RIMADYL ZENECARP Carprofen all same NSAIDS warning usage

[malernee]

BRAND NAME: RIMADYL (ZENECARP IN THE U.K.)
AVAILABLE IN 25 mg, 75 mg & 100 mg CAPLETS and chewable tablets

BACKGROUND
Carprofen is a member of the class of drugs known as NSAIDS (non-steroidal anti-inflammatory drugs), the same class as such common over-the-counter remedies as Advil (Ibuprofen), Aleve (Naproxen), Orudis (ketoprofen), and Aspirin. The chief use for such drugs in the dog has been pain relief, usually joint pain or post-surgical pain relief.

The problem with this class of drugs has been unacceptable (even life-threatening) side effects. Problems have in the past been related to:

stomach ulceration - even perforation and rupture of the stomach can occur. This is not only painful but life-threatening.

platelet deactivation - platelets are the cells controlling the ability to clot blood and, as a general rule, it is preferable not to promote bleeding. We would prefer platelets to remain active and able to function should we need them.

decreased blood supply to the kidney - this could tip a borderline patient in to kidney failure.
The veterinary profession has been in need of an NSAID that could effectively relieve pain without the above risks. In 1997, Pfizer Animal Health released this medication for dogs in the U.S. as the answer to this need. This medication had been available in the U.K. since 1994 and has earned a reputation for effectiveness and safety.

HOW THIS MEDICATION IS USED
Carprofen is used in the treatment of pain and is usually given twice a day. It takes 1-3 hours after oral administration for a dose of carprofen to reach its maximum effect.

Carprofen is approved only for canine use officially and dogs may safely take this medication long term with no ill effects. Injectable carprofen, only available in the U.K., is commonly used for post-operative pain relief in the cat but only one or two doses are typically given.. Do not use this medication in a cat without specific veterinary guidance.

SIDE EFFECTS
There is an approximately 4% or less chance of a dog on Carprofen showing any of the following side effects: nausea, appetite change, diarrhea, lethargy or constipation. If a dog develops nausea, vomiting, or appetite loss while on carprofen, it is important that the medication be discontinued and that blood testing be done to rule out a liver necrosis syndrome that occurs in one in 5000 dogs on carprofen. This syndrome is rare but can be fatal if early warning signs are ignored. This syndrome has been described primarily in Labrador retrievers taking carprofen for longer than 3 weeks.

Platelet deactivation was not found in the testing of this medication; however, Carprofen is not recommended for animals with known bleeding disorders.

Carprofen should not be used in patients with pre-existing liver disease, inflammatory bowel disease, or with known tendency towards GI ulceration.

INTERACTIONS WITH OTHER DRUGS
Drugs of the NSAID class should not be used concurrently as the potential for the aforementioned side effects increases. For similar reasons, NSAIDS should not be used in conjunction with corticosteroid hormones such as prednisone, dexamethasone etc. The University of California at Davis recommends a two week “rest” period when changing from any NSAID to carprofen or from carprofen to another NSAID.

If carprofen is used concurrently with phenobarbital, it is especially important that appropriate liver monitoring be performed. (Our hospital recommends bile acids testing every 6 months for dogs on phenobarbital.)

ACE inhibitors such as enalapril or captopril may not be as effective in the presence of carprofen. (ACE inhibitors are used in the treatment of hypertension or heart failure.)

CONCERNS AND CAUTIONS
Carprofen has not been tested in pregnant or nursing females and thus is not recommended for use in such individuals.

Hepatic necrosis syndrome in large breed dogs (especially Labrador retrievers) is a rare condition (one in 5000 at most). It is important to put this in proper perspective and follow the guidelines as described here. Many exaggerated reports and rumors have surfaced on the internet and it is important to consider only confirmed and properly investigated information.

*****

CVM Update

December 1, 1999

UPDATE ON RIMADYL®

FDA's Center for Veterinary Medicine (CVM) has recently compiled and reviewed adverse drug experience (ADE) reports received for 1998. During
this period, the Center received a substantial number of ADE reports for carprofen (trade name Rimadyl®) and consumer inquiries regarding the safety
of this product.

CVM has released the "1998 Annual Adverse Drug Experience (ADE) Summary" which includes information about ADEs to all veterinary drugs,
including Rimadyl®. This ADE summary is on our Home Page . Copies are also available from CVM's Communications Staff at FDA/Center for
Veterinary Medicine, HFV-12, 7500 Standish Place, Rockville, MD 20855, 301-594-1755. FDA also published a descriptive overview of the 1998
ADE reports in the November/December issue of the FDA Veterinarian. This report also is available from the Communications Staff and our Home
Page at the above address.

FDA approved Rimadyl® for dogs on October 25, 1996, after a comprehensive review of the product’s safety and efficacy. Rimadyl® is a
non-steroidal anti-inflammatory drug (NSAID) indicated for use in relief of pain and inflammation associated with osteoarthritis in dogs. NSAIDs are
commonly used in human medicine for relief of pain and include such drugs as aspirin, ibuprofen, and naproxen. Rimadyl® is one of two NSAID
products currently approved for use in dogs. The active ingredient in Rimadyl®, carprofen, is not approved for use in humans. The drug is available by
veterinary prescription only. The approved drug sponsor is Pfizer Animal Health of Exton, PA.

Pre-approval studies for Rimadyl® included a clinical trial involving 297 dogs administered either the drug or a placebo for 14 days. Similar adverse
clinical signs were observed in both the carprofen and placebo-treated groups. These signs included an increase in vomiting, diarrhea, lethargy,
behavioral changes, constipation, and an increase in liver enzymes. Safety studies revealed no remarkable side effects associated with long-term drug
administration. Based on the studies submitted to CVM, the risk of Rimadyl® was thought to be negligible.

Of all the ADE reports CVM received in 1998, thirty-nine percent (39%) or 3626 involved Rimadyl®. The number of ADE reports received by CVM
for Rimadyl® is considerably more than that received for other animal drugs. For any one ADE report, there is no absolute certainty that the suspected
drug caused the effect. The adverse effects in these reports are consistent with those expected for NSAIDs. They typically involve the gastrointestinal
system, renal/urinary system, hematopoietic (blood) system, neurological system, and the liver. Approximately 13% of the 1998 Rimadyl® ADE
reports for dogs involved death of the dog, either on their own or by means of euthanasia.

In spite of the high standards for safety and effectiveness that exist for FDA approval, not everything is known about a drug when it is first marketed.
Due to the limited number of animals and controlled nature of pre-marketing clinical trials, only the most common adverse effects will be observed.
Uncommon effects or problems may not be discovered until after the drug has been widely used.

Based on adverse experience reports received since Rimadyl® was marketed, a number of actions have been taken to provide the most current
product safety information to veterinarians and dog owners. In 1997, shortly after Rimadyl® was marketed, CVM began receiving ADE reports
involving the drug. In May 1997, CVM asked Pfizer to change the adverse reaction section of the label.

CVM also asked Pfizer to send a "Dear Doctor" letter to veterinarians informing them of the adverse effects reported with product use. In August
1997, Pfizer mailed a "Dear Doctor" letter to all veterinarians who had purchased the product. By September 1997, Pfizer had revised Rimadyl®
labeling to include an extensive adverse reaction section. The possibility of a fatal outcome was mentioned elsewhere on the label, but death was also
added to the adverse reactions section in the spring of 1999. In addition, at CVM’s request, Pfizer developed and distributed an information sheet
containing safety information for veterinarians to give to owners at the time Rimadyl® is dispensed.

A number of factors might contribute to the high number of ADE reports received for Rimadyl®:

type of drug – NSAIDs as a pharmaceutical class are commonly associated with adverse affects on a variety of body systems, particularly the
gastrointestinal system. Adverse effects on the kidney and liver have also been documented.

wide use -- Rimadyl® has been administered to 2.5 million dogs over its first two years of marketing. This represents a high level of use for a recently
approved drug.

duration of use -- Rimadyl® is intended for daily administration to dogs, possibly on a long-term basis. While Rimadyl®-related adverse effects are
reported to occur shortly after drug initiation, long-term use may result in a higher risk for adverse effects. A substantial portion of dogs receive
Rimadyl® continuously for more than 30 days.

senior dog use – Over 85% of Rimadyl® ADE reports involved dogs greater than six years of age. Rimadyl® is intended for use in osteoarthritis, a
disease condition more pronounced in older dogs. Older dogs in general may be more susceptible to carprofen-related adverse effects.

marketing of the drug -- Pfizer’s direct-to-consumer marketing strategy and professional support encourages the submission of a higher number of
ADE reports. For instance, Rimadyl® is one of the few animal drugs that provides a toll-free number on the label for reporting ADE reports to the drug
company, which facilitates reporting.

Most of the ADEs reported by owners directly to CVM involved owners of dogs who said they were not aware of the potential adverse effects
associated with Rimadyl® use. Adequate communication between the veterinarian and client should result in an awareness of the risk and benefit of
drug use and alternate therapies that are available. Additionally, communication should establish the importance of evaluation of the dog prior to
Rimadyl® initiation and the necessity of periodic follow-up evaluations if drug use is continued long-term. Animal owners have told CVM that adequate
communication is not occurring in many instances.

CVM will continue to evaluate ADE reports received for Rimadyl® compared to the benefits of NSAID therapy. In many dogs, the use of NSAIDs is
not an elective therapeutic choice, but the primary therapy available for maintaining an acceptable standard of life due to the long-term debilitating
effects of osteoarthritis. As an NSAID with potentially serious side effects, however, the use of Rimadyl® should be carefully considered before being
incorporated in any therapeutic plan. Moreover, dog owners should have an active role in making that decision. CVM, along with drug sponsors, is
actively pursuing a number of avenues to improve the management of NSAID safety issues in order to minimize the risks and maximize the benefits of
using these products in dogs.
******


Hepatocellular Toxicosis Associated with Administration of Carprofen in 21 Dogs

<<J Am Vet Med Assoc 212[12]:1895-1901 Jun 15'98 Reports of Original Studies 27 Refs

* Catriona M. MacPhail, DVM; Michael R. Lappin, DVM, PhD; Dennis J. Meyer, DVM; Steven G. Smith, DVM; Cynthia R. L. Webster, DVM, MS; P. Jane Armstrong, DVM, MS
* Dept. of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523

- A diagnosis of hepatocellular toxicosis attributable to carprofen administration was made in 21 dogs on the basis of development of clinical signs and clinicopathologic abnormalities associated with hepatic disease and histopathologic documentation of hepatic necrosis. Clinical signs of toxicosis were anorexia, vomiting, and icterus. Hyperbilirubinemia and high serum activities of alanine transaminase, alkaline phosphatase, and aspartate transaminase were the most notable clinicopathologic abnormalities. In 7 of 9 dogs in which urinalyses were performed, abnormalities suggestive of renal tubular disease were detected. Clinical course of toxicosis was variable; however, most dogs had resolution of clinical signs and improvement or resolution of biochemical abnormalities with discontinuation of the drug and administration of supportive care. As with any medication, clients should be informed of possible adverse effects and reactions associated with administration of carprofen. In the event of those signs, clients should be instructed to immediately discontinue administration of carprofen to their dog and contact their veterinarian.

