DEATH BY PRESCRIPTION
Rothschild, Matthew
DEATH BY PRESCRIPTION BY MATTHEW ROTHSCHILD Frank Israel was eighty-four years old and suffering from arthritis when his doctor prescribed Feldene (piroxi-cam), an antiarthritic drug manufactured...
...A paper detailing the toxic effects of Feldene was submitted to the British Medical Journal in 1982...
...What's more, he added, "a conclusion by FDA that ADRs [Adverse Drug Reactions] were not reported as required by agency regulations does not imply any particular regulatory action by the agency...
...Pfizer may have been sitting on these data for as long as two-and-a-half years, the FDA found...
...When Pfizer found out about the submission, it swung into action...
...In these matters, it is generally better not to stir the pot any further," Roger Sachs, medical director of Pfizer Labs, wrote in an internal company document...
...the company settled for less than a million dollars...
...DEATH BY PRESCRIPTION BY MATTHEW ROTHSCHILD Frank Israel was eighty-four years old and suffering from arthritis when his doctor prescribed Feldene (piroxi-cam), an antiarthritic drug manufactured by the Pfizer Corporation, which has been on the U.S...
...I don't imagine that we tell every country what every other country has got in their documents," Pfizer's chairman Pratt swore in his deposition...
...I'm willing to take all bets that pharmacists and drug companies would file a class-action suit against it...
...market did Pfizer mention in its package insert that Feldene could cause fatalities...
...How Pfizer and the FDA pushed a lethal capsule died of congestive heart failure...
...The reasons for approving Feldene in the first place and for letting Pfizer get off scot-free transcend this specific instance of corporate malfeasance...
...For its part, Pfizer continues to maintain that Feldene is safe and effective...
...The spontaneous reports to us represent only a tiny fraction of the total number," said Robert J. Temple, director of the FDA's Office of Drug Research and Review, at a public hearing on Feldene in February 1986...
...A decision to take regulatory action, and what that regulatory action might be, is made only after careful consideration of all the circumstances relating to the deficiency in question...
...sixteen of these were rushed through in December...
...It can also cause congestive heart failure and such phototoxic reactions as burning, itching, redness, and small swellings on the skin after brief exposure to light...
...The company's computer file "was not designed to allow retrieval of the data broken down the way we need it...
...The balance is a delicate one...
...One of these involved a fatality...
...One was a wrongful-death suit brought by the three daughters of Cerina Weidenbacher, who died after allegedly taking the drug...
...When all his vital signs got low, I took him into the hospital," recalls Mary Israel, his widow, who lives part of the year in St...
...Other European countries followed suit during the next two years, and the adverse reports began to appear...
...At least 1.75 million elderly American people now receiving this drug are at risk of developing life-threatening gastrointestinal reactions," he estimates...
...While this continues to be an important aspect of FDA's mission, we believe, at the same time, we should work towards facilitating the prompt development and approval of safe and effective therapies...
...Frank was taking Feldene, and he died," she says...
...Pfizer has never provided either of these warnings to doctors or consumers in the United States...
...market, Pfizer took out an advertisement in the Medical Tribune and disseminated a press kit that claimed Feldene was "unsurpassed by aspirin...
...M.R...
...But it did not perform any new tests...
...The most widely sold nonsteroidal anti-inflammatory drug in the world, Feldene is marketed in 106 countries to more than twenty million people...
...Pfizer faces a $3.25 million suit filed in Milwaukee by the widow of Charles Karpfinger, a ninety-year-old man who, according to the claim, developed an ulcer after taking Feldene and subsequently died...
...By the analyses we usually depend on, the pivotal studies do not demonstrate statistically significant proof of effectiveness...
...The law requires the manufacturer to demonstrate "substantial evidence" of efficacy by conducting two "adequate and well-controlled studies...
