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| Saturday, January 08, 2005 commentary: | ||
Lawmaker calls for investigation into FDA attempts to engage in character assassination of whistleblower Dr. David GrahamNews summary:
Source: http://www.washingtonpost.com/wp-dyn/articles/A11215-2004Nov24.html
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Dr. David Graham, who works in the FDA's office of drug safety, has said he was not allowed to publish his data questioning the safety of Vioxx, a pain medication principally used to treat osteroarthritis. Additionally, an FDA official sent email messages to the medical journal Lancet trying to persuade the journal not to publish the data.
Citing its own safety concerns, manufacturer Merck voluntarily pulled Vioxx from the market in late September.
Graham testified in November before a Senate committee that the FDA fumbled in its handling of safety concerns around Vioxx and had mishandled concerns about five other widely used drugs. He contended that FDA has an inherent conflict of interest that triggers "denial, rejection and heat" when safety questions emerge about products it has approved.
The FDA denies the allegations, and controversy over the agency's role continues.
But the question of publication of the Vioxx data appears to be settled. The FDA told Graham Monday that he could go ahead and publish his research, which shows that 88,000 to 139,000 people have had heart attacks that could be linked to Vioxx, with 30 percent to 40 percent of them fatal, said Graham's attorney, Tom Devine.
The report will be resubmitted to the Lancet, a British medical journal, which is expected to publish it, Devine said. Lancet editor Richard Horton has been sharply critical of the FDA as well.
Devine, legal director of the Government Accountability Project, said the FDA go-ahead is a positive sign.
"For the short-term at least, the FDA has decided to stop suppressing controversial research on Vioxx," he said.
Graham could not be reached for comment but Devine said of his client: "He's pleased and relieved."
The FDA did not respond to a request for comment.
from: http://www.newstarget.com/002476.html
| Saturday, January 08, 2005 commentary: | ||
Medical community blames Dr. David Graham for warning about prescription drugs; medical McCarthyism now in full swingHere's how twisted the medical community is these days: when FDA researcher (and now, public safety hero) Dr. David Graham raised safety questions about five prescription drugs in Senate testimony, the drug companies, FDA officials and old-school doctors actually accused him of starting a panic in the minds of patients.How's that for distortion? Now telling the truth about the dangerous side effects of prescription drugs is being characterized as starting a panic. Apparently, Big Pharma and the FDA would much rather people be dead than panicked. After all, dead people don't ask many questions, nor do they sue drug companies for damages. Big Pharma wants to keep everybody in the dark, and the Fraud and Drug Administration is doing its best to enforce that ignorance through indimitation and deceit. There is something wickedly evil about our national pharmaceutical industry and the corruption at the FDA. When the very people trying to warn the public about the safety hazards of dangerous drugs are discredited and blamed for raising awareness, we are neck-deep in nothing less than an era of medical McCarthyism. God help us all.
from: http://www.newstarget.com/002813.html
News summary:
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Health - Canadian Press
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FDA gives whistle-blower scientist permission to publish Vioxx safety data
WASHINGTON (AP) - The U.S. Food and Drug Administration (news - web sites) has given a whistle-blower scientist permission to publish data indicating that as many as 139,000 people had heart attacks that may be linked to Vioxx, the scientist's lawyer said Monday. Dr. David Graham, who works in the FDA (news - web sites)'s office of drug safety, has said he was not allowed to publish his data questioning the safety of Vioxx, a pain medication principally used to treat osteroarthritis. Additionally, an FDA official sent email messages to the medical journal Lancet trying to persuade the journal not to publish the data.
Citing its own safety concerns, manufacturer Merck & Co. voluntarily pulled Vioxx from the market in late September.
Graham testified in November before a U.S. Senate committee that the FDA fumbled in its handling of safety concerns around Vioxx and had mishandled concerns about five other widely used drugs. He contended that the FDA has an inherent conflict of interest that triggers "denial, rejection and heat" when safety questions emerge about products it has approved.
The FDA denies the allegations, and controversy over the agency's role continues.
But the question of publication of the Vioxx data appears to be settled. The FDA told Graham Monday that he could go ahead and publish his research, which shows that 88,000 to 139,000 people have had heart attacks that could be linked to Vioxx, with 30 per cent to 40 per cent of them fatal, said Graham's lawyer, Tom Devine.