[malernee]

Drug Bites Man: Most Arthritic Dogs Do Great on This Pill, Except Those That Die
A Surprised FDA and Pfizer Strive for Right Response for Remedy Gone Awry
What to Say in the TV Ads
By Chris Adams, Staff Reporter of The Wall Street Journal

The Wall Street Journal, 3/13/00


--------------------------------------------------------------------------------

You might call it a made-for-TV drug. Approved for human use in the U.S. but not marketed that way, an arthritis medicine called Rimadyl languished for nearly 10 years in developmental limbo, then emerged in a surprising new form: Instead of a human drug, it was now a drug for arthritic dogs. And it became a hit.

With the aid of slick commercials featuring once-lame dogs bounding happily about, Rimadyl changed the way veterinarians treated dogs. "Clients would walk in and say, `What about this Rimadyl?'" says George Siemering, who practices in Springfield, Va.

Today, those TV spots are gone. The reason has to do with dogs like Montana.

A six-year-old Siberian husky with stiff back legs, Montana hobbled out of a vet's office in Brooklyn, N.Y., six months ago accompanied by his human, Angela Giglio, and a supply of Rimadyl pills. At first, the drug appeared to work. But then Montana lost his appetite. He went limp, wobbling instead of walking. Finally he didn't walk at all. He ate leaves, vomited, had seizures and, eventually, was put to sleep. An autopsy showed the sort of liver damage associated with a bad drug reaction.

Pet drugs are big business -- an estimated $3 billion world-wide -- and Rimadyl is one of the bestsellers. It has been given to more than four million dogs in the U.S. and more abroad, brought Pfizer Inc. tens of millions of dollars in sales, and pleased many veterinarians and dog owners. But the drug has also stirred a controversy, with other pet owners complaining that nobody warned them of its risks.

Montana's owner, Ms. Giglio, is among them. After she informed Pfizer and the Food and Drug Administration of her relatively youthful dog's death, Pfizer offered her $440 "as a gesture of good will" and to cover part of the medical costs. Insulted by the offer and a stipulation that she agree to tell no one about the payment except her tax preparer, she refused to sign and didn't take the money. "There's just no way in my conscience or heart I can release them from blame," she says.

After reports of bad reactions and deaths started streaming in to the FDA, the agency suggested that Pfizer mention "death" as a possible side effect in a warning letter to vets, on labels and in TV ads. Pfizer eventually did use the word with vets and on labels, but when given an ultimatum about the commercials -- mention "death" in the audio or end the ads -- Pfizer chose to drop them.

Pfizer's director of animal-products technical services, Edward W. Kanara, says that when reports started coming in, "we acted extremely promptly based on the information we had." Pfizer points out that reported adverse events involve less than 1% of treated dogs.

Since Rimadyl's 1997 launch, the FDA has received reports of about 1,000 dogs that died or were put to sleep and 7,000 more that had bad reactions after taking the drug, records and official estimates indicate. The FDA says such events are significantly underreported.

While the numbers include cases "possibly" related to Rimadyl, it is hard to be sure. Many dogs given the arthritis drug are older, and few are autopsied after they die. Pfizer says it analyzed cases of Rimadyl-treated dogs that died in 1998 and found a link to Rimadyl to be "likely" in 12% of cases and "not likely" in 22%; it says there was too little information for a judgment about the others.

Despite these problems, the FDA says Rimadyl deserves to be on the market, provided vets take the proper precautions. These include advising dog owners what bad reactions to watch for and periodically doing liver-function or other lab tests.

Within a few weeks, Pfizer will begin affixing a safety sheet directly to packages of Rimadyl pills. It is the first time either FDA officials or Pfizer can recall such a step being taken in the world of animal drugs.

Rimadyl -- generically carprofen -- is an anti-inflammatory medicine. Developer Roche Laboratories expected to market it for people in 1988 and received FDA approval, but shelved the plan after concluding the market for such drugs was too crowded. In addition, some outside experts expressed concerns; a commentary in a pharmaceutical journal noted unusual liver-function readings in 14% to 20% of test subjects and opined that "until additional data on carprofen are available, older compounds should probably be tried initially."

The idea of switching the product to the animal-drug track soon arose. A couple of corporate transactions later, it ended up in the hands of Pfizer's animal-drug unit. There, it was treated to the kind of sophisticated marketing Pfizer does well. A survey of 885 dog owners was done. Besides shedding light on favorite dog names (Jake, Ginger, Lady), the poll revealed that one-fifth of dog owners would be willing to spend "whatever it took" to buy an aging dog an extra year or two of life. No fewer than 53% agreed that "my dog is a better companion than other members of my family."

The FDA requires safety and efficacy testing for animal drugs just as for human ones, but animal-drug tests are smaller. Pfizer says about 500 dogs got Rimadyl in various trials, which is no more than a fifth of the number of subjects in comparable human-drug trials. Some dogs showed unusual liver-function readings and one young beagle on a high dose died, but for the most part, the FDA and Pfizer didn't find side effects alarming. The drug was approved for an early-1997 launch. That same year, the FDA made it easier to market drugs directly to consumers on TV.

Soon, Pfizer was running commercials in which a once-stiff yellow Labrador retriever named Lady bounded over a fallen tree as she fetched tennis balls beside a lake. In another ad, a dog leapt through a window and slid down a banister. There were also full-page magazine ads and a public-relations campaign, whose results, the PR firm later said, included 1,785 print stories, 856 radio reports and 245 TV news reports "generating 25.5 million positive impressions on the product." Early on, vets were floored by the drug's effects.

"The results in some cases have been pretty darn close to miraculous," says David Whitten of the Hilldale Veterinary Hospital in Southfield, Mich. "I'm using this drug on my own dog. It has been effective. But as with all medications, side effects are certainly a problem." Indeed, within months of the launch, vets at Colorado State University in Fort Collins noticed troubling reactions. Labrador retrievers seemed particularly affected. Since the safety studies for Rimadyl had emphasized testing on young beagles, Pfizer went back to conduct another, small test just on Labs; it says that test showed no particular problem.

Bill Keller, an FDA veterinary-medicine official, notes that "any time you take a product from the investigation and put it into actual practice, you're going to see things you didn't expect." But reports about Rimadyl came in by the hundreds. The FDA had received just over 3,000 animal-drug bad-reaction reports in 1996, the year before Rimadyl's launch; in 1998, the drug's first full year, Rimadyl alone produced more than that many. They swamped the FDA's tiny Center for Veterinary Medicine in Rockville, Md. Pfizer was scrambling as well. "Basically, their response," says Dr. Keller, " was `Tell us what you want us to do. We love the fact that it's selling so well, but we don't know what to do with all these adverse reactions.'"

The FDA and Pfizer discussed a "Dear Doctor" letter to be sent to vets. FDA records show the agency found parts of an early Pfizer draft "unacceptable as they are promotional in tone. . . ." It was revised. The records also show Pfizer disagreed with the FDA's suggestion that the letter cite "death" as a possible side effect. To get the letter out, the FDA told Pfizer it was "agreeing to your exclusion of the 'death' syndrome from the letter at this time. However, we will revisit the 'death' syndrome issue and other potential side effects for possible inclusion in labeling at a later date." So the term didn't appear in the first warning Pfizer sent, in mid-1997.

Meanwhile, dog owners were asking for Rimadyl. "It was their advertising that sold me on the drug," says Michelle Walsh, a Phoenix woman who says her miniature schnauzer was given it and later died. Not that vets needed much convincing. They saw clear benefits from the drug. On top of that, they could get points from Pfizer for each Rimadyl purchase they made; points were redeemable for PalmPilots, Zip drives for PCs and other equipment.

Although Pfizer's letter told vets to explain to owners the signs of a bad reaction to Rimadyl, such as vomiting, lethargy or diarrhea, it is evident that a great many didn't. The FDA's Dr. Keller says, "There are a lot of veterinarians who don't think they need to take the time, or who forget, or for whatever reason are not providing animal owners with this information."

Donna Allen, whose chow-mix, Maggie, started on Rimadyl last summer, says, " All my vet did was give me this little bag of pills, with no information." She says Maggie "didn't want to take it, but I made her." After four weeks, Maggie began to vomit violently, Ms. Allen says. The dog vanished from their home outside Birmingham, Ala., and later was found lying in a ditch. Ms. Allen loaded her into a truck and sped 35 miles to a veterinary clinic, but the five-year-old dog died. Her vet wouldn't implicate Rimadyl in the death until Ms. Allen urged him to send the dog's internal organs to the University of Illinois vet school, where an examination showed liver toxicity. Maggie was buried under a marker adorned with the figure of an angel. And Ms. Allen took to the streets, delivering a letter to all the vets in the area urging them to "understand that Rimadyl helps certain dogs, but it is poison to other dogs."

As the complaints poured in, the FDA told Pfizer it would have to revisit the label issue. Pfizer had referred to "fatal outcomes" on the label as a possible effect of the drug class to which Rimadyl belonged, but not specifically of this drug. Now the agency asked that Pfizer cite "death" prominently as a possible side effect of the drug. Describing the back and forth with Pfizer, the FDA's Dr. Keller says, "They did it. They weren't enthusiastic about it, but they have always been cooperative. And that's part of the nature of the game we play with industry."

But the FDA also wanted the word "death" in the audio of commercials. Pfizer indicated this "would be devastating to the product," FDA minutes of a February 1999 meeting show. A company spokesman says that "putting 'death' on a 30-second commercial and in proper context was something we didn't think was possible." Rather than do so, it eventually pulled the commercials. Pfizer says it now will do traditional marketing to vets, making sure they know the proper way to use the drug.