...Another suit, filed in Ventura, California, seeks an undetermined amount of money in actual and punitive damages for the death of Mary Price, a sixty-year-old woman who, according to the claim, died from gastrointestinal bleeding after taking Feldene...
...We can't regulate doctors...
...The FDA found this to be illegal...
...Feldene users are elderly...
...Pfizer may be less fortunate on the legal front, for it faces challenges in court from alleged Feldene victims or families of alleged Feldene victims...
...The chief advantage of Feldene is convenience: Unlike other antiarthritic drugs, it is administered just once a day...
...Or, if the violation is committed "with the intent to defraud or mislead," up to three years in prison or a fine of not more than $10,000, or both...
...I assume the only possible reason would have been the normal data flow delay that's involved in our organization...
...If the FDA agreed to the partial ban, it would amount to "intervention in the practice of medicine," Nida says...
...Frank A. Silvestri, a New Orleans attorney representing the family of a Feldene victim, pressed Pratt: "When you say that there were no unanticipated or unexpected results, would it be fair to say that you anticipated a certain number of people who would take this drug would experience fatalities...
...I said, 'Frank, I'm going home...
...This application was rejected in December 1979, and the company resubmitted an application in May 1980...
...According to FDA documents and the testimony of FDA officials before a Congressional subcommittee, the Pfizer studies were terribly flawed...
...None was forthcoming...
...A condensed version appeared in 1985 in the publication, Smith noted...
...The overwhelming majority of the fatalities attributed to Feldene have been elderly people...
...These are not the only victims of Feldene...
...Under the heading "Action," the Pfizer official recommended that the company "Contact editor (well known to Pfizer) to discuss paper as well as Pfizer reply...
...they want to please business...
...Pfizer's chairman Pratt acknowledges that the company tried to have Arnold and Porter put the heat on the FDA...
...He was well until he took it...
...Not until two years after placing Feldene on the U.S...
...Vodra called to tell me of the concern of his client, Pfizer, about long delays in the approval of piroxicam [Feldene]," Crout noted in a memorandum of the conversation...
...Those figures, based on a November 1985 FDA printout, may greatly underestimate the total number of adverse reactions to Feldene...
...As a result, Harter warned, "we should recognize that this 'safety' data base is 'softer' than we are accustomed to...
...The total number of these was twenty-six, with twenty-three of the twenty-six involving deaths of patients," Jones reported in another document...
...Her husband "died from Feldene," she says...
...Wolfe says elderly people have trouble clearing the drug, which has an exceptionally long half-life...
...The ads were canceled, says Feather, though some of the offending material reappeared in other advertisements...
...Commissioner Hayes also alluded to a shift in the FDA's priorities that may have had something to do with giving Feldene the nod...
...The ad campaign prompted another slap on the wrist...
...it simply reanalyzed the old data...
...Feldene can cause stomach and intestinal bleeding, ulcers, intestinal perforation, hematemesis (vomiting of blood), and melena (blood in the stools...
...In the United States, it is sold by prescription in ten-milligram and twenty-milligram capsules for the treatment of rheumatoid arthritis and osteoarthritis...
...Again, the FDA rejected it, this time in April 1981...
...Pfizer also expressed concern about another paper on Feldene in 1982...
...It wouldn't be productive...
...The film "makes claims for the safety and effectiveness of an unapproved product currently under study by Pfizer Pharmaceuticals which is in violation of the Food, Drug, and Cosmetic Act," the FDA's Mary Doug Tyson informed Pfizer on June 17, 1981...
...physicians and optimally to FDA reviewers as well during the deliberations about Feldene's safety and ad-' verse reaction labeling...
...In September 1981, Pfizer resubmitted its application yet again...
...She, too, had arthritis and took Feldene for seven months...
...Special care should be taken when prescribing, especially with the elderly and those with a past history of ulcer disease...
...she settled for $5,000...
...Mr...
...market since 1982...
...These institutional handicaps are not going to change from Administration to Administration...