The report will be resubmitted to the Lancet, a British medical journal, which is expected to publish it, Devine said. Lancet editor Richard Horton has been sharply critical of the FDA as well.
Devine, legal director of the Government Accountability Project, said the FDA go-ahead is a positive sign.
"For the short-term at least, the FDA has decided to stop suppressing controversial research on Vioxx," he said.
Graham could not be reached for comment but Devine said of his client: "He's pleased and relieved."
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In testimony Thursday before the Senate Finance Committee, Food and Drug Administration reviewer David Graham cited Meridia, Crestor, Accutane, Bextra and Serevent. Drug makers defended the use and safety of their products.
Graham contended the country is "virtually defenseless" against a repeat of the Vioxx debacle. Dr. Steven Galson of the FDA rejected that comment as having "no basis in fact."
Merck & Co. pulled Vioxx from the market on Sept. 30 after a study indicated the popular painkiller doubled the risk of heart attacks and stroke when taken for longer than 18 months.
The committee chairman, Sen. Charles Grassley, suggested an independent board of drug safety may be needed to ensure the safety of medications after FDA approval. An "awful lot of red flags" were raised before Vioxx was withdrawn, said Grassley, R-Iowa., and the agency disdained, rather than listened to, its own reviewers.
Graham contended that FDA has an inherent conflict of interest that triggers "denial, rejection and heat" when safety questions emerge about products it has approved.
In his view, the five most worrisome drugs that demand speedy action:
Meridia, a weight-loss drug. He said the agency should consider whether its benefits outweigh the risks of higher blood pressure and stroke among people taking it. "I don't think Meridia passes that test," Graham said.
Crestor, an anti-cholesterol drug. He said the government should evaluate the occurrence of renal failure and other serious side effects among people taking Crestor. Two of three other statin competitors prevent heart attack and stroke and do not cause renal failure, he said.
Accutane, an acne drug linked to birth defects. Graham said the drug represents a 20-year "regulatory failure" by the FDA and sales should be restricted immediately.
Bextra, a painkiller. Graham said the drug poses the same heart attack and stroke risk as Vioxx. He recommended designing studies to look at the drug's cardiovascular risks.
Serevent, an asthma treatment. He said the drug was shown, with 90 percent certainty in a long-term trial in England, to cause deaths due to asthma. GlaxoSmithKline, told by the FDA to do a large, clinical trial, begged off. "We've got case reports of people dying, clutching their Serevent inhaler," Graham said. "But Serevent is still on the market."
Galson, acting director of the FDA's Center for Drug Evaluation and Research, said the agency already has taken steps to alert consumers to those drugs' safety concerns. That includes heightened warnings for Serevent; a tougher risk-management plan to ensure pregnant women don't use Accutane; and an upcoming advisory committee hearing regarding Bextra.
"Each of these do have special safety issues, but they're under evaluation and we're watching them carefully," Galson said.
Tim Lindberg, a spokesman for Abbott Laboratories, said "science continues to support the safe use of Meridia to treat obesity."
AstraZeneca PLC, maker of Crestor, has confidence in the drug, spokeswoman Emily Denney said. "To date, the FDA has not given us any indication of a major concern regarding Crestor," she said.
Carolyn Glynn, spokeswoman for Roche Holdings AG, a maker of Accutane, acknowledged that the drug carries risk and said it is reserved for serious cases. "This drug is extremely beneficial as long as it's used safely and appropriately," she said.
Susan Bro, a Pfizer spokeswoman, said Bextra did not increase the risk of serious cardiovascular events in a recent analysis of nearly 8,000 arthritis patients who took the drug from six weeks to 52 weeks. She said Bextra has been found to be safe and effective when used as indicated.
GlaxoSmithKline, maker of Serevent, issued a similar statement about its product.
In his testimony, Graham said the FDA's Office of New Drugs unrealistically maintains a drug is safe unless reviewers establish with 95 percent certainty that it is not.
That rule does not protect consumers, Graham told the Senate committee. "What it does is it protects the drug," he said.