Another "Dear Doctor" letter will soon go out, and the company will start attaching a safety sheet to pill packages. Pfizer acknowledges it has a perception problem with some dog owners; a consumer group, for instance, has mounted a campaign dubbed BARKS, for Be Aware of Rimadyl's Known Side-effects. The company is contacting dog owners who have told their stories on the Internet, and it is offering to pay medical and diagnostic expenses for some dogs who may have been harmed by Rimadyl.

But Pfizer stands firmly behind the value of the drug, of which it says sales have continued to grow. Most vets also remain strongly behind Rimadyl. Owners, too, generally say they think the drug is important -- they just want to know the risks. Atlantan Roger Williams gave his mixed-breed terrier, William, Rimadyl for more than a year and believes it contributed to the dog's death. "But if I had to do it all over, I would give my dog Rimadyl again," he says. "The difference is I would have known what to expect. Without Rimadyl, William was miserable. And what's the point of living another three years if you're miserable?"

[malernee]

LAWSUIT OVER VETERINARY DRUG SETTLED

FOR IMMEDIATE RELEASE – Johns Island, South Carolina - August 18, 2004

Jean Townsend of Johns Island, South Carolina announced today that a
settlement has been reached with Pfizer, Inc. in what appears to be the first lawsuit
of its kind in this country – a lawsuit over injuries that led to the death of
Ms. Townsend's chocolate lab, George. Ms. Townsend originally brought a
class action lawsuit against Pfizer in October of 1999, two years after the tragic
death of George. The lawsuit alleged that after initial approval by the FDA,
the drug Rimadyl®, which was the subject of an unprecedented multi-million
dollar advertising campaign, was marketed without a complete understanding of
the serious side-effects that could result from the drug. Ms. Townsend also
alleged that neither she nor her vet were adequately warned of the potential
side-effects. After administering the drug for only 14 days, George developed
severe internal bleeding and ultimately liver failure. George was euthanized on
October 13, 1997. In reaching the settlement, Pfizer has admitted no
wrong-doing.
"It was truly horrible," said Townsend of the experience. "But the most
troubling aspect of the ordeal was when I later learned that similar side-effects
had been reported to Pfizer and the FDA months before I first gave the drug to
my dog. Yet even after my pet became sick, I continued to give him the pills
because they were supposed to make him feel better. I had no idea that he
was suffering from the side-effects of Rimadyl®. It is devastating to live with
the realization that I gave my beloved pet medicine to help him when, in
fact, it was killing him." After reporting George's death to Pfizer, Ms. Townsend
was offered a $249.33 settlement, but the offer came with the condition that
the settlement remain confidential. Ms. Townsend refused.
In the months following George's death, Ms. Townsend began researching this
drug on the internet and soon discovered dozens of other pet owners who had
similar experiences with Rimadyl®. Fueled by the growing number of people whose
dogs had become sick or died after taking the drug, Ms. Townsend, along with
other concerned pet owners, started a campaign to raise awareness of the
potential for serious side-effects with this and other veterinary medicines. As
part of that campaign, Ms. Townsend and others met with FDA officials as well as
Pfizer veterinarians, urging them to step-up efforts to more thoroughly inform
pet owners of the potential for serious side-effects with veterinary
medicines.
Unsatisfied with the response of the FDA and Pfizer, Ms. Townsend turned to
the legal system and filed a class-action lawsuit. In her suit, Ms. Townsend
sought reimbursement of the $734.00 in veterinary expenses she had incurred
trying to save George, as well as establishing a class action on behalf of the
hundreds of other dog owners whose pets had become ill or died.
In the meantime, reports of adverse reactions to Rimadyl® continued to rise,
and in 1998, Rimadyl® accounted for almost 39% of all Adverse Drug Experience
Reports received by the FDA. The reports were so numerous that in December of
1999, the FDA took the extraordinary step of issuing a public statement on
the drug.
Within months of Ms. Townsend's suit and the "Update on Rimadyl®" issued by
the FDA, Pfizer announced significant changes in packaging, and that it would
begin dispensing a Client Information Sheet to be included with veterinary
prescriptions of Rimadyl®. The Client Information Sheet, modeled after similar
drug information sheets included with many human drugs, was to provide pet
owners with easily understandable information about the potential side-effects and
what to do if side-effects occur.
Ms. Townsend reports that as part of the settlement, Pfizer made cash offers
to over 300 other dog owners across the country to settle claims for death or
injury to the dog, veterinary expenses, property damage, emotional distress
and punitive damages. These individual offers averaged over $1000.00 per animal
and did not include a confidentiality provision.
Speaking about the lawsuit and the settlement, Ms. Townsend said, "I am
pleased that through this suit, hundreds of other pet owners will be reimbursed for
veterinary expenses and the loss of their pets. Of course, no amount of
money would ever replace the loss of my friend George, and the loss of so many
other beloved companions." But to Ms. Townsend, (who donated her settlement
proceeds to a local veterinarian to perform surgery on a pet whose owners could
not afford the surgery) the issue is far more than the money paid by Pfizer. It
is the growing public awareness that the medications we give our pets can
have serious side-effects. "We, as pet owners, have the right to know as much
about the good and bad sides of veterinary medicines as we do the medicines we
give ourselves."

For further information please contact:

Jean Townsend - Luswinton@aol.com
1769 Clark Hills Circle
Johns Island, SC 2955
843.559.2134

[guest]

Last July while controversy was swirling around the human cox2 inhibitor
Vioxx, the FDA benignly approved Previcox (firocoxib) for dogs.
Previcox was developed by Merck, the developers of Vioxx, and is
structurally related to Vioxx. It is the most extreme cox2 inhibitor
approved for dogs to date. By the way, Deramaxx (deracoxib) is closely
structurally related to Celebrex. All four drugs are NSAIDs of the
coxib class, as is the human drug Bextra. While Rimadyl is supposedly
more selective for cox2 than cox1, it is not a NSAID of the coxib class.
Below are links to information about Previcox. All is European
information except the FDA Freedom of Information Summary for Previcox.
The Previcox label is not available on the FDA CVM website, although it
is listed at the end of the FOI summary as an attachment.--Cass, not a
vet or vet tech

http://www.emea.eu.int/vetdocs/PDFs/EPA ... 204en6.pdf
http://www.emea.eu.int/vetdocs/PDFs/EPA ... -PI-en.pdf
http://www.fda.gov/cvm/efoi/section2/141-230.pdf

[guest]

Below is the explanation from the FDA as to why the Previcox (firocoxib)
aka doggie vioxx label is not available at the FDA CVM website as part
of the FOI summary:

This is in reply to your inquiry about the package insert and Client
Information Sheet for Previcox.

The package insert and client information sheet are not on the CVM
website for the FOI Summary for this NADA. The information is listed on
Dockets website; however, the part that you want is illegible.
Therefore, you will need to file a written (not e-mail) Freedom of
Information (FOI) request for these documents. This is a link to
information on filing a FOI request --
http://www.fda.gov/opacom/backgrounders/foiahand.html
I hope this information is helpful.

[guest]

When I look at the efficacy data for Rimadyl, Deramaxx, Zubrin, Etogesic
and Metacam, it is barely better than the placebo--where they have a
placebo-controlled study. They frequently pick and choose their measure
of efficacy, FDA has set no standard. In one of the Deramaxx studies,
the vets saw no improvement, but the owners did so they used that. If
forced-plate tests are good, but other measures bad, they will use the
other measures.
Given the small number of dogs in the trials, the juggling of measures
of efficacy AND the fact that it is generally within the margin of error
better than a placebo, I would say that to date, none of these companies
have demonstrated efficacy.
It has been a long time, but if you look at the original Rimadyl
studies, placebo accounted for something like 34% improvement on average
while Rimadyl measured 37%. For that 3%, how many dogs have died? And
could the 37% not be a placebo effect?

[guest]

human studies of these type drugs for osteoarthritis Conclude NSAIDs can reduce short term pain in osteoarthritis slightly better than placebo, but the current analysis does not support long term use of NSAIDs.


Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2
inhibitors, in osteoarthritic knee pain: meta-analysis of randomised
placebo controlled trials -- Bjordal et al., 10.1136/bmj.38273.626655.63
-- BMJ
Address:http://bmj.bmjjournals.com/cgi/content/abstract/bmj.38273.626655.63v1?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&andorexacttitle=and&andorexacttitleabs=and&fulltext=NSAIDs&andorexactfulltext=and&searchid=1101513454613_21459&stored_search=&FIRSTINDEX=30&sortspec=relevance&resourcetype=1,2,3,4
Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2
inhibitors, in osteoarthritic knee pain: meta-analysis of randomised
placebo controlled trials
Jan Magnus Bjordal 1, Anne Elisabeth Ljunggren 1, Atle Klovning 1, Lars
Slørdal 2
1 Department of Public Health and Primary Health Care, University of
Bergen, 5018 Bergen, Norway
2 Department of Laboratory Medicine, Children's and Women's Health,
Norwegian University of Science and Technology, 7489 Trondheim, Norway
Objective To estimate the analgesic efficacy of non-steroidal
anti-inflammatory drugs (NSAIDs), including selective cyclo-oxygenase-2
inhibitors (coxibs), in patients with osteoarthritis of the knee.
Design Systematic review and meta-analysis of randomised placebo
controlled trials.
Studies reviewed 23 trials including 10 845 patients, median age of 62.5
years. 7807 patients received adequate doses of NSAIDs and 3038 received
placebo. The mean weighted baseline pain score was 64.2 mm on 100 mm
visual analogue scale (VAS), and average duration of symptoms was 8.2
years.
Main outcome measure Change in overall intensity of pain.
Results Methodological quality of trials was acceptable, but 13 trials
excluded patients before randomisation if they did not respond to
NSAIDs. One trial provided long term data for pain that showed no
significant effect of NSAIDs compared with placebo at one to four years.
The pooled difference for pain on visual analogue scale in all included
trials was 10.1 mm (95% confidence interval 7.4 to 12. or 15.6% better
than placebo after 2-13 weeks. The results were heterogeneous, and the
effect size for pain reduction was 0.32 (0.24 to 0.39) in a random
effects model. In 10 trials that did not exclude non-responders to NSAID
treatment the results were homogeneous, with an effect size for pain
reduction of 0.23 (0.15 to 0.31).
Conclusion NSAIDs can reduce short term pain in osteoarthritis of the
knee slightly better than placebo, but the current analysis does not
support long term use of NSAIDs for this condition. As serious adverse
effects are associated with oral NSAIDs, only limited use can be
recommended.
© 2004 BMJ Publishing Group Ltd