...We will normally ask for cancellation of offending advertising material," he says...
...This is a business environment, an anticonsumer environment," he says...
...Since Feldene was introduced in the United States in April 1982, the FDA [U.S...
...In October 1982, Pfizer submitted twenty-six adverse drug reports from Britain, all dated August 26,1982...
...Marvin Frank stated that Pfizer had no intention of 'schlepping around the world' to find other adverse drug reactions," Jones noted...
...Jessie Sprague was eighty-one...
...The National Council of Senior Citizens has urged the FDA to take the drug completely off the market...
...Feldene is the latest in a series of drug-company scandals, akin to A.H...
...If they accept that, I wouldn't call that killing...
...An additional suit against Pfizer has been filed in Chicago, and several other lawyers are researching possible Feldene actions...
...Pfizer was in the same boat as the other companies," she says...
...M.R...
...Optimally" was putting it lightly...
...If the situation persists, then we might seek more formal means, such as seizing the product, which has rarely been done, or prosecuting the company...
...At the moment, the FDA is considering the petition by Sidney Wolfe's Health Research Group to ban Feldene for patients aged sixty and over...
...I'll see you tomorrow.' I didn't even kiss him goodbye...
...Feather told Pfizer there was "no evidence" to demonstrate superiority to aspirin...
...Other legal actions loom...
...Vodra said he was trying to calm Pfizer but that the situation was getting worse and Pfizer was considering appeals to the Bureau Director and Commissioner...
...Dotti Pease, an FDA consumer safety officer who worked on the Feldene case, elaborates on what some of those "circumstances" might have been...
...If the finding is alarming, it shall be reported immediately...
...Penalties for violating these regulations are up to one year in prison or a fine of $ 1,000, or both...
...Many of their career employees have left...
...But for Pfizer, Feldene has been a gold mine...
...A decision is expected soon, but the FDA press office indicates the agency may side with Pfizer...
...Only three of the thirty represent significant therapeutic advances, the FDA admits...
...If your question is why it took so long, I don't know that," Pratt answered...
...Approval of the New Drug Application for Feldene clearly presented problems," Arthur Hull Hayes, then FDA Commissioner, testified before the House subcommittee on intergovernmental relations and human resources...
...Edmund T. Pratt Jr., chief executive officer and chairman of the board of Pfizer, said in a deposition on August 12, 1985, "There has been no basic, unexpected result from the launching of the product...
...Pratt replied, "Yes, I think that's a fair assumption...
...Not a single adverse reaction warning, precaution, or contraindication was discussed," Tyson wrote, "implying an absolute safety profile which has not been demonstrated to date...
...Despite that complication, we believe that it is our obligation to look at the studies provided, to see whether, although less than optimal in design, they can be considered adequate and well-controlled...
...In the United States alone, eight million prescriptions for Feldene were sold in 1984, worth $226 million to the company...
...as an alleged example of agency inefficiency...
...There's nothing in the Food and Drug Administration regulations that provides for what Sid Wolfe calls for," says press officer Ed Nida...
...Pfizer had failed to meet this requirement, the FDA found...
...Banging the Drums Pfizer has gone to great lengths to market Feldene, and in its aggressive advertising campaign, it has run afoul of the law...
...The agency has always served effectively as the public's protector against unsafe and ineffective drugs," he testified...
...The concomitant use of aspirin in so many pivotal studies has made it difficult to demonstrate any other drug effect," concluded John G. Harter, FDA's group leader on the Feldene application, in an internal FDA memo dated March 9, 1982...
...they speak to certain political and institutional conditions of the regulatory process...
...A letter to the editor praising Feldene could initiate a public debate and create more adverse publicity...
...But Feldene also represents a case study in how the FDA fails to perform its regulatory function...
...Silvestri offers a different explanation...
...Piroxicam [Feldene] produces an unnecessarily high incidence of severe ulcer disease," it concluded...