Grassley accused the FDA of attempting to intimidate Graham. Sen. Jeff Bingaman, D-N.M., urged President Bush to name a new leader at the FDA, where Lester Crawford is the acting commissioner.
Graham said he fears continued intimidation.
"I was frightened before," he told reporters after the hearing. "Senior management at the FDA did everything in their power to intimidate me prior to my testimony," he said.
Corporate Crime Reporter
Devout Christian David Graham Details Showdown with FDA
19 Corporate Crime Reporter 1(1), January 3, 2005
David Graham said last week that his Catholic faith guided him in blowing the whistle on his employer, the Food and Drug Administration (FDA), for its failure to pull Merck’s popular painkiller Vioxx off the market.
Merck voluntarily pulled the drug off the market in September after a study it conducted showed that Vioxx doubled the risk of heart attacks.
“I’m a Catholic Christian, and though I continually fall short of modeling the Gospel in my life, I have always tried to do so,” Graham said in accepting the Joe. A. Callaway Award for Civic Courage last week in downtown Washington, D.C. “In reflecting on this award, I recall the verse from the New Testament scriptures where Jesus spoke to his disciples about service and instructed them to remember that we must remain humble, for there is no honor in doing what we were told to do.”
“To paraphrase this verse, I have done nothing more than my duty,” Graham said.
Graham is married had has six children. His wife is a lawyer who home schools her children.
During his thirty-minute acceptance speech, and a short question-and-answer period that followed, Graham portrayed his action in speaking out publically against the FDA and the drug industry as a Christian duty of conscience.
“For the past 20 years, I have worked at the FDA as a post-marketing drug safety researcher,” Graham told a group of about 65, including drug safety activists, some FDA colleagues, and members of his family gathered to witness the awards ceremony. “Education I received at the Johns Hopkins School of Medicine taught me to act in the best interests of my patients, regardless of personal cost or inconvenience. My religious faith taught me to preserve their lives to the best of my ability and to do nothing to intentionally injure or harm them. And when I became an epidemiologist at FDA, the entire nation – all 290 million people – became my patients, a responsibility I’ve taken to heart.”
Graham became something of a celebrity in Washington after going before the Senate Finance Committee and caustically ripping apart the FDA for failing to protect American consumers.
At that hearing, Graham estimated that between 88,000 and 139,000 people in the United States had suffered heart attacks or stroke as result of taking Vioxx and that as many as 40 percent of those, or about 55,000, died as a result.
But at the awards ceremony last week, he didn’t use the 55,000 number, instead at one point referring to 40,000 dead, and at another talking about 30,000 to 40,000 dead.
In any event, he stuck with his Senate testimony that the Vioxx dead represented “what may be the single greatest drug safety catastrophe in the history of this country or the history of the world.”
Graham said that had he known about “the cost and the extreme difficulty of working in an environment that routinely dismisses or twists the truth about drug safety and punishes you severely for speaking the truth, I’m certain that I would have chosen a different path.”
Graham quoted Robert Frost famous poem, Road Not Taken – “Two roads diverged in a wood, and I took the one less traveled by, And that has made all the difference.”
“In many ways, this has been a description of my career,” Graham said. “Please understand, I am not a hero and I’m not endowed with extraordinary courage, despite the honor that has been bestowed on my today. At each divergence of the roads where I faced an important decision, I can honestly say that it was conscience not courage that compelled me.”
“For me it was clear what I had to do and I set about to do that and tried not to think about what would happen afterwards,” Graham said. “Fear is the single greatest enemy of doing the right thing. It is fear that works in all of our hearts to deter us from doing what is right. To me, it is the compulsion of my conscience that overcame my human fear, and this certitude that somehow or another, things would work out for the good -- the Lord would provide for me.”
Graham said that earlier this year, he wanted to publish his study of heart attack risks of Vioxx in the peer reviewed literature, but that “the FDA reacted violently to that.”
While he was trying to convince his superiors to let him publish his study, Merck was voluntarily pulling Vioxx off the market.
“The FDA would not have pulled Vioxx off the market,” Graham said. “The FDA saw no problem with 100,000 people having heart attacks because of Vioxx.”
