PNAS | August 29, 2000 | vol. 97 | no. 18 | 10197-10202
PubMed
PubMed Citation
Articles by Shinmura, K.
Articles by Bolli, R.
Medical Sciences
Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits
Ken Shinmura, Xian-Liang Tang, Yang Wang, Yu-Ting Xuan, Si-Qi Liu, Hitoshi Takano, Aruni Bhatnagar, and Roberto Bolli*
The Experimental Research Laboratory, Division of Cardiology, University of Louisville, and Jewish Hospital Heart and Lung Institute, Louisville, KY 40292
Communicated by Eugene Braunwald, Partners HealthCare System, Inc., Boston, MA, June 15, 2000 (received for review March 15, 2000)
We examined the role of cyclooxygenase-2 (COX-2) in the late phase of ischemic preconditioning (PC). A total of 176 conscious rabbits were used. Ischemic PC (six cycles of 4-min coronary occlusions/4-min reperfusions) resulted in a rapid increase in myocardial COX-2 mRNA levels (+231 ± 64% at 1 h; RNase protection assay) followed 24 h later by an increase in COX-2 protein expression (+216 ± 79%; Western blotting) and in the myocardial content of prostaglandin (PG)E2 and 6-keto-PGF1 (+250 ± 85% and +259 ± 107%, respectively; enzyme immunoassay). Administration of two unrelated COX-2 selective inhibitors (NS-398 and celecoxib) 24 h after ischemic PC abolished the ischemic PC-induced increase in tissue levels of PGE2 and 6-keto-PGF1. The same doses of NS-398 and celecoxib, given 24 h after ischemic PC, completely blocked the cardioprotective effects of late PC against both myocardial stunning and myocardial infarction, indicating that COX-2 activity is necessary for this phenomenon to occur. Neither NS-398 nor celecoxib lowered PGE2 or 6-keto-PGF1 levels in the nonischemic region of preconditioned rabbits, indicating that constitutive COX-1 activity was unaffected. Taken together, these results demonstrate that, in conscious rabbits, up-regulation of COX-2 plays an essential role in the cardioprotection afforded by the late phase of ischemic PC. Therefore, this study identifies COX-2 as a cardioprotective protein. The analysis of arachidonic acid metabolites strongly points to PGE2 and/or PGI2 as the likely effectors of COX-2-dependent protection. The recognition that COX-2 mediates the antistunning and antiinfarct effects of late PC impels a reassessment of current views regarding this enzyme, which is generally regarded as detrimental.
RIMADYL ZENECARP Carprofen all same NSAIDS warning usage
26 posts
• Page 2 of 2 • 1, 2
cox2 drugs produce cardiovascular ischemia in rabbits study
by guest » Tue Jan 04, 2005 11:52 am
- guest
April 28, 1999, FDA Stakeholders meeting
by guest » Thu Jan 06, 2005 7:05 am
I thought some of our newer subscribers would like to read the statement
given by Bob Sinclair at the April 28, 1999, FDA Stakeholders meeting in Overland
Park, Kansas. The transcript can be viewed at:
http://www.fda.gov/ohrms/dockets/docket ... r00003.txt
The following is quoted from that transcript:
QUOTE:
QUOTE:
MR. BREENE: Our next speaker is Robert Sinclair.
MR. SINCLAIR: Good afternoon. My name is Bob Sinclair. My wife, Jane, and
I are from West Bloomfield, Michigan. We are here with our colleague, Jean
Townsend from John's Island, South Carolina. We'd like to thank the CVM for
the opportunity to attend this meeting and offer some views.
As consumers and dog owners, we feel strongly that the communication efforts
of the FDA can be improved so that users of animal health products can have
better access to understandable and timely information. The quality of life
of the hundred million-plus American companion animals and
their owners and households will benefit when the agency treats information
about animal health products the way it treats information about human health
products.
Question 2 in the March 22nd Federal Register notice, let me offer two
comments. First, FDA can prove the timeliness of publishing adverse drug
experience reports, particularly when new drugs are introduced in the market.
Delays in the exchange of information between the FDA and consumers can have
serious implications for the companion animals that they care for.
Many manufacturers are required to submit ADAA reports to the Agency.
Availability of evaluations of these reports to the general public, in our view,
should not await preparation and subsequent publication of annual summaries.
An example, Pfizer introduced Rimidil Purprophen for dogs in January 1997.
Clearly ADE reports were received during the '97 calendar year, but the '97
FDA summary of ADE reports on veterinary drugs was not published until
October 29, 1998. Dog owners were denied access to this important information
for an unacceptably long period of time, in our view. For months during
which the volume of ADE reports about Rimidil was building, owners were
purchasing and administering the drug to their pets with little knowledge about
adverse effects. Dear Doctor letters may be issued, and they were, and label
changes may occur, and they did, but there is no assurance that balanced
risk/benefit information is available to consumers. Lack of information about
Rimidil's potentially toxic side effects seriously affected the quality of
life of our toy poodle, Misty, and caused the death of Jean Townsend's chocolate
lab,
George.
We detailed Misty's story in reports submitted last October, and in February
Georgia's necropsy report was sent to Pfizer and to the FDA/CVM. Second,
various means can be employed to disseminate balanced information about
animal health products to consumers. Internet web site updates plus post read
line bulletins to veterinary facilities and other communication techniques come
to mind.
In view of the time, I'm going to edit this on the fly and go right on to the
next
point.
Question 3 in the notice asks, "What actions do you propose for educating
the public about the concept of balancing risks against benefits in public
health decision-making?" We have several responses to this question.
Direct to consumer so-called DTC advertising posts, we believe FDA can
re-institute its earlier policy requiring that DTC advertising of human and animal
prescription drugs in all media include a brief summary -- quote, "a brief
summary" -- of hazards and contraindications.
After broadcast advertising restrictions were eased on August 8th, 1997, it
became apparent that procedures are not in place to assure that balanced
information is, in fact, delivered in all media.
Unbalanced TV commercials encourage animal owners to unknowingly demand
drugs like Rimidil that may
cause their pets to suffer lethal or sublethal side effects. Coupled with
unavailability of label information or patient information leaflets, animal
owners hoping to help their pets cannot evaluate the risks versus the benefits
and make informed decisions.
We suggest a new regulation. We suggest that FDA can initiate rule-making
towards a federal regulation requiring that consumer information prepared and
supplied by the manufacturer must absolutely be delivered to animal owners
when prescription drugs are purchased.
Drugs suppliers and veterinary practitioners who fail to provide such
information to animal owners would be held in violation of this regulation. And
obviously means to monitor compliance and enforce the proposed regulation would
be required.
Blister pack and tube packaging include inserts that do provide information,
but many animal prescription drugs are dispensed in small vet-supplied
containers without either label information or PILs, containing balanced
risk/benefit information. Typically these containers indicate the name of the drug,
the dosage and the condition for which it was prescribed. Animal owners are
not assured receipt of accurate guidelines advising that their animals should
be carefully and objectively monitored.
We -- Jean and I -- we never received such guidance about Rimidil. The only
information that was provided verbally to us was that Rimidil is, quote,
"safer than aspirin and has less GI effects." Something clearly is wrong in
the risk/benefits communication process between the manufacturer/distributor,
the veterinarian, and the consumer/owner of the animal receiving the drug.
A veterinary drug database. Many users don't understand possible risks
without personally conducting exhaustive research which they may or may not be
able to pursue. Information about new human drugs is readily accessible by
consumers from the FDA home page, a database of veterinary prescription drug
information that can be accessed from the CVM home page we recommend should be
created. The FOI summaries don't answer the need. Consumers cannot readily
access information about a new animal drugs like Etogesic as they can about a
new human drug like Celobrex (phonetics).
U.S. approval status reports.
We believe the FDA can do a better job of informing the public about the
U.S. approval status of drugs approved and being used successfully in other
countries. Cartofovet, penicillin polysulfate sodium (phonetics), for example,
has been available in Australia, New Zealand, Canada, the United Kingdom and
Ireland for years. This therapy for osteoarthritis in dogs is not available
in the United States, and we do not know how to determine its status.
We think the public needs to know. We think the CVM could explain its
position on fighting this promotional advertising works advising material to the
American public.
Here are four copies -- or copies of four letters from the Agency to Pfizer
dated April 4, October 8, December 19 and December 21, 1998. Each of these
letters discussed fair balance and advised that Pfizer was found in violation
of the FFDC act and applicable regulations. The public, we believe,
deserves to know the results of these actions. Pfizer has claimed Rimidil is safer
than aspirin. This is a bogus claim.
And I'll skip. I'm getting signs telling me to stop talking. So I'll again
edit further on the fly. The claim that Rimidil is safer than aspirin is
wrong. That was documented in the October '98 summary of '97 ADE reports
highlighted in the January-February issue of the FDA Veterinarian and discussed
in articles appearing in
recent issues of APC Veterinary News and Dog World.
The Pfizer commercials continue. The golden retriever is still jumping over
garbage cans, leaping to the second floor and sliding down banisters. We
think that and merchandising materials, toy dogs, desk pads, calendars, lack
fair balance of risk/benefit information.
We'd also like to know why -- we'd like CVM to comment on why the U.S.
Dosage for Rimidil after one week is twice that in Australia, the United Kingdom
and Europe where adverse experiences seem to be less than in this national
market.
Let me close by describing a personal experience that occurred in March at a
specialty show the day before the Detroit Dog Show. A lady that we met
brought her six-year-old dog for obedience trials and a beautiful
fourteen-year-old along for the ride. In conversation, the owner said that her vet had
just put the older dog on Rimidil. We asked why. Her answer? "Oh, no
symptoms. She just slowing down a little and the vet said Rimidil is very
popular now."
Jean, Jane and I are here in part seeking closure and for those who record
the remote, statistically insignificant judgment, I say that for Misty and
George and many others, it was a hundred percent. As you people in CVM well
know, the premarket testing rarely indicates the full range of problems. Our
plea is simply one for better communications, improvements in the exchange
of information about animal drugs.
The so-called action plan for the provision of useful prescription medicine
information approved for human drugs by Secretary Shalala January 13, '97, we
recommend be adopted for animal drugs. What we miss today is the guarantee
that information about the drugs we give to our animals is timely, accurate,
up-to-date, unbiased, specific, and comprehensive and is presented in an
understandable and legible format and is useful.
Thank you very much for your time.
(Applause.)
MR. BREEN: Does the CVM panel have any clarifying questions it wishes to
ask?
(No response.)
END QUOTE
given by Bob Sinclair at the April 28, 1999, FDA Stakeholders meeting in Overland
Park, Kansas. The transcript can be viewed at:
http://www.fda.gov/ohrms/dockets/docket ... r00003.txt
The following is quoted from that transcript:
QUOTE:
QUOTE:
MR. BREENE: Our next speaker is Robert Sinclair.
MR. SINCLAIR: Good afternoon. My name is Bob Sinclair. My wife, Jane, and
I are from West Bloomfield, Michigan. We are here with our colleague, Jean
Townsend from John's Island, South Carolina. We'd like to thank the CVM for
the opportunity to attend this meeting and offer some views.
As consumers and dog owners, we feel strongly that the communication efforts
of the FDA can be improved so that users of animal health products can have
better access to understandable and timely information. The quality of life
of the hundred million-plus American companion animals and
their owners and households will benefit when the agency treats information
about animal health products the way it treats information about human health
products.
Question 2 in the March 22nd Federal Register notice, let me offer two
comments. First, FDA can prove the timeliness of publishing adverse drug
experience reports, particularly when new drugs are introduced in the market.
Delays in the exchange of information between the FDA and consumers can have
serious implications for the companion animals that they care for.
Many manufacturers are required to submit ADAA reports to the Agency.
Availability of evaluations of these reports to the general public, in our view,
should not await preparation and subsequent publication of annual summaries.
An example, Pfizer introduced Rimidil Purprophen for dogs in January 1997.
Clearly ADE reports were received during the '97 calendar year, but the '97
FDA summary of ADE reports on veterinary drugs was not published until
October 29, 1998. Dog owners were denied access to this important information
for an unacceptably long period of time, in our view. For months during
which the volume of ADE reports about Rimidil was building, owners were
purchasing and administering the drug to their pets with little knowledge about
adverse effects. Dear Doctor letters may be issued, and they were, and label
changes may occur, and they did, but there is no assurance that balanced
risk/benefit information is available to consumers. Lack of information about
Rimidil's potentially toxic side effects seriously affected the quality of
life of our toy poodle, Misty, and caused the death of Jean Townsend's chocolate
lab,
George.
We detailed Misty's story in reports submitted last October, and in February
Georgia's necropsy report was sent to Pfizer and to the FDA/CVM. Second,
various means can be employed to disseminate balanced information about
animal health products to consumers. Internet web site updates plus post read
line bulletins to veterinary facilities and other communication techniques come
to mind.
In view of the time, I'm going to edit this on the fly and go right on to the
next
point.
Question 3 in the notice asks, "What actions do you propose for educating
the public about the concept of balancing risks against benefits in public
health decision-making?" We have several responses to this question.
Direct to consumer so-called DTC advertising posts, we believe FDA can
re-institute its earlier policy requiring that DTC advertising of human and animal
prescription drugs in all media include a brief summary -- quote, "a brief
summary" -- of hazards and contraindications.
After broadcast advertising restrictions were eased on August 8th, 1997, it
became apparent that procedures are not in place to assure that balanced
information is, in fact, delivered in all media.
Unbalanced TV commercials encourage animal owners to unknowingly demand
drugs like Rimidil that may
cause their pets to suffer lethal or sublethal side effects. Coupled with
unavailability of label information or patient information leaflets, animal
owners hoping to help their pets cannot evaluate the risks versus the benefits
and make informed decisions.
We suggest a new regulation. We suggest that FDA can initiate rule-making
towards a federal regulation requiring that consumer information prepared and
supplied by the manufacturer must absolutely be delivered to animal owners
when prescription drugs are purchased.
Drugs suppliers and veterinary practitioners who fail to provide such
information to animal owners would be held in violation of this regulation. And
obviously means to monitor compliance and enforce the proposed regulation would
be required.
Blister pack and tube packaging include inserts that do provide information,
but many animal prescription drugs are dispensed in small vet-supplied
containers without either label information or PILs, containing balanced
risk/benefit information. Typically these containers indicate the name of the drug,
the dosage and the condition for which it was prescribed. Animal owners are
not assured receipt of accurate guidelines advising that their animals should
be carefully and objectively monitored.
We -- Jean and I -- we never received such guidance about Rimidil. The only
information that was provided verbally to us was that Rimidil is, quote,
"safer than aspirin and has less GI effects." Something clearly is wrong in
the risk/benefits communication process between the manufacturer/distributor,
the veterinarian, and the consumer/owner of the animal receiving the drug.
A veterinary drug database. Many users don't understand possible risks
without personally conducting exhaustive research which they may or may not be
able to pursue. Information about new human drugs is readily accessible by
consumers from the FDA home page, a database of veterinary prescription drug
information that can be accessed from the CVM home page we recommend should be
created. The FOI summaries don't answer the need. Consumers cannot readily
access information about a new animal drugs like Etogesic as they can about a
new human drug like Celobrex (phonetics).
U.S. approval status reports.
We believe the FDA can do a better job of informing the public about the
U.S. approval status of drugs approved and being used successfully in other
countries. Cartofovet, penicillin polysulfate sodium (phonetics), for example,
has been available in Australia, New Zealand, Canada, the United Kingdom and
Ireland for years. This therapy for osteoarthritis in dogs is not available
in the United States, and we do not know how to determine its status.
We think the public needs to know. We think the CVM could explain its
position on fighting this promotional advertising works advising material to the
American public.
Here are four copies -- or copies of four letters from the Agency to Pfizer
dated April 4, October 8, December 19 and December 21, 1998. Each of these
letters discussed fair balance and advised that Pfizer was found in violation
of the FFDC act and applicable regulations. The public, we believe,
deserves to know the results of these actions. Pfizer has claimed Rimidil is safer
than aspirin. This is a bogus claim.
And I'll skip. I'm getting signs telling me to stop talking. So I'll again
edit further on the fly. The claim that Rimidil is safer than aspirin is
wrong. That was documented in the October '98 summary of '97 ADE reports
highlighted in the January-February issue of the FDA Veterinarian and discussed
in articles appearing in
recent issues of APC Veterinary News and Dog World.
The Pfizer commercials continue. The golden retriever is still jumping over
garbage cans, leaping to the second floor and sliding down banisters. We
think that and merchandising materials, toy dogs, desk pads, calendars, lack
fair balance of risk/benefit information.
We'd also like to know why -- we'd like CVM to comment on why the U.S.
Dosage for Rimidil after one week is twice that in Australia, the United Kingdom
and Europe where adverse experiences seem to be less than in this national
market.
Let me close by describing a personal experience that occurred in March at a
specialty show the day before the Detroit Dog Show. A lady that we met
brought her six-year-old dog for obedience trials and a beautiful
fourteen-year-old along for the ride. In conversation, the owner said that her vet had
just put the older dog on Rimidil. We asked why. Her answer? "Oh, no
symptoms. She just slowing down a little and the vet said Rimidil is very
popular now."
Jean, Jane and I are here in part seeking closure and for those who record
the remote, statistically insignificant judgment, I say that for Misty and
George and many others, it was a hundred percent. As you people in CVM well
know, the premarket testing rarely indicates the full range of problems. Our
plea is simply one for better communications, improvements in the exchange
of information about animal drugs.
The so-called action plan for the provision of useful prescription medicine
information approved for human drugs by Secretary Shalala January 13, '97, we
recommend be adopted for animal drugs. What we miss today is the guarantee
that information about the drugs we give to our animals is timely, accurate,
up-to-date, unbiased, specific, and comprehensive and is presented in an
understandable and legible format and is useful.
Thank you very much for your time.
(Applause.)
MR. BREEN: Does the CVM panel have any clarifying questions it wishes to
ask?
(No response.)