...He also said that piroxicam is being used widely in the political arena...
...Under pressure from the Irish government, Pfizer in 1981—before the FDA approved Feldene for the United States-agreed to warn doctors in Ireland that elderly patients using Feldene faced an increased risk of gastrointestinal bleeding...
...As a result of the Feldene, she says, he had gastrointestinal hemorrhaging and eventually Matthew Rothschild is managing editor of The Progressive...
...Pfizer has no intention of 'schlepping around the world' to find adverse reactions to Feldene, the company's counsel told the FDA Far from reporting these adverse reactions within fifteen working days, Pfizer sat on the data for as long as thirty months...
...But sometimes the company has found it in its interest not to enter the public debate...
...While the FDA deliberated on Pfizer's application, people were dying in Europe as a result of taking Feldene...
...Mark Novitch, then acting Commissioner of Food and Drugs, responded in a letter dated November 3 of that year: "The decision to approve the drug would not have been affected had the agency known about them," Novitch wrote to Weiss...
...Pfizer originally submitted a new-drug application for Feldene to the FDA in March 1978...
...the drug went on sale in September 1979...
...The reaction onset dates were between one month and two-and-a-half years prior to them being reported to Pfizer, New York...
...Another woman, who chooses not to disclose her name pending a possible lawsuit against Pfizer, had a similar experience...
...She stopped using the drug only when she entered the hospital in January 1986 with gastrointestinal bleeding...
...Her daughter, Anna Perdue, blames the Feldene...
...We recently became aware of a paper submitted to BMJ discussing twenty cases of gastrointestinal hemorrhage from a district hospital in the U.K.," noted an internal Pfizer memorandum dated July 26, 1982...
...There are too many countries...
...She died the next month of congestive heart failure...
...We feel such reports should have been available as a minimum to Pfizer's U.S...
...55 per cent of the U.S...
...In spite of discussions between authors and Pfizer U.K., the conclusion of the paper was that Feldene 'carries an unacceptably high incidence of side effects.' [Two Pfizer representatives] visited the editor of the BMJ to make him aware of the deficiencies of the report and the discrepancy between data presented and conclusions drawn...
...She remains outraged about Feldene: "This thing is a killer," she says...
...He took it three months, and then he disintegrated...
...Feldene was shown to be statistically superior to aspirin' are misleading...
...The FDA is simply outgunned by multinational companies, which have more resources—money, power, influence—than the agency that supposedly regulates them...
...The company is even considering an increase in the dosage of Feldene from ten and twenty milligrams to a "loading dose" of thirty milligrams, forty milligrams, or sixty milligrams...
...Representative Ted Weiss, New York Democrat, who heads the House subcommittee on intergovernmental relations and human resources, asked the FDA about this in 1983...
...He, too, encountered opposition from Pfizer...
...He was a very strong man...
...Roujeau, helped conduct a study on Feldene and submitted an article in France...
...Pratt: "Oh, I suspect, as part of our process of keeping the public well informed, if we thought an article was unfair, we would not try to kill it...
...But part of the problem with the FDA is built into the regulatory system...
...In all four of them (two for rheumatoid arthritis and two for osteoarthritis), patients took aspirin along with Feldene...
...At the reception, Pfizer showed a film promoting Feldene...
...Evaluating the safety of the drug also revealed problems...
...The conclusion of the paper is that we may be using too high doses and thus the paper is potentially dangerous...
...Marvin Frank, Pfizer's senior food and drug counsel, responded for the company: "Dr...
...Pratt, the head of Pfizer, was asked by lawyer Silvestri why the company didn't report foreign adverse reactions more promptly...
...The FDA did not find out about Fel-dene's dubious record in Europe until six months after the agency had approved the drug...
...We didn't make a big deal about it because all the companies were doing the same thing...
...Why didn't the FDA take action against Pfizer for failing to report promptly, as the law required, the foreign adverse reactions to Feldene...