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Food and Drug Administration
Rockville MD 20857
FEE! 2 3 2004
PADA 141-213
Ms. Beverly D. Crowley
Specialist, Pharmaceutical Regulatory Affairs
Boehringer lngelheim Vetmedica, Inc.
15th & Oak Streets
P.O. Box 338
Elwood, KS 66024
Dear Ms. Crowley,
The Division of Surveillance (DOS) has reviewed a detailer (MET-3-1003.10), customer
brochure (MET-3-1003.1 l), mini-detailer (MET-3.25) included by Boehringer Ingelheim
Vetmedica, Inc. (BIV) in a Drug Experience Report submitted to the Center for Veterinary
Medicine (CVM) on June 19,2003. CVM has also reviewed the direct mailer (MET-3-
1003.5B), and an advertisement in Veterinary Forum (July 2003) for MetacamB
(meloxicam). These materials contain statements that are false or misleading in violation
of section 502(a) and (n) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 352(a)
and (n), and that encourage use of METACAM in conditions other than those for which
CVM has reviewed safety and effectiveness data.
Background
METACAM is indicated for the control of pain and inflammation associated with
osteoarthritis in dogs. (62 FR 42967; July 21,2003 (to be codified at 21 CFR
520.1350).) According to the FDA-approved professional labeling, METACAM is a
non-steroidal anti-inflammatory drug (NSAID) for oral use in dogs only. The
Precautions section of the labeling includes the following language:
As a class, cyclo-oxygenase inhibitory NSAIDs may be associated
with gastrointestinal and renal toxicity. Sensitivity to drugassociated
adverse events varies with the individual patient.
Patients at greatest risk for renal toxicity are those that are
dehydrated, on concomitant diuretic therapy, or those with existing
renal, cardiovascular, andor hepatic dysfunction. Concurrent
administration of potentially nephrotoxic drugs should be carefully
approached. NSAlDs may inhibit the prostaglandins that maintain
normal homeostatic function. Such anti-prostaglandin effects may
result in clinically significant disease in patients with underlying or
pre-existing disease that has not been previously diagnosed. Since
many NSAIDS possess the potential to produce gastrointestinal
ulceration, concomitant use of MetacamB Oral Suspension with
other anti-inflammatory drugs, such as NSAlDs or corticosteroids,
should be avoided or closely monitored.
Moreover, the labeling discloses several adverse reactions, including gastrointestinal
abnormalities, which were the most common adverse reactions associated with the drug
in field safety trials:
Field safety was evaluated in 306 dogs. Based on the results of
two studies, GI abnormalities (vomiting, soft stools, diarrhea, and
inappetance) were the most common adverse reactions associated
with the administration of meloxicam. During two field studies,
certain adverse reactions were observed. Of the dogs that took
meloxicam (n=l57), forty experienced vomiting, nineteen
experienced diarrhedsoft stool, five experienced inappetance, and
one each experienced bloody stool, bleeding gums after dental
procedure, lethargy/swollen carpus, and epiphora. Of the dogs that
took the placebo (n=149), twenty-three experienced vomiting,
eleven experienced diarrhedsoft stool, and one experienced
inappetance.
Misleading Mechanism of Action Claims
The materials state: "METACAM@ is the first NSAID proven in vivo in dogs to be
COX-1 sparing/COX-2 inhibiting." They state, further: "COX-1 sparing is
demonstrated by not inhibiting PGE;! brostaglandin E2) in the gastric mucosa". These
statements are misleading, because they suggest that these attributes are clinically
significant, when this has not been demonstrated by substantial evidence or substantial
clinical experience. The disclaimer that "clinical relevance has not been shown,"
appearing in two of the pieces, is presented in a footnote in fine print, and is, therefore,
insufficient to correct the overall misleading impression created by the materials.
Misleading Comparative Claims
The materials contain a table reporting the results of a study suggesting that meloxicam
is superior to in such areas as "return to normal by day 60" and "owner
assessment--simificant response at day 30." The materials thus claim that meloxicam is
superior to , when this has not been demonstrated by substantial evidence or
substantial cllnical experience. The study cited to support these statements is not
suflicient because of the low numbaof animals. Moreover, the table is misleading
because it highlights one dog in the -treated group that experienced toxic
idiosyncratic hepatitis (vomiting, &orexia, lethargy, and jaundice) without disclosing
that one dog in the meloxicam treatment group experienced vomiting and was dropped
&om the study.
Unsubstantiated Safety Claims
I
The materials state: "Global incidence of reported GI side effects is 0.0001 3%." This
statement implies that, of all animals treated worldwide with METACAM, only 13 in
every 100,000 exhibited gastrointestinal side effects. To support this statement, the
materials cite "Clinical Expert Statement for renewal of METACAM Oral .Suspension
for dogs (3/2000-6/2002)." We have not reviewed this document and are not aware of
data sufficient to calculate a reliable incidence rate for gastrointestinal side effects. As
noted, the PI for METACAM discloses a rate of GI adverse events that is significantly
higher than 0.0001 3 percent.
With respect to risks associated with METACAM, the materials state that, as with any
medication, side effects may occur. The materials state, further, that side effects are
usually mild, but may be serious. According to the materials, the most common side
effects reported in field studies were vomiting and soft stoovdiarrhea. The materials
state that dogs should be evaluated for pre-existing medical conditions before treatment,
and refer the reader to the package insert for more information.
The materials fail to disclose (as described in the Precautions section of FDA-approved
professional labeling) the risks of concurrent administration of NSAIDs and
corticosteroids or potentially nephrotoxic drugs. They are, therefore, misleading.
Conclusion and Requested Action
As discussed above, the materials violate section 502(a) and (n) of the FDCA (21
U.S.C. 352(a) and (n)) because they contain misleading mechanism of action,
superiority, and safety claims, and because they omit important risk information.
DOS requests that BIV immediately cease the dissemination of promotional materials for
METACM the same as or similar to those described above. Please submit a written
response to this letter on or before March 3 1 , 2004, describing your intent to comply with
this request, listing all promotional materials for METACAM the same as or similar to
those described above, and explaining your plan for discontinuing use of such materials.
Please direct your response to me at the Food and Drug Administration, Division of
Surveillance, HFV-216, 7500 Standish Place, Rockville, Maryland 20855. In all future
correspondence regarding this matter, please refer to the NADA number. We remind you
that only written communications are considered official.
The violations discussed in this letter do not necessarily constitute an exhaustive list. It is
your responsibility to ensure that your promotional materials for METACAM comply
with each applicable requirement of the Act and FDA implementing regulations.
Sincerely, - __
r, DVM, M.Sc. 'c-
Post-Approval Review Team, HFV-216
Division of Surveillance
Center for Veterinary Medicine

[malernee]

Medicine Fueled by Marketing Intensified Trouble for Pain Pills
By BARRY MEIER

Published: December 19, 2004



Pfizer used the theme "Celebrate" in its promotional campaign for Celebrex to appeal to baby boomers beginning to suffer from arthritis.





RELATED


The Overview: Drug Trial Finds Big Health Risks in 2nd Painkiller (December 18, 2004)


News Analysis: Pricey Drug Trials Turn Up Few New Blockbusters (December 18, 2004)









his article was reported by Barry Meier, Gina Kolata and Andrew Pollack and written by Mr. Meier.

In the mid-1990's, the medical community reached an inescapable conclusion. Researchers at the Stanford University Medical School and elsewhere who had long been monitoring arthritis and rheumatism patient records had found that thousands of patients, perhaps as many as 16,500, were dying annually from bleeding ulcers and other problems caused by widely used painkillers like ibuprofen.

Within a few years, a new class of pain relievers, the so-called COX-2 inhibitors, burst onto the market with the promise they might reduce that toll. Sales of the best known products, Celebrex and Vioxx, quickly skyrocketed - thanks in part to changes in federal rules in 1997 that made it much easier for drug makers to advertise medications directly to consumers on television, in newspapers and in magazines.

Now, though, the flight path of these blockbuster drugs has been aborted. On Friday, Pfizer the maker of Celebrex, which is expected to end up with sales of $3.3 billion this year, disclosed that a patient trial by the National Cancer Institute had found significant risks of heart attacks. Vioxx, which was made by Merck and had sales of $2.5 billion last year, was pulled from the market in late September after similar findings.

In some ways, the story of the COX-2 drugs, a class that includes another troubled Pfizer medication, Bextra, is part of an age-old search for safer pain treatments. And some doctors say that they have helped. But it is also perhaps the clearest instance yet of how the confluence of medicine and marketing can turn hope into hype - and how difficult it is for the Food and Drug Administration to monitor the safety of drugs after they have been approved for the market. Celebrex and Vioxx, after fast-track approval from the F.D.A., hit the nation's pharmacies as revolutionary drugs that could not only treat arthritis patients' pain, but potentially save their lives.

But having spent hundreds of millions of dollars to develop their drugs, the makers of Celebrex and Vioxx, cheered on by Wall Street, had every motivation to expand their markets beyond the older people most at risk of ulcers to encourage the drugs' use by millions more people of all ages. That was so even as, at least in the case of Vioxx, there was evidence as early as 2000 that a COX-2 drug could cause heart problems.

"You have to realize that these medications, they are not candies, they are not placebos," said Dr. Gurkirpal Singh, a Stanford professor who has worked on the arthritis database project. A big problem with the COX-2 drugs, he said, has been the tendency of doctors to use them indiscriminately. "Like all medications, you have to identify which people will benefit the most, and which won't."

Since the drugs' release, the companies have spent hundreds of millions of dollars on television, newspaper and magazine advertising for them and, by some estimates, at least as much on marketing and promoting the drugs to doctors. As a result, many medical experts now say that Celebrex and Vioxx, selling for $2 or $3 a pill, have been too widely prescribed to patients who could safely obtain the same pain benefits from over-the-counter drugs costing pennies apiece.

Potentially wasted money, though, is not the main point about the sales push, now that there is clinical evidence that all the COX-2 drugs on the market can, in some circumstances, increase a user's likelihood of strokes or heart attacks.