END QUOTE
- guest
Merck's Ad Blitz Draws Fire TV ads
by guest » Thu Jan 06, 2005 10:07 am
Merck's Ad Blitz Draws Fire
By Melissa Davis
Senior Writer
1/5/2005 7:07 AM EST
Click here for more stories by Melissa Davis
After three years on the tube, skating icon Dorothy Hamill may need to hunt for yet a third career.
In part that's because the Olympic gold medalist returned to the spotlight as a television pitchwoman for Vioxx, the blockbuster painkiller Merck (MRK:NYSE - commentary - research) yanked off the market last fall. But another factor is that Hamill's ads exemplify a type of advertising that some people would like to see banned altogether -- so-called direct-to-consumer prescription drug advertising.
Indeed, Hamill's own commercials -- which helped make Vioxx a household name -- could very well fuel the crusade against DTC spots. Ads for Pfizer's (PFE:NYSE - commentary - research) Celebrex, a drug similar to Vioxx, have already been pulled from the market. Both of the heavily marketed painkillers, known as Cox-2 inhibitors, have been linked to heart attacks.
Some high-profile medical experts were calling for a crackdown on DTC drug advertising even before the Vioxx recall. They insisted that the ads, supposedly designed to "educate" the public, actually did more harm than good.
Now, their warnings are starting to sound more prescient than ever.
"When one considers that the majority of DTC drug ads are now on television -- and that this means a hasty 30- or 60-second spot -- it is hard to imagine that much more than the name and the claimed therapeutic indication could ever be conveyed," Arnold Relman, the retired editor-in-chief of the New England Journal of Medicine, testified in July 2003 before the U.S. Senate Special Committee on Aging. "There simply isn't time to provide any useful information about side effects or complications."
In this third of five articles probing Merck's troubles in the wake of the Vioxx scandal, TheStreet.com examines how a tectonic shift in the drug industry's advertising practices -- along with a hands-off stance by regulators -- set the scene for a disaster that has proved hazardous to consumers and Merck investors alike.
During Vioxx's first full year on the market, Merck spent an estimated $160 million marketing the painkiller directly to the public. Millions of consumers, including those swayed by media ads, wound up using the drug.
Many never knew that Vioxx could lead to heart attacks. And some, experts believe, never really needed the risky medicine at all.
Critics blame DTC advertising made possible by a government agency with close ties to the drug industry.
"Most of the most heavily advertised drugs are, in fact, no more effective or safe than other drugs, but billions of dollars 'must' be spent to try to convince doctors and patients otherwise," the consumer watchdog organization Public Citizen declared last April.
"These recent expensive campaigns have probably been much more successful than in years past because the FDA has all but stopped enforcing the laws concerning false and misleading prescription drug advertising -- with an 85% decrease in enforcement actions between 1998 and the end of 2003."
Prior to the Vioxx recall, DTC prescription drug advertising ranked as a growing $3 billion industry. Of the top 25 advertisers in 2002, Public Citizen reported, four were giant drug companies. Pfizer, the maker of Celebrex, stood out as the biggest spender in its group. Johnson & Johnson (JNJ:NYSE - commentary - research) came in second, followed by GlaxoSmithKline (GSK:NYSE - commentary - research). Merck -- despite its heavy Vioxx advertising -- placed fourth.
All spent more than $1 billion on DTC advertising annually, Public Citizen reported. Don Strong, an Oklahoma City attorney representing thousands of Vioxx plaintiffs, understands why.
"When you're spending that kind of money," he says, "you're going to be successful selling whatever you're selling."
Bald Spot
The rise of Rogaine, a blockbuster treatment for male pattern baldness, helps illustrate that point.
Deep Pockets
Biggest spenders on DTC prescription drug advertising in 2003
Figures in millions of dollars. Source: Med Ad News.
Michael Montagne, a professor at the Massachusetts College of Pharmacy, remembers the evolution of DTC prescription drug advertising quite well. Until the 1980s, he says, DTC really didn't exist within the industry because of uncertainties about the liabilities that might erupt. He calls Rogaine, with its "negligible" potential for serious risks, a good first choice to test the waters.
He says the FDA, which oversees drug marketing, eventually suggested a brief moratorium on the new DTC advertising so that it could study its potential effects. But, he says, the agency found no good reason to halt the ads and, over time, their popularity soared.
Vioxx Pain Lingers
Mess Shows FDA Flaws
Wednesday: Ads Added to Vioxx Sizzle
Thursday: Sizing Up Coutroom Foes
Friday: CEO's Ultimate Challenge
Like Rogaine, prescription drugs such as Prozac, Viagra and -- yes -- Vioxx have gone on to become common, everyday names.
Montagne readily admits that DTC drug advertising works quite well. He says an "amazing correlation" exists between money spent advertising a drug and its sales. From a consumer's perspective, however, he sees little value in such advertising and therefore remains fundamentally against it.
Michael Weinstein, president of the AIDS Healthcare Foundation, believes that DTC advertising has actually hurt the drug industry. He says that drug companies now seem far more interested in marketing their current drugs than in developing new ones. As a result, he says, AIDS patients have been forced to rely on government institutions -- and others outside of "Big Pharma" -- for any new breakthrough treatments.
"The big drug companies are spending more on marketing than they are on research," Weinstein said simply. "They have killed the goose that laid the golden egg. ... Now, they're based on sleazy ads on TV."
But outrage is rising. Indeed, DTC critics -- feeling vindicated by the Vioxx recall -- are now crying out from as far away as New Zealand.
"The chorus of opposition to DTC drug advertising that warned it would lead to heavy promotion of unsafe and unnecessary pharmaceuticals has been proven correct," says Sue Kedgley, a spokeswoman for the powerful Green Party in New Zealand. "If DTC advertising had been banned three years ago, then thousands of New Zealanders would not now be facing increased risks of cardiac problems -- because most of them would not have been prescribed Vioxx."
Death Penalty
Kedgley went on to blame the New Zealand government for failing to heed clear warnings about Vioxx advertisements.
She noted that the FDA had reprimanded Merck in 2001 for using Vioxx ads that were "false, lacking in fair balance or otherwise misleading." She found it "shocking" that her government had allowed Vioxx ads to keep running anyway.
Back in the U.S., Public Citizen did its part to counter such advertising. It placed Vioxx on its "worst pills" list after learning about the big study that exposed cardiac risks in 2001. It then publicized an eight-page warning letter sent from the FDA to Merck about its Vioxx advertising that same year.
But it also asked the FDA -- and ultimately Congress -- to do more.
"The FDA already has authority to bring criminal charges against companies such as Merck that repeatedly flout existing laws and regulations -- and should start using it," Public Citizen urged in November 2001. But "it would be nice if Congress would also rise to the obvious occasion and give the agency pocketbook authority as well."
Relman has pushed for an even more potent cure.
"We need more -- not less -- regulation of consumer ads. ... [And] if the law allows," he declares, "I would favor a total ban on DTC ads."
By Melissa Davis
Senior Writer
1/5/2005 7:07 AM EST
Click here for more stories by Melissa Davis
After three years on the tube, skating icon Dorothy Hamill may need to hunt for yet a third career.
In part that's because the Olympic gold medalist returned to the spotlight as a television pitchwoman for Vioxx, the blockbuster painkiller Merck (MRK:NYSE - commentary - research) yanked off the market last fall. But another factor is that Hamill's ads exemplify a type of advertising that some people would like to see banned altogether -- so-called direct-to-consumer prescription drug advertising.
Indeed, Hamill's own commercials -- which helped make Vioxx a household name -- could very well fuel the crusade against DTC spots. Ads for Pfizer's (PFE:NYSE - commentary - research) Celebrex, a drug similar to Vioxx, have already been pulled from the market. Both of the heavily marketed painkillers, known as Cox-2 inhibitors, have been linked to heart attacks.
Some high-profile medical experts were calling for a crackdown on DTC drug advertising even before the Vioxx recall. They insisted that the ads, supposedly designed to "educate" the public, actually did more harm than good.
Now, their warnings are starting to sound more prescient than ever.
"When one considers that the majority of DTC drug ads are now on television -- and that this means a hasty 30- or 60-second spot -- it is hard to imagine that much more than the name and the claimed therapeutic indication could ever be conveyed," Arnold Relman, the retired editor-in-chief of the New England Journal of Medicine, testified in July 2003 before the U.S. Senate Special Committee on Aging. "There simply isn't time to provide any useful information about side effects or complications."
In this third of five articles probing Merck's troubles in the wake of the Vioxx scandal, TheStreet.com examines how a tectonic shift in the drug industry's advertising practices -- along with a hands-off stance by regulators -- set the scene for a disaster that has proved hazardous to consumers and Merck investors alike.
During Vioxx's first full year on the market, Merck spent an estimated $160 million marketing the painkiller directly to the public. Millions of consumers, including those swayed by media ads, wound up using the drug.
Many never knew that Vioxx could lead to heart attacks. And some, experts believe, never really needed the risky medicine at all.
Critics blame DTC advertising made possible by a government agency with close ties to the drug industry.
"Most of the most heavily advertised drugs are, in fact, no more effective or safe than other drugs, but billions of dollars 'must' be spent to try to convince doctors and patients otherwise," the consumer watchdog organization Public Citizen declared last April.
"These recent expensive campaigns have probably been much more successful than in years past because the FDA has all but stopped enforcing the laws concerning false and misleading prescription drug advertising -- with an 85% decrease in enforcement actions between 1998 and the end of 2003."
Prior to the Vioxx recall, DTC prescription drug advertising ranked as a growing $3 billion industry. Of the top 25 advertisers in 2002, Public Citizen reported, four were giant drug companies. Pfizer, the maker of Celebrex, stood out as the biggest spender in its group. Johnson & Johnson (JNJ:NYSE - commentary - research) came in second, followed by GlaxoSmithKline (GSK:NYSE - commentary - research). Merck -- despite its heavy Vioxx advertising -- placed fourth.
All spent more than $1 billion on DTC advertising annually, Public Citizen reported. Don Strong, an Oklahoma City attorney representing thousands of Vioxx plaintiffs, understands why.
"When you're spending that kind of money," he says, "you're going to be successful selling whatever you're selling."
Bald Spot
The rise of Rogaine, a blockbuster treatment for male pattern baldness, helps illustrate that point.
Deep Pockets
Biggest spenders on DTC prescription drug advertising in 2003
Figures in millions of dollars. Source: Med Ad News.
Michael Montagne, a professor at the Massachusetts College of Pharmacy, remembers the evolution of DTC prescription drug advertising quite well. Until the 1980s, he says, DTC really didn't exist within the industry because of uncertainties about the liabilities that might erupt. He calls Rogaine, with its "negligible" potential for serious risks, a good first choice to test the waters.
He says the FDA, which oversees drug marketing, eventually suggested a brief moratorium on the new DTC advertising so that it could study its potential effects. But, he says, the agency found no good reason to halt the ads and, over time, their popularity soared.
Vioxx Pain Lingers
Mess Shows FDA Flaws
Wednesday: Ads Added to Vioxx Sizzle
Thursday: Sizing Up Coutroom Foes
Friday: CEO's Ultimate Challenge
Like Rogaine, prescription drugs such as Prozac, Viagra and -- yes -- Vioxx have gone on to become common, everyday names.
Montagne readily admits that DTC drug advertising works quite well. He says an "amazing correlation" exists between money spent advertising a drug and its sales. From a consumer's perspective, however, he sees little value in such advertising and therefore remains fundamentally against it.
Michael Weinstein, president of the AIDS Healthcare Foundation, believes that DTC advertising has actually hurt the drug industry. He says that drug companies now seem far more interested in marketing their current drugs than in developing new ones. As a result, he says, AIDS patients have been forced to rely on government institutions -- and others outside of "Big Pharma" -- for any new breakthrough treatments.
"The big drug companies are spending more on marketing than they are on research," Weinstein said simply. "They have killed the goose that laid the golden egg. ... Now, they're based on sleazy ads on TV."
But outrage is rising. Indeed, DTC critics -- feeling vindicated by the Vioxx recall -- are now crying out from as far away as New Zealand.
"The chorus of opposition to DTC drug advertising that warned it would lead to heavy promotion of unsafe and unnecessary pharmaceuticals has been proven correct," says Sue Kedgley, a spokeswoman for the powerful Green Party in New Zealand. "If DTC advertising had been banned three years ago, then thousands of New Zealanders would not now be facing increased risks of cardiac problems -- because most of them would not have been prescribed Vioxx."
Death Penalty
Kedgley went on to blame the New Zealand government for failing to heed clear warnings about Vioxx advertisements.
She noted that the FDA had reprimanded Merck in 2001 for using Vioxx ads that were "false, lacking in fair balance or otherwise misleading." She found it "shocking" that her government had allowed Vioxx ads to keep running anyway.
Back in the U.S., Public Citizen did its part to counter such advertising. It placed Vioxx on its "worst pills" list after learning about the big study that exposed cardiac risks in 2001. It then publicized an eight-page warning letter sent from the FDA to Merck about its Vioxx advertising that same year.
But it also asked the FDA -- and ultimately Congress -- to do more.
"The FDA already has authority to bring criminal charges against companies such as Merck that repeatedly flout existing laws and regulations -- and should start using it," Public Citizen urged in November 2001. But "it would be nice if Congress would also rise to the obvious occasion and give the agency pocketbook authority as well."
Relman has pushed for an even more potent cure.
"We need more -- not less -- regulation of consumer ads. ... [And] if the law allows," he declares, "I would favor a total ban on DTC ads."
- guest
fda Cox2 inhibitor known potential cardiovascular event
by guest » Mon Jan 10, 2005 3:35 pm
CMAJ • January 4, 2005; 172 (1). doi:10.1503/cmaj.045206.
© 2005 Canadian Medical Association or its licensors
This Article
-------------------------------------
Editorial
--------------------------------------------------------------------------------
Français à la page suivante
Vioxx: lessons for Health Canada and the FDA
Last fall the COX-2 inhibitor rofecoxib (Vioxx), a heavily marketed and successful drug with a low risk of gastrointestinal bleeding, was withdrawn from the market because of an increased risk of cardiovascular disease, mainly myocardial infarction and stroke.1 The drug was originally approved by the FDA (and Health Canada) in 1999, despite evidence in the original clinical trials of a nonstatistically significant increase in risk of cardiovascular events and despite the known potential for cardiovascular events associated with any drug that interferes with cyclooxygenase-2 enzyme regulators of prostacyclin — a potent vasodilator and inhibitor of platelet aggregation.
Why did it take 4 years for the increased risk of serious cardiovascular adverse events to emerge? It has now become clear that both the FDA and (by inference) Health Canada were aware of the increased risk of cardiovascular adverse events long before the drug was withdrawn from the market. There is also email evidence that the manufacturer tried to play down the risk in promotional material for doctors. In the wake of these revelations, Merck's market value dropped US$28 billion almost overnight, and a sideshow of lawsuits began.
There was no need to fast-track approval of this me-too COX-2 inhibitor (celecoxib had already been approved). Moreover, the regulators did not take into account the fact that the risks, if real, would likely be magnified once the drug came into general use.
Both the FDA and Health Canada put their emphasis and resources into assessing drug benefits, not harms. The bar for approval is low, requiring only that the agent be more effective than placebo. Pre-marketing approval trials are too small to flush out all of the risks of a drug. The built-in bias toward approving drugs without adequate assurance of their safety and with only a fragmentary and underfunded mechanism for postapproval surveillance based on physician reporting of isolated adverse events is a fundamental and (often literally) fatal flaw. Even a simple cumulative meta-analysis of postapproval ongoing trials of rofecoxib would have revealed — by December 2000, 4 years before the drug was withdrawn — a statistically significant excess risk of cardiovascular events associated with rofecoxib.2
Physicians and patients are aware that no drug is risk-free. Physicians are increasingly aware of the interplay of relative and absolute risks, especially when drugs move out of the controlled confines of the RCT into the Wild West of clinical practice.3 Relative benefit and risk rates shown in trials may change, but absolute benefits and risks rates will change: patients in practice are older and sicker than those in clinical trials. Physicians and patients need accurate measures of adverse event frequency.
Using an active surveillance system that targeted serious adverse events would have sounded the alarm much earlier. Both the FDA and Health Canada have failed miserably in carrying out this important aspect of their public mandates. Their current emphasis on partnerships with industry and rapid drug approval conflicts with the public's expectation that these agencies exist to protect them by restricting approval to drugs that have been thoroughly tested and are likely to be free of serious risks. The shift in balance from benefit to harm that can occur when a drug is in widespread use means that regulatory agencies should also shift their priorities. But can they?
The costs and difficulties of postmarketing surveillance are not trivial, and large numbers of patients are needed to allow the detection of rare (but important) adverse events. Nonetheless, we need to find sensible ways to proceed, such as Laupacis and colleagues' recent proposal to obtain postmarketing surveillance data using provincial databases and pharmacare programs.4
The FDA and Health Canada have demonstrated their structural inability to do ongoing safety monitoring of new drugs and devices, and industry is far too conflicted to be able to carry out this important task. We need new national agencies to monitor drug safety independently from the approvals process. Only then can physicians and patients be assured an unbiased safety assessment of the drugs they are prescribing and taking. — CMAJ
References
Sibbald B. Rofecoxib (Vioxx) voluntarily withdrawn from market. CMAJ 2004;171(9):1027-8.[Free Full Text]
Jüni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet [serial online]. November 5, 2004 Available: http://image.thelancet.com/extras/04art10237web.pdf (accessed 2004 Nov 26).
