Evelyn Pringle
A little over a year after the Volkow study reported that Provigil (modafinil), affects the same brain chemicals as stimulants and may be addictive, on July 20, 2010, in the Atlanta Science News Examiner, Kevin Murnane reported that research showed modafinil "produces some effects that are similar to abused stimulants, such as cocaine."
In what may turn out to be the final nail in the modafinil coffin, rhesus monkeys were given modafinil prior to undergoing behavioral, neurochemical, and brain imaging studies for a study led by Monica Andersen, conducted at the Yerkes National Primate Research Center at Emory University, in the June 2010, "Psychopharmacology" journal.
"Similar to other stimulants, these researchers found that modafinil increased movement or locomotion in their subjects," Murnane wrote. "Furthermore, an acute bolus of modafinil elicited a return or reinstatement of cocaine self-administration that had been previously diminished through extinction training."
"These behavioral effects are very consistent with those of other stimulant-type drugs," he reported.
Mechanistically, the researchers found "using Positron Emission Tomography (PET) imaging that modafinil bound to and occupied a protein in the brain called the dopamine transporter," he explained. "This protein is the same one that cocaine binds to."
"Furthermore, they found that modafinil increased dopamine neurotransmission," Murnane said. "This is the same mechanism thought to mediate the euphoric and addictive properties of cocaine."
He pointed out that the findings "closely paralleled those of a study by Volkow and colleagues in human subjects that was published in the March 2009 issue of the Journal of the American Medical Association."
"Collectively, these studies show that modafinil has similar behavioral and pharmacological effects to stimulant-type drugs of abuse, such as cocaine," he wrote.
"These data indicate that modafinil has the potential to be abused or produce dependence," Murnane said. "Accordingly, closer monitoring of the modafinil supply and abuse patterns may be warranted."
In June 2010, when the European Medicines Agency recommended restricting the use of modafinil for the treatment of narcolepsy only, on Pharmalot, Ed Silverman said the issue to watch was what this meant for Cephalon’s Nuvigil. For the moment, EMA may have given Cephalon a boost, "especially since the FDA keeps delaying approval to use Nuvigil for jet-lag disorder and studies for other indications have either flopped or will take quite awhile to complete," he wrote.
"A similar step to restrict Nuvigil, of course, would make it harder to broaden the Nuvigil market," he pointed out, and noted that the drug's label states: "Psychiatric adverse experiences have been reported in patients treated with modafinil. Modafinil and armodafinil (NUVIGIL) are very closely related. Therefore, the incidence and type of psychiatric symptoms associated with armodafinil are expected to be similar to the incidence and type of these events with modafinil."
However, the Frazer, Pennsylvania-based firm's Annual Report for 2009, does not show Nuvigil as approved for use in any other country besides the US.
Unprecedented Price Gouging
On November 18, 2008, Pharmalot reported that Cephalon had raised the price on Provigil by 28% since March 2008. The drug was then 74% more expensive than four years earlier, with an average wholesale price of $8.71 per pill.
The price hikes were in preparation for the expected launch of Nuvigil in 2009. By sharply raising prices, Cephalon hoped to convert patients to Nuvigil before cheap generic versions of Provigil came on the market.
A year later, Dow Jones reported that in November 2009, Cephalon had raised the price on Provigil by 29%, to $13.62 a pill, and that the cost of Nuvigil, launched in June 2009, with patent protection until 2023, was $8.98 per tablet. Five years earlier, "Provigil's cost was $5.53 per pill," Dow Jones noted on December 22, 2009.
Nuvigil Launch
In launching Nuvigil, in addition to promotional efforts in the field, Cephalon "initiated patient sampling programs, discount programs for patients, a significant number of key opinion leader/speaker presentations, and a contracting plan with certain health care payers," Bob Roche, of Cephalon's Worldwide Pharmaceutical Operations, said in an August 4, 2009 Earnings Call, posted by "Seeking Alpha."
Sampling programs included regular distribution of samples to doctors and a free 7-day coupon for patients to print out from an online website.
Cephalon also implemented a "Co-Pay Assistance Program," which provides up to $50 of co-pay assistance per prescription. "To make things easier for patients, this program is administered automatically in many pharmacies, making co-pay assistance coupons or cards unnecessary," Roche said.