...Pfizer is the fourth largest pharmaceutical company in the country, with more than $4 billion in sales last year...
...By the time she got home from the hospital, Frank was dead...
...The FDA asked the company to refrain from future showings of the film...
...Indeed, the company expected the drug would kill some people...
...FDA regulations stipulate that any company exploring the possibility of marketing a new drug in the United States must "promptly investigate and report to the FDA and to all investigators any findings associated with the use of the drug that may suggest significant hazards, contraindications, side effects, and precautions pertinent to the safety of the drug...
...Statements such as...
...I think these delays were intended so that Feldene could continue to be vigorously marketed in this country," he wrote to the FDA on February 13, 1986...
...The Act restricts "promotional claims of safety or effectiveness while the drug is under investigation to establish its safety or effectiveness...
...Since these adverse reports all came from one country and were all given the same date, the FDA asked Pfizer what assurance it had that there were no other adverse reactions or deaths from other countries...
...Robins's Dalkon Shield and Eli Lilly's Oraflex, in which giant pharmaceutical companies—as a matter of corporate policy—place profits before human life...
...The paper was initially rejected by the British Medical Journal, but not because of pressure from Pfizer, according to Richard Smith, the assistant editor...
...When the FDA asks for more information, even though you don't believe it's justified, you try to do what you can to satisfy them, so sometimes you do more trials," said chairman Pratt in his deposition...
...In the tradition of Washington lobbying, Pfizer hired a powerful law firm, Arnold and Porter, to plead its case before the FDA...
...Last year, the FDA set a record by approving thirty new drugs...
...It then took no action after the company repeatedly violated the law, both in its advertising of Feldene (see sidebar) and, most blatantly, in its tardy reporting of fatalities and other adverse drug reactions...
...I read that Feldene causes bleeding, and that's what happened to Frank...
...The Norwegian authorities have submitted a paper to the European Journal of Clinical Pharmacology on 103 adverse reactions reported with Feldene during one year," the same Pfizer document noted...
...Also in 1981, after British authorities presented evidence linking Feldene to three fatal congestive heart failures, Pfizer agreed to warn doctors there that Feldene could induce congestive heart failure...
...Wolfe has petitioned the FDA to ban, "as an imminent hazard to the public health," the use of Feldene in patients aged sixty and over...
...Pfizer was required by law to furnish that information...
...It could not be specifically determined as to when the Pfizer [International] facility found out about these reactions," Betty L. Jones of the FDA's Regulatory Management Branch stated in an internal document, "but record review found it may have been eight months to two-and-a-half years prior to it being reported to Pfizer New York...
...I would call that making it more accurate...
...The other was filed by a woman who said she had minor reactions to the drug...
...But Pfizer disregarded this...
...I stayed till four in the morning...
...While the Food and Drug Administration (FDA) was still considering Pfizer's Feldene application, the company sponsored a cocktail and buffet reception at a meeting of the American Rheumatism Association in Boston...
...We believed we were being unreasonably delayed," he said in his deposition...
...But when the delay gets interminable, then you try to find ways around it...
...Petersburg Beach, Florida, and part in Shermans Dale, Pennsylvania...
...By that time, it was too late...
...Pfizer also tried "to use data transformations and to insert dummy values in order to show effectiveness," Harter stated...
...We find the information contained in this press-kit labeling piece to be misleading and in some cases false," Kenneth R. Feather, acting chief of the FDA's Drug Advertising Regulatory Branch, wrote to Pfizer on July 13, 1982...
...From your International Division, there are twenty-six reports of reactions, many of which are serious, occurring in 1979, 1980, and 1981," wrote William J. Gyarfas, the FDA's director of the division of oncology and radiopharmaceutical drug products, to Pfizer in a letter dated December 9, 1982...
...Nowhere is this more obvious than in the agency's haste to approve new drugs...