On Friday, Pfizer characterized the cancer trial findings as an anomaly requiring further study and said it was not ready to withdraw the drug. But the news of the trial results was enough to send drug stocks plummeting and to cast grave doubts on the future of the entire COX-2 drug category. Only a few weeks ago, the F.D.A. ordered Pfizer to put a label warning on Bextra, noting that it could pose cardiac risks to patients recovering from heart surgery.

Pfizer and Merck have repeatedly said that their marketing has been accurate and responsible. "We market all of our medicines consistent with regulation," said a spokeswoman for Pfizer. "Doctors and patients are in the best position to say which drugs are most appropriate for them."

But the rapid rise and now shaky future of this class of drugs, some researchers say, is emblematic of the way drug companies' efforts to spur the use of costly new medicines can distort the medical realities of safety and effectiveness.

Too often, marketing can drown out medical science, said Dr. James F. Fries, the director for the Stanford arthritis database project, which receives funding from the National Institutes of Health. "Here, it was not a fair battle."

The roots of Celebrex and Vioxx reach back to the early 1990's. At the time, Harvey R. Herschman and colleagues at the University of California, Los Angeles were screening large numbers of genes trying to find ones that might be involved in cancer. The screen turned up a gene that was in many ways similar to a known gene for an enzyme called cyclooxygenase or COX.

It had long been understood that COX spurred the production in the body of chemicals called prostaglandins that contributed to pain, inflammation and fever. But it had always been thought that there was only one COX enzyme. Now in Dr. Herschman's laboratory emerged evidence of a new one, which came to be called COX-2. Similar discoveries were made about the same time in the laboratories of Donald A. Young at the University of Rochester and Daniel L. Simmons at Brigham Young University.

"It was totally unexpected, completely serendipitous," Dr. Herschman said of his own discovery, adding that he believed that to be true of the other labs as well.

But the implications were immediately clear to Philip Needleman, who had already hypothesized the existence of a second COX enzyme and had begun to characterize its role in the body. The original COX, now called COX-1, seemed to be present everywhere in the body and contributed to vital functions like protecting the stomach lining. COX-2 seemed to be present mostly during times of inflammation. So if a drug could be made to block COX-2 but not COX-1, the thinking went, it could relieve pain without causing ulcers.

Convinced of the importance of the discovery, Dr. Needleman had moved from Washington University in St. Louis to Monsanto in 1989 to lead an all-out effort to develop a COX-2 inhibitor. The result of Dr. Needleman's effort was celecoxib, or Celebrex. Monsanto's drug division, Searle, eventually was acquired by Pharmacia, which in turn was gobbled up by Pfizer, in a rush of mergers that swept the drug industry over the past decade to satisfy Wall Street's desire for rapid growth.

Thinking that Celebrex and Vioxx would help cut the rate of gastrointestinal bleeding, the F.D.A. took only six months to review the applications for both drugs, an accelerated process used only for drugs deemed medically important. But in both cases, the F.D.A. decided that the drugs had not sufficiently demonstrated that they reduced the rate of serious gastrointestinal problems compared with existing painkillers like aspirin and ibuprofen. So the drugs' labels contained the same warnings as the older drugs about such side effects.

Merck later conducted studies that persuaded the F.D.A. to change the label, but Pfizer's results were never convincing enough for the agency to remove the warning from Celebrex's labeling. In other words, the world's best-selling COX-2 has never been proven to the F.D.A.'s satisfaction to have the stomach-protecting benefits that originally were supposed to be the point of that category of drugs.

By the time they reached the market, the COX-2 drugs were marketed by makers as not simply improved versions of older treatments but as entirely new drugs.

"They wanted to use this as a discontinuity with the past," said Dr. Fries, the Stanford professor.

The audience also went beyond those at the highest risk of stomach bleeding - principally people over 65 years who have suffered from gastrointestinal problems or might be at risk for them.

Dorothy Hamill, the 1976 Olympic figure skating gold medalist, was the middle-aged celebrity face of Vioxx. Television commercials for Celebrex presented actors engaged in activities like riding bicycles and performing tai chi to the strains of the song "Celebrate" by the 1970's band Three Dog Night. The song's choice echoed more than the drug's name; it was also selected to appeal to a critical audience, baby boomers beginning to suffer from arthritis.

Celebrex has been one of the most heavily promoted prescription drugs in advertising aimed at consumers. For the first nine months of this year, Pfizer spent almost $71.2 million on Celebrex, up about 55 percent from almost $46.1 million spent in the same period a year ago, according to data from the research firm TNS Media Intelligence/CMR. The effect of such advertising, many doctors say, was to drive to consumer demand for COX-2 drugs far beyond the bulk of those patients who really benefit from them.

Dr. Elizabeth Tindall, the president of the American College of Rheumatology, a professional group, said her group believed that COX-2's are an appropriate treatment for patients at high risk of stomach problems. But "we weren't saying to anyone if you have a 23-year-old with ankle pain put them on this drug," said Dr. Tindall, who practices in Portland, Ore. "That was the impression that the TV advertising was giving."




Within little more than a year, the drugs had grabbed about 40 percent of the market from traditional anti-inflammatory drugs like ibuprofen. Some efforts were made to determine who would most benefit from the drugs. Researchers at Stanford developed a scoring tool that physicians could use to determine, based on a patient's age and medical history, whether they were at high risk for stomach bleeding and, as a result, candidates for drugs like Celebrex and Vioxx.

Dr. Singh, the Stanford professor, said that most patients did not fall in the high-risk category.

Few groups or individuals, however, used the scoring tool. One organization that did was Kaiser Permanente, one of the nation's largest health care systems. Dr. David Campen, a medical director at Kaiser, said that because of the scoring system only about 5 percent of Kaiser's patients received a COX-2.

Beyond their heavily promoted use as prescription-strength painkillers, COX-2's have been extensively studied for other potential uses, like fighting or even preventing cancer. And, perhaps ironically for the drug companies, it was cancer prevention studies that ultimately provided clinical evidence that Vioxx and Celebrex posed cardiac risks.

For years scientists have pursued evidence that aspirin-like drugs may help control the occurrence of polyps in people at risk of colon cancer. But there was a problem with testing such drugs as cancer preventatives in healthy people: the drugs could cause ulcers and bleeding.

So when Vioxx and Celebrex were developed as drugs that might act like aspirin, without the risks of bleeding, cancer researchers saw their chance. In fact, based on tests Searle had conducted with the National Cancer Institute, the F.D.A. approved Celebrex for patients at high-risk of getting colon cancer.

By last year, more than a dozen studies of Vioxx and Celebrex were under way with people at high risk for cancers of the lung, breast, skin, prostate, colon, mouth, bladder or esophagus. They were being studied along with standard treatments in patients who already had cancer.

The trials that disclosed the dangers involved healthy people who had already had polyps removed from their colons and who were randomly assigned to take a placebo or a COX-2 inhibitor. Each study sought to learn if taking a COX-2 inhibitor prevented the subsequent formation of polyps.

That answer is not yet known and the researchers have not released those data. But in both studies, the participants taking the COX-2 inhibitor had more heart attacks and strokes than those taking a placebo. The problem was seen in the Vioxx trial after 18 months and after a longer period in the Celebrex trial among patients taking high doses.

For all their early promise, the future of COX-2's is uncertain.

Dr. Lester Crawford, the F.D.A.'s acting commissioner, said Friday that doctors should consider switching their Celebrex patients to other drugs. He said the F.D.A. had "great concerns" about Celebrex and Pfizer's Bextra and was considering regulatory measures that could include forcing Celebrex's withdrawal or placing severe warnings on its label.

Merck has a successor to Vioxx, called Arcoxia, pending approval at the F.D.A. But the agency, which has a panel planning to hold hearings on the entire class of drugs early next year, has tabled that application for now.

Some physicians, like Dr. Tindall, the rheumatologist in Portland, said they were concerned that if Celebrex or Bextra, or perhaps both, were withdrawn from the market that some patients who need such drugs will not get them. Indeed, many former Vioxx patients have complained about the withdrawal of that drug, saying it was the only pain medication that worked for them.

As it turns out, deaths and hospitalizations from stomach problems related to the use of ibuprofen and aspirin peaked in 1992 and had already dropped significantly before the appearance of Celebrex and Vioxx, according to data collected by Stanford University. In 1999, the year of the two drugs introductions, those problems also had another sharp decline.

Dr. Fries of Stanford said the drop-off over the past decade reflected, among other things, the use of lower doses of various painkillers. There has also been growing use of less toxic ones, not only COX-2's but other medications, like Mobic, that other drug makers began to sell in response to concerns about stomach bleeding. Many doctors also have patients taking medications like Prilosec to offset the stomach irritation of some painkillers.

In terms of stomach bleeding, the relative risks of some other less irritating painkillers like Mobic appear indistinguishable from COX-2's, Dr. Fries said. But because of the expense and difficulty of conducting broad-based clinical trials, there have been no studies comparing those drugs with one another and with the COX-2's.

Dr. Fries said the story of the COX-2's was emblematic of the consumer marketing forces that now propel the drug industry.

It is a market, he said, in which the lure of the new can run ahead of science.

"You have to have a new generation of drugs," said Dr. Fries. And under that model, "the old ones are dangerous, and the new ones are safe." Or until proven otherwise.

[guest]

What are approved NSAIDS in the United States?

The complete list of approved NSAIDs is very long. The following list contains only NSAIDs that are commonly used:

Aspirin
Salsalate (Amigesic)
Diflunisal (Dolobid)
Ibuprofen (Motrin)
Ketoprofen (Orudis)
Nabumetone (Relafen)
Piroxicam (Feldene)
Naproxen (Aleve, Naprosyn)
Diclofenac (Voltaren)
Indomethacin (Indocin)
Sulindac (Clinoril)
Tolmetin (Tolectin)
Etodolac (Lodine)
Ketorolac (Toradol)
Oxaprozin (Daypro)
Celecoxib (Celebrex)

[malernee]

FDA Novartis Late with Dog Painkiller Reports
Tue Dec 28, 2004 11:40 AM ET



WASHINGTON (Reuters) - Novartis AG failed to give the government prompt, accurate reports about deaths of dogs treated with a painkiller in the same class of medicines now linked to heart problems in humans, U.S. regulators have charged in a letter.
The drug, Deramaxx, is a COX-2 inhibitor approved for relieving arthritis and post-surgical pain in dogs.

