Posted on 11/05/2004 1:35:46 PM PST by neverdem
In a series of testy e-mail exchanges with his bosses, a federal drug-safety reviewer contends that an effort to publish his study demonstrating the dangers of Vioxx was delayed and demeaned by top officials at the Food and Drug Administration.
The e-mail and meeting notes also show that Dr. David Graham, an official in the F.D.A.'s Office of Drug Safety, is seeking to launch a study of the safety of Bextra and Mobic, two arthritis pills that are similar to Vioxx. Merck withdrew Vioxx in September after finding that it caused an increase in the risk of heart attacks.
The proposed study of Bextra and Mobic would use data from the California Medicaid program, according to a note written Oct. 29 by Dr. Graham about a meeting held between Dr. Graham and his boss, Dr. Paul Seligman, director of the Office of Drug Safety.
The exchanges are part of a stream of e-mail suggesting a tense environment in the F.D.A. office. In one note, Dr. Graham reports that the atmosphere has gotten so bad that Dr. Seligman has said he was going to resign.
In the note from the meeting of Oct. 29, Dr. Graham wrote that Dr. Seligman said to him: "This only confirms what I suspected, that the staff don't trust me. You can't lead if the staff don't trust you. That's why I have a letter of resignation I am handing in next Tuesday.''
Dr. Seligman could not be reached for comment.
In e-mail dated Oct. 25, 2004, Dr. Graham said one of his bosses, Dr. Anne Trontell, referred to his Vioxx study's conclusions "as nothing more than a scientific rumor."
Dr. Graham defended his study and chided Drs. Trontell and Seligman for taking weeks to decide whether they would approve the study's publication in the Lancet, a leading medical journal. Dr. Trontell is the office's deputy director. Dr. Graham's study concluded that Vioxx, also known as rofecoxib, had a dangerous effect on the heart. The study has been submitted to the Lancet for peer review and possible publication. Meanwhile, the F.D.A. posted a version of the study on its Web site on Tuesday, after certain parts of the study were first published in The Wall Street Journal.
"For all the center claims in its operating principles that respect for others is a core value, my experience with rofecoxib was just the opposite from management, once the results from this study and their potential implications came to light in August," Dr. Graham wrote in e-mail dated Oct. 26.
The e-mail and notes, which were made available to The New York Times, come in the midst of a Congressional inquiry into whether the agency has been slow to respond to findings that antidepressants may cause children to become suicidal and that Vioxx may be harmful to the heart in some cases. Senator Charles E. Grassley, Republican of Iowa, who is chairman of the Senate Finance Committee, has criticized the agency for failing to respond more quickly to these findings and for suppressing the findings of its own drug safety reviewers that concluded that the drugs were risky.
In the case of antidepressants, Dr. Andrew Mosholder, another reviewer at the Office of Drug Safety, concluded last fall that depressed children should not be prescribed most antidepressants because they have failed to show any benefit against depression and may cause some to become suicidal.
Top agency officials refused to allow Dr. Mosholder to testify about his findings at a public meeting in February because they disagreed with his conclusions. A second study conducted by researchers at Columbia University confirmed Dr. Mosholder's conclusions in August, and the agency has since decided to place a "black-box" warning on the labels of antidepressants warning of the suicide risk.
In his notes on an Oct. 29 meeting with Dr. Seligman, Dr. Graham writes that he, Dr. Mosholder and others in the Office of Drug Safety feel that "the review and clearance process had been turned into a battleground, full of contention and intimidation because our managers, the people who fill out our performance evaluations, had created a system where it was taking a great risk to stand firm in our scientific beliefs."
Indeed, according to the meeting note written by Dr. Graham, Dr. Mosholder recently asked to have his name removed from a textbook chapter on risk management "because under the current climate, he's afraid to do anything that will set him up for retaliation or adverse disciplinary action.''
The e-mail responses from Drs. Seligman and Trontell are mostly brief requests from seemingly harried bosses asking for more time to review Dr. Graham's manuscript.
Top agency officials have said they have no convincing evidence that either Bextra or its cousin Celebrex is unsafe, but independent researchers have speculated that the entire class of medicines known as Cox-2 inhibitors may be harmful to the heart. Bextra, Celebrex and Vioxx are all Cox-2 inhibitors. The F.D.A. will hold an advisory panel meeting in January to discuss these concerns.
Mobic is made by Boehringer Ingelheim Pharma. They could not be reached. Officials at F.D.A. and Pfizer did not immediately have comment.
Steve Galson, director of F.D.A.'s Center for Drug Evalution and Research, said the back-and-forth between Dr. Graham and his bosses is part of a scientific peer review that "is a totally normal process that takes place all over the government dozens of times a day.''
He said he would consider Dr. Graham's request to perform studies on the safety of Bextra and Mobic, but he said other studies are under way into the safety of Bextra that might provide better evidence.
