Suits use Yale study tying PPA to strokes



Yale researchers who uncovered the correlation between the drug phenylpropanolamine, or PPA, and life-threatening strokes in 1999 are still feeling the resonating effects of their research, as the first of thousands of suits against the companies that produced PPA are finally being decided.

PPA was the active ingredient in cold remedies such as Alka Seltzer Plus and Dimetapp, and in the diet drug Dexatrim. However, as individual cases and clinical studies increasingly suggested that PPA might lead to hemorrhagic stroke, the Food and Drug Administration, or FDA, mandated that PPA producers conduct an epidemiologic study. After researchers found a correlation between the drug and stroke, victims used the information to sue pharmaceutical companies — and the research was called into question.

In 1991, pharmaceutical companies commissioned Yale School of Medicine faculty members Dr. Lawrence Brass, professor of neurology and epidemiology and public health; Dr. Walter Kernan, associate professor of internal medicine; and Dr. Catherine Viscoli, research scientist at the Yale School of Nursing, among others, to take part in what was named the “Yale Hemorrhagic Stroke Project.”

Hemorrhagic stroke is a blood vessel rupture in the brain that typically kills more than a third of all victims within a month. The study enrolled patients who had taken PPA shortly before their strokes. Researchers uncovered a statistically significant association between the drug and the strokes in women, and the FDA ordered a withdrawal of the product in November 2000.

Brass said because there are a variety of alternatives to PPA, the FDA accepted a weaker association with stroke than other studies might demand.

“Our study was not designed to look for ‘why’,” Brass said. “We were asked by the FDA to help them make a policy decision — and they set the parameters for the degree of certainty — The FDA decided to take it off the market, even though the absolute risk is really small. We estimated the risk was one [stroke] for 1 or 2 million doses. That’s almost in the range of aspirin safety.”

Brass also said the cause of such strokes is often hard to identify, so for lack of any other explanation, many individual stroke cases were blamed on PPA.

“The problem with stroke is that no matter what tests you do, if you take out gallons of blood, or [do imaging] until they glow in the dark — you can’t find a clear etiology,” Brass said. “In an individual case, it’s extremely hard to say, and because you don’t find anything else going on — it’s easy to say it’s PPA.”

Despite the difficulty in identifying PPA’s connection to strokes, researchers found the designated level statistical significance and the study’s scientific advisory group directed them to contact the FDA immediately. Pharmaceutical companies, who were contacted the same day, accused researchers of a breach of contract, and filed a suit that was subsequently dismissed.

“As I recall, the contract had given [pharmaceutical companies] a period of review time that we understood to be reviewing the manuscript,” Viscoli said. “We weren’t in breach of contract because we didn’t release the manuscript — we contacted the FDA verbally.”

Many products containing PPA may still be circulating in U.S. households. In a lawsuits concerning PPA, a survey commissioned by plaintiffs estimated that in 2002, 3.5 million homes in the United States still had products containing the drug.

The first few of over 2,500 suits filed against pharmaceutical companies are finally being decided in courts in California and New Jersey. However, because the suits were filed before the Yale researchers’ findings were made public, the few recently settled were determined in favor of the defense.

“That’s the limitation of the legal system with respect to malpractice in this country,” Brass said. “Juries can be pretty smart, and people can be very smart, but some of the concepts people need to understand can be very difficult to convey over the course of a few weeks. Justice isn’t served in that approach.”

The lawyers for the pharmaceutical companies have attacked the study and the researchers, suggesting they attempted to show a correlation in order to get their study published.

In one suit in Seattle, lawyers attempted to prove the study was unreliable and have it deemed inadmissible in court. The Honorable Judge Barbara Jacobs Rothstein chastised the defense for its approach and officially deemed the research to be of the highest quality. While Yale never made a public statement in support of its researchers, the Yale General Counsel’s office represented the researchers and their work.

Brass said he would rather see questions over the quality their research — issues that have thus far been raised by no one outside of the drug companies — settled in a scientific forum.

“Our feeling was that the courtroom and media was not the place to determine the quality of medical research. No one has written the New England Journal of Medicine [where the study was published] and said ‘we have serious concerns about this research.’ That’s the way scientific discourse should take place,” Brass said. “Supposed experts in the field are willing to say we somehow put the public at risk by publishing the results. They’re willing to do that in the courtroom while paid tens of thousands of dollars, but they are not willing to write a letter to be judged in a peer-reviewed forum — that’s the worst kind of professional. That’s despicable.”

None of the researchers, however, expressed ill will to the companies. Kernan said they were permitted freedom in the lab and never felt pressured to make a certain finding.

“Industry worked closely with us on the study,” Kernan said. “They need to get more credit than they were given for how they conducted themselves during the research. The investigators were focused on conducting the research, finalizing it, and getting it out. We weren’t hindered, substantially, by anything industry did or didn’t do.”

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