“The week before Vioxx came off the market, I was in a meeting with very senior people from the Office of New Drugs and my own Office of Drug Safety,” Graham said. “And the things they were saying to me was – why on earth were you studying Vioxx and heart attacks? We have no regulatory problem with this drug. We in the Office of New Drugs didn’t approve your study. We don’t want you studying that.”
“In a sense, Merck did a public service in pulling Vioxx from the market,” Graham said. “I really can’t comment on Merck’s motivations – how altruistic they were. But if you look at the evidence and literature, it is clear that prior to the marketing of these drugs – Vioxx and Celebrex – there were strong theoretical reasons why one would expect that these drugs might increase the risk of heart attack. And for that reason, FDA needs to be held accountable. FDA was fully aware of these theoretical concerns and knew also that these drugs, being in the class of drugs for pain relief – that they would be used by tens of millions of people.”
Congress became interested in the drug safety problem only after Merck pulled Vioxx off the market.
After all, Graham said – “this drug was given to 27 million people, Merck is a big company, it’s capitalization dropped 27 billion in one day.”
The three big painkillers in this class – Vioxx, Celebrex and Bextra – combined made over $4 billion in profits this year.
"And who knows how many people had heart attacks because of them?” Graham asked.
Graham told the gathering that when Senator Charles Grassley (R-Iowa) began asking questions about Vioxx, “I knew my goose was cooked.”
“They were going to have a hearing, and I would be asked to testify. I was happy to tell the truth,” Graham said. “I wasn’t so happy at the prospect of being unemployed.”
“In any event, the time came to testify,” he said. “I suppose I could have given a watered down version of the truth. But had I done that, I wouldn’t be able to live with myself, because I know that I would have done wrong. And being a physician to 290 million Americans, wouldn’t know who it was who died because I failed to speak the truth, or who ended up with a heart attack and didn’t die because I failed to speak the truth. But rest assured, there would be many of those people and I would be complicit in the injury that they suffered and the suffering that their families experienced when a loved one dies suddenly from a heart attack.”
Graham said that “in Dante’s inferno, there are levels of hell.”
“And there are levels of courage, too,” he said. “The disaster that I face, losing my job, that’s pretty terrible. I have six kids to support. Some of them are of college age. Some of them are young. And that is something to worry about. But it is not like losing your life. Go back to the Holocaust. People who risked their lives hiding Jews from the Nazis, recognizing that if they were betrayed or caught, they would have lost their lives – they didn’t have to do that. But conscience drove them to do it. It was recognizing the image of God, that we are all God’s children, we are all his sons and daughters.”
Graham said that on the weekend before his fateful testimony before Grassley’s Senate Committee, his bosses launched a three-pronged attack against his credibility.
“They contacted Senator Grassley and tried to convince him that I wasn’t worth his support, that I was a liar, that I was a cheat, that I was a bully, that I was a demagogue, that I was untrustworthy,” Graham said. “At that same time, they contacted the Government Accountability Project with the same line. They thought – maybe we can get Senator Grassley to not support him, or maybe we can get GAP not to defend him. And then let’s go for the hat trick – the editor of The Lancet. My center director contacted the editor of The Lancet and accused me of scientific misconduct.”
“Scientific misconduct is the highest crime a scientist can commit,” Graham said with a touch of bitterness. “Scientific misconduct is a betrayal of all that science stands for. Scientific misconduct, if you have committed it, is a career-ender.”
“Needless to say, it wasn’t true,” he continued. “By the end of the weekend, the editor of The Lancet had communicated to the center director that I had handled myself in the finest tradition of scientists, that there was no scientific misconduct, that there were no scientific problems with the paper and that it should be published. And the Center director agreed that it could be published.”
“It was supposed to be published on-line the day before my Senate hearing, so we would have the numbers in my testimony. The 100,000 heart attack number would be in The Lancet before the testimony – it would have scientific credibility. But my managers set a trap – so that if I allowed it to be published, they could fire me. So, I was forced to withdraw the article from publication on the eve of its publication.”
“I was still able to give my testimony. But that weekend, when I was supposed to be writing my testimony, was shattered by having to deal with this three-pronged attack. Fortunately, I was able to put together the testimony. I had no idea that the testimony that I gave would attract the attention that it did. I had no intention when I testified to become a public figure, but your face is plastered in the newspapers and this is what happens.”