Barratt A, Wyer PC, Hatala R, McGinn T, Dans AL, Keitz S, et al. Evidence-Based Medicine Teaching Tips Working Group. Tips for learners of evidence-based medicine: 1. Relative risk reduction, absolute risk reduction and number needed to treat. CMAJ 2004;171(4):353-8.[Free Full Text]
Laupacis A, Paterson JM, Mamdani M, Rostom A, Anderson GM. Gaps in the evaluation and monitoring of new pharmaceuticals: proposal for a different approach. CMAJ 2003;169(11):1167-70.[Free Full Text]
© 2005 Canadian Medical Association or its licensors
This Article
-------------------------------------
Editorial
--------------------------------------------------------------------------------
Français à la page suivante
Vioxx: lessons for Health Canada and the FDA
Last fall the COX-2 inhibitor rofecoxib (Vioxx), a heavily marketed and successful drug with a low risk of gastrointestinal bleeding, was withdrawn from the market because of an increased risk of cardiovascular disease, mainly myocardial infarction and stroke.1 The drug was originally approved by the FDA (and Health Canada) in 1999, despite evidence in the original clinical trials of a nonstatistically significant increase in risk of cardiovascular events and despite the known potential for cardiovascular events associated with any drug that interferes with cyclooxygenase-2 enzyme regulators of prostacyclin — a potent vasodilator and inhibitor of platelet aggregation.
Why did it take 4 years for the increased risk of serious cardiovascular adverse events to emerge? It has now become clear that both the FDA and (by inference) Health Canada were aware of the increased risk of cardiovascular adverse events long before the drug was withdrawn from the market. There is also email evidence that the manufacturer tried to play down the risk in promotional material for doctors. In the wake of these revelations, Merck's market value dropped US$28 billion almost overnight, and a sideshow of lawsuits began.
There was no need to fast-track approval of this me-too COX-2 inhibitor (celecoxib had already been approved). Moreover, the regulators did not take into account the fact that the risks, if real, would likely be magnified once the drug came into general use.
Both the FDA and Health Canada put their emphasis and resources into assessing drug benefits, not harms. The bar for approval is low, requiring only that the agent be more effective than placebo. Pre-marketing approval trials are too small to flush out all of the risks of a drug. The built-in bias toward approving drugs without adequate assurance of their safety and with only a fragmentary and underfunded mechanism for postapproval surveillance based on physician reporting of isolated adverse events is a fundamental and (often literally) fatal flaw. Even a simple cumulative meta-analysis of postapproval ongoing trials of rofecoxib would have revealed — by December 2000, 4 years before the drug was withdrawn — a statistically significant excess risk of cardiovascular events associated with rofecoxib.2
Physicians and patients are aware that no drug is risk-free. Physicians are increasingly aware of the interplay of relative and absolute risks, especially when drugs move out of the controlled confines of the RCT into the Wild West of clinical practice.3 Relative benefit and risk rates shown in trials may change, but absolute benefits and risks rates will change: patients in practice are older and sicker than those in clinical trials. Physicians and patients need accurate measures of adverse event frequency.
Using an active surveillance system that targeted serious adverse events would have sounded the alarm much earlier. Both the FDA and Health Canada have failed miserably in carrying out this important aspect of their public mandates. Their current emphasis on partnerships with industry and rapid drug approval conflicts with the public's expectation that these agencies exist to protect them by restricting approval to drugs that have been thoroughly tested and are likely to be free of serious risks. The shift in balance from benefit to harm that can occur when a drug is in widespread use means that regulatory agencies should also shift their priorities. But can they?
The costs and difficulties of postmarketing surveillance are not trivial, and large numbers of patients are needed to allow the detection of rare (but important) adverse events. Nonetheless, we need to find sensible ways to proceed, such as Laupacis and colleagues' recent proposal to obtain postmarketing surveillance data using provincial databases and pharmacare programs.4
The FDA and Health Canada have demonstrated their structural inability to do ongoing safety monitoring of new drugs and devices, and industry is far too conflicted to be able to carry out this important task. We need new national agencies to monitor drug safety independently from the approvals process. Only then can physicians and patients be assured an unbiased safety assessment of the drugs they are prescribing and taking. — CMAJ
References
Sibbald B. Rofecoxib (Vioxx) voluntarily withdrawn from market. CMAJ 2004;171(9):1027-8.[Free Full Text]
Jüni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet [serial online]. November 5, 2004 Available: http://image.thelancet.com/extras/04art10237web.pdf (accessed 2004 Nov 26).
Barratt A, Wyer PC, Hatala R, McGinn T, Dans AL, Keitz S, et al. Evidence-Based Medicine Teaching Tips Working Group. Tips for learners of evidence-based medicine: 1. Relative risk reduction, absolute risk reduction and number needed to treat. CMAJ 2004;171(4):353-8.[Free Full Text]
Laupacis A, Paterson JM, Mamdani M, Rostom A, Anderson GM. Gaps in the evaluation and monitoring of new pharmaceuticals: proposal for a different approach. CMAJ 2003;169(11):1167-70.[Free Full Text]
- guest
novaritis deramaxx unprompt unaccurate report deaths
by guest » Tue Jan 25, 2005 2:49 pm
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.
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
duramaxx novartis reports wrong dates for death first year
by guest » Tue Jan 25, 2005 3:03 pm
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.
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
metacam meloxicam FDA finds violations
by guest » Thu Feb 10, 2005 8:21 am
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 drug-
associated 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
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 drug-
associated 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
- guest
Deramaxx Comprehensive report to FDA
by guest » Thu Feb 10, 2005 8:40 am
Deramaxx Comprehensive report
--------------------------------------------------------------------------------
Page 1 of 17
RE: DOCKET NUMBER 2004D-0468
DRAFT GUIDANCE FOR DRUG SPONSORS ON NSAIDS FOR USE IN ANIMALS AVAILABLE FOR
REVIEW AND COMMENT
To: VIA REGULAR MAIL
Division of Dockets Management (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Room 1061
Rockville, MD 20852
VIA EMAIL: (lwilmot@cvm.fda.gov)
Dr. Linda Wilmot
Center for Veterinary Medicine (HV-114)
Food and Drug Administration
7500 Standish Place
Rockville, MD 20855
(301) 827-0135
RE: DOCKET NUMBER 2004N-0559
JOINT MEETING OF THE ARTHRITIS ADVISORY COMMITTEE AND THE DRUG SAFETY AND RISK
MANAGEMENT ADVISORY COMMITTEE
To: Kimberly Littleton Topper
Center for Drug Evaluation and Research (HFD-21)
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
Email: topperk@cder.fda.gov
Fax: 301-827-6801
Page 2 of 17
NSAIDS IN VETERINARY MEDICINE TODAY
DERAMAXX: A COMPREHENSIVE DOCUMENTATION OF PROBLEMS
TABLE OF CONTENTS
1. Deramaxx - FDA Chronology
2. The Present Situation
3. Informed Consent
4. General Overview of Proposed Solutions
5. Specific Recommendations to the FDA/CVM
6. Table of references: (List all footnotes)
Prepared February 1, 2005
http://www.fda.gov/OHRMS/DOCKETS/98fr/03-29744.pdf 1
http://www.fda.gov/cvm/efoi/section2/141-203.pdf 2
Page 3 of 17
DERAMAXX - FDA CHRONOLOGY
On 8/21/02 Deramaxx received FDA approval “for the control of post operative pain and inflammation
associated with orthopedic surgery in dogs.” 1
Testing to that point included the study of only 217 animals supposedly representative of 43 breeds,
however, it should be mentioned that all toxicity and safety studies were performed on one breed, namely
beagles, only. 2
The 2 week Pharmacokinetics and Toxicity Study involved 12 beagles. All dogs survived to the end of the
study. Conclusions were: (1) Non linear elimination of deracoxib occurs at doses of 10 mg/kg and above;
(2) Elevated doses > 25 mg/kg are associated with COX-1 inhibition as evidenced by gastrointestinal
signs; (3) The frequency and severity of the gastrointestinal lesions increased with escalating doses. The
gastrointestinal lesions reported in deracoxib treated dogs at exaggerated doses are consistent with
known non steroidal anti-inflammatory drug (NSAID) induced adverse events.
The 21 day Safety study involved 40 beagles. All dogs survived to study termination. There was a dose
related increase in BUN values associated with administration of deracoxib tablets at all doses. No clear
dose or test article relationship could be determined for histopathological changes noted.
The 13 week Capsule Study in Dogs with a 4 week Recovery period involved 48 beagles. Its purpose
was: (a) To evaluate subchronic toxicity of deracoxib when administered to dogs; (b) To evaluate the
reversibility of any toxic effects following a 4 week recovery period; ©) To determine absorption of the test
article and the relationship of plasma concentration with dosage and duration of dosage. It was noted that
1 dog died of bacteria septicemia associated with renal abscess. Conclusions were that Deracoxib
administered in capsules once daily for a period of 13 weeks, at doses up to 8 mg/kg body weight did not
produce toxicity in HEALTHY (emphasis added) dogs; and that the relationship between deracoxib
administration and a renal abscess in one dog given 8 mg/kg is not clear. NO WHERE IS THE
REVERSIBILITY OF ANY TOXICITY DISCUSSED, NOR IS IT MENTIONED THAT ALL DOGS
SURVIVED TO THE END OF THE STUDY.
Additionally, dosage instructions at this time were “3-4 mg/kg/day (1.4-1.8 mg/lb/day) as a single daily
dose, as needed for seven days”.
Thus, Deramaxx was approved for “ the control of post operative pain and inflammation associated with
orthopedic surgery in dogs.”
Thereafter, and on January 16, 2003, the FDA objected to “Novartis’ dissemination of promotional
materials that are in violation of the Federal Food, Drug and Cosmetic Act (FDCA) and the FDA’s
applicable implementing regulations.” More specifically, the letter referred to Drug Experience Reports
dated August 30 through September 17, 2002, concerning Deramaxx. The FDA had received a number
of industry and veterinarian complaints regarding the misleading claims in Novartis’ September 9, 2002
http://www.fda.gov/cvm/index/regulatory/w011603na.pdf 3
http://www.fda.gov/cvm/efoi/section2/141-203s021103.pdf 4
Page 4 of 17
letter to veterinarians. 3
The statement “targeting the COX-2 enzyme while sparing the COX-1 enzyme” and similar statements
throughout the promotions suggested that this conclusion had clinical significance. This statement was
based upon in-vitro studies using cloned canine cyclooxygenase, the clinical relevance of which had not
been shown. Novartis thus violated 21 C.F.R. Section 202.1(e)(3)(1) which requires that an otherwise
misleading statement must include the appropriate qualification in the same part.
The FDA additionally objected to the opening paragraph of the letter which claimed Deramaxx as the “first
and only....Coxib class drug” as misleading. Novartis’ characterization failed to identify the product as
NSAID and did not place appropriate recognition that Coxib was a subclass of the NSAID class of drugs.
FDA approved labeling required the phrase “non-steroidal, anti-inflammatory of the coxib class”
The FDA concluded that this promotional activity minimized risks and implied a safer more effective
product than other drugs in the same drug class. It noted particular concern because these specific
limitations were discussed with HFV-110 during the application review, YET DESPITE DOCUMENTED
VERBAL ASSERTIONS THAT IT WOULD NOT, NOVARTIS PROMOTED THE COX-2 VS. COX-1
SELECTIVITY OF THE PRODUCT.
The FDA requested that Novartis immediately cease dissemination of these and similarly violative
promotional pieces and to promote it’s product only in accord with the labeling provided in the approved
application.
On February 11, 2003, the FDA authorized the new and expanded use of Deramaxx. Dosing changes
accompanied each use. The field study tested 209 client owned dogs representing 41 different breeds for
43 days. Only 105 dogs received Deramaxx at the dosage of 1-2 mg/kg (0.45 - 0.90 mg/lb) administered
once daily. 4
Lameness assessments together with owner evaluations are offered as proof of the effectiveness of
Deramaxx for the control of pain and inflammation associated with osteoarthritis. BUN, potassium and
phosphorus values were elevated post study. Novartis noted that these changes in clinical pathology
values were not considered clinically significant.
A 6 month Target Animal Safety Study was also performed to evaluate the safety of Deramaxx
administered orally on a daily basis for 6 months. Sixty HEALTHY beagles were used. All dogs survived to
termination of the study. Conclusions were that: “Deramaxx tablets were clinically well tolerated by dogs
when administered at doses up to 10 mg/kg/day for 26 weeks even though, there was a dose-dependent
increase in BUN values at doses > 6 mg/kg/day. Focal renal tubular degeneration /regeneration was seen
http://dil.vetmed.vt.edu/GreenBookUpdat ... 003_05.htm 5
6
http://a257.g.akamaitech.net/7/257/2422 ... v/2003/03-
9532.htm
http://www.fda.gov/cvm/index/retulatory/w042303n.pdf 7
Page 5 of 17
at doses > 6 mg/kg/day”. 5 6
On April 23,2003, the FDA again requested that Novartis immediately cease dissemination of all
advertising and labeling materials for Deramaxx which contained certain claims or representations. The 7
FDA specifically referred to the following DER submissions by Novartis:
“ Your “Dosing Card” submission of September 24, 2002
Your “Sales Aid” submission of October 8, 2002
Your “Sales Aid on CD” submission of October 17, 2002
Your “Direct Mailer” submission of October 23, 2002
Your “Trade Ad” submission of October 25, 2002
Your “Trade Ad” submission of November 7, 2002
It went on to advise Novartis of its receipt of “additional industry complaint letters regarding marketing
practices used in promoting the product Deramaxx (deracoxib).” The FDA further advised of its review of
“these promotional materials and concluded that they contain false or misleading statements in violation of
the Federal Food, Drug and Cosmetic Act (FDCA) and its implementing regulations.” In addition, the FDA
noted that “the promotional materials contain information that suggests the use of this product for
indications that are not provided for in the labeling.”
The FDA specifically noted that “These promotional materials present data from in vitro studies (COX-2
selectivity, Cox-1 sparing, IC50 Ratio) in a way that suggests clinical significance when no clinical benefit
has been established via substantial evidence”
It also noted that “These promotional materials imply or state that Deramaxx is safer and more effective
than other non-steroidal anti-inflammatory drugs”. In this regard, the FDA advised, “We are particularly
concerned because CVM’s objection to this claim was thoroughly discussed with Novartis representatives
during application review. Representatives of Novartis agreed with CVM’s Office of New Animal Drug
Evaluation that there would be no mention of a “different class for COX-2 selective NSAIDs and presently
approved NSAIDS.” Meeting memos and Minutes were footnoted to highlight these conversations.
The FDA additionally objected to the fact that “These promotional materials contain suggestions that the
drug is effective for managing induced synovial inflammation at the 1mg/kg dose”. It went on to say, “Your
product is approved at 3-4 mg/kg for post-operative pain. Promotion of the product at 1-2 mg/kg for
induced synovial inflammation suggest use of the product for osteoarthritis. At the time of dissemination of
these promotional materials, we were not aware of substantial evidence or substantial clinical experience to
demonstrate such efficacy. This representation was misleading because it suggests a use that has not
been established by substantial evidence or substantial clinical experience.”
http://www.fda.gov/cvm/index/safety/DDL ... 122203.pdf 8
Page 6 of 17
The FDA also objected to Novartis failure to “communicate the full extent of risk associated with NSAID
therapy” in it’s promotional materials.
NOT UNTIL December 22, 2003, ELEVEN MONTHS AFTER the FDA’s initial request to cease
disseminating the violative and promotional pieces, did Novartis re-label its product. Only after marketing
the drug under its new application, did Novartis revise it’s previously misleading informational material
which had been disseminated widely in 2002 and 2003. On December 22, 2003, Novartis issued it’s first
“Dear Doctor” letter in which it noted that Deramaxx was “our coxib-class nonsteroidal anti-inflammatory
drug (NSAID). Novartis went on to talk about the new information that had come to light, and advised that
it had updated the package insert to include a section reporting VOLUNTARY post-approval adverse
events. 8
The updated section of the Deramaxx label warned, in decreasing order of frequency, of numerous
adverse reactions, namely, Gastrointestinal, Hematological, Hepatic, Neurological/Behavioral/Special
sense, Urinary, Cardiovascular/Respiratory, and Dermatological/Immunological reactions. It went on to
warn, “In rare situations, death has been reported as an outcome of the adverse events listed above.”
Novartis additionally notified Veterinarians that formerly “precautionary” information had been moved to the
“Warnings section” of the label, namely:
“Sensitivity to drug-associated adverse events varies with the individual patient. As a class,
cyclooxygenase inhibitor NSAIDs may be associated with gastrointestinal and renal toxicity. Patients at
greatest risk for NSAID toxicity are those that are dehydrated, on concomitant diuretic therapy, or those
with existing renal, cardiovascular, and/or hepatic dysfunction. Since many NSAIDs posses the potential to
produce gastrointestinal ulceration, concomitant use of DERAMAXX tablets with other anti-inflammatory
drugs, such as NSAIDS or corticosteroids, should be avoided or closely monitored.”
Dosage and administration changes were also provided to the Doctors. “The approved dose for controlling
pain and inflammation associated with orthopedic surgery is 3-4 mg/kg/day as a single daily dose, as
needed, not to exceed 7 days.” This change in labeling put a maximum time period during which
Deramaxx at post surgical doses. Novartis went on to advise “ For control of pain and inflammation
associated with osteoarthritis, the approved dose is 1-2 mg/kg/day as a single daily dose as needed.”
Recommended Guidelines for Deramaxx use were also provided and include:
1) “Examine all dogs before prescribing any medication, including Deramaxx;
2) Conduct appropriate laboratory tests in dogs that may be at risk including:
a. senior pets
b. pets with history of liver disease, inflammatory bowel disease, renal disease or any
other chronic condition.
3) Evaluate potential drug interactions in dogs being treated with concurrent medications, especially
steroids or other NSAIDS.
4) Observe appropriate washout periods when switching from one NSAID to another or when
following corticosteroid use with NSAID therapy. The length of the washout period will vary,
depending upon the patient’s condition and other drugs involved.
5) Establish baselines and periodically monitor hematology and serum biochemical data in long-term
patients.
6) Provide pet owners with the Deramaxx Owner Information Sheet included with each Deramaxx
product shipment and share all potential benefits and possible side effects with them before
sending them home with Deramaxx. (Note: Veterinarians can order updated veterinary inserts and
http://www.kentuckypetgazette.com/novartis.htm 9
Also, http://www.fda.gov/foi/warning_letters/g5108d.htm
Page 7 of 17
updated client information sheets free of charge at any time by calling 1-877-PET-LIT-1 and
requesting item number DER 030041B for the revised veterinary insert or item number
DER030040046B for the revised client information sheet).
