SINCE the withdrawal of the drug Vioxx in September, local doctors are continuing to prescribe other drugs in the same 'cox-2 inhibitor' class, such as Arcoxia, Celebrex, Mobic and Bextra, but an editorial to run in the February 2005 Annals of Internal Medicine recommends that doctors should avoid prescribing any of those drugs for patients who may be at risk of heart attack.

Also, a new concern about the pain killer Bextra, a drug not widely prescribed in Bermuda, has led to strengthened warnings by manufacturer Pfizer, and to additional questions about the US Food and Drug Administration's (FDA) relationship with Pfizer.

Vioxx, a drug taken by thousands of Bermudians over the last four years, was withdrawn from the market by manufacturer Merck on September 30 after allegations that Merck had covered up evidence that Vioxx was responsible for a higher incidence of heart attack and stroke than test patients given a placebo or other drugs.

Last Wednesday, the board of Merck appointed a seven-member special committee of outside directors to investigate the company's actions and to respond to shareholder litigation.

A local pharmaceutical source confirmed that Bextra is prescribed in Bermuda, but at only a fraction of the number of prescriptions which had been filled for Vioxx.

"When Vioxx was withdrawn, doctors prescribed more Arcoxia, Celebrex and Mobic than Bextra," she said. All of those drugs are called 'cox-2 inhibitors', different drugs which were developed to deal with pain and inflammation and which inhibited the cox-2 enzyme, but which were more gentle on the stomach than aspirin and some other traditional pain killers, and were presumed to lower the incidence of ulcers and gastrointestinal bleeding.

Last week, the FDA warned of potential heart problems associated with the use of Bextra, particularly in people who have recently had heart bypass surgery, and said that it would be strengthening label warnings to that effect, as well as warning of the possibility of severe skin reactions to the drug.

The wide and negative US media coverage of the FDA in the wake of the "whistle-blower" testimony of Dr. David Graham to the Senate Finance Committee has clearly put the FDA and other drug manufacturers on the defensive.

Dr. Graham testified to the Committee, chaired by Senator Charles Grassley, that the FDA had put him under heavy pressure not to give negative testimony on Vioxx, and that when he refused, FDA managers attempted to malign his reputation and denigrate the quality of his work.

Unfortunately for the FDA and its Commissioner Dr. Lester Crawford, Dr. Graham, a devout Catholic who sees his work on drug research as a vocation, gave damning and credible testimony about the dangers of Vioxx and of a culture of pandering to drug companies that made the FDA dangerously ineffective in assessing the safety of drugs that had already been approved.

During that testimony, Dr. Graham also warned that Bextra and other drugs prescribed here, Accutane, Crestor and Serevent, should come under further scrutiny.

Last week on CNN, broadcaster and commentator Lou Dobbs interviewed Dr. Graham and began by saying that the US owed him a great debt. He asked Dr. Graham about his current position with the FDA.

"I think my position is tenuous," answered Dr.Graham. "I continue to do the work I love and am very effective at, but in an environment of hostility, of threats, of intimidation, where if management had its way, I would be gone in a nanosecond, or transferred somewhere I couldn't be effective."

Dobbs said that most people in the country had looked to the FDA to serve the consumers of prescription drugs, but it seemed that the public was not the FDA's main constituent. Dr. Graham agreed, and said: "The problem with the management and the culture of the FDA, at least in the Centre for Drugs where I work, is that the (drug) industry is the client, first and foremost, and the public, if seen as a client at all, comes a distant second."

Dobbs reported that Vanderbilt University drug safety expert Dr. Alistair Wood had been on his broadcast the previous evening, had given Dr. Graham great credit for testifying against Merck, and had estimated that some 150,000 people world-wide had died of heart attacks as a result of Vioxx. Dobbs asked why other FDA scientists "and men and women of conscience and commitment to public service" had not also spoken out.

"The FDA manages by terror," responded Dr. Graham. "People (at the FDA) become terrorised, become threatened, they're afraid, afraid for their careers, for their livelihood, for their scientific credibility.

