concerns.

As early as 1982, an FDA report warned that PPA had "the ability to cause cardiovascular effects, cerebral hemorrhage and cardiac arrhythmias."

Two years later, a memo from the medical services department at Sandoz Pharmaceuticals, which made the PPA products Triaminic and Tavist-D, referred to PPA as "an agent known to cause hypertension and stroke."

Yet the drug companies accelerated their marketing of PPA, winning FDA approval to sell prescription PPA products on an over-the-counter basis and introducing flavorful new formulas for children.

Upon learning that the 1999 study had found a stroke link, the drug makers opened a relentless assault on its methodology and on the integrity of the Yale University researchers who conducted it.

They did so despite having paid for the five-year, $5-million study themselves, approving its protocol and handpicking investigators who had previously expressed skepticism about a link between PPA and stroke.

Some documents show that the companies hoped to survive the 2000 cold season without pulling PPA products. Rarely do the internal memos indicate concern by corporate officials that PPA might pose a threat to the public.

Early in November 2000, for instance, two weeks after an FDA advisory panel concluded that PPA could be hazardous, an official with Bayer, which made Alka-Seltzer Plus with PPA, drafted a proposed "PPA Crisis Action Plan." Its stated objectives: "Delay mandatory implementation of FDA recommendation. Blunt PR impact by highlighting questionable study conclusions as they pertain to cough/cold products. Begin shipping PPA-free product as soon as possible."

Terry Tottenham, a lawyer for Bayer, said the plan was not implemented. But records and interviews show the industry largely followed that course.
The FDA eventually recommended the withdrawal of more than 100 PPA products, including popular cough and cold brands such as Robitussin CF and Dimetapp, and appetite suppressants such as Dexatrim and Acutrim. FDA officials said they did not move faster because the industry's efforts to discredit the Yale results effectively delayed the delivery of a final report.

"There were obvious concerns that we weren't getting the data because it was being held up by the people who sponsored the study," said Dr. Charles J. Ganley, director of the FDA's Division of Over-the-Counter Drug Products.

By Kevin Sack and Alicia Mundy