7) Advise pet owners to watch for early signs of drug intolerance including vomiting, diarrhea and lack
of appetite, and if they see the signs, discontinue use immediately and contact you.”
Thus, it was not until December 22, 2003, in the “Dear Doctor” letter, that the veterinary community was
notified of the proper classification of this drug and the numerous adverse effects associated with its use.
It is unknown at present whether the general public was ever notified of these labeling changes and
adverse reactions through television, the same medium that was used to make them aware of this new
drug.
Thereafter, and on 11/29/04, the FDA issued a WARNING LETTER to Novartis regarding its compliance
with the ADE reporting requirements. 9
It began, “ During the period of January 20 through January 23, 2004, an inspection was conducted at the
headquarters of your veterinary pharmaceutical operations in the United States of America (USA), known
as Novartis Animal Health US, Inc. (Novartis), which are located at 3200 Northline Avenue, Suite 300 in
Greensboro, North Carolina. The inspection disclosed significant deviations from the adverse drug
experience (ADE) reporting requirements of Section 512(l) of the Federal Food, Drug, and Cosmetic Act
(the Act) and Title 21, Code of Federal Regulations (21 CFR), Sections (§§) 510.300 {effective prior to June
30, 2003) and 514.80 (effective on June 30, 2003)”.
It further identified:
The violations include, but are not limited to, the following areas: “
1. Problems associated with your reporting practices of ADEs:
Novartis failed to submit timely and accurate information to the FDA regarding serious ADEs
associated with the administration of its FDA approved animal drug product Deramaxx™
(Deracoxib), New Animal Drug Application (NADA) 141-203, during its first year of marketing.
An example of this type of deviation is the recording of the date sent to FDA {box 2b of the FDA
1932). Our inspection revealed significant discrepancies between what was written in box 2b of the
FDA 1932 and the postmarked date of the submission and/or the date FDA received the
submission. Some of Novartis’ initial and follow-up ADE reports, including ones involving death,
were postmarked and/or received by FDA between 21 and 100 or more days after the date
recorded in box 2b of the FDA 1932, indicating that the date recorded in box 2b is incorrect.
Another example is Case # US200302088, which was reported to Novartis on February 19, 2003
(as indicated in box 2a of the FDA 1932). The form indicates that it was sent to FDA on January 9,
2004, over 10 months after it was reported to Novartis. This information should have been reported
to FDA in a timely manner, within 15 working days of receipt. Moreover, the report was not
received by FDA until January 27, 2004, again indicating that the date recorded in box 2b was
incorrect.
A third example is the revised submission for Case # US200207030, which was submitted with
your response dated February 25, 2004. Our investigators reviewed the entire correspondence file
between the owner of this animal and Novartis. The FDA 1932 submitted with your response fails
Page 8 of 17
to include specific details regarding the results of blood work performed on this dog on September
9, 2002 (a baseline) and further work performed in October 2002 and November 2002, which was
transmitted to Novartis by the owner between November 2002 and January 2003, in violation of 21
CFR § 514.80(b)(2)(ii). This information should have been promptly reported to FDA within 15
working days of receipt.
Your written response dated February 25, 2004, included revised standard operating procedures
(SOPs), which were supposed to address the observed deficiencies. The revised SOP 5.2 (Volume
1, page 650) does not identify how your firm will prevent incorrect information from being reported
to FDA as was noted during the inspection.
Your written response dated April 23, 2004, indicates that Novartis has employed additional
personnel for the receipt, investigation, and transmittal of ADE reports. The response further states
that your firm has also involved corporate quality, compliance, and pharmacovigilance groups to
assist in this process. But following your response FDA has continued to receive late ADE reports
along with cover letters. For example, some of these letters were dated April 28, 2004; May 12,
2004; May 28, 2004; July 29, 2004; August 20, 2004; and September 21, 2004.
Problems associated with your reporting practices of ADEs related to experimental studies:
Your firm failed to submit timely information to the FDA regarding post-approval studies involving
new animal drugs. Two specific failures were identified during the inspection.
The first one was the failure to submit information from completed pilot studies as part of the
clinical experience in the annual Drug Experience Report (DER), as required by 21 CFR §
510.300(a)(1) (effective prior to June 30, 2003 and 514.80(b)(4)(iii) (effective on June 30, 2003).
Our investigators identified over pilot studies in your master study list. Dr. Tebbit stated that
Novartis has never submitted information about their pilot studies as part of the annual DER,
unless they are part of an Investigational New Animal Drug Application (INADA) or a pivotal study.
The second one was the failure to submit serious, unexpected ADEs involving animals
under study to the FDA within 15 working days of first receiving the information, as
required by 21 CFR § 510.300(b)(2)(l) (effective prior to June 30, 2003) and 514.80(b)(2)(I)
(effective on June 30, 2003).
One study involving Deramaxx (Deracoxib), NADA 141-203, in cats involved a late submission of ™
ADEs. The experiment, which was completed in July 2003, involved 14 animal deaths and other
serious ADEs. These ADEs were not reported to the FDA within the required 15 working days
time frame, but were reported only after the conclusion of the inspection of your facility, on
February 24, 2004.
Although your submission dated February 24,2004, indicates that it was Novartis’ intent to
disclose the safety information from the cat study, your firm failed to disclose this information from
other studies found in the master study List.
For example, a protocol entitled "The Acute Safety Study of an Injectable Deracoxib (SD-6746)
Formulation In Dogs” was submitted to the FDA under the INADA 010-865 on April 15, 2002. This
was approximately three months after the master study list indicates the pilot study was
completed. The study clinical data was not received by the FDA until October 2004.
FDA acknowledges that your firm has revised its SOPS and obtained principal investigator
agreements to submit all 15-day ADEs in post approval studies as drug experiences. But your
response does not clarify that you also understand that you must submit ADEs in the periodic drug
experience report as clinical data, unless they were previously reported, as required by 21 CFR §
514.80(b)(4)(iv)©).”
The FDA went on to advise:
“The specific violations noted in this letter are serious and may be symptomatic of serious
http://www.fda.gov/medwatch/articles/me ... .htm#lssrd 10
Page 9 of 17
underlying problems.
1. You should take prompt action to correct these deficiencies. Failure to promptly correct
these deviations may result in regulatory action without further notice. These actions may
include, but are not limited to, seizure and/or injunction. Federal agencies are advised of
all Warning Letters about drugs so they may take this information into account when
considering the award of contracts.
We request that you reply in writing within fifteen (15) working days of receipt of this letter
describing the corrective actions you have implemented, or are planning to implement, to prevent
a recurrence of the violations noted above. Please include copies of any available documentation
demonstrating that corrections have been made. If corrective actions cannot be completed within
fifteen (15) working days, state the reason for the delay and the time within which the conditions
will be completed.”
Thereafter, and on December 1, 2004, Novartis issued another “Dear Colleagues” letter in which the
DERAMAXX Update: Clinical Experience with DERAMAXX was provided. This update contained a
“summary and analysis of the adverse drug experiences (ADEs) reported to the FDA during the first 18
months of DERAMAXX use.”
Novartis further stated that “review and analysis of these data have shown that six of 10 reported ADEs in
canine osteoarthritis resulted in unintentional overdose”. It went on to urge prescription of this drug
“according to recommended guidelines for dosing, patient selection and product administration” and
stressed the two different dosing regimens for DERAMAXX.
Please note, this update, was based on 1680 Adverse Drug Events (ADEs) As of January, 3, 2005, ADEs
numbered 2400, thus a discrepancy exists in the present number of reported ADEs and those at the time
of publication of this Novartis document. This update additionally fails to consider the ADE violations
noted by the FDA in it’s November 29, 2004 warning letter to Novartis, just 2 days prior to the issuance of
this update.
The foregoing chronology is submitted to reveal the story of Deramaxx through the eyes of a pet owners
across the country. Documentation of the human-animal bond and the positive effects on human health
and well-being of animal companionship is extensive, and at this time, statistics reveal that the
overwhelming majority of owners consider their pets as members of their family. This chronology, the
facts of which were deciphered from Freedom of Information material and other internet material, reveals
extremely minimal testing for a veterinary drug to enter the market, blatant disregard by the drug
manufacturer to represent the product accurately in its informational material, and numerous warnings and
violations issued by the FDA to the drug manufacturer without any apparent immediate compliance. Per
the chronology above, it took Novartis 11 months to re-label it’s product as originally approved by the FDA,
yet during this 11 month period, it expanded the market for this product by obtaining approval for it’s use
for the control of pain and inflammation of osteoarthritis. Furthermore, Novartis has failed to timely file
ADE’s with the FDA.
Additionally, when one considers underreporting of Adverse Drug Events, namely, that the FDA receives
by direct report less than 1% of suspected serious ADE, the concern of the pet owner is magnified. 10
http://www.fda.gov/cvm/index/ade/ade_cum.htm 11
Page 10 of 17
As of January 3, 2005, the FDA reported the following information
Deracoxib - Oral Dog
Reviews: 2352
Treated: 2400
Reacted: 2371
Died: 515 11
If underreporting has occurred as estimated, then deaths following the administration of this drug are
actually closer to 51,000 in number. Additionally, 515 deaths as of January 1, 2003 represents a 21%
mortality rate. This corresponds roughly with the 20.7% death and euthanasia (secondary to side effects)
rate published by Novartis in it’s December 1, 2004 letter to “Colleagues”.
THE PRESENT SITUATION
Animals, specifically dogs, have become central parts of our lives to the extent that they are cared about as
if children to millions of people, and valued beyond all monetary considerations. Technology and medicine
are advancing at rapid rates, resulting in the proliferation of an ever increasing number of drugs available
for both humans and animals. Drug companies are motivated by profit margins. Their reason for
existence is to sell the greatest amount of drugs possible and maximize their earnings.
In human medicine, there is (at least theoretically) a value placed on human life more relatively
proportionate to its actual value to others. In veterinary medicine, this is not the case, as animals are still legally
*property* and thus considered worth, at maximum, purchase or replacement value, which is an
infinitesimal fraction of their actual value to owners. (Note recent work on creating new class of property
*sentient property* for this/related reasons). Physicians are consequently held to a higher level of liability
for malpractice. In addition, and IMPORTANTLY, there exists the *intermediary* of the pharmacist
involved in dispensing of medication to humans, which position oversees the safety of each prescription for
the individual patient.
In veterinary medicine, there is no intermediary position of “pharmacist”. THE VETERINARIAN IS THE
PHARMACIST, leaving millions upon millions of animal owners IN the sole hands of their veterinarian, with
drug companies and the FDA/federal government purportedly behind them, each and every time
medication is dispensed to them. Dispensing drugs for animals is akin to dispensing them for children: in
both cases the patient cannot speak for themselves, evaluate the drug, or even report side effects as they
occur. Therefore, extra precautions are prerequisite and essential when dispensing medications to either
children or animals.
The points above have tragically resulted in a situation today that has genuinely reached crisis proportions:
Tens of thousands of animals are being unnecessarily killed each year by side effects of drugs dispensed
to them by veterinarians. They are dying unnecessary deaths which could have been, and CAN BE
prevented, leaving legions of grief-stricken owners with no notion of how to cope with
the death of their beloved animal friend in which they themselves unknowingly participated.
INFORMED CONSENT
January 15, 2004 Emerging issues regarding informed consent
Page 11 of 17
“The staff at the Food and Drug Administration's Center for Veterinary Medicine has conducted a two-year
review of consumer messages to our adverse drug experience hotline. The review indicates increasing
concern by consumers about risk and benefit of commonly prescribed, approved animal drugs.
The CVM established the hotline, (888) FDA-VETS, in 1996 to receive calls about adverse experiences to
approved animal drugs. We expected many of these reports to come from practicing veterinarians, but our
review indicates that a majority of the calls in the past few years have come from consumers,
particularly dog owners who find our link on the Internet.
The CVM considers the drug label the first source of important facts for veterinarians. The label is the
result of considerable scientific regulatory review before CVM approves the drug. It represents known
safety and efficacy for any one drug. The label also gives veterinarians important information about
whether the drug is suitable for the individual or subgroup within a species of animal.
Additionally, whenever manufacturers distribute a client information sheet, this means that either the
manufacturer or the CVM wishes to convey more facts about safety or efficacy in lay terms to pet owners.
The staff at CVM monitors and evaluates adverse drug experience reports and complaints of inefficacy for
approved and unapproved, marketed products. For approved products, this evaluation of postmarket safety
and efficacy incorporates knowledge gained from the premarket studies as well as from scrutiny of
peer-reviewed studies related to the drug, or the disease that the drug is intended to cure or prevent.
From the hotline, we have learned that pet owners increasingly rely on Internet sources for information
when their pets have problems. They have told us that, during their Internet searches, they often find label
information and client information sheets.
Frequent comments from pet owners who contact the CVM hotline include these:
* They did not receive a client information sheet when one was available for a drug that was
prescribed for their pet.
* The medication they received from their veterinarian was not dispensed in the CVM-approved
container but was broken into aliquots that were taken home without the client information sheet or
approved label.
* The veterinarian did not conduct or recommend blood testing before and after prescribing the drug, even
though baseline testing and/or periodic monitoring was recommended on the label. Common examples
include heartworm products and nonsteroidal, anti-inflammatory drugs.
* After reading client information sheets and labels on the Internet about a drug prescribed for their pet,
they discovered that their pet may have fallen into a category of animal for which a precaution or
contraindication existed.”
These comments represent a complete breakdown and failure of the institution of veterinary medicine. It
also represents an unacceptable failure of federal government medical safety oversight programs.
Dr. Victoria Hampshire, author of this article, went on to say:
“Given these findings, we have the following reminders for practitioners:
http://www.avma.org/onlnews/javma/jan04/040115f.asp 12
http://www.fdanews.com/dailies/drugdail ... 001-1.html 13
_
Page 12 of 17
* Drugs that come with client information sheets are intended to be dispensed in the manufacturer's
container, with the sheets accompanying the prescription.
* Product precautions, contraindications, safety information, and warnings should help identify
animal patients that are not good candidates for the medication.
* Labels change? if you have a large inventory of a product with a long shelf life, you may want to
contact the manufacturer or CVM to obtain the most recent label. A long shelf life makes it likely
that some of the product won't be dispensed in the near future. Often, this information is also
posted on pharmaceutical companies' official Web sites.” 12
Dr. Hampshire’s “reminders” should be pursued as mandates for all veterinary practitioners.
Additionally, the FDA news Drug Daily Bulletin, Thursday, Jan, 27, 2005, Vol. 2, No. 19 states:
“Public Confidence in Drug Companies Declining, Poll Shows
The mounting safety concerns swirling around the pharmaceutical industry are beginning to have a
profound effect on the American public’s perception of drug companies, according to a recent online poll.
Sixty percent of U.S. adults are “not very confident” or “not confident at all” that drugmakers will publicly
disclose information about possible side effects of their products as soon as they have that data, according
to a new Harris Interactive survey, which polled 2,404 U.S. adults between Jan. 4 and Jan. 7. Only 5
percent of the survey respondents indicated they are “very confident” that drugmakers will publicly disclose
side-effect information in a timely manner.......” -Drug Industry Daily 13
GENERAL OVERVIEW OF PROPOSED SOLUTIONS:
1. The FDA must hold the drug companies responsible for performing thorough safety studies and
reporting results accurately and thoroughly for all new veterinary drugs. Omission, manipulation
and distortion of data must be curtailed. Close monitoring of all related activities is necessary.
Compliance failures must be dealt with swiftly and forcefully in “real time”. “Real time” ADE
reporting is a critical and essential component of the monitoring the efficacy and safety of new
veterinary drugs. An overhaul and upgrade of the ADE reporting system is essential to make the
information contained therein easily accessible to the public.
2. Drug companies MUST provide timely, accurate FDA-approved product literature and updates
to veterinarians. These materials must contain clear statements that a Client Information Sheet
*must* be provided to every client to whom the “new” drug is dispensed.
How Items 1 and 2 can be accomplished :
A. Strong citizen input to FDA demanding:
Page 13 of 17
1. Better ADE reporting in “real time”
2. Swift enforcement of labeling violations
3. Correction of all labeling violations to all media vehicles
4. No direct to consumer advertising or promotion allowed for the first 2 years of new
drug approval
5. Citizen review committees - public involvement in the drug approval process
B. Pet owners who have been affected by this drug should consult with attorneys regarding:
1. Individual lawsuits
a. “property” claims;
b. claims with respect to failure to obtain client information sheets and lack of
informed consent that can be backed by state pharmacy regulations to the extent
that vets are not exempt from them.
c. “patient” claims by the “guardian” of the pet
d. “sentient property” claims
e. “Deceptive trade practices” claims
f. “Mail fraud” claims
2. Class Action lawsuits
C. Inform and Advise Legislators of these problems
D. National media campaign raising awareness and support for the above
3. Veterinarians MUST be REQUIRED to provide:
A. A Client Information Sheet (CIS) to every client to whom the drug is dispensed; and
B. Verbal client education regarding potential side effects, and what to do if any are
observed in their pet.
4. Veterinarians must be held to similar standards as pharmacists for every
medication they dispense to a patient.
How Items 3 and 4 can be accomplished:
A. Influence and Petition American Association of State Veterinary Boards to call for all
State Veterinary Board regulations to mandate this (leaving veterinarians unsupported in
lawsuits for failure to do so).
B. Make direct appeal to AVMA to call for State Boards to mandate this.
C. Make direct appeals to/demands for individual State Boards to mandate this
Page 14 of 17
D. National “Educate Your Vet” campaign- “VIS*s (Veterinary Information Sheets)
designed for clients to give to their vets- “Dear Dr.” letter respectfully, supportively
indicating clients can no longer accept less than full information/disclosure w/ drugs.
E. Mass petitions (includes some of above).
Filing with the State Veterinary Board may well be easier and more effective than filing Malpractice claims.