Graham confided to the group that “my Scottish terrier bit part of my nose off on the left side.”
“The nose that you see here is the result of reconstructive surgery,” Graham said. “I need to let my plastic surgeon know that most of the photographs have been coming from the left side and nobody has commented on how bad a job he did. So, I think he must have done a pretty good job. By the way, the dog is still a happy member of the family. He is forgiven. But he is minus some androgen-producing glands.”
It became clear from listening to Graham’s talk that he blames the FDA, not the drug companies, for the drug safety problems afflicting the country.
“On 911, 3,000 people died,” Graham said. “With Vioxx, ten to fifteen times that number died, but it didn’t happen one at a time – maybe on your street, maybe on my street, maybe lasitional 60,000 people had non-fatal heart attacks, one at a time. It happens below the radar screen. But it is a national catastrophe nonetheless. The FDA and FDA alone is responsible for it”
“It is not the fault of the drug companies,” he said. “We’ll let the courts decide what their liability is. For me, I can focus on FDA. FDA had a sacred trust, it betrayed that trust, it betrayed the American people. One hundred thousand people paid a high price for that just with Vioxx. I don’t know how many have paid that price with Bextra, with Celebrex, with any of the other drugs that FDA took too long to withdraw from the market.”
Graham said that the big drug companies “have been lobbying like crazy” in recent weeks to prevent Congress from reorganizing the FDA.
“The last thing on earth drug companies want to see is strong post-marketing drug safety because if there is strong post-marketing drug safety, it is going to cost companies more money to research the drugs before they get to market, and they are going to run the risks of a drug being removed from the market,” he said.
Under current federal law, the FDA must guarantee that drugs are safe and effective.
Graham said that the FDA requires that drug companies prove that they are “at least 95 percent certain that this drug has an effect – it lowers you blood pressure, it lowers your cholesterol, it lowers your blood sugar – we are 95 percent confident it does that.”
But when it comes to safety, the FDA takes that statistical model and turns it on its head, Graham said.
“Rather than saying – we are 95 percent certain that the drug is safe to a given level, they say – we are not 95 percent certain that it will kill, so I guess it doesn’t. And the FDA gives that drug a free pass.”
Graham also called for strong job protection for government workers who, like himself “commit the truth.”
Graham said that a recent FDA Office of Inspector General survey found that two-thirds of FDA medical officers are not confident that the products that are approved are safe and that 18 percent felt that they have been pressured to change their conclusions.
“I can guarantee you, there are other whistleblowers at FDA,” Graham said. “There are many whistleblowers at FDA. Fear has them by the throat. And they struggle with their conscience and they struggle with the wrong that they see, and they are paralyzed by their fear. And they are looking to see – can that Graham fellow get away with committing the truth?”
“It remains to be seen whether I can get away with committing the truth,” he said. “But it shouldn’t be that way.”
The Joe A. Callaway award was established to recognize individuals in any area of endeavor who, with integrity and at some personal risk, take a public stand to advance truth and justice, and who challenge unsatisfactory conditions in pursuit of the common good.
The award was also given this year to Mark Livingston, a pharmaceutical quality control specialist who was involved in the launching of Wyeth Pharmaceuticals’ Prevnar pediatric vaccine.
In the fall of 2003, Livingston filed a lawsuit in federal court alleging that Wyeth Pharmaceuticals compromised the manufacturing process of bulk vaccine to meet demand.
Corporate Crime Reporter
1209 National Press Bldg.
Washington, D.C. 20045
202.737.1680
from: http://www.forbes.com/2004/12/13/cx_mh_1213faceoftheyear.html
The drug, Deramaxx, is a COX-2 inhibitor approved for relieving arthritis and post-surgical pain in dogs.
Similar drugs for people are under heavy scrutiny after studies associated them with heart attacks and strokes. One of the drugs, Merck & Co Inc.'s Vioxx, was pulled from the market because of safety risks.
Death has been reported "in rare situations" when dogs were treated with Deramaxx, according to the drug's label instructions.
The Food and Drug Administration, in a warning letter dated Nov. 29, said Novartis Animal Health Services should have forwarded complaints about deaths and health problems in dogs given Deramaxx within 15 working days, but in some cases delayed as long as 10 months. Some reports, including ones involving deaths, appeared to have incorrect dates, the FDA said.