"In my own example, FDA management did everything possible to destroy my credibility as a scientist, to destroy my personal livelihood, and to destroy my family life. And they did this to defend an indefensible position. Vioxx was not safe, and should probably never have been approved, and certainly should have been taken off the market long before it was, and that was the FDA's responsibility and the FDA's failing."

Dr. Graham was asked to comment on the importance of the political support offered by Senator Grassley, and answered: "It has been absolutely indispensable, and I owe the Senator a debt of gratitude that I will never be able to repay. When I met him, I told him that, and he just smiled and said 'thank you'. He's a very humble man, but he and his staff are committed to what they are doing."

Dr. Graham told Dobbs that the FDA was incapable of reform, and that only external pressure and imposition of change would change the focus of the agency so that the people came before the drug industry.

"When I testified that I estimated that Vioxx had caused between 88,000 and 139,000 excess heart attack deaths, (FDA manager) Dr. Sandra Kweder said that these were not 'real deaths'," said Dr. Graham, "and (FDA scientist) Dr. Woodcock said it was 'only a model', as if our estimates of additional deaths were not real. We have an agency in denial, denying that it failed the American people, that it made a mistake."

Senator Grassley, also praised by Graham's lawyer Tom Devine as Graham's "political angel", has spoken and written letters to Commissioner Crawford condemning the FDA's treatment of Dr. Graham and its failure to enforce drug safety in exceptionally blunt terms.

Last week, Senator Grassley wrote to Dr. Crawford that, "over the past months, many problems, concerns, and new drug safety controversies have been brought to light". He reminded Crawford that Graham "had stated (to the Committee) that there were a number of drugs on the market that needed to be looked at seriously", including Bextra, and asked the FDA to "describe how it has evaluated the risks associated" with Bextra.

His level of trust in the FDA is such that he asked Commissioner Crawford to "provide all documents relating to communications between the FDA and Pfizer", and to "provide the Committee with a briefing for each of the following drugs: Meridia (not available in Bermuda), Crestor, Accutane, Bextra, and Serevent (all of which are available here)."

It is a mark of the FDA's capitulation to political and media pressure that not only have they already strengthened warnings on one of the other drugs which Dr. Graham testified gave him concern, but that they have also announced the convening of a panel in February 2005 to review all 'cox-2 inhibitors'.

That decision appears to be timely: an editorial which will run in the February 2005 issue of the Annals of Internal Medicine discusses "where we stand now" with the risk of heart attack from 'cox-2 inhibitors' and concludes that "further study is urgently needed".

"Cyclooxygenase-2 inhibitors . . . have been an enormous financial success, with more than $5 billion in sales in the US in 2003," the editorial stated. "That market took a huge hit recently with the withdrawal of rofecoxib (Vioxx) after the release of the worrisome data on the excessive cardiac morbidity attributed to rofecoxib in a trial. The nearly simultaneous report by Pfizer Inc. of the adverse cardiac effects of valdecoxib (Bextra) after cardiac surgery raised the issue of whether other drugs in the class are safe to use."

The authors, Dr. Axel Finckh of Brigham and Women's Hospital, and Dr. Mark Aronson of Beth Israel Deaconess Medical Centre, both in Boston, point to evidence from a study which "offers evidence for a differential effect on cardiotoxicity among cox-2 inhibitors".

However, they write that "the role of cox-2 inhibition" in the genesis of artery disease "is complex and not fully understood". They conclude that because Vioxx and Bextra have been associated with increased risk of death from heart attack, that "physicians should avoid cox-2 inhibitors as a first-line agent in patients with cardiovascular risk factors and average risk for gastrointestinal toxicity".

In light of the uncertainty about a "class effect" of cox-2 inhibitors, they recommend using a non-aspirin and non-steroidal anti-inflammatory, and only celecoxib (Celebrex) for patients at high risk of "gastrointestinal toxicity". They concluded that "further study is urgently needed to document the safety of cox-2 inhibitors".