Challenging a veterinarian on lack of informed consent and failure to provide Client Information Sheets
may prove more productive. Each pet owner should consider each of these alternatives individually and in
accordance with their respective state laws.
SPECIFIC SOLUTIONS FOR THE FDA REGARDING NSAIDS IN GENERAL
AND DERAMAXX IN PARTICULAR:
1. PACKAGING AND LABELING - ALL NSAIDS - FDA MANDATE THAT NSAIDS BE
DISPENSED IN APPROVED CONTAINERS ONLY FOR THE FIRST 1-2 YEARS AFTER
PRODUCT APPROVAL
Given the data heretofore mentioned which indicates: that veterinarians operate at the pharmacist
level when dispensing drugs: that clients rarely, if ever, receive Client Information Sheets provided
by the drug companies to the veterinarian; that veterinarians often and in usual practice purchase
drugs in bulk and repackage them for client use; and that the FDA has no direct jurisdiction over
vets who are regulated by State Veterinary Boards, it is recommended that NSAIDS be dispensed
in approved and appropriately labeled containers only.
BLACK BOX WARNINGS - The most critical warnings that should be black boxed are:
A.) PROVIDE THE CLIENT INFORMATION SHEET - Early treatment of a problem is
critical to successful treatment
B.) Provide a profile of the signs associated with typical severe reaction: low RBC, high
WBC, High BUN and creatinine, elevated liver values with clinical signs being diarrhea
and vomiting, likely with blood and inappetance. This black box warning could be limited
to the typical profile that probably accounts for 95% of all severe reaction cases.
There are certainly other signs that come up, but generally, these are either not likely to
result in a severe reaction, related to some obvious pre-existing condition (known renal
failure, hepatic or cardio impairment as an example), or are relatively rare, i.e., everything
is relatively normal, but signs of congestive heart failure.
DOSAGE - With any NSAID, the name of the game is finding the LOWEST POSSIBLE
EFFECTIVE DOSE. It should be emphasized that dosing should be at the low end of the range
and the pill given on an “as needed” as opposed to “daily” basis
2. ADE REPORTING
Besides upgrading ADE reporting to “real time” and swiftly and appropriately penalizing
manufacturers for the failure to comply, the current system of ADE reporting only encompasses
unscored data. Scored data regarding death and euthanasia associated with adverse reaction is
not made available. The FDA and manufacturers discount the publicly available data, yet the FDA
Page 15 of 17
has the scored data. The public shouldn't have to file FOIA requests to get it.
3. NO DIRECT TO CONSUMER ADVERTISING OR PROMOTION FOR THE FIRST ONE-TWO
YEARS
This is being advocated for the human drugs. It is equally applicable to veterinary drugs. Pet
owners would be better served if manufacturers spend their advertising dollars on further research
into the safety and efficacy of these drugs and better “real-time” ADE reporting for the first few
years.
4. PUBLIC INVOLVEMENT IN THE APPROVAL PROCESS
At present, a drug obtains FDA approval without any opportunity for the public to comment on the
safety and efficacy studies. There is no real mechanism for the public to comment on this after
approval status is obtained. The FDA needs to change this to allow in the final stages for a public panel
to review and comment on the adequacy of the research done in support of a new drug
application.
5. DERAMAXX - PROBLEMS REQUIRING FURTHER INVESTIGATION (AND SUSPENDED
SHIPMENT UNTIL THE ISSUES ARE RESOLVED)
a.) NSAID HEART problems. There is enough evidence and details of one well documented case
being submitted to the FDA to warrant a requirement that Novartis investigate adverse cardiac
effects of Deramaxx. At present, in a question and answer format, Novartis is currently stating
that dogs are different than humans and this is not an issue. The fact which undermines this
assertion is that dogs are and have been used extensively in studying toxicity and other issues in
the development of human Cox-2 inhibitors for humans. Cardio infarcts do not resolve and there
is little room for compensation. Most will tend to get worse over time because they are subject to
constant blood flows.
b.) NEUROLOGICAL effects from long-term use. It is known that Cox-2 is used constitutively in
the brain therefore Cox-2 inhibition has to have an effect. What is it? Is it permanent? This needs
to be studied.
c.) SULFA allergy effects. Deramaxx is a sulfanomide drug. There are certain breeds
(Dobermans, white-coated northern and so on) with known sulfa allergies. A specific warning on
this needs to be studied. At present, the label says it might be an issue.
d.) VARIABLE METABOLISM effects. The studies in support of Deramaxx found that there was
variable metabolism of the drug. There is an extensive body of literature on variations in the
metabolism of Celebrex, a close chemical cousin of Deramaxx, in dogs. The product label states
that there was variation, but does not go beyond this to say that it could result in the death of
some dogs. The manufacturers of Deramaxx and other NSAIDS need to develop a screening
procedure that identifies slow metabolizers, the dogs who are most likely to experience adverse reactions.
Searle, the developer of Deramaxx, studied this issue when they developed the drug. That
information needs to be made public and if it is inadequate to draw any conclusions, studied
further since it is clear that this is the reason for most of the severest reactions to the drug.
Deramaxx is specifically marketed for osteoarthritis, a condition experienced by older or senior
dogs. It is this same group of senior dogs that are normally, the slower metabolizers.
e.) REVERSIBILITY OF TOXIC EFFECTS - Because documented adverse side effects of
Deramaxx include serious and sometimes fatal organ system damage or failure, the issue of
reversibility is a crucial one in order to substantiate claims of safety . It needs to be addressed
Page 16 of 17
scientifically and much more adequately than has been done. If organ system damage is only
partially or slightly reversible, the dog might not die right then, however, it’s life is still harmed or
shortened.
In this same regard, the FDA should consider providing treatment guidelines for Deramaxx drug
toxicity, especially given Novartis claims of ineffective treatment and drug overdose events.
Regarding the documentation of the extent of damage done by this drug, the FDA has an up close
and personal view day in and day out with benefit of the full clinical record. The FDA should
compel the manufacturer to present a “profile” when post-market experience indicates there are
serious side effects.
Page 17 of 17
TABLE OF REFERENCES
1. http://www/fda.gov/OHRMS/DOCKETS/98fr/03-29744.pdf
2. http://www.fda.gov/cvm/efoi/section2/141-203.pdf
3. http://www.fda.gov/cvm/index/regulatory/w011603na.pdf
4. http://www.fda.gov/cvm/efoi/section2/141-203s021103.pdf
5. http://dil.vetmed.vt.edu/GreenBookUpdat ... 003_05.htm
6. http://a257.g.akamaitech.net/7/257/2422 ... v/2003/03-
9532.htm
7. http://www.fda.gov/cvm/index/retulatory/w042303n.pdf
8. http://www.fda.gov/cvm.index/safety/DDL ... 122203.pdf
9. http://www.kentuckypetgazette.com/novartis.htm
Also, http://www.fda.gov/foi/warning_letters/g5108d.htm
10. http://www.fda.gov/medwatch/articles/me ... .htm#lssrd
11. http://www.fda.gov/cvm/index/ade/ade_cum.htm
12. http://www.avma.org/onlnews/javma/jan04/040115f.asp
13. http://www.fdanews.com/dailies/drugdail ... 35001-1.ht
--------------------------------------------------------------------------------
Page 1 of 17
RE: DOCKET NUMBER 2004D-0468
DRAFT GUIDANCE FOR DRUG SPONSORS ON NSAIDS FOR USE IN ANIMALS AVAILABLE FOR
REVIEW AND COMMENT
To: VIA REGULAR MAIL
Division of Dockets Management (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Room 1061
Rockville, MD 20852
VIA EMAIL: (lwilmot@cvm.fda.gov)
Dr. Linda Wilmot
Center for Veterinary Medicine (HV-114)
Food and Drug Administration
7500 Standish Place
Rockville, MD 20855
(301) 827-0135
RE: DOCKET NUMBER 2004N-0559
JOINT MEETING OF THE ARTHRITIS ADVISORY COMMITTEE AND THE DRUG SAFETY AND RISK
MANAGEMENT ADVISORY COMMITTEE
To: Kimberly Littleton Topper
Center for Drug Evaluation and Research (HFD-21)
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
Email: topperk@cder.fda.gov
Fax: 301-827-6801
Page 2 of 17
NSAIDS IN VETERINARY MEDICINE TODAY
DERAMAXX: A COMPREHENSIVE DOCUMENTATION OF PROBLEMS
TABLE OF CONTENTS
1. Deramaxx - FDA Chronology
2. The Present Situation
3. Informed Consent
4. General Overview of Proposed Solutions
5. Specific Recommendations to the FDA/CVM
6. Table of references: (List all footnotes)
Prepared February 1, 2005
http://www.fda.gov/OHRMS/DOCKETS/98fr/03-29744.pdf 1
http://www.fda.gov/cvm/efoi/section2/141-203.pdf 2
Page 3 of 17
DERAMAXX - FDA CHRONOLOGY
On 8/21/02 Deramaxx received FDA approval “for the control of post operative pain and inflammation
associated with orthopedic surgery in dogs.” 1
Testing to that point included the study of only 217 animals supposedly representative of 43 breeds,
however, it should be mentioned that all toxicity and safety studies were performed on one breed, namely
beagles, only. 2
The 2 week Pharmacokinetics and Toxicity Study involved 12 beagles. All dogs survived to the end of the
study. Conclusions were: (1) Non linear elimination of deracoxib occurs at doses of 10 mg/kg and above;
(2) Elevated doses > 25 mg/kg are associated with COX-1 inhibition as evidenced by gastrointestinal
signs; (3) The frequency and severity of the gastrointestinal lesions increased with escalating doses. The
gastrointestinal lesions reported in deracoxib treated dogs at exaggerated doses are consistent with
known non steroidal anti-inflammatory drug (NSAID) induced adverse events.
The 21 day Safety study involved 40 beagles. All dogs survived to study termination. There was a dose
related increase in BUN values associated with administration of deracoxib tablets at all doses. No clear
dose or test article relationship could be determined for histopathological changes noted.
The 13 week Capsule Study in Dogs with a 4 week Recovery period involved 48 beagles. Its purpose
was: (a) To evaluate subchronic toxicity of deracoxib when administered to dogs; (b) To evaluate the
reversibility of any toxic effects following a 4 week recovery period; ©) To determine absorption of the test
article and the relationship of plasma concentration with dosage and duration of dosage. It was noted that
1 dog died of bacteria septicemia associated with renal abscess. Conclusions were that Deracoxib
administered in capsules once daily for a period of 13 weeks, at doses up to 8 mg/kg body weight did not
produce toxicity in HEALTHY (emphasis added) dogs; and that the relationship between deracoxib
administration and a renal abscess in one dog given 8 mg/kg is not clear. NO WHERE IS THE
REVERSIBILITY OF ANY TOXICITY DISCUSSED, NOR IS IT MENTIONED THAT ALL DOGS
SURVIVED TO THE END OF THE STUDY.
Additionally, dosage instructions at this time were “3-4 mg/kg/day (1.4-1.8 mg/lb/day) as a single daily
dose, as needed for seven days”.
Thus, Deramaxx was approved for “ the control of post operative pain and inflammation associated with
orthopedic surgery in dogs.”
Thereafter, and on January 16, 2003, the FDA objected to “Novartis’ dissemination of promotional
materials that are in violation of the Federal Food, Drug and Cosmetic Act (FDCA) and the FDA’s
applicable implementing regulations.” More specifically, the letter referred to Drug Experience Reports
dated August 30 through September 17, 2002, concerning Deramaxx. The FDA had received a number
of industry and veterinarian complaints regarding the misleading claims in Novartis’ September 9, 2002
http://www.fda.gov/cvm/index/regulatory/w011603na.pdf 3
http://www.fda.gov/cvm/efoi/section2/141-203s021103.pdf 4
Page 4 of 17
letter to veterinarians. 3
The statement “targeting the COX-2 enzyme while sparing the COX-1 enzyme” and similar statements
throughout the promotions suggested that this conclusion had clinical significance. This statement was
based upon in-vitro studies using cloned canine cyclooxygenase, the clinical relevance of which had not
been shown. Novartis thus violated 21 C.F.R. Section 202.1(e)(3)(1) which requires that an otherwise
misleading statement must include the appropriate qualification in the same part.
The FDA additionally objected to the opening paragraph of the letter which claimed Deramaxx as the “first
and only....Coxib class drug” as misleading. Novartis’ characterization failed to identify the product as
NSAID and did not place appropriate recognition that Coxib was a subclass of the NSAID class of drugs.
FDA approved labeling required the phrase “non-steroidal, anti-inflammatory of the coxib class”
The FDA concluded that this promotional activity minimized risks and implied a safer more effective
product than other drugs in the same drug class. It noted particular concern because these specific
limitations were discussed with HFV-110 during the application review, YET DESPITE DOCUMENTED
VERBAL ASSERTIONS THAT IT WOULD NOT, NOVARTIS PROMOTED THE COX-2 VS. COX-1
SELECTIVITY OF THE PRODUCT.
The FDA requested that Novartis immediately cease dissemination of these and similarly violative
promotional pieces and to promote it’s product only in accord with the labeling provided in the approved
application.
On February 11, 2003, the FDA authorized the new and expanded use of Deramaxx. Dosing changes
accompanied each use. The field study tested 209 client owned dogs representing 41 different breeds for
43 days. Only 105 dogs received Deramaxx at the dosage of 1-2 mg/kg (0.45 - 0.90 mg/lb) administered
once daily. 4
Lameness assessments together with owner evaluations are offered as proof of the effectiveness of
Deramaxx for the control of pain and inflammation associated with osteoarthritis. BUN, potassium and
phosphorus values were elevated post study. Novartis noted that these changes in clinical pathology
values were not considered clinically significant.
A 6 month Target Animal Safety Study was also performed to evaluate the safety of Deramaxx
administered orally on a daily basis for 6 months. Sixty HEALTHY beagles were used. All dogs survived to
termination of the study. Conclusions were that: “Deramaxx tablets were clinically well tolerated by dogs
when administered at doses up to 10 mg/kg/day for 26 weeks even though, there was a dose-dependent
increase in BUN values at doses > 6 mg/kg/day. Focal renal tubular degeneration /regeneration was seen
http://dil.vetmed.vt.edu/GreenBookUpdat ... 003_05.htm 5
6
http://a257.g.akamaitech.net/7/257/2422 ... v/2003/03-
9532.htm
http://www.fda.gov/cvm/index/retulatory/w042303n.pdf 7
Page 5 of 17
at doses > 6 mg/kg/day”. 5 6
On April 23,2003, the FDA again requested that Novartis immediately cease dissemination of all
advertising and labeling materials for Deramaxx which contained certain claims or representations. The 7
FDA specifically referred to the following DER submissions by Novartis:
“ Your “Dosing Card” submission of September 24, 2002
Your “Sales Aid” submission of October 8, 2002
Your “Sales Aid on CD” submission of October 17, 2002
Your “Direct Mailer” submission of October 23, 2002
Your “Trade Ad” submission of October 25, 2002
Your “Trade Ad” submission of November 7, 2002
It went on to advise Novartis of its receipt of “additional industry complaint letters regarding marketing
practices used in promoting the product Deramaxx (deracoxib).” The FDA further advised of its review of
“these promotional materials and concluded that they contain false or misleading statements in violation of
the Federal Food, Drug and Cosmetic Act (FDCA) and its implementing regulations.” In addition, the FDA
noted that “the promotional materials contain information that suggests the use of this product for
indications that are not provided for in the labeling.”
The FDA specifically noted that “These promotional materials present data from in vitro studies (COX-2
selectivity, Cox-1 sparing, IC50 Ratio) in a way that suggests clinical significance when no clinical benefit
has been established via substantial evidence”
It also noted that “These promotional materials imply or state that Deramaxx is safer and more effective
than other non-steroidal anti-inflammatory drugs”. In this regard, the FDA advised, “We are particularly
concerned because CVM’s objection to this claim was thoroughly discussed with Novartis representatives
during application review. Representatives of Novartis agreed with CVM’s Office of New Animal Drug
Evaluation that there would be no mention of a “different class for COX-2 selective NSAIDs and presently
approved NSAIDS.” Meeting memos and Minutes were footnoted to highlight these conversations.
The FDA additionally objected to the fact that “These promotional materials contain suggestions that the
drug is effective for managing induced synovial inflammation at the 1mg/kg dose”. It went on to say, “Your
product is approved at 3-4 mg/kg for post-operative pain. Promotion of the product at 1-2 mg/kg for
induced synovial inflammation suggest use of the product for osteoarthritis. At the time of dissemination of
these promotional materials, we were not aware of substantial evidence or substantial clinical experience to
demonstrate such efficacy. This representation was misleading because it suggests a use that has not
been established by substantial evidence or substantial clinical experience.”
http://www.fda.gov/cvm/index/safety/DDL ... 122203.pdf 8
Page 6 of 17
The FDA also objected to Novartis failure to “communicate the full extent of risk associated with NSAID
therapy” in it’s promotional materials.
NOT UNTIL December 22, 2003, ELEVEN MONTHS AFTER the FDA’s initial request to cease
disseminating the violative and promotional pieces, did Novartis re-label its product. Only after marketing
the drug under its new application, did Novartis revise it’s previously misleading informational material
which had been disseminated widely in 2002 and 2003. On December 22, 2003, Novartis issued it’s first
“Dear Doctor” letter in which it noted that Deramaxx was “our coxib-class nonsteroidal anti-inflammatory
drug (NSAID). Novartis went on to talk about the new information that had come to light, and advised that
it had updated the package insert to include a section reporting VOLUNTARY post-approval adverse
events. 8
The updated section of the Deramaxx label warned, in decreasing order of frequency, of numerous
adverse reactions, namely, Gastrointestinal, Hematological, Hepatic, Neurological/Behavioral/Special
sense, Urinary, Cardiovascular/Respiratory, and Dermatological/Immunological reactions. It went on to
warn, “In rare situations, death has been reported as an outcome of the adverse events listed above.”
