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Profile: David Graham
David Graham was a participant or observer in the following events:
FDA scientist David Graham has analyzed data on 1.4 million Kaiser Permanente patients who took Vioxx, Celebrex, or another non-steroidal anti-inflammatory drug (NSDAID) between 1999 and 2003. Based on his findings, Graham believes there have been more than 27,000 heart attacks and sudden cardiac deaths in the US that would not have occurred had those patients been prescribed Celebrex instead of Vioxx. [Washington Post, 10/8/2004] When the FDA reviews a summary of his study, which Graham will present in France on August 25 (see August 25, 2004), his conclusion triggers “an explosive response from the Office of New Drugs.” Graham later tells Congress, “I was pressured to change my conclusions and recommendations, and basically threatened that if I did not change them, I would not be permitted to present the paper at the conference. One Drug Safety manager recommended that I should be barred from presenting the poster at the meeting.” [US Congress, 11/18/2004 ] In an August 12 e-mail, John Jenkins, director of the Office of New Drugs, suggests “watering down” the report’s conclusions because the FDA is “not contemplating” a warning against high-doses of Vioxx. In response, Graham says, “I’ve gone about as far as I can without compromising my deeply-held conclusions about this safety question.” In another e-mail, a different top official expresses concern about how the report might impact Merck. The person writes that the company should be warned beforehand “so they can be prepared for [the] extensive media attention that this will likely provoke.” [Wall Street Journal, 10/8/2004; Washington Post, 10/8/2004]
David Graham, associate science director for the FDA’s Office of Drug Safety, presents the findings of a study on Vioxx in a poster exhibit at an international medical conference in Bordeaux, France. According to Graham’s research, thousands of Americans have died from taking the drug. In his study, he analyzed data on 1.4 million Kaiser Permanente patients that took Vioxx, Celebrex, or another non-steroidal anti-inflammatory drug (NSDAID) between 1999 and 2003. According to Graham’s analysis of the data, the risk of having a heart attack or dying from heart problems is 3.2 times higher for Vioxx patients than people who do not use painkillers, and twice as high for those using Celebrex. Based on these figures, Graham estimates that more than 27,000 Americans have had heart attacks or died from sudden cardiac deaths as a result of taking Vioxx instead of Celebrex. In response to Graham’s study, Merck, the maker of Vioxx, issues a statement insisting that its drug is safe. Alise Reicin, vice president of clinical research at Merck, claims that numerous studies comparing the drug to a dummy pill found “no difference in the risk of having a serious cardiovascular event.” FDA spokeswoman Laura Alvey says the FDA has no plans to ban the drug. “Removing the drug from the market is not on the table,” she says. [Associated Press, 8/26/2004] Prior to the event, FDA officials had pressured him to water down his conclusions (see Mid-August 2004).
At a meeting attended by several officials and managers of the reviewing office of the FDA, David Graham, who recently presented a paper linking Vioxx to the deaths of more than 27,000 Americans, is asked by the director of the FDA reviewing office why he “even thought to study Vioxx and heart attacks because FDA had made its labeling change and nothing more needed to be done,” according to Graham’s later testimony to Congress. Also during the meeting, a senior manager from the Office of Drug Safety refers to Graham’s study as “a scientific rumor.” [US Congress, 11/18/2004 ]
David Graham, associate science director for the FDA’s Office of Drug Safety, appears before the Senate Committee on Finance to testify on the agency’s ability to protect the American public from harmful drugs. Graham, a twenty-year veteran of the agency, tells the committee that “the FDA, as currently configured, is incapable of protecting America against another Vioxx. We are virtually defenseless.” Graham was an early critic of Vioxx, a painkiller that was recalled in September (see September 30, 2004) because of its link to heart problems. Graham recounts how in August (see Mid-August 2004), the FDA tried to suppress a study he led which found that “nearly 28,000 excess cases of heart attack or sudden cardiac death were caused by Vioxx.” He says the study’s findings were “extremely conservative” and that “a more realistic and likely… estimate ranges from 88,000 to 139,000 Americans” of which “30-40 percent [or 26,400-55,600] probably died.” He notes that this figure is the “rough equivalent of 500 to 900 aircraft dropping from the sky… [or] 2-4 aircraft every week, week in and week out, for the past 5 years.” [US Congress, 11/18/2004 ] The remainder of Graham’s testimony focuses on problems within the FDA’s Office of Drug Safety (ODS). He makes the following points:
The Office of New Drugs (ONS), which approves all new drugs, is the same division that is responsible for taking regulatory action against those drugs after they have been released on the market. This is an inherent conflict of interest, he notes, because when a problem arises, recognizing it would require the ONS to acknowledge that it had made a mistake. Instead, the office’s “immediate reaction [to a problem] is almost always one of denial, rejection, and heat.” [US Congress, 11/18/2004 ]
The Office of Drug Safety (ODS) is subordinate to the Office of New Drugs, and consequently the management of the former sees its mission as pleasing the latter. [US Congress, 11/18/2004 ]
The culture of the FDA’s Center for Drug Evaluation and Research (CDER) “views the pharmaceutical industry it is supposed to regulate as its client, over-values the benefits of the drugs it approves and seriously under-values, disregards, and disrespects drug safety.” [US Congress, 11/18/2004 ]
The Office of New Drugs refuses to take regulatory action on any drug unless it can be shown with 95 percent or greater certainty that it is unsafe. However “to demonstrate a safety problem with 95 percent certainty, extremely large studies are often needed… [and] those large studies cannot be done.” Graham suggests the 95 percent rule makes as much sense as a person with a 100-chamber pistol loaded with 90 bullets saying that the gun is safe. “Because there is only a 90 percent chance that a bullet will fire when I pull the trigger, CDER would conclude that the gun is not loaded and that the drug is safe.” [US Congress, 11/18/2004 ]
The British medical journal Lancet publishes a paper by FDA scientist David Graham suggesting that tens of thousands of Americans probably died from taking Vioxx, a painkiller that was recalled in September (see September 30, 2004). His study looked at data on 1.4 million Kaiser Permanente patients that took Vioxx, Celebrex, or another non-steroidal anti-inflammatory drug (NSDAID) between 1999 and 2003. The data showed that the risk of having a heart attack or dying from heart problems was 1.6 times higher for patients taking standard-dose Vioxx compared with those using Celebrex. The risk was 3.6 times higher for those on high doses. Graham notes that Vioxx’s potential impact on the patient population was likely severe. Using the risk factors from Merck-sponsored randomized clinical trials, and extrapolating these to the estimated 106.7 million Vioxx patients, Graham says that the drug may have caused cardiovascular problems for 88,000-140,000 Americans. It is estimated that 44 percent of acute myocardial infarction’s are fatal. [Graham et al., 2005 ; London Times, 1/25/2005] In November, Graham told Congress that senior managers at the FDA’s Office of Drug Safety had delayed giving Graham permission to publish this study, even after it had been accepted by Lancet. [US Congress, 11/18/2004 ]
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