"Novartis failed to submit timely and accurate information to the FDA regarding serious (adverse drug experiences) associated with the administration of its FDA-approved animal drug product Deramaxx ... during its first year of marketing," the FDA said.
The company also failed to submit proper information about post-approval studies of Deramaxx, the FDA charged. The drug is known generically as deracoxib.
Novartis officials could not immediately be reached for comment.
The FDA sends dozens of warning letters per year. Most of the issues raised are resolved without further regulatory action, although the letters sometimes lead to tougher steps such as product seizures.
The warning letter to Novartis is posted on the FDA Web site at http:/www.fda.gov/foi/warning_letters/g5108d.pdf
DEPARTMENT OF HEAILTH AND HUMAN SERVICES
& Food and Drug Admiaktrrtlon
Atlanta District Office
68 8th Street, NJL
Atlanta, Geargia 30309
November 29,2004
VIA FEDERAL EXPRESS
George Gunn, Global Head
Novartis Animal Health Services AG
Werk Rosental
Schwarzwaldafiee 215
WRO-132.550
CH-4058 Basei
Switzerland
Dear Mr. Gunn:
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 Tie 21, Code of Federal Regulations (21 CFR), Sections (@) 510.300 {effective prior to June 30,2003) and 514.80 (effective on June 30, 2003). Upon the conclusion of the inspection on January 23, 2004, a Form FDA 483 - Inspectional Observations (FDA 483) was issued to and discussed with Dr. Guy L. Tebbi, Vice President, Regulatory Affairs. In addition, as noted below, a number of similar deviations have occurred since the FDA 483 was issued. For example, you sent a letter on September 29, 2004, submitting two late ADEs and describing corrective actions Novartis has taken as a result.
The primary purpose of the inspectjon was to determine Novartis’ compliance with the ADE reporting requirements of the Act and its regulations. The inspection included, but was not limited to, a review of Novartis’ ADE reports for lack of expected effectiieness (LOE) complaints concerning your heartworm prescription drug products Interceptor@ and Sentinel@ for ail marketing years subsequent to their approval.
The Form FDA 1932 “Veterinary Adverse Drug Reaction, Lack of Effectiveness,
Product Defect Report” (FDA 1932) is used to report ADEs and product/manufacturing defects. 21 CFR QQ 514.80(b)(l), (b)(2), and (b)(rl)(iv). ADEs include, among other events, LOEs and ADEs occurring in humans from exposure during manufacture, testing, handling, or use, 21 CFR § 514.3.
The inspection disclosed significant deviations from the applicable requirements of the Act and regulations. Upon its conclusion on January 23, 2004, a Form FDA 483 - Inspectional Observations (FDA 483) was issued to and discussed with Dr. Guy L. Tebbit, Vice President, Regulatory Affairs. A copy of the FDA 483 is enclosed for your review.
We would like to point out to you that in item # 1 of the FDA 483 we made reference to Case # US209302009. Upon further review, we have determined that this incident was reported appropriately to the FDA and should not have been induded in the FDA 483. We apologize for any confusion caused by this inadvertent error.
We acknowledge the receipt of several pieces of correspondence from Novartis
containing responses to the inspectional observations found in the FDA 483. Your
responses were dated as follows: February 4, 2004; February 25, 2004; an undated letter from Dr. Tebbi (possibiy April l&2004); April 19.2004; April 23,2004; and June 3,2004. We will address some of our concerns with those responses in the discussion that follows.
Based on our evaluation of the information obtained during the course of the inspection, the documentation related to Novartis’ ADE reports submitted to FDA over the last six (6) years, and Novartis’ written responses foliowing the inspection, we have determined that your firm has failed to comply with the ME reporting requirements of Section 512(l) of the Act and 21 CFR 99 510.300 (effectiie prior to June 30,2003) and 514.80 (effective on June 30,2003).
The violations include, but are not limited to, the foilowing areas: Problems associated with your renortina wactkes of ADEs:
Novartis failed to submit timely and accutite information to the FDA regarding serious ADEs associated with the administration of its FDA approved animal drug product Derarnaxx” (Deraooxib), 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 signHicant 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 IQ, 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, tha 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 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 6 514.80(b)(2)(I). This informatbn should have been promptly mported 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 (Voltime 1, page 650) does not identify how your fmn witl 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 tt~at you firm has also invoke 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 fetters. 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 21,204.