Novartis additionally notified Veterinarians that formerly “precautionary” information had been moved to the
“Warnings section” of the label, namely:
“Sensitivity to drug-associated adverse events varies with the individual patient. As a class,
cyclooxygenase inhibitor NSAIDs may be associated with gastrointestinal and renal toxicity. Patients at
greatest risk for NSAID toxicity are those that are dehydrated, on concomitant diuretic therapy, or those
with existing renal, cardiovascular, and/or hepatic dysfunction. Since many NSAIDs posses the potential to
produce gastrointestinal ulceration, concomitant use of DERAMAXX tablets with other anti-inflammatory
drugs, such as NSAIDS or corticosteroids, should be avoided or closely monitored.”
Dosage and administration changes were also provided to the Doctors. “The approved dose for controlling
pain and inflammation associated with orthopedic surgery is 3-4 mg/kg/day as a single daily dose, as
needed, not to exceed 7 days.” This change in labeling put a maximum time period during which
Deramaxx at post surgical doses. Novartis went on to advise “ For control of pain and inflammation
associated with osteoarthritis, the approved dose is 1-2 mg/kg/day as a single daily dose as needed.”
Recommended Guidelines for Deramaxx use were also provided and include:
1) “Examine all dogs before prescribing any medication, including Deramaxx;
2) Conduct appropriate laboratory tests in dogs that may be at risk including:
a. senior pets
b. pets with history of liver disease, inflammatory bowel disease, renal disease or any
other chronic condition.
3) Evaluate potential drug interactions in dogs being treated with concurrent medications, especially
steroids or other NSAIDS.
4) Observe appropriate washout periods when switching from one NSAID to another or when
following corticosteroid use with NSAID therapy. The length of the washout period will vary,
depending upon the patient’s condition and other drugs involved.
5) Establish baselines and periodically monitor hematology and serum biochemical data in long-term
patients.
6) Provide pet owners with the Deramaxx Owner Information Sheet included with each Deramaxx
product shipment and share all potential benefits and possible side effects with them before
sending them home with Deramaxx. (Note: Veterinarians can order updated veterinary inserts and
http://www.kentuckypetgazette.com/novartis.htm 9
Also, http://www.fda.gov/foi/warning_letters/g5108d.htm
Page 7 of 17
updated client information sheets free of charge at any time by calling 1-877-PET-LIT-1 and
requesting item number DER 030041B for the revised veterinary insert or item number
DER030040046B for the revised client information sheet).
7) Advise pet owners to watch for early signs of drug intolerance including vomiting, diarrhea and lack
of appetite, and if they see the signs, discontinue use immediately and contact you.”
Thus, it was not until December 22, 2003, in the “Dear Doctor” letter, that the veterinary community was
notified of the proper classification of this drug and the numerous adverse effects associated with its use.
It is unknown at present whether the general public was ever notified of these labeling changes and
adverse reactions through television, the same medium that was used to make them aware of this new
drug.
Thereafter, and on 11/29/04, the FDA issued a WARNING LETTER to Novartis regarding its compliance
with the ADE reporting requirements. 9
It began, “ During the period of January 20 through January 23, 2004, an inspection was conducted at the
headquarters of your veterinary pharmaceutical operations in the United States of America (USA), known
as Novartis Animal Health US, Inc. (Novartis), which are located at 3200 Northline Avenue, Suite 300 in
Greensboro, North Carolina. The inspection disclosed significant deviations from the adverse drug
experience (ADE) reporting requirements of Section 512(l) of the Federal Food, Drug, and Cosmetic Act
(the Act) and Title 21, Code of Federal Regulations (21 CFR), Sections (§§) 510.300 {effective prior to June
30, 2003) and 514.80 (effective on June 30, 2003)”.
It further identified:
The violations include, but are not limited to, the following areas: “
1. Problems associated with your reporting practices of ADEs:
Novartis failed to submit timely and accurate information to the FDA regarding serious ADEs
associated with the administration of its FDA approved animal drug product Deramaxx™
(Deracoxib), New Animal Drug Application (NADA) 141-203, during its first year of marketing.
An example of this type of deviation is the recording of the date sent to FDA {box 2b of the FDA
1932). Our inspection revealed significant discrepancies between what was written in box 2b of the
FDA 1932 and the postmarked date of the submission and/or the date FDA received the
submission. Some of Novartis’ initial and follow-up ADE reports, including ones involving death,
were postmarked and/or received by FDA between 21 and 100 or more days after the date
recorded in box 2b of the FDA 1932, indicating that the date recorded in box 2b is incorrect.
Another example is Case # US200302088, which was reported to Novartis on February 19, 2003
(as indicated in box 2a of the FDA 1932). The form indicates that it was sent to FDA on January 9,
2004, over 10 months after it was reported to Novartis. This information should have been reported
to FDA in a timely manner, within 15 working days of receipt. Moreover, the report was not
received by FDA until January 27, 2004, again indicating that the date recorded in box 2b was
incorrect.
A third example is the revised submission for Case # US200207030, which was submitted with
your response dated February 25, 2004. Our investigators reviewed the entire correspondence file
between the owner of this animal and Novartis. The FDA 1932 submitted with your response fails
Page 8 of 17
to include specific details regarding the results of blood work performed on this dog on September
9, 2002 (a baseline) and further work performed in October 2002 and November 2002, which was
transmitted to Novartis by the owner between November 2002 and January 2003, in violation of 21
CFR § 514.80(b)(2)(ii). This information should have been promptly reported to FDA within 15
working days of receipt.
Your written response dated February 25, 2004, included revised standard operating procedures
(SOPs), which were supposed to address the observed deficiencies. The revised SOP 5.2 (Volume
1, page 650) does not identify how your firm will prevent incorrect information from being reported
to FDA as was noted during the inspection.
Your written response dated April 23, 2004, indicates that Novartis has employed additional
personnel for the receipt, investigation, and transmittal of ADE reports. The response further states
that your firm has also involved corporate quality, compliance, and pharmacovigilance groups to
assist in this process. But following your response FDA has continued to receive late ADE reports
along with cover letters. For example, some of these letters were dated April 28, 2004; May 12,
2004; May 28, 2004; July 29, 2004; August 20, 2004; and September 21, 2004.
Problems associated with your reporting practices of ADEs related to experimental studies:
Your firm failed to submit timely information to the FDA regarding post-approval studies involving
new animal drugs. Two specific failures were identified during the inspection.
The first one was the failure to submit information from completed pilot studies as part of the
clinical experience in the annual Drug Experience Report (DER), as required by 21 CFR §
510.300(a)(1) (effective prior to June 30, 2003 and 514.80(b)(4)(iii) (effective on June 30, 2003).
Our investigators identified over pilot studies in your master study list. Dr. Tebbit stated that
Novartis has never submitted information about their pilot studies as part of the annual DER,
unless they are part of an Investigational New Animal Drug Application (INADA) or a pivotal study.
The second one was the failure to submit serious, unexpected ADEs involving animals
under study to the FDA within 15 working days of first receiving the information, as
required by 21 CFR § 510.300(b)(2)(l) (effective prior to June 30, 2003) and 514.80(b)(2)(I)
(effective on June 30, 2003).
One study involving Deramaxx (Deracoxib), NADA 141-203, in cats involved a late submission of ™
ADEs. The experiment, which was completed in July 2003, involved 14 animal deaths and other
serious ADEs. These ADEs were not reported to the FDA within the required 15 working days
time frame, but were reported only after the conclusion of the inspection of your facility, on
February 24, 2004.
Although your submission dated February 24,2004, indicates that it was Novartis’ intent to
disclose the safety information from the cat study, your firm failed to disclose this information from
other studies found in the master study List.
For example, a protocol entitled "The Acute Safety Study of an Injectable Deracoxib (SD-6746)
Formulation In Dogs” was submitted to the FDA under the INADA 010-865 on April 15, 2002. This
was approximately three months after the master study list indicates the pilot study was
completed. The study clinical data was not received by the FDA until October 2004.
FDA acknowledges that your firm has revised its SOPS and obtained principal investigator
agreements to submit all 15-day ADEs in post approval studies as drug experiences. But your
response does not clarify that you also understand that you must submit ADEs in the periodic drug
experience report as clinical data, unless they were previously reported, as required by 21 CFR §
514.80(b)(4)(iv)©).”
The FDA went on to advise:
“The specific violations noted in this letter are serious and may be symptomatic of serious
http://www.fda.gov/medwatch/articles/me ... .htm#lssrd 10
Page 9 of 17
underlying problems.
1. You should take prompt action to correct these deficiencies. Failure to promptly correct
these deviations may result in regulatory action without further notice. These actions may
include, but are not limited to, seizure and/or injunction. Federal agencies are advised of
all Warning Letters about drugs so they may take this information into account when
considering the award of contracts.
We request that you reply in writing within fifteen (15) working days of receipt of this letter
describing the corrective actions you have implemented, or are planning to implement, to prevent
a recurrence of the violations noted above. Please include copies of any available documentation
demonstrating that corrections have been made. If corrective actions cannot be completed within
fifteen (15) working days, state the reason for the delay and the time within which the conditions
will be completed.”
Thereafter, and on December 1, 2004, Novartis issued another “Dear Colleagues” letter in which the
DERAMAXX Update: Clinical Experience with DERAMAXX was provided. This update contained a
“summary and analysis of the adverse drug experiences (ADEs) reported to the FDA during the first 18
months of DERAMAXX use.”
Novartis further stated that “review and analysis of these data have shown that six of 10 reported ADEs in
canine osteoarthritis resulted in unintentional overdose”. It went on to urge prescription of this drug
“according to recommended guidelines for dosing, patient selection and product administration” and
stressed the two different dosing regimens for DERAMAXX.
Please note, this update, was based on 1680 Adverse Drug Events (ADEs) As of January, 3, 2005, ADEs
numbered 2400, thus a discrepancy exists in the present number of reported ADEs and those at the time
of publication of this Novartis document. This update additionally fails to consider the ADE violations
noted by the FDA in it’s November 29, 2004 warning letter to Novartis, just 2 days prior to the issuance of
this update.
The foregoing chronology is submitted to reveal the story of Deramaxx through the eyes of a pet owners
across the country. Documentation of the human-animal bond and the positive effects on human health
and well-being of animal companionship is extensive, and at this time, statistics reveal that the
overwhelming majority of owners consider their pets as members of their family. This chronology, the
facts of which were deciphered from Freedom of Information material and other internet material, reveals
extremely minimal testing for a veterinary drug to enter the market, blatant disregard by the drug
manufacturer to represent the product accurately in its informational material, and numerous warnings and
violations issued by the FDA to the drug manufacturer without any apparent immediate compliance. Per
the chronology above, it took Novartis 11 months to re-label it’s product as originally approved by the FDA,
yet during this 11 month period, it expanded the market for this product by obtaining approval for it’s use
for the control of pain and inflammation of osteoarthritis. Furthermore, Novartis has failed to timely file
ADE’s with the FDA.
Additionally, when one considers underreporting of Adverse Drug Events, namely, that the FDA receives
by direct report less than 1% of suspected serious ADE, the concern of the pet owner is magnified. 10
http://www.fda.gov/cvm/index/ade/ade_cum.htm 11
Page 10 of 17
As of January 3, 2005, the FDA reported the following information
Deracoxib - Oral Dog
Reviews: 2352
Treated: 2400
Reacted: 2371
Died: 515 11
If underreporting has occurred as estimated, then deaths following the administration of this drug are
actually closer to 51,000 in number. Additionally, 515 deaths as of January 1, 2003 represents a 21%
mortality rate. This corresponds roughly with the 20.7% death and euthanasia (secondary to side effects)
rate published by Novartis in it’s December 1, 2004 letter to “Colleagues”.
THE PRESENT SITUATION
Animals, specifically dogs, have become central parts of our lives to the extent that they are cared about as
if children to millions of people, and valued beyond all monetary considerations. Technology and medicine
are advancing at rapid rates, resulting in the proliferation of an ever increasing number of drugs available
for both humans and animals. Drug companies are motivated by profit margins. Their reason for
existence is to sell the greatest amount of drugs possible and maximize their earnings.
In human medicine, there is (at least theoretically) a value placed on human life more relatively
proportionate to its actual value to others. In veterinary medicine, this is not the case, as animals are still legally
*property* and thus considered worth, at maximum, purchase or replacement value, which is an
infinitesimal fraction of their actual value to owners. (Note recent work on creating new class of property
*sentient property* for this/related reasons). Physicians are consequently held to a higher level of liability
for malpractice. In addition, and IMPORTANTLY, there exists the *intermediary* of the pharmacist
involved in dispensing of medication to humans, which position oversees the safety of each prescription for
the individual patient.
In veterinary medicine, there is no intermediary position of “pharmacist”. THE VETERINARIAN IS THE
PHARMACIST, leaving millions upon millions of animal owners IN the sole hands of their veterinarian, with
drug companies and the FDA/federal government purportedly behind them, each and every time
medication is dispensed to them. Dispensing drugs for animals is akin to dispensing them for children: in
both cases the patient cannot speak for themselves, evaluate the drug, or even report side effects as they
occur. Therefore, extra precautions are prerequisite and essential when dispensing medications to either
children or animals.
The points above have tragically resulted in a situation today that has genuinely reached crisis proportions:
Tens of thousands of animals are being unnecessarily killed each year by side effects of drugs dispensed
to them by veterinarians. They are dying unnecessary deaths which could have been, and CAN BE
prevented, leaving legions of grief-stricken owners with no notion of how to cope with
the death of their beloved animal friend in which they themselves unknowingly participated.
INFORMED CONSENT
January 15, 2004 Emerging issues regarding informed consent
Page 11 of 17
“The staff at the Food and Drug Administration's Center for Veterinary Medicine has conducted a two-year
review of consumer messages to our adverse drug experience hotline. The review indicates increasing
concern by consumers about risk and benefit of commonly prescribed, approved animal drugs.
The CVM established the hotline, (888) FDA-VETS, in 1996 to receive calls about adverse experiences to
approved animal drugs. We expected many of these reports to come from practicing veterinarians, but our
review indicates that a majority of the calls in the past few years have come from consumers,
particularly dog owners who find our link on the Internet.
The CVM considers the drug label the first source of important facts for veterinarians. The label is the
result of considerable scientific regulatory review before CVM approves the drug. It represents known
safety and efficacy for any one drug. The label also gives veterinarians important information about
whether the drug is suitable for the individual or subgroup within a species of animal.
Additionally, whenever manufacturers distribute a client information sheet, this means that either the
manufacturer or the CVM wishes to convey more facts about safety or efficacy in lay terms to pet owners.
The staff at CVM monitors and evaluates adverse drug experience reports and complaints of inefficacy for
approved and unapproved, marketed products. For approved products, this evaluation of postmarket safety
and efficacy incorporates knowledge gained from the premarket studies as well as from scrutiny of
peer-reviewed studies related to the drug, or the disease that the drug is intended to cure or prevent.
From the hotline, we have learned that pet owners increasingly rely on Internet sources for information
when their pets have problems. They have told us that, during their Internet searches, they often find label
information and client information sheets.
Frequent comments from pet owners who contact the CVM hotline include these:
* They did not receive a client information sheet when one was available for a drug that was
prescribed for their pet.
* The medication they received from their veterinarian was not dispensed in the CVM-approved
container but was broken into aliquots that were taken home without the client information sheet or
approved label.
* The veterinarian did not conduct or recommend blood testing before and after prescribing the drug, even
though baseline testing and/or periodic monitoring was recommended on the label. Common examples
include heartworm products and nonsteroidal, anti-inflammatory drugs.
* After reading client information sheets and labels on the Internet about a drug prescribed for their pet,
they discovered that their pet may have fallen into a category of animal for which a precaution or
contraindication existed.”
These comments represent a complete breakdown and failure of the institution of veterinary medicine. It
also represents an unacceptable failure of federal government medical safety oversight programs.
Dr. Victoria Hampshire, author of this article, went on to say:
“Given these findings, we have the following reminders for practitioners:
http://www.avma.org/onlnews/javma/jan04/040115f.asp 12
http://www.fdanews.com/dailies/drugdail ... 001-1.html 13
_
Page 12 of 17
* Drugs that come with client information sheets are intended to be dispensed in the manufacturer's
container, with the sheets accompanying the prescription.
* Product precautions, contraindications, safety information, and warnings should help identify
animal patients that are not good candidates for the medication.
* Labels change? if you have a large inventory of a product with a long shelf life, you may want to
contact the manufacturer or CVM to obtain the most recent label. A long shelf life makes it likely
that some of the product won't be dispensed in the near future. Often, this information is also
posted on pharmaceutical companies' official Web sites.” 12
Dr. Hampshire’s “reminders” should be pursued as mandates for all veterinary practitioners.
Additionally, the FDA news Drug Daily Bulletin, Thursday, Jan, 27, 2005, Vol. 2, No. 19 states:
“Public Confidence in Drug Companies Declining, Poll Shows
The mounting safety concerns swirling around the pharmaceutical industry are beginning to have a
profound effect on the American public’s perception of drug companies, according to a recent online poll.
Sixty percent of U.S. adults are “not very confident” or “not confident at all” that drugmakers will publicly
disclose information about possible side effects of their products as soon as they have that data, according
to a new Harris Interactive survey, which polled 2,404 U.S. adults between Jan. 4 and Jan. 7. Only 5
percent of the survey respondents indicated they are “very confident” that drugmakers will publicly disclose
side-effect information in a timely manner.......” -Drug Industry Daily 13
GENERAL OVERVIEW OF PROPOSED SOLUTIONS:
1. The FDA must hold the drug companies responsible for performing thorough safety studies and
reporting results accurately and thoroughly for all new veterinary drugs. Omission, manipulation
and distortion of data must be curtailed. Close monitoring of all related activities is necessary.
Compliance failures must be dealt with swiftly and forcefully in “real time”. “Real time” ADE
reporting is a critical and essential component of the monitoring the efficacy and safety of new
veterinary drugs. An overhaul and upgrade of the ADE reporting system is essential to make the
information contained therein easily accessible to the public.