Similar drugs for people are under heavy scrutiny after studies associated them with heart attacks and strokes. One of the drugs, Merck & Co Inc.'s Vioxx, was pulled from the market because of safety risks.

Death has been reported "in rare situations" when dogs were treated with Deramaxx, according to the drug's label instructions.

The Food and Drug Administration, in a warning letter dated Nov. 29, said Novartis Animal Health Services should have forwarded complaints about deaths and health problems in dogs given Deramaxx within 15 working days, but in some cases delayed as long as 10 months. Some reports, including ones involving deaths, appeared to have incorrect dates, the FDA said.

"Novartis failed to submit timely and accurate information to the FDA regarding serious (adverse drug experiences) associated with the administration of its FDA-approved animal drug product Deramaxx ... during its first year of marketing," the FDA said.

The company also failed to submit proper information about post-approval studies of Deramaxx, the FDA charged. The drug is known generically as deracoxib.

Novartis officials could not immediately be reached for comment.

The FDA sends dozens of warning letters per year. Most of the issues raised are resolved without further regulatory action, although the letters sometimes lead to tougher steps such as product seizures.

The warning letter to Novartis is posted on the FDA Web site at http:/www.fda.gov/foi/warning_letters/g5108d.pdf

[malernee]

jama artile House of Coxibs

Arthritis Medicines and Cardiovascular Events—"House of Coxibs"
Eric J. Topol, MD


JAMA. 2005;293:(DOI 10.1001/jama.293.3.366).

Physicians, patients, and the general public are confronted with an acute confusional state regarding the cardiovascular safety of medicines for arthritis. Since September 30, 2004, the day that rofecoxib was precipitously withdrawn, there has hardly been a day without significant news on the general topic of cyclooxygenase 2 (COX-2) inhibitors. On December 9, 2004, the US Food and Drug Administration (FDA) issued a black box warning for valdecoxib for life-threatening skin reactions and cardiovascular risk.1 Just over a week later, on December 17, 2004, the National Cancer Institute announced the premature cessation of a trial of celecoxib known as Adenoma Prevention with Celecoxib (APC) due to a significant excess of cardiovascular death, myocardial infarction (MI), and stroke.2

The principal cardiovascular event data for APC are summarized in the Figure. This was a trial of 2026 patients, with randomization to 1 of 3 groups: placebo; celecoxib, 200 mg twice daily; or celecoxib, 400 mg twice daily. The patients, each of whom had an adenomatous polyp removed before enrollment, were followed up for a mean of 33 months (of a planned 60 months) while taking the study drug, with the primary objective of limiting the development of colorectal cancer.



l
The difference for events between the 400-mg and 800-mg dose was not significant (OR, 0.7 [95% CI, 0.4-1.4]; P=.30). OR indicates odds ratio; CI, confidence interval. The dose response trend across all groups, P=.007.







A significant excess of major cardiovascular events was demonstrated, with a dose-response effect (odds ratio, 2.5 for celecoxib 400-mg dose, and 3.4 at the 800-mg dose, vs placebo) (Figure). The absolute excess of major cardiovascular events of 13/1000 patients at the 400-mg dose and 21/1000 patients at the 800-mg dose is similar in magnitude to the results of trials with rofecoxib and valdecoxib.1, 3 However, it is not possible to meaningfully interpret interdrug differences because the patient populations in the various trials were different; the drug doses, strength, and duration of therapy were different; and each of the drugs in the coxib class are distinct molecules with specific biological properties. While celecoxib is the least COX-2 selective in the class of 5 agents that have gone through pivotal trials,4 lumiracoxib is the most selective. A trial of 18 325 patients, the largest in the field, demonstrated only modest (not statistically significant) excess of cardiovascular risk when lumiracoxib was compared with naproxen, but not when compared with ibuprofen.5 Importantly, there have not been any direct comparative (head-to-head) trials of one of the agents vs another, which is the only way to definitively establish likeness or difference between the drugs.

Notwithstanding these concerns, several epidemiologic studies have considered large populations of patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors.6-10 In general, these studies found an increased cardiovascular hazard for rofecoxib, especially at higher doses, but not for celecoxib. Some studies therefore concluded that celecoxib did not carry any risk for MI or stroke.

But in randomized trials, a signal for potential cardiovascular risk with celecoxib was present. As my colleagues and I described in a 2001 review11 of the Celecoxib Long-term Arthritis Safety Study (CLASS),12 the MI rate was 1.6% in the celecoxib group (at a dosage of 400 mg twice per day) and 1.2% in the diclofenac or ibuprofen group for the 1739 patients taking low-dose aspirin. This numerical excess, albeit not statistically significant, was also found in the 6229patients not taking aspirin in the trial. Notably, the study drug duration was only 6 months. Underlying this finding were 2 other mechanistic issues. In experimental models of coronary artery occlusion, celecoxib had been found to be prothrombotic.13 On the other hand, in patients with coronary artery disease, celecoxib has been associated with reduction of C-reactive protein and improvement of endothelial dysfunction.14 Based on data available in 2001 for celecoxib and rofecoxib, my colleagues and I concluded: "It is mandatory to conduct a trial specifically assessing cardiovascular risk and benefit of these agents. Until then, we urge caution in prescribing these agents to patients at risk for cardiovascular morbidity."11 Unfortunately, no such trials were ever initiated and the official warnings for the coxib drugs took years to materialize.

In the wake of the high density of new data on coxibs, several important issues now need to be confronted. First, is there any continuing role for coxibs? Only rofecoxib has been shown to reduce gastrointestinal complications compared with naproxen, but valdecoxib and celecoxib have never been definitively confirmed to protect against gastrointestinal complications. While coxib superiority over NSAIDs for relief of arthritic pain has not been shown, many individual patients report pain relief with a coxib but not an NSAID. With the considerably higher cost, marginal efficacy, and known cardiovascular risks of the remaining agents on the market, valdecoxib and celecoxib, it would seem prudent, at the least, to avoid using these agents as first-line therapy. A contraindication is appropriate for patients with established coronary or cerebrovascular disease. Indeed, the only trials of patients with established coronary artery disease were performed with valdecoxib and parecoxib (an intravenous formulation) and the cardiovascular risk was quite apparent.15-16 Ray and colleagues recently reasonably concluded: "We recommend that clinicians stop prescribing valdecoxib except in extraordinary circumstances."17 Furthermore, Lester Crawford, the acting commissioner of the FDA, has declared "great concerns" about celecoxib and valdecoxib and is now considering forcing the withdrawal of celecoxib or placing a black box on its label.18

With celecoxib, only one trial has thus far shown cardiovascular hazard. While this clearly confirms a class effect, there has not yet been independent replication. Unlike rofecoxib, in which 3 independent randomized trials19 and a cumulative meta-analysis20 confirmed excess cardiovascular risk, a trial conducted in parallel to APC for the same indication has not shown any hazard for celecoxib. The celecoxib dose-response effect for cardiovascular events in APC is not shared by the data for rofecoxib.20 It will be important to have a full analysis of the APC data, with timing of the event curve divergence, and careful examination of the cardiovascular risk profile of patients with events. Until more detailed information is available, it appears that celecoxib use should be restricted. A welcome new precedent was set by the FDA and manufacturer with the agreement to stop marketing celecoxib to consumers while the review of all available data is ongoing.

Second, the NSAID benchmark safety has now been called into question. The pattern from multiple trials of coxibs, with different control NSAID comparators, has helped establish some useful findings. Naproxen appeared to be the only NSAID with some cardioprotective effect. Juni et al20 reviewed all of the trials studying this agent and suggested that it is associated with a 14% reduction of MI, which is less than that of aspirin at 23%. On the other hand, ibuprofen appears to act in the opposite direction of naproxen, with an approximate 10% increase in MI as judged from the very large lumiracoxib trial that fortunately included these 2 different NSAIDs as controls.5 From the body of data available, it appeared that naproxen may be the safest NSAID from a cardiovascular standpoint.

However, on December 20, 2004, the National Institutes of Health and FDA announced the premature cessation of the Alzheimer Disease Anti-inflammatory Prevention Trial (ADAPT).21 While the trial of approximately 2400 patients with an average of 3 years of follow-up (of a planned 5-7 years) was being reviewed for potential adverse cardiovascular events with celecoxib, an excess of cardiovascular events was found in the patients assigned to naproxen vs placebo. This was the first time in a placebo-controlled trial that naproxen has been associated with an excess of MI events. But the trial was interrupted and not designed to assess cardiovascular events for naproxen, and the events have not been adjudicated by cardiologists. Given the large body of evidence from multiple epidemiologic studies and randomized trials6, 20 supporting a modest degree of cardioprotection with naproxen, it seems premature to judge any possible untoward cardiovascular effect of naproxen until the final data from ADAPT become available.

Third, there are major concerns about how an entire drug class has gone awry with respect to unleashing significant cardiovascular hazard. A "house of cards" is defined as a flimsy situation that is in danger of collapsing or failing. From the outset, the coxib class of medicines seemed destined for potential collapse. These drugs were mass-marketed from the moment they were commercially available in the new world of direct-to-consumer advertising, with unrealistic expectations about pain relief, marked gastrointestinal protection, and safety. Rather than a sufficient waiting period after approval to firmly establish safety in the large, representative "real world" population, the unbridled promotion exacerbated the public health problem. This is so poignantly clear for an indication such as arthritis, which is one of the most common conditions requiring medication. Furthermore, one has to question the wisdom of allowing direct-to-consumer advertising for lifestyle medications that have no capability of preserving life or preventing major events such as MI or stroke. Here the paradox of actually promoting these events is all the more difficult to accept.

In recent weeks there has been considerable speculation on how the FDA authority and configuration can be bolstered to preempt a coxib-like problem in the future. There is ample evidence of the overemphasis and resource allocation for initial drug approval, with little priority for postmarketing surveillance.22 An independent drug safety agency or center that compartmentalizes the vital functions of approval and surveillance seems to be gathering broad support.23 Importantly, providing more authority to the FDA to shape and require the execution of vital trials is perhaps the most important lesson from the coxibs. Currently, for the FDA to mandate that a trial be performed in the postapproval phase of a drug, it has to confront the manufacturer that the drug in question may be withdrawn from the market. There is hardly a precedent for such a drastic step in the history of the FDA. Unfortunately, manufacturers of coxibs were not willing to initiate dedicated cardiovascular trials on their own accord. With early results of coxibs that brought out their prothrombotic potential, rapid initiation of follow-up randomized clinical trials was absolutely necessary. Furthermore, nearly half of "real world" patients with arthritis have coexisting cardiovascular disease,24 and essentially no trials addressed this vacuum of knowledge. Accordingly, legislation is needed to empower the FDA to require industry to conduct trials that are deemed necessary to ensure the safety profile of a drug. Had coxib trials been conducted 5 years ago in patients with established cardiovascular disease, when the benefit and risk were indeterminate, clinicians would have quickly learned the risk and potentially avoided a major cardiovascular calamity.