Problems associated with VOW rmxtinu m@lees of ADEs related TV
exmrlmental studies: Vour firm failed to submit timely informatiin 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 5 510.300(a)(l) (effective prior to June 30,2003 and 514.8O(b)(4)(111) (effective on June 30, 2003). Our investigators identified over e 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 fkst receiving the information, as required by 21 CfR Q 510.300(b)(2)(1) (effectiie ptior to June 30, 2003) and 514.80(b)(2)(i) (effective on June 30,2003).
One study involving Demmaxx” (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 AD&. These ADEs were not reported to the FDA within the required 15 working days titneframet, but were reported only after the conclusion of the inspection of y~~ut facility, on February 24,2004.
Atthough your submission dated February 24,2004, indicates that it was Novartis’ intent to disclose the safety information fmm the cat study, your firm failed to diidose this information from other studies found in the master study Ilst.
For example, a protocol entiied The Acute Safety Study of an Injectable Deracoxib (SD-8746) Formulation In Dogs” was submitted to the FDA under the INADA 010-885 on April 15, 2002. Thll was approximately three months after the master study list indicates the pilot study was ckmpleted. The study dlnical 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 15day ADEs in post approval studies as drug
experiences. But your response does not darify 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 6 514.8O(b)(4)(iv)(C).
Problems associated with VOW remrtina ~racdces of human exDo%ure ADEs:
ClomicalmQD (Clomipramine Hydrochloride), NADA 141-120, has the potential for
human abuse and carries the following human warning statement on its label:
Human S&b@ ReMva to PossessJon, Handling and Administtatton: uNot fbr use In humans. Keep out of lleach of chiltin. In case of accidental Ingestion seek medical attentlan Immediately. In childmn, accIdenta ingestion should be
regarded as serious. There is no specific antidote for clomlpramine. Overdose In humans causes antichollnerglc Mbcts including el%Hs on the central
nervous (e.g. convularions) and ca~lovascular (e.g. arrhythmias, tachycaWa) systems. People with known hypersensM&y to clomlprsmne should administer the
prroduct with caution. s Our review of your submissions involving human adverse experience events for Clomicalm@ since April 23.2004, indicates that your firm should improve its reporting of follow-up information. All adverse drug events that are on the 1!5day report must be promptly investigated and significant new information must be reported to FDA within 15 working days of receiving such information. 21 CFR Q 514.80(b)(2)(ii). For example, significant new information would include instances where humans experienced any Side effects from taking this dnrg.
Neither this fetter nor the FDA 483 which was issued to and discussed with Dr. Tebbit is intended to be an all-inclusive list of deficiencies at your firm. It is your responsibility to ensure adherence to each requirement of the Act and its regulations. The specific violations noted in this letter are serious and may be symptomatic of serious underlying problems. You should take prompt action to correct these d8fiCi8ndeS. Failure to promptly correct these deviations may result in regulatory action without further notice. These actions may indude, 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. [WHAT CONTRACTS?]
We request that you rep& in writing within fifteen (15) working days of receipt of this letter describing the corrective actions you have implemented, or are ptanning to implement, to prevent a recurrence of the violations noted above. Please indude
copies of any available documentation demonstrating that correcths have been made.
If corrective actions cannot be comp~qted within ffie8n (15) working days, stat8 th8 reason for the delay and the time within which the con-&ions will be completed.
Your written response and any pertinent documentation should be addressed to Philip S. Campbell, Compliance Officer, at the address noted in the letterhead.
Sincerely yours, ,
Mary H. Woleske
District Director
Atlanta District
Enclosure
* * * * * * *
COMMENT/NOTE: The above FDA letter to Novartis was downloaded in the ".pdf" format just as it appeared above, other than the highlighted areas, which may or may not have appeared in the original on-line and my own comment(s) written in red and bracketed. While it is only my personal opinion, it appears to me that Dr. Graham's "exposure" of the FDA's sloppy attitude, indifference to life and "coziness" with the drug industry, via the current Senate investigative hearings, is setting many a rat scurrying to protect their own heinies, "clues" being provided by the yellow highlighting.