2. Drug companies MUST provide timely, accurate FDA-approved product literature and updates
to veterinarians. These materials must contain clear statements that a Client Information Sheet
*must* be provided to every client to whom the “new” drug is dispensed.
How Items 1 and 2 can be accomplished :
A. Strong citizen input to FDA demanding:
Page 13 of 17
1. Better ADE reporting in “real time”
2. Swift enforcement of labeling violations
3. Correction of all labeling violations to all media vehicles
4. No direct to consumer advertising or promotion allowed for the first 2 years of new
drug approval
5. Citizen review committees - public involvement in the drug approval process
B. Pet owners who have been affected by this drug should consult with attorneys regarding:
1. Individual lawsuits
a. “property” claims;
b. claims with respect to failure to obtain client information sheets and lack of
informed consent that can be backed by state pharmacy regulations to the extent
that vets are not exempt from them.
c. “patient” claims by the “guardian” of the pet
d. “sentient property” claims
e. “Deceptive trade practices” claims
f. “Mail fraud” claims
2. Class Action lawsuits
C. Inform and Advise Legislators of these problems
D. National media campaign raising awareness and support for the above
3. Veterinarians MUST be REQUIRED to provide:
A. A Client Information Sheet (CIS) to every client to whom the drug is dispensed; and
B. Verbal client education regarding potential side effects, and what to do if any are
observed in their pet.
4. Veterinarians must be held to similar standards as pharmacists for every
medication they dispense to a patient.
How Items 3 and 4 can be accomplished:
A. Influence and Petition American Association of State Veterinary Boards to call for all
State Veterinary Board regulations to mandate this (leaving veterinarians unsupported in
lawsuits for failure to do so).
B. Make direct appeal to AVMA to call for State Boards to mandate this.
C. Make direct appeals to/demands for individual State Boards to mandate this
Page 14 of 17
D. National “Educate Your Vet” campaign- “VIS*s (Veterinary Information Sheets)
designed for clients to give to their vets- “Dear Dr.” letter respectfully, supportively
indicating clients can no longer accept less than full information/disclosure w/ drugs.
E. Mass petitions (includes some of above).
Filing with the State Veterinary Board may well be easier and more effective than filing Malpractice claims.
Challenging a veterinarian on lack of informed consent and failure to provide Client Information Sheets
may prove more productive. Each pet owner should consider each of these alternatives individually and in
accordance with their respective state laws.
SPECIFIC SOLUTIONS FOR THE FDA REGARDING NSAIDS IN GENERAL
AND DERAMAXX IN PARTICULAR:
1. PACKAGING AND LABELING - ALL NSAIDS - FDA MANDATE THAT NSAIDS BE
DISPENSED IN APPROVED CONTAINERS ONLY FOR THE FIRST 1-2 YEARS AFTER
PRODUCT APPROVAL
Given the data heretofore mentioned which indicates: that veterinarians operate at the pharmacist
level when dispensing drugs: that clients rarely, if ever, receive Client Information Sheets provided
by the drug companies to the veterinarian; that veterinarians often and in usual practice purchase
drugs in bulk and repackage them for client use; and that the FDA has no direct jurisdiction over
vets who are regulated by State Veterinary Boards, it is recommended that NSAIDS be dispensed
in approved and appropriately labeled containers only.
BLACK BOX WARNINGS - The most critical warnings that should be black boxed are:
A.) PROVIDE THE CLIENT INFORMATION SHEET - Early treatment of a problem is
critical to successful treatment
B.) Provide a profile of the signs associated with typical severe reaction: low RBC, high
WBC, High BUN and creatinine, elevated liver values with clinical signs being diarrhea
and vomiting, likely with blood and inappetance. This black box warning could be limited
to the typical profile that probably accounts for 95% of all severe reaction cases.
There are certainly other signs that come up, but generally, these are either not likely to
result in a severe reaction, related to some obvious pre-existing condition (known renal
failure, hepatic or cardio impairment as an example), or are relatively rare, i.e., everything
is relatively normal, but signs of congestive heart failure.
DOSAGE - With any NSAID, the name of the game is finding the LOWEST POSSIBLE
EFFECTIVE DOSE. It should be emphasized that dosing should be at the low end of the range
and the pill given on an “as needed” as opposed to “daily” basis
2. ADE REPORTING
Besides upgrading ADE reporting to “real time” and swiftly and appropriately penalizing
manufacturers for the failure to comply, the current system of ADE reporting only encompasses
unscored data. Scored data regarding death and euthanasia associated with adverse reaction is
not made available. The FDA and manufacturers discount the publicly available data, yet the FDA
Page 15 of 17
has the scored data. The public shouldn't have to file FOIA requests to get it.
3. NO DIRECT TO CONSUMER ADVERTISING OR PROMOTION FOR THE FIRST ONE-TWO
YEARS
This is being advocated for the human drugs. It is equally applicable to veterinary drugs. Pet
owners would be better served if manufacturers spend their advertising dollars on further research
into the safety and efficacy of these drugs and better “real-time” ADE reporting for the first few
years.
4. PUBLIC INVOLVEMENT IN THE APPROVAL PROCESS
At present, a drug obtains FDA approval without any opportunity for the public to comment on the
safety and efficacy studies. There is no real mechanism for the public to comment on this after
approval status is obtained. The FDA needs to change this to allow in the final stages for a public panel
to review and comment on the adequacy of the research done in support of a new drug
application.
5. DERAMAXX - PROBLEMS REQUIRING FURTHER INVESTIGATION (AND SUSPENDED
SHIPMENT UNTIL THE ISSUES ARE RESOLVED)
a.) NSAID HEART problems. There is enough evidence and details of one well documented case
being submitted to the FDA to warrant a requirement that Novartis investigate adverse cardiac
effects of Deramaxx. At present, in a question and answer format, Novartis is currently stating
that dogs are different than humans and this is not an issue. The fact which undermines this
assertion is that dogs are and have been used extensively in studying toxicity and other issues in
the development of human Cox-2 inhibitors for humans. Cardio infarcts do not resolve and there
is little room for compensation. Most will tend to get worse over time because they are subject to
constant blood flows.
b.) NEUROLOGICAL effects from long-term use. It is known that Cox-2 is used constitutively in
the brain therefore Cox-2 inhibition has to have an effect. What is it? Is it permanent? This needs
to be studied.
c.) SULFA allergy effects. Deramaxx is a sulfanomide drug. There are certain breeds
(Dobermans, white-coated northern and so on) with known sulfa allergies. A specific warning on
this needs to be studied. At present, the label says it might be an issue.
d.) VARIABLE METABOLISM effects. The studies in support of Deramaxx found that there was
variable metabolism of the drug. There is an extensive body of literature on variations in the
metabolism of Celebrex, a close chemical cousin of Deramaxx, in dogs. The product label states
that there was variation, but does not go beyond this to say that it could result in the death of
some dogs. The manufacturers of Deramaxx and other NSAIDS need to develop a screening
procedure that identifies slow metabolizers, the dogs who are most likely to experience adverse reactions.
Searle, the developer of Deramaxx, studied this issue when they developed the drug. That
information needs to be made public and if it is inadequate to draw any conclusions, studied
further since it is clear that this is the reason for most of the severest reactions to the drug.
Deramaxx is specifically marketed for osteoarthritis, a condition experienced by older or senior
dogs. It is this same group of senior dogs that are normally, the slower metabolizers.
e.) REVERSIBILITY OF TOXIC EFFECTS - Because documented adverse side effects of
Deramaxx include serious and sometimes fatal organ system damage or failure, the issue of
reversibility is a crucial one in order to substantiate claims of safety . It needs to be addressed
Page 16 of 17
scientifically and much more adequately than has been done. If organ system damage is only
partially or slightly reversible, the dog might not die right then, however, it’s life is still harmed or
shortened.
In this same regard, the FDA should consider providing treatment guidelines for Deramaxx drug
toxicity, especially given Novartis claims of ineffective treatment and drug overdose events.
Regarding the documentation of the extent of damage done by this drug, the FDA has an up close
and personal view day in and day out with benefit of the full clinical record. The FDA should
compel the manufacturer to present a “profile” when post-market experience indicates there are
serious side effects.
Page 17 of 17
TABLE OF REFERENCES
1. http://www/fda.gov/OHRMS/DOCKETS/98fr/03-29744.pdf
2. http://www.fda.gov/cvm/efoi/section2/141-203.pdf
3. http://www.fda.gov/cvm/index/regulatory/w011603na.pdf
4. http://www.fda.gov/cvm/efoi/section2/141-203s021103.pdf
5. http://dil.vetmed.vt.edu/GreenBookUpdat ... 003_05.htm
6. http://a257.g.akamaitech.net/7/257/2422 ... v/2003/03-
9532.htm
7. http://www.fda.gov/cvm/index/retulatory/w042303n.pdf
8. http://www.fda.gov/cvm.index/safety/DDL ... 122203.pdf
9. http://www.kentuckypetgazette.com/novartis.htm
Also, http://www.fda.gov/foi/warning_letters/g5108d.htm
10. http://www.fda.gov/medwatch/articles/me ... .htm#lssrd
11. http://www.fda.gov/cvm/index/ade/ade_cum.htm
12. http://www.avma.org/onlnews/javma/jan04/040115f.asp
13. http://www.fdanews.com/dailies/drugdail ... 35001-1.ht
- guest
Rimadyl Questionnaire class action
by guest » Sat May 28, 2005 9:24 am
Law Office of Kelly M. Heitkamp, P.C.
Judson Plaza, Suite 168 Telephone: (903) 295-7800
1121 Judson Road Facsimile: (903) 553-1222
Longview, Texas 75601 KMHeitkamp@hotmail.com
March 27, 2005
Dear Client:
Attached is a Rimadyl Questionnaire which we request that you print and complete and
forward to our office at 1121 Judson Road, Suite 168, Longview, Texas 75601. This is one
of many forms you will be asked to fill out to give us a better idea of how to handle your
case.
It is our intention to file suit for you very soon, but you should understand that the
veterinarians we have hired or will hire to review these records will control our decision as
to whether or not you have a case. If the experts find that your case does not meet the
criteria, then suit will not be filed for you, and you will be notified of such decision.
We will try to keep you informed as to what is going on, and ask for your cooperation in
completing and forwarding the enclosed questionnaire as quickly as possible.
Yours very truly,
Kelly M. Heitkamp
RIMADYL QUESTIONNAIRE Date _______________
REPRESENTATIVE OF DECEASED ANIMAL
First Name:________________________ MI: _____ Last Name: _________________________
Street Address: ___________________________ City:_____________________ State: _______
Zip: ______________________ County: __________________ Phone: ____________________
Work Phone: __________________________ Cell Phone: ______________________________
E-Mail Address: ________________________________________________________________
COMPANION’S INFORMATION
Companion’s Name: ____________________________________________________________
Date of Birth: _________________________________ Age: ____________________________
Dosage Taken: __________________________ Date First Used Rimadyl:__________________
Date Last Used Rimadyl Before Incident: ____________________________________________
Date of Last Use of Rimadyl Use EVER: ____________________________________________
Symptoms:
Clot in lungs? YES NO Date:
Clot in legs? YES NO Date:
Blood clot anywhere? YES NO Date:
Kidney failure? YES NO Date:
Gastric ulceration YES NO Date:
Vomiting blood? YES NO Date:
Diarrhea? YES NO Date:
Eating habits? YES NO Date:
Liver disease YES NO Date:
Other: YES NO Date:
Did a veterinarian treat your animal for any of the above problems: YES NO
If yes, name of veterinarian:_______________________________________________________
Address of veterinarian: __________________________________________________________
Phone number: _________________________________________________________________
Did your animal have surgery for any of the above listed problems? YES NO
Was your animal hospitalized for any of the above listed problems? YES NO
If yes, how long was your animal in the hospital? ______________________________________
When was your animal in the hospital? ______________________________________________
Which hospitals? _______________________________________________________________
Has your animal been treated by a board certified specialist? YES NO
If yes, name of veterinarian:_______________________________________________________
Address of veterinarian: __________________________________________________________
Phone number: _________________________________________________________________
Is your animal deceased? YES NO
If yes, was deceased taking Rimadyl at the time of death? YES NO
Date of Death: _______________________________ Was death sudden? YES NO
If yes, was there a necropsy? YES NO If yes, necropsy findings: _________________________
**PLEASE SEND US A COPY OF ALL VETERINARIAN RECORDS OF
YOUR PET FOR A PERIOD BEGINNING ONE YEAR
PRIOR TO DEATH****
Background Information:
Veterinarian who prescribed Rimadyl:
Name: ________________________________________________________________________
Address: ____________________________ City: _____________________________________
State: ____________________ Zip: _________________ Phone: _________________________
Reason Rimadyl was prescribed: ___________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
Permission to file a lawsuit against any veterinarian and/or specialist who treated your animal
(circle one) Y N
List ALL medical conditions your pet has been treated for before the use of Rimadyl:
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
List ALL other medications that your pet has been prescribed before the use of Rimadyl:
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
List ALL other medications your pet was taking while using Rimadyl:
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
*** You must obtain a copy of records
from your veterinarian where you purchased
your Rimadyl and forward to our office ***
Judson Plaza, Suite 168 Telephone: (903) 295-7800
1121 Judson Road Facsimile: (903) 553-1222
Longview, Texas 75601 KMHeitkamp@hotmail.com
March 27, 2005
Dear Client:
Attached is a Rimadyl Questionnaire which we request that you print and complete and
forward to our office at 1121 Judson Road, Suite 168, Longview, Texas 75601. This is one
of many forms you will be asked to fill out to give us a better idea of how to handle your
case.
It is our intention to file suit for you very soon, but you should understand that the
veterinarians we have hired or will hire to review these records will control our decision as
to whether or not you have a case. If the experts find that your case does not meet the
criteria, then suit will not be filed for you, and you will be notified of such decision.
We will try to keep you informed as to what is going on, and ask for your cooperation in
completing and forwarding the enclosed questionnaire as quickly as possible.
Yours very truly,
Kelly M. Heitkamp
RIMADYL QUESTIONNAIRE Date _______________
REPRESENTATIVE OF DECEASED ANIMAL
First Name:________________________ MI: _____ Last Name: _________________________
Street Address: ___________________________ City:_____________________ State: _______
Zip: ______________________ County: __________________ Phone: ____________________
Work Phone: __________________________ Cell Phone: ______________________________
E-Mail Address: ________________________________________________________________
COMPANION’S INFORMATION
Companion’s Name: ____________________________________________________________
Date of Birth: _________________________________ Age: ____________________________
Dosage Taken: __________________________ Date First Used Rimadyl:__________________
Date Last Used Rimadyl Before Incident: ____________________________________________
Date of Last Use of Rimadyl Use EVER: ____________________________________________
Symptoms:
Clot in lungs? YES NO Date:
Clot in legs? YES NO Date:
Blood clot anywhere? YES NO Date:
Kidney failure? YES NO Date:
Gastric ulceration YES NO Date:
Vomiting blood? YES NO Date:
Diarrhea? YES NO Date:
Eating habits? YES NO Date:
Liver disease YES NO Date:
Other: YES NO Date:
Did a veterinarian treat your animal for any of the above problems: YES NO
If yes, name of veterinarian:_______________________________________________________
Address of veterinarian: __________________________________________________________
Phone number: _________________________________________________________________
Did your animal have surgery for any of the above listed problems? YES NO
Was your animal hospitalized for any of the above listed problems? YES NO
If yes, how long was your animal in the hospital? ______________________________________
When was your animal in the hospital? ______________________________________________
Which hospitals? _______________________________________________________________
Has your animal been treated by a board certified specialist? YES NO
If yes, name of veterinarian:_______________________________________________________
Address of veterinarian: __________________________________________________________
Phone number: _________________________________________________________________
Is your animal deceased? YES NO
If yes, was deceased taking Rimadyl at the time of death? YES NO
Date of Death: _______________________________ Was death sudden? YES NO
If yes, was there a necropsy? YES NO If yes, necropsy findings: _________________________
**PLEASE SEND US A COPY OF ALL VETERINARIAN RECORDS OF
YOUR PET FOR A PERIOD BEGINNING ONE YEAR
PRIOR TO DEATH****
Background Information:
Veterinarian who prescribed Rimadyl:
Name: ________________________________________________________________________
Address: ____________________________ City: _____________________________________
State: ____________________ Zip: _________________ Phone: _________________________
Reason Rimadyl was prescribed: ___________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
Permission to file a lawsuit against any veterinarian and/or specialist who treated your animal
(circle one) Y N
List ALL medical conditions your pet has been treated for before the use of Rimadyl:
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
List ALL other medications that your pet has been prescribed before the use of Rimadyl:
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
List ALL other medications your pet was taking while using Rimadyl:
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
*** You must obtain a copy of records
from your veterinarian where you purchased
your Rimadyl and forward to our office ***
- guest
VETERINARY COX-2 INHIBITORS: IS A REVIEW IN ORDER?
by guest » Sun Aug 28, 2005 5:37 am
VETERINARY COX-2 INHIBITORS: IS A REVIEW IN ORDER?
LETTER TO THE FDA
Please feel free to post this letter far and wide.
----- Original Message -----
From: "Edward Murray"
To: "Victoria Hampshire DVM" ; "Marcia K Larkins"
; "Stephen Fasenfeld" ; "Sundlof, Stephen F" ; "Crawford, Lester, D.V.M."
Sent: Friday, February 11, 2005 10:58 AM
Subject: Review of Veterinary Cox-2 Inhibitors
Dear Doctors Crawford and Sundlof,
I just had an opportunity to read the November/December 2004 FDA Veterinarian and was particularly disturbed by the policy decision reflected in the Page 3 Ask CVM article (below) with respect to review of the safety of veterinary Cox 2 inhibitors.
As you are well aware, the possible link between the human Cox 2 inhibitors and heart failure did NOT come to light as a result of ADRs submitted voluntarily to the FDA, but was found in large-scale studies and epidemiological analysis.