The combination of mass promotion of a medicine with an unknown and suspect safety profile cannot be tolerated in the future. An aggressive position going forward is necessary not only for ensuring the safety of prescription medicines but also to restore a solid foundation of public trust.


AUTHOR INFORMATION

Corresponding Author: Eric J. Topol, MD, Desk F25, 9500 Euclid Ave, Cleveland Clinic Foundation, Cleveland, OH 44195 (topole@ccf.org).

Financial Disclosure: Dr Topol reports no conflict of interest/relationship with any manufacturer of COX-2 inhibitors or NSAIDs.

Disclaimer: The views expressed herein represent the author’s and are not intended to represent the institutions with which he is affiliated.

Editorials represent the opinions of the authors and THE JOURNAL and not those of the American Medical Association.

Author Affiliations: Department of Cardiovascular Medicine, Cleveland Clinic Foundation; Office of the Provost, Cleveland Clinic Lerner College of Medicine; Case Western Reserve University, Cleveland, Ohio.


REFERENCES

1. US Food and Drug Administration. Bextra label updated with boxed warning concerning severe skin reactions and warning regarding cardiovascular risk. FDA Talk Paper. December 9, 2004. Available at: http://www.fda.gov/bbs/topics/ANSWERS/2 ... 01331.html Accessed December 21, 2004.
2. US Department of Health and Human Services. NIH halts use of COX-2 inhibitor in large cancer prevention trial. NIH News. December 17, 2004. Available at: http://www.nih.gov/news/pr/dec2004/od-17.htm. Accessed December 21, 2004.
3. Topol EJ. Failing the public health: rofecoxib, Merck, and the FDA. N Engl J Med. 2004;351:1707-1710. FULL TEXT
4. Topol EJ, Falk GW. A coxib a day won’t keep the doctor away. Lancet. 2004;364:639-640. MEDLINE
5. Farkouh ME, Kirshner H, Harrington RA. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomized controlled trial. Lancet. 2004;364:675-684. MEDLINE
6. Solomon DH, Schneeweiss S, Glynn RJ, et al. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation. 2004;109:2068-2073. ABSTRACT/FULL TEXT
7. Ray WA, Stein CM, Hall K, Daugherty JR, Griffin MR. Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease: an observational cohort study. Lancet. 2002;359:118-123. MEDLINE
8. Kimmel SE, Berlin JA, Reilly M, et al. Patients exposed to rofecoxib and celecoxib have different odds of nonfatal myocardial infarction. Ann Intern Med. Available at: http://www.acponline.org/journals/annals/myo_infar.htm. Published online December 7, 2004. Accessed December 20, 2004.
9. Graham DJ, Campen D, Cheetham C, et al. Risk of acute cardiac events among patients treated with cyclooxygenase-2 selective and non-selective nonsteroidal anti-inflammatory drugs [abstract]. Pharmacoepidemiol Drug Saf. 2004;13:S287-S288.
10. Mamdani M, Juurlink DN, Lee Douglas S, et al. Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study. Lancet. 2004;363:1751-1756. MEDLINE
11. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286:954-959. ABSTRACT/FULL TEXT
12. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS Study: a randomized controlled trial. JAMA. 2000;284:1247-1255. ABSTRACT/FULL TEXT
13. Hennan JK, Huang J, Barrett TD. Effects of selective cyclooxygenase-2 inhibition on vascular responses and thrombosis in canine coronary arteries. Circulation. 2001;104:820-825. ABSTRACT/FULL TEXT
14. Chenevard R, Hurlimann D, Bechir M, et al. Selective COX-2 inhibition improves endothelial function in coronary artery disease. Circulation. 2003;107:405-409. ABSTRACT/FULL TEXT
15. Bextra [package insert]. Available at: http://www.fda.gov/cder/foi/label/2004/21341lbl.pdf. Accessed December 21, 2004.
16. Ott E, Nussmeier NA, Duke PC, et al. Efficacy and safety of the cyclooxygenase inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg. 2003;125:1481-1487. ABSTRACT/FULL TEXT
17. Ray WA, Griffin MR, Stein CM. Cardiovascular toxicity of valdecoxib [letter]. N Engl J Med. 2004;351:2767. FULL TEXT
18. Harris G. Drug trial finds big health risks in 2nd painkiller. New York Times. December 18, 2004:A1.
19. Topol EJ. Rofecoxib, Merck and the FDA [letter]. N Engl J Med. In press.
20. Juni P, Nartey L, Reichenbach S, et al. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet. 2004;364:2021-2029. MEDLINE
21. FDA statement on naproxen. Available at: http://www.fda.gov/bbs/topics/news/2004/NEW01148.html. Accessed December 21, 2004.
22. Harris G, Schwartz J. Regulation redefined: the FDA shifts focus; at FDA strong drug ties and less monitoring. New York Times. December 6, 2004:A1.
23. Fontanarosa PB, Rennie D, DeAngelis C. Postmarketing surveillance: lack of vigilance, lack of trust. JAMA. 2004;292:2647-2650. FULL TEXT
24. Cox ER, Frisse M, Behm A, Fairman KA. Over-the-counter pain reliever and aspirin use within a sample of long-term cyclooxygenase 2 users. Arch Intern Med. 2004;164:1243-1246. FULL TEXT

[malernee]

Corporate Crime Reporter



Devout Christian David Graham Details Showdown with FDA

19 Corporate Crime Reporter 1(1), January 3, 2005


David Graham said last week that his Catholic faith guided him in blowing the whistle on his employer, the Food and Drug Administration (FDA), for its failure to pull Merck’s popular painkiller Vioxx off the market.


Merck voluntarily pulled the drug off the market in September after a study it conducted showed that Vioxx doubled the risk of heart attacks.


“I’m a Catholic Christian, and though I continually fall short of modeling the Gospel in my life, I have always tried to do so,” Graham said in accepting the Joe. A. Callaway Award for Civic Courage last week in downtown Washington, D.C. “In reflecting on this award, I recall the verse from the New Testament scriptures where Jesus spoke to his disciples about service and instructed them to remember that we must remain humble, for there is no honor in doing what we were told to do.”


“To paraphrase this verse, I have done nothing more than my duty,” Graham said.


Graham is married had has six children. His wife is a lawyer who home schools her children.


During his thirty-minute acceptance speech, and a short question-and-answer period that followed, Graham portrayed his action in speaking out publically against the FDA and the drug industry as a Christian duty of conscience.


“For the past 20 years, I have worked at the FDA as a post-marketing drug safety researcher,” Graham told a group of about 65, including drug safety activists, some FDA colleagues, and members of his family gathered to witness the awards ceremony. “Education I received at the Johns Hopkins School of Medicine taught me to act in the best interests of my patients, regardless of personal cost or inconvenience. My religious faith taught me to preserve their lives to the best of my ability and to do nothing to intentionally injure or harm them. And when I became an epidemiologist at FDA, the entire nation – all 290 million people – became my patients, a responsibility I’ve taken to heart.”


Graham became something of a celebrity in Washington after going before the Senate Finance Committee and caustically ripping apart the FDA for failing to protect American consumers.

At that hearing, Graham estimated that between 88,000 and 139,000 people in the United States had suffered heart attacks or stroke as result of taking Vioxx and that as many as 40 percent of those, or about 55,000, died as a result.


But at the awards ceremony last week, he didn’t use the 55,000 number, instead at one point referring to 40,000 dead, and at another talking about 30,000 to 40,000 dead.


In any event, he stuck with his Senate testimony that the Vioxx dead represented “what may be the single greatest drug safety catastrophe in the history of this country or the history of the world.”


Graham said that had he known about “the cost and the extreme difficulty of working in an environment that routinely dismisses or twists the truth about drug safety and punishes you severely for speaking the truth, I’m certain that I would have chosen a different path.”


Graham quoted Robert Frost famous poem, Road Not Taken – “Two roads diverged in a wood, and I took the one less traveled by, And that has made all the difference.”


“In many ways, this has been a description of my career,” Graham said. “Please understand, I am not a hero and I’m not endowed with extraordinary courage, despite the honor that has been bestowed on my today. At each divergence of the roads where I faced an important decision, I can honestly say that it was conscience not courage that compelled me.”


“For me it was clear what I had to do and I set about to do that and tried not to think about what would happen afterwards,” Graham said. “Fear is the single greatest enemy of doing the right thing. It is fear that works in all of our hearts to deter us from doing what is right. To me, it is the compulsion of my conscience that overcame my human fear, and this certitude that somehow or another, things would work out for the good -- the Lord would provide for me.”

Graham said that earlier this year, he wanted to publish his study of heart attack risks of Vioxx in the peer reviewed literature, but that “the FDA reacted violently to that.”


While he was trying to convince his superiors to let him publish his study, Merck was voluntarily pulling Vioxx off the market.


“The FDA would not have pulled Vioxx off the market,” Graham said. “The FDA saw no problem with 100,000 people having heart attacks because of Vioxx.”


“The week before Vioxx came off the market, I was in a meeting with very senior people from the Office of New Drugs and my own Office of Drug Safety,” Graham said. “And the things they were saying to me was – why on earth were you studying Vioxx and heart attacks? We have no regulatory problem with this drug. We in the Office of New Drugs didn’t approve your study. We don’t want you studying that.”


“In a sense, Merck did a public service in pulling Vioxx from the market,” Graham said. “I really can’t comment on Merck’s motivations – how altruistic they were. But if you look at the evidence and literature, it is clear that prior to the marketing of these drugs – Vioxx and Celebrex – there were strong theoretical reasons why one would expect that these drugs might increase the risk of heart attack. And for that reason, FDA needs to be held accountable. FDA was fully aware of these theoretical concerns and knew also that these drugs, being in the class of drugs for pain relief – that they would be used by tens of millions of people.”


Congress became interested in the drug safety problem only after Merck pulled Vioxx off the market.