Andrew McCormick, a spokesman for Pfizer, said he could not comment on e-mail that he had not seen.
Dr. David Campen, Dr. Graham's co-author on the Vioxx study and a top medical director at Kaiser Permanente, which provided data for the Vioxx study, supported Dr. Graham's view of events, including the proposal for a new study.
"This has been a real challenge for us with respect to the support we have received from F.D.A.,'' Dr. Campen said. "There were a number of e-mails that were generated within F.D.A. that were really an effort to delay publication of our study."
Mobic is almost a Cox-2 and definitely will kill pain. (It selectively blocks the cox-2 just not as completely as Viox.) I am taking it presently for some torn cartilage in my knee. It flares up every once in a while. Mobic is slow to work but it does.
All of the Cox-2's will eventually be banned unfortunately. If Viox causes the problems (that were discussed at the time of its introduction) they all will to some degree or another.
Remember, the story of tagamet. The folks at zantac attacked the makers of tagamet saying that it was very dangerous. They became the industry leader, well low and behold after 2 years zantac was demonstrated to have all the "bad" side effects of tagamet. You can't escape the side effects of a drug class.
IMHO, all the cox-2's are dangerous. Besides all of those arthritis drugs are obsolete. I have a topical cream which puts them all to shame. Generic and affordable pain relief. If you can put a finger on your pain, I can get rid of it in 15 to 20 minutes. Close the pain clinics, needles are obsolete!
Amen,
DrMike
Do you mean reversible inhibition versus irreversible inhibition of cyclooxygenase-2?
FReepmail me if you want on or off my health and science ping list.
I was not aware that viox irreversibly inhibited the cox-2??? Is that true?
OK I will bite. What is it?
I don't know. That's what I thought you were alluding to, but from biochemistry I vaguely remember that's how various enzymes can be altered, poisoning various vital systems, e.g. nerve agents, insecticides, etc.
The heart and stroke side effect of these drugs was discussed when they were introduced. This is another example of drug companies and the FDA being in bed with each other. They were on there way toward getting them approved for children! I wish the individuals who "ignored" this issue were able to be touched but alas it will only be the stockholders and lackeys that pay for this. I can't comprehend sitting at a desk and collect a 100 or so a year and knowing that people were going to die for me to collect my money.
Researchers ought to dig the data further to determine who is most susceptible, and by looking at other medications being taken (vs. Vioxx alone) determine what may seem to have a protective effect. I thought this was the whole idea behind a drug being prescription, namely it has to be administered under a doctor's direction because of concerns that it can't just be popped like candy with safety. Not that it can't have serious ill effects if used wrongly.
Aspirin irreversibly inhibit platelet aggregation in clot formation, IIRC, but since platelets have a lifspan of about 9 days, if we didn't maintain a constant supply of new platelets, everyone on a daily dose of aspirin would be bleeding to death. The same goes with vital enzymes. An organism will synthesize new enzymes to replace the poisoned enzymes as long as it wasn't poisoned to death.
From what I have read this is a result of Cox-2 inhibition. I don't know what could have a protective effect.
I thought this was the whole idea behind a drug being prescription, namely it has to be administered under a doctor's direction because of concerns that it can't just be popped like candy with safety.
It was routinely prescribed for long term use for arthritis etc.. I think it should still be marketed for short term use but they will be so gunshy by the time the lawyers take them to the bank it will never happen. Celebrex is next. If this drug just caused you to go nuts and kill yourself and/or others it would never be proved.
A question I have had for a long time. Is this inhibition of platelet aggregation by aspirin a result of the inhibition of the Cox-1/Cox-2 or is it the result of some other mechanism?
Do you find any problems with the medical community as a whole being a DO? I know how much most doctors hate chiropractic and some DOs manipulate also. It has helped me in the past. I have a crushed disc in the middle of my thorax with constant chest pain. I don't want to let anyone cut on me because mistakes on your spine can only make things worse. Is there any validity to the theory that the enervation caused by disc problems can affect your health?
No, not if you know what you're doing.
I know how much most doctors hate chiropractic and some DOs manipulate also. It has helped me in the past.
Some really smart DOs have practices that are almost exclusively focused on osteopathic manipulative techniques, OMT. Other than some extremely rare and catastrophic adverse effects with cervical OMT, there's no downside with other parts of the body if the OMT is done correctly. There are no adverse drug reactions. I don't use it much though. It's very time consuming, and billing for it can be a pain.
I have a crushed disc in the middle of my thorax with constant chest pain. I don't want to let anyone cut on me because mistakes on your spine can only make things worse.
You might want to check this Artificial Spinal Disk Gains Approval From the F.D.A.
Is there any validity to the theory that the enervation caused by disc problems can affect your health?
I never checked it out specifically, but IIRC, chronic pain causes changes to parts of the nervous system.
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