While I fully understand that there are significant differences between dogs and humans, I see no reason to assume a priori that there cannot be similar effects from Cox 2 inhibition and every reason to think that if such a link exists, it is highly unlikely that it will show up in the adverse event reports submitted to CVM, especially with the agency saying that the possibility is unlikely and thereby discouraging reporting of such links.
Because of my website (www.vetnsaids.com), many owners who suspect adverse reactions to Deramaxx contact me. I do not maintain formal statistics on this, but my impression is that somewhere between 2%-5% have reported cardiac effects. These range from deaths from some form of cardiomyopathy, to congestive heart failure and thromoboembolisms.
In many cases, I have seen the clinical records, labs and necropsy reports which show more classical NSAID adverse reactions such as renal impairment and gastric ulceration in these cases and have questions about whether the proximate cause of death was heart failure. Nevertheless, I have now seen enough of these, and encouraged the owners to report them to your agency, to believe that this is an area requiring further investigation.
There are several recent cases which appear to show a possible link between Deramaxx and heart failures. A veterinarian is reviewing two of these and will be submitting further information on them to the agency. There was an EKG done a few months before the start of Deramaxx in one case and ultra-sound in the other which showed no heart problems.
In the other cases, there is a less clear record prior to the start of Deramaxx, but a clear report on the cause of death based on necropsies that pointed to heart failure, although all of these also had signs of classical NSAID toxicity. I have encouraged the owners to report these so that your staff can investigate them further.
All of these cases occured as acute reactions after just a few doses. There is another case that I am aware of where the dog is currently at U Penn which may be a case of CHF that occured in a dog who was coincidentally on Deramaxx for approximately three months. I am trying to get further details on another case of CHF as well as classic reaction to Deramaxx that was referred to Michigan State Veterinary Teaching Hospital and hope that the vet or owner has or is planning to file an ADE.
Recognizing that anecdotes are not data, I think there is nonetheless every reason to look into the possibility of a link between Cox 2 inhibition and heart-related issues in dogs and find it disappointing that the agency isn't being more proactive on this issue given the known limitations of voluntary adverse event reporting. (See citation below.)
The FDA Veterinarian article raises another issue of considerable importance.
With the number of reported deaths possibly linked to Deramaxx (601) now surpassing even those for ProHeart6 (599) which you recalled, I find it somewhat disturbing that the agency can conclude that these drugs are safe "when used according to the label and when dog owners are informed about common NSAID side effects," given the tremendous amount of information you have that they are NOT being used in accordance with label instructions and certainly that few owners are being fully informed about common NSAID side effects at least in terms of the numbers being given the Client Information Sheets on drugs for which they are available.
While I recognize that you have no authority with respect to what veterinarians do, the very fact that these two pre-conditions for safe use appear not to be standard practice means that in reality, the drugs are not safe in actual use. While the agency cannot order veterinarians to practice good medicine, I would think that if you recalled these drugs until the manufacturers find a way to encourage use according to the label recommendations and get veterinanians to distribute the Client Information Sheets, the manufacturers would become very creative in addressing this issue.
A group of owners has come up with a novel solution to this problem which I pass on to you because it might be something the agency itself could do. Given the abysmal failure of veterinarians to distribute Client Information Sheets, this group is in the process of creating Veterinarian Information Sheets which owners can provide their vets.
The VIS states that owners expect their vets to closely adhere to label recommendations for use of the drugs given their companion animals as well as that they will be provided written information on the risks and safe use of the drugs that are being prescribed and dispensed for their companions, including Client Information Sheets for those drugs which include these as an integral part of the product label.
My guess is that this citizen initiative will have a real impact on this problem more so if the FDA were to launch a parallel effort to reach veterinarians with this message.
Respectfully,
Edward Murray
2226 West Sunset Drive
Stillwater, OK 74074
e.murray@vetnsaids.com
Understanding Deramaxx
http://www.vetnsaids.com
Underreporting
Another major concern with any spontaneous reporting system is underreporting of adverse events (16, 30-32). It has been estimated that rarely more than 10% of serious ADRs, and 2-4% of non-serious reactions, are reported to the British spontaneous reporting program (30). A similar estimate is that the FDA receives by direct report less than 1% of suspected serious ADRs(32). This means that cases spontaneously reported to any surveillance program, which comprise the numerator, generally represent only a small portion of the number that have actually occurred. The effect of underreporting can be somewhat lessened if submitted reports, irrespective of number, are of high quality.
The Clinical Impact of Adverse Event Reporting http://www.fda.gov/medwatch/articles/me ... .htm#lssrd
32. Scott HD, Rosenbaum SE, Waters WJ, Colt AM, Andrews LG, Juergens JP, et al. Rhode Island physicians' recognition and reporting of adverse drug reactions. R I Med J 1987;70:311-316
Ask CVM
FDA VETERINARIAN
NOVEMBER/DECEMBER 2004
Page 3
http://www.fda.gov/cvm/Documents/Nov-Dec04.pdf
Q: I understand that FDA is reviewing the safety of "Cox 2 inhibitors" human
drugs used for pain relief. Will FDA also be reviewing Cox 2 inhibitors approved for use in animals?
A: No. At this time, FDA does not plan to review the safety of veterinary
Cox 2 inhibitor products.
The Center for Veterinary Medicine considers the approved veterinary nonsteroidal anti-inflammatory drugs (NSAIDS), including drugs classified as Cox 2 inhibitors, to be safe and effective when used according to the label and when dog owners are informed about common NSAID side effects. CVM is constantly screening new Adverse Drug Event (ADE) reports, including those for cardiac ADEs, to determine if the reports contain any unexpected side effects. We have not seen any unexpected side effects for NSAID products.
The concern in human medicine is that the use of Cox 2 inhibitors can lead to heart ailments or strokes. We do not receive many ADEs involving those signs for veterinary NSAIDs or other drugs. Part of the reason for that is the considerable difference between the diagnostic procedures for pets and for humans and the difference in reporting of ADEs. While it is extremely common for physicians to diagnose heart attacks and strokes in humans, it is extremely uncommon for veterinarians to diagnose them in dogs. Most veterinarians do not order MRIs or CT scans for animals, even though those are common diagnostic tools for humans.
Another reason is that dogs rarely suffer lethal heart attacks. Dogs grow good collateral circulation in the heart, but humans do not.
CVM will continue to monitor these and other veterinary drugs and look for unusual frequency and severity of side effects.
If, as in the case of the human drugs, we find new and conflicting scientific data on adverse events associated with an approved drug, we will take appropriate action.
LETTER TO THE FDA
Please feel free to post this letter far and wide.
----- Original Message -----
From: "Edward Murray"
To: "Victoria Hampshire DVM" ; "Marcia K Larkins"
; "Stephen Fasenfeld" ; "Sundlof, Stephen F" ; "Crawford, Lester, D.V.M."
Sent: Friday, February 11, 2005 10:58 AM
Subject: Review of Veterinary Cox-2 Inhibitors
Dear Doctors Crawford and Sundlof,
I just had an opportunity to read the November/December 2004 FDA Veterinarian and was particularly disturbed by the policy decision reflected in the Page 3 Ask CVM article (below) with respect to review of the safety of veterinary Cox 2 inhibitors.
As you are well aware, the possible link between the human Cox 2 inhibitors and heart failure did NOT come to light as a result of ADRs submitted voluntarily to the FDA, but was found in large-scale studies and epidemiological analysis.
While I fully understand that there are significant differences between dogs and humans, I see no reason to assume a priori that there cannot be similar effects from Cox 2 inhibition and every reason to think that if such a link exists, it is highly unlikely that it will show up in the adverse event reports submitted to CVM, especially with the agency saying that the possibility is unlikely and thereby discouraging reporting of such links.
Because of my website (www.vetnsaids.com), many owners who suspect adverse reactions to Deramaxx contact me. I do not maintain formal statistics on this, but my impression is that somewhere between 2%-5% have reported cardiac effects. These range from deaths from some form of cardiomyopathy, to congestive heart failure and thromoboembolisms.
In many cases, I have seen the clinical records, labs and necropsy reports which show more classical NSAID adverse reactions such as renal impairment and gastric ulceration in these cases and have questions about whether the proximate cause of death was heart failure. Nevertheless, I have now seen enough of these, and encouraged the owners to report them to your agency, to believe that this is an area requiring further investigation.
There are several recent cases which appear to show a possible link between Deramaxx and heart failures. A veterinarian is reviewing two of these and will be submitting further information on them to the agency. There was an EKG done a few months before the start of Deramaxx in one case and ultra-sound in the other which showed no heart problems.
In the other cases, there is a less clear record prior to the start of Deramaxx, but a clear report on the cause of death based on necropsies that pointed to heart failure, although all of these also had signs of classical NSAID toxicity. I have encouraged the owners to report these so that your staff can investigate them further.
All of these cases occured as acute reactions after just a few doses. There is another case that I am aware of where the dog is currently at U Penn which may be a case of CHF that occured in a dog who was coincidentally on Deramaxx for approximately three months. I am trying to get further details on another case of CHF as well as classic reaction to Deramaxx that was referred to Michigan State Veterinary Teaching Hospital and hope that the vet or owner has or is planning to file an ADE.
Recognizing that anecdotes are not data, I think there is nonetheless every reason to look into the possibility of a link between Cox 2 inhibition and heart-related issues in dogs and find it disappointing that the agency isn't being more proactive on this issue given the known limitations of voluntary adverse event reporting. (See citation below.)
The FDA Veterinarian article raises another issue of considerable importance.
With the number of reported deaths possibly linked to Deramaxx (601) now surpassing even those for ProHeart6 (599) which you recalled, I find it somewhat disturbing that the agency can conclude that these drugs are safe "when used according to the label and when dog owners are informed about common NSAID side effects," given the tremendous amount of information you have that they are NOT being used in accordance with label instructions and certainly that few owners are being fully informed about common NSAID side effects at least in terms of the numbers being given the Client Information Sheets on drugs for which they are available.
While I recognize that you have no authority with respect to what veterinarians do, the very fact that these two pre-conditions for safe use appear not to be standard practice means that in reality, the drugs are not safe in actual use. While the agency cannot order veterinarians to practice good medicine, I would think that if you recalled these drugs until the manufacturers find a way to encourage use according to the label recommendations and get veterinanians to distribute the Client Information Sheets, the manufacturers would become very creative in addressing this issue.
A group of owners has come up with a novel solution to this problem which I pass on to you because it might be something the agency itself could do. Given the abysmal failure of veterinarians to distribute Client Information Sheets, this group is in the process of creating Veterinarian Information Sheets which owners can provide their vets.
The VIS states that owners expect their vets to closely adhere to label recommendations for use of the drugs given their companion animals as well as that they will be provided written information on the risks and safe use of the drugs that are being prescribed and dispensed for their companions, including Client Information Sheets for those drugs which include these as an integral part of the product label.
My guess is that this citizen initiative will have a real impact on this problem more so if the FDA were to launch a parallel effort to reach veterinarians with this message.
Respectfully,
Edward Murray
2226 West Sunset Drive
Stillwater, OK 74074
e.murray@vetnsaids.com
Understanding Deramaxx
http://www.vetnsaids.com
Underreporting
Another major concern with any spontaneous reporting system is underreporting of adverse events (16, 30-32). It has been estimated that rarely more than 10% of serious ADRs, and 2-4% of non-serious reactions, are reported to the British spontaneous reporting program (30). A similar estimate is that the FDA receives by direct report less than 1% of suspected serious ADRs(32). This means that cases spontaneously reported to any surveillance program, which comprise the numerator, generally represent only a small portion of the number that have actually occurred. The effect of underreporting can be somewhat lessened if submitted reports, irrespective of number, are of high quality.
The Clinical Impact of Adverse Event Reporting http://www.fda.gov/medwatch/articles/me ... .htm#lssrd
32. Scott HD, Rosenbaum SE, Waters WJ, Colt AM, Andrews LG, Juergens JP, et al. Rhode Island physicians' recognition and reporting of adverse drug reactions. R I Med J 1987;70:311-316
Ask CVM
FDA VETERINARIAN
NOVEMBER/DECEMBER 2004
Page 3
http://www.fda.gov/cvm/Documents/Nov-Dec04.pdf
Q: I understand that FDA is reviewing the safety of "Cox 2 inhibitors" human
drugs used for pain relief. Will FDA also be reviewing Cox 2 inhibitors approved for use in animals?
A: No. At this time, FDA does not plan to review the safety of veterinary
Cox 2 inhibitor products.
The Center for Veterinary Medicine considers the approved veterinary nonsteroidal anti-inflammatory drugs (NSAIDS), including drugs classified as Cox 2 inhibitors, to be safe and effective when used according to the label and when dog owners are informed about common NSAID side effects. CVM is constantly screening new Adverse Drug Event (ADE) reports, including those for cardiac ADEs, to determine if the reports contain any unexpected side effects. We have not seen any unexpected side effects for NSAID products.
The concern in human medicine is that the use of Cox 2 inhibitors can lead to heart ailments or strokes. We do not receive many ADEs involving those signs for veterinary NSAIDs or other drugs. Part of the reason for that is the considerable difference between the diagnostic procedures for pets and for humans and the difference in reporting of ADEs. While it is extremely common for physicians to diagnose heart attacks and strokes in humans, it is extremely uncommon for veterinarians to diagnose them in dogs. Most veterinarians do not order MRIs or CT scans for animals, even though those are common diagnostic tools for humans.
Another reason is that dogs rarely suffer lethal heart attacks. Dogs grow good collateral circulation in the heart, but humans do not.
CVM will continue to monitor these and other veterinary drugs and look for unusual frequency and severity of side effects.
If, as in the case of the human drugs, we find new and conflicting scientific data on adverse events associated with an approved drug, we will take appropriate action.
- guest
manufacturer-associated NSAID trial bias
by guest » Sun Aug 28, 2005 8:42 am
1: Arch Intern Med. 1994 Jan 24;154(2):157-63.Related Articles, Links
Rochon PA, Gurwitz JH, Simms RW, Fortin PR, Felson DT, Minaker KL, Chalmers TC.
Geriatric Research Education and Clinical Center, Brockton/West Roxbury Veterans Affairs Medical Center, Boston, Mass.
BACKGROUND: To study the relation between reported drug performance in published trials and support of the trials by the manufacturer of the drug under evaluation, we studied a sample of trials of nonsteroidal anti-inflammatory drugs (NSAIDs) used in the treatment of arthritis.
METHODS: All randomized control trials of NSAIDs published between September 1987 and May 1990 identified by MEDLINE were reviewed. If an article met the following criteria (n = 61), it was selected: trials involving adult patients with osteoarthritis or rheumatoid arthritis (n = 180), use of nonsalicylate NSAIDs marketed in the United States (n = 101), randomized control trial (n = 81), duration of the trial 4 or more days (n = 78), and use of an efficacy outcome measure (n = 61). Reviewers, "blinded" to manufacturer status, evaluated the narrative interpretation of results and extracted numeric data on efficacy and toxicity. Manufacturer-associated trials were defined as those that acknowledged an association with a pharmaceutical manufacturer. Because of the scarcity of non-manufacturer-associated trials (n = 9), we report only on the manufacturer-associated articles.
RESULTS: Fifty-two publications (85.2%) representing 56 trials were associated with a manufacturer. The manufacturer-associated drug was reported as comparable with (71.4%) or superior to (28.6%) the comparison drug in all 56 trials. These narrative claims of superiority were usually justified with trial data. Of the trials identifying one drug as less toxic (n = 22), the manufacturer-associated drug's safety was reported as superior to the comparison drug in 86.4% of cases. Justification for the narrative interpretation of the trial findings regarding less toxicity was provided in only 12 (54.5%) of 22 trials.
CONCLUSION: The manufacturer-associated NSAID is almost always reported as being equal or superior in efficacy and toxicity to the comparison drug. These claims of superiority, especially in regard to side effect profiles, are often not supported by trial data. These data raise concerns about selective publication or biased interpretation of results in manufacturer-associated trials.
PMID: 8285810 [PubMed - indexed for MEDLINE]
Rochon PA, Gurwitz JH, Simms RW, Fortin PR, Felson DT, Minaker KL, Chalmers TC.
Geriatric Research Education and Clinical Center, Brockton/West Roxbury Veterans Affairs Medical Center, Boston, Mass.
BACKGROUND: To study the relation between reported drug performance in published trials and support of the trials by the manufacturer of the drug under evaluation, we studied a sample of trials of nonsteroidal anti-inflammatory drugs (NSAIDs) used in the treatment of arthritis.
METHODS: All randomized control trials of NSAIDs published between September 1987 and May 1990 identified by MEDLINE were reviewed. If an article met the following criteria (n = 61), it was selected: trials involving adult patients with osteoarthritis or rheumatoid arthritis (n = 180), use of nonsalicylate NSAIDs marketed in the United States (n = 101), randomized control trial (n = 81), duration of the trial 4 or more days (n = 78), and use of an efficacy outcome measure (n = 61). Reviewers, "blinded" to manufacturer status, evaluated the narrative interpretation of results and extracted numeric data on efficacy and toxicity. Manufacturer-associated trials were defined as those that acknowledged an association with a pharmaceutical manufacturer. Because of the scarcity of non-manufacturer-associated trials (n = 9), we report only on the manufacturer-associated articles.
RESULTS: Fifty-two publications (85.2%) representing 56 trials were associated with a manufacturer. The manufacturer-associated drug was reported as comparable with (71.4%) or superior to (28.6%) the comparison drug in all 56 trials. These narrative claims of superiority were usually justified with trial data. Of the trials identifying one drug as less toxic (n = 22), the manufacturer-associated drug's safety was reported as superior to the comparison drug in 86.4% of cases. Justification for the narrative interpretation of the trial findings regarding less toxicity was provided in only 12 (54.5%) of 22 trials.
CONCLUSION: The manufacturer-associated NSAID is almost always reported as being equal or superior in efficacy and toxicity to the comparison drug. These claims of superiority, especially in regard to side effect profiles, are often not supported by trial data. These data raise concerns about selective publication or biased interpretation of results in manufacturer-associated trials.
PMID: 8285810 [PubMed - indexed for MEDLINE]
- guest
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