After all, Graham said – “this drug was given to 27 million people, Merck is a big company, it’s capitalization dropped 27 billion in one day.”


The three big painkillers in this class – Vioxx, Celebrex and Bextra – combined made over $4 billion in profits this year.


"And who knows how many people had heart attacks because of them?” Graham asked.

Graham told the gathering that when Senator Charles Grassley (R-Iowa) began asking questions about Vioxx, “I knew my goose was cooked.”


“They were going to have a hearing, and I would be asked to testify. I was happy to tell the truth,” Graham said. “I wasn’t so happy at the prospect of being unemployed.”


“In any event, the time came to testify,” he said. “I suppose I could have given a watered down version of the truth. But had I done that, I wouldn’t be able to live with myself, because I know that I would have done wrong. And being a physician to 290 million Americans, wouldn’t know who it was who died because I failed to speak the truth, or who ended up with a heart attack and didn’t die because I failed to speak the truth. But rest assured, there would be many of those people and I would be complicit in the injury that they suffered and the suffering that their families experienced when a loved one dies suddenly from a heart attack.”


Graham said that “in Dante’s inferno, there are levels of hell.”


“And there are levels of courage, too,” he said. “The disaster that I face, losing my job, that’s pretty terrible. I have six kids to support. Some of them are of college age. Some of them are young. And that is something to worry about. But it is not like losing your life. Go back to the Holocaust. People who risked their lives hiding Jews from the Nazis, recognizing that if they were betrayed or caught, they would have lost their lives – they didn’t have to do that. But conscience drove them to do it. It was recognizing the image of God, that we are all God’s children, we are all his sons and daughters.”


Graham said that on the weekend before his fateful testimony before Grassley’s Senate Committee, his bosses launched a three-pronged attack against his credibility.


“They contacted Senator Grassley and tried to convince him that I wasn’t worth his support, that I was a liar, that I was a cheat, that I was a bully, that I was a demagogue, that I was untrustworthy,” Graham said. “At that same time, they contacted the Government Accountability Project with the same line. They thought – maybe we can get Senator Grassley to not support him, or maybe we can get GAP not to defend him. And then let’s go for the hat trick – the editor of The Lancet. My center director contacted the editor of The Lancet and accused me of scientific misconduct.”


“Scientific misconduct is the highest crime a scientist can commit,” Graham said with a touch of bitterness. “Scientific misconduct is a betrayal of all that science stands for. Scientific misconduct, if you have committed it, is a career-ender.”


“Needless to say, it wasn’t true,” he continued. “By the end of the weekend, the editor of The Lancet had communicated to the center director that I had handled myself in the finest tradition of scientists, that there was no scientific misconduct, that there were no scientific problems with the paper and that it should be published. And the Center director agreed that it could be published.”


“It was supposed to be published on-line the day before my Senate hearing, so we would have the numbers in my testimony. The 100,000 heart attack number would be in The Lancet before the testimony – it would have scientific credibility. But my managers set a trap – so that if I allowed it to be published, they could fire me. So, I was forced to withdraw the article from publication on the eve of its publication.”


“I was still able to give my testimony. But that weekend, when I was supposed to be writing my testimony, was shattered by having to deal with this three-pronged attack. Fortunately, I was able to put together the testimony. I had no idea that the testimony that I gave would attract the attention that it did. I had no intention when I testified to become a public figure, but your face is plastered in the newspapers and this is what happens.”


Graham confided to the group that “my Scottish terrier bit part of my nose off on the left side.”


“The nose that you see here is the result of reconstructive surgery,” Graham said. “I need to let my plastic surgeon know that most of the photographs have been coming from the left side and nobody has commented on how bad a job he did. So, I think he must have done a pretty good job. By the way, the dog is still a happy member of the family. He is forgiven. But he is minus some androgen-producing glands.”


It became clear from listening to Graham’s talk that he blames the FDA, not the drug companies, for the drug safety problems afflicting the country.


“On 911, 3,000 people died,” Graham said. “With Vioxx, ten to fifteen times that number died, but it didn’t happen one at a time – maybe on your street, maybe on my street, maybe lasitional 60,000 people had non-fatal heart attacks, one at a time. It happens below the radar screen. But it is a national catastrophe nonetheless. The FDA and FDA alone is responsible for it”


“It is not the fault of the drug companies,” he said. “We’ll let the courts decide what their liability is. For me, I can focus on FDA. FDA had a sacred trust, it betrayed that trust, it betrayed the American people. One hundred thousand people paid a high price for that just with Vioxx. I don’t know how many have paid that price with Bextra, with Celebrex, with any of the other drugs that FDA took too long to withdraw from the market.”


Graham said that the big drug companies “have been lobbying like crazy” in recent weeks to prevent Congress from reorganizing the FDA.


“The last thing on earth drug companies want to see is strong post-marketing drug safety because if there is strong post-marketing drug safety, it is going to cost companies more money to research the drugs before they get to market, and they are going to run the risks of a drug being removed from the market,” he said.


Under current federal law, the FDA must guarantee that drugs are safe and effective.


Graham said that the FDA requires that drug companies prove that they are “at least 95 percent certain that this drug has an effect – it lowers you blood pressure, it lowers your cholesterol, it lowers your blood sugar – we are 95 percent confident it does that.”


But when it comes to safety, the FDA takes that statistical model and turns it on its head, Graham said.


“Rather than saying – we are 95 percent certain that the drug is safe to a given level, they say – we are not 95 percent certain that it will kill, so I guess it doesn’t. And the FDA gives that drug a free pass.”


Graham also called for strong job protection for government workers who, like himself “commit the truth.”


Graham said that a recent FDA Office of Inspector General survey found that two-thirds of FDA medical officers are not confident that the products that are approved are safe and that 18 percent felt that they have been pressured to change their conclusions.


“I can guarantee you, there are other whistleblowers at FDA,” Graham said. “There are many whistleblowers at FDA. Fear has them by the throat. And they struggle with their conscience and they struggle with the wrong that they see, and they are paralyzed by their fear. And they are looking to see – can that Graham fellow get away with committing the truth?”


“It remains to be seen whether I can get away with committing the truth,” he said. “But it shouldn’t be that way.”


The Joe A. Callaway award was established to recognize individuals in any area of endeavor who, with integrity and at some personal risk, take a public stand to advance truth and justice, and who challenge unsatisfactory conditions in pursuit of the common good.


The award was also given this year to Mark Livingston, a pharmaceutical quality control specialist who was involved in the launching of Wyeth Pharmaceuticals’ Prevnar pediatric vaccine.


In the fall of 2003, Livingston filed a lawsuit in federal court alleging that Wyeth Pharmaceuticals compromised the manufacturing process of bulk vaccine to meet demand.


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[guest]

FDA slams Novartis on dog painkiller like Vioxx

If deaths are similar to vioxx why no animal investigation by the fda like the human one? Do you think honest vets and clients would be buying these cox2 drugs for their patients and pets if they had all the withheld information?



FDA slams Novartis on dog painkiller
Agency says drugmaker withheld data showing deaths with drug similar to Vioxx.
December 28, 2004: 12:54 PM EST

WASHINGTON (Reuters) - Novartis AG failed to give the government prompt, accurate reports about deaths of dogs treated with a painkiller in the same class of medicines now linked to heart problems in humans, U.S. regulators have charged in a letter.

Novartis (up $0.23 to $50.33, Research) officials could not immediately be reached for comment.

The drug, Deramaxx, is a COX-2 inhibitor approved for relieving arthritis and post-surgical pain in dogs.



Similar drugs for people are under heavy scrutiny after studies associated them with heart attacks and strokes. One of the drugs, Merck & Co. Inc.'s (up $0.33 to $32.28, Research) Vioxx, was pulled from the market because of safety risks.

Death has been reported "in rare situations" when dogs were treated with Deramaxx, according to the drug's label instructions.

The Food and Drug Administration, in a warning letter dated Nov. 29, said Novartis Animal Health Services should have forwarded complaints about deaths and health problems in dogs given Deramaxx within 15 working days, but in some cases delayed as long as 10 months. Some reports, including ones involving deaths, appeared to have incorrect dates, the FDA said.

"Novartis failed to submit timely and accurate information to the FDA regarding serious (adverse drug experiences) associated with the administration of its FDA-approved animal drug product Deramaxx ... during its first year of marketing," the FDA said.

The company also failed to submit proper information about post-approval studies of Deramaxx, the FDA charged. The drug is known generically as deracoxib.

The FDA sends dozens of warning letters per year. Most of the issues raised are resolved without further regulatory action, although the letters sometimes lead to tougher steps such as product seizures.

[guest]

Nimesulide, a cyclooxygenase-2 preferential inhibitor, impairs renal function in the newborn rabbit.

Prevot A, Mosig D, Martini S, Guignard JP.

Nephrology Unit, Department of Pediatrics, Lausanne University Medical Center, CH 1011 Lausanne, Switzerland.

Tocolysis with nonsteroidal anti-inflammatory drugs (NSAIDs) has been widely accepted for several years. Recently, the use of the cyclooxygenase-2 (COX2) preferential NSAID nimesulide has been proposed. However, data reporting neonatal acute renal failure or irreversible end-stage renal failure after maternal ingestion of nimesulide question the safety of this drug for the fetus and the neonate. Therefore, this study was designed to define the renal effects of nimesulide in newborn rabbits. Experiments were performed in 28 newborn rabbits. Renal function and hemodynamic parameters were measured using inulin and para-aminohippuric acid clearances as markers of GFR and renal blood flow, respectively. After a control period, nimesulide 2, 20, or 200 microg/kg was given as an i.v. bolus, followed by a 0.05, 0.5, or 5 microg.kg(-1).min(-1) infusion. Nimesulide administration induced a significant dose-dependent increase in renal vascular resistance (29, 37, and 92%, respectively), with a concomitant decrease in diuresis (-5, -23, and -44%), GFR (-12, -23, and -47%), and renal blood flow (-23, -23, and -48%). These results are in contrast with recent reports claiming that selective COX2 inhibition could be safer for the kidney than nonselective NSAIDs. These experiments confirm that prostaglandins, by maintaining renal vasodilation, play a key role in the delicate balance regulating neonatal GFR. We conclude that COX2-selective/preferential inhibitors thus should be prescribed with the same caution as nonselective NSAIDs during pregnancy and in the neonatal period.

PMID: 14605244 [PubMed - indexed for MEDLINE]