...On February 10, 1984, a letter to the editor was published in the Arizona Republic on the subject of Feldene...
...M 'Keeping the Public Well Informed* Whenever Pfizer became aware of a negative article on Feldene that was being considered for publication in medical journals in Europe, it did all it could to squelch the stories...
...Research support for this article was provided by the Fund for Investigative Journalism...
...Switzerland was the first country to permit Pfizer to market Feldene...
...We would try to modify it by discussion with the author or the publisher, and by bringing information available to them that we think brings into doubt the validity of their article...
...The company has already settled two such suits...
...Nevertheless, the FDA decided on April 6, 1982, to approve Feldene for use in the United States...
...Shortly after launching Feldene in the U.S...
...Pfizer has been unruffled by the reports of fatalities attributed to Feldene...
...On March 11, 1982, one month before the agency approved Feldene, William Vodra of Arnold and Porter telephoned J. Richard Crout, the director of the FDA's Bureau of Drugs...
...A little more than a year ago, my uncle died," a reader wrote, "and on his death certificate the cause of death was given as 'overexposure to Feldene.'" When a Pfizer representative saw the letter, she sent it to headquarters to see about a possible public reply...
...Studies identified by the sponsor as pivotal were carried out among patients who were also receiving aspirin...
...Pfizer's chairman, Edmund T. Pratt Jr., was asked at a deposition by lawyer Frank Silvestri about this practice of the company: Silvestri: "Do you know whether or not this company has ever attempted to kill any articles that were unfavorable to Feldene...
...The regulations also require pharmaceutical companies, once their drugs are on the market in the United States, to furnish "as soon as possible, and in any event within fifteen working days of its receipt by the applicant, complete records or reports concerning any information of the following kinds: information concerning any unexpected side effect, injury, toxicity, or sensitivity reaction or any unexpected incidence or severity thereof associated with clinical uses, studies, investigations, or tests...
...It's a different kind of organization...
...They are being replaced by political people...
...The majority of these reports came from Germany and Canada and were received by Pfizer International in August and September 1983...
...They can't really come up with the data on case-report forms," Harter said...
...A French physician, J.C...
...It's not anyone buying anybody off, or pressure from any company...
...From a consumer's point of view, this is the worst FDA in the last twenty-five years," says Ben Gordon, research analyst for the National Council of Senior Citizens...
...Pfizer dumped another batch of tardy foreign adverse reactions on the FDA between July and November 1983...
...If it's going to kill you to get rid of the arthritis," says Perdue, who lives in Dayton, Ohio, "then it's really not worth it...
...The FDA bent the rules in the first place to allow Pfizer to market the drug in the United States...
...Sidney Wolfe, director of Public Citizen Health Research Group in Washington, D.C., in a January petition to the FDA...
...These included almost two dozen fatalities...
...The paper was eventually published in 1984...
...Our paper," he wrote in the British publication The Lancet on November 30,1985, "has been accepted by a French journal but publication has been delayed for several months by the intervention of the company marketing piroxicam [Feldene] in France...
...The hospital called to tell her he had died of massive bleeding in the bowels...
...Jones concluded that "Pfizer's system for requesting and reporting of international adverse drug reactions is inadequate," but added "there was no evidence of criminal activity...
...Feldene brought in $400 million in sales in 1984, making it the company's most lucrative pharmaceutical product...
...Food and Drug Administration] has received a total of 2,621 nonfatal and 182 fatal adverse reaction reports associated with the drug's use," wrote Dr...
...We believed that we were past the time it should have been approved here, and that we needed to do everything we could to get that approval that should have been given to us...
...And by that I mean, people would take the drug and die...
...Pfizer was aware of this, but did not inform the FDA as required by law...
...According to Gordon, the change is purely ideological...
...The FDA's primary reason for not granting approval was that Pfizer had not conducted the necessary tests...
Vol. 50 • June 1986 • No. 6