In testimony Thursday before the Senate Finance Committee, Food and Drug Administration reviewer David Graham cited Meridia, Crestor, Accutane, Bextra and Serevent. Drug makers defended the use and safety of their products.
Graham contended the country is "virtually defenseless" against a repeat of the Vioxx debacle. Dr. Steven Galson of the FDA rejected that comment as having "no basis in fact."
Merck & Co. pulled Vioxx from the market on Sept. 30 after a study indicated the popular painkiller doubled the risk of heart attacks and stroke when taken for longer than 18 months.
The committee chairman, Sen. Charles Grassley, suggested an independent board of drug safety may be needed to ensure the safety of medications after FDA approval. An "awful lot of red flags" were raised before Vioxx was withdrawn, said Grassley, R-Iowa., and the agency disdained, rather than listened to, its own reviewers.
Graham contended that FDA has an inherent conflict of interest that triggers "denial, rejection and heat" when safety questions emerge about products it has approved.
In his view, the five most worrisome drugs that demand speedy action:
Meridia, a weight-loss drug. He said the agency should consider whether its benefits outweigh the risks of higher blood pressure and stroke among people taking it. "I don't think Meridia passes that test," Graham said.
Crestor, an anti-cholesterol drug. He said the government should evaluate the occurrence of renal failure and other serious side effects among people taking Crestor. Two of three other statin competitors prevent heart attack and stroke and do not cause renal failure, he said.
Accutane, an acne drug linked to birth defects. Graham said the drug represents a 20-year "regulatory failure" by the FDA and sales should be restricted immediately.
Bextra, a painkiller. Graham said the drug poses the same heart attack and stroke risk as Vioxx. He recommended designing studies to look at the drug's cardiovascular risks.
Serevent, an asthma treatment. He said the drug was shown, with 90 percent certainty in a long-term trial in England, to cause deaths due to asthma. GlaxoSmithKline, told by the FDA to do a large, clinical trial, begged off. "We've got case reports of people dying, clutching their Serevent inhaler," Graham said. "But Serevent is still on the market."
Galson, acting director of the FDA's Center for Drug Evaluation and Research, said the agency already has taken steps to alert consumers to those drugs' safety concerns. That includes heightened warnings for Serevent; a tougher risk-management plan to ensure pregnant women don't use Accutane; and an upcoming advisory committee hearing regarding Bextra.
"Each of these do have special safety issues, but they're under evaluation and we're watching them carefully," Galson said.
Tim Lindberg, a spokesman for Abbott Laboratories, said "science continues to support the safe use of Meridia to treat obesity."
AstraZeneca PLC, maker of Crestor, has confidence in the drug, spokeswoman Emily Denney said. "To date, the FDA has not given us any indication of a major concern regarding Crestor," she said.
Carolyn Glynn, spokeswoman for Roche Holdings AG, a maker of Accutane, acknowledged that the drug carries risk and said it is reserved for serious cases. "This drug is extremely beneficial as long as it's used safely and appropriately," she said.
Susan Bro, a Pfizer spokeswoman, said Bextra did not increase the risk of serious cardiovascular events in a recent analysis of nearly 8,000 arthritis patients who took the drug from six weeks to 52 weeks. She said Bextra has been found to be safe and effective when used as indicated.
GlaxoSmithKline, maker of Serevent, issued a similar statement about its product.
In his testimony, Graham said the FDA's Office of New Drugs unrealistically maintains a drug is safe unless reviewers establish with 95 percent certainty that it is not.
That rule does not protect consumers, Graham told the Senate committee. "What it does is it protects the drug," he said.
Grassley accused the FDA of attempting to intimidate Graham. Sen. Jeff Bingaman, D-N.M., urged President Bush to name a new leader at the FDA, where Lester Crawford is the acting commissioner.
Graham said he fears continued intimidation.
"I was frightened before," he told reporters after the hearing. "Senior management at the FDA did everything in their power to intimidate me prior to my testimony," he said.
May my beloved partner ROMI rest in peace - no matter wherever her bits and pieces/frozen carcass may be held hostage.
[what's in YOUR "urn" ?]
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