However, patients covered by government plans like Medicare and Medicaid do not qualify for the co-pay assistance, CEO, Frank Baldino, pointed out in the call.
Cephalon also developed a data base of approximately 50,000 individuals who requested information on Nuvigil and mailed "these people a launch kit, with a free seven-day coupon and information on our Co-Pay Assistance Program," he said.
The company also planned to implement an online, "Wake Information Support and Education Program," as part of a professional education and support campaign designed for doctors in the sleep/wake field, Roche reported. "In addition to information on sleep and wakefulness issues, physicians can, with just a click of a mouse get information on NUVIGIL, order samples, request coupons, ask questions, or request to see a sales representative," he explained.
In the first quarter of 2010, Cephalon also launched a Nuvigil shift work disorder campaign. There are "15 million shift workers in the United States and approximately 1/3 of them suffer from excessive sleepiness associated with shift work disorder," Baldino reported in a May 4, 2010 Earnings Call.
A non-branded radio campaign was launched "in select markets where shift work is a significant part of the working population," said Robert Repella in the call. We "expect to see the benefits coming out of that as we move through the year.”
Cephalon also started a program with WebMD in the first quarter, he said. We've had "over 7 million visits to their website related to either NUVIGIL or disease area content.”
Today it's doubtful that shift workers in the US make enough money to pay for Provigil or Nuvigil. In August 2010, one hundred 250mg tablets of Nuvigil cost $1,080, or $10.80 per tablet, and the price for 100 tablets of 200mg of Provigil was $1,855, or $18.55 per pill, at DrugStore.com.
If generic Provigil was to hit the market, patients who converted to Nuvigil would likely be pressured by payers to switch back to a cheaper Provigil generic. In the meantime, the same drug, sold as Modalert, can currently be purchased online from other countries for as low as $120 per hundred, at EuroDrugstore.
Off-Label Marketing Schemes
Back on November 8, 2007, Ed Silverman’s Pharmalot reported that Cephalon had struck a deal with the US Attorney in Philadelphia to pay $425 million to settle off-label marketing charges. He noted that the settlement was no surprise because the firm had been under a microscope for off-label marketing for some time and had received an FDA warning letter in February 2007, ordering an end to promotional materials claiming Provigil could be used to treat fatigue.
The underlying lawsuits were filed in 2003, by three former employees, Bruce Boise, Michael Makalusky, and Lucia Paccione, and another whistleblower, Joseph Piacentile, in federal court in the Eastern District of Pennsylvania, under the False Claims Act, arising from false claims submitted to Medicaid, Medicare and other federal insurance programs that do not provide coverage for such off-label uses.
About six months after the settlement became known, on April 30, 2008, Cephalon announced the hiring of Gerald Pappert, former Attorney General of Pennsylvania, as Executive Vice President and General Counsel. Pappert was First Deputy Attorney General from 1997 to 2003 and Attorney General from 2003 to 2005.
When he took over as attorney general, Pappert "launched a vigorous fight to lower the cost of prescription drugs for Pennsylvanians," the AG’s website states.
"I will ensure that prescription drugs are priced fairly, and I will take action against those who defraud our Commonwealth programs or cheat us through illegal pricing and other schemes," he promised, after being sworn into office in February 2004.
The same month, Pappert was appointed to the Pharmaceutical Pricing and Prescription Drug Abuse task forces, of the National Association of Attorneys General, "which were formed to ensure that pharmaceuticals are priced fairly and to prevent the illegal use and sale of prescription drugs, respectively," according to February 4, 2004 press release.
In May 2004, Pappert reported that Cephalon's Actiq, a narcotic lollipop, was showing up in illegal sales in Philadelphia under the street nickname "perc-o-pops," according to the September 30, 2008 Philadelphia Inquirer.
In September 2004, the US attorney in Philadelphia subpoenaed documents about Cephalon's sales and marketing of Actiq, Provigil, and Gabitril, an epilepsy drug, the Inquirer reported
During his tenure in Harrisburg, Pappert filed a lawsuit accusing 13 drug companies of price-fixing in March 2004. "As Attorney General, I am committed to doing everything I can to reduce the price of prescription drugs for the Commonwealth and its citizens," he said, in a March 10, press release on the suit.
He explained that many consumers purchase drugs, either by themselves or through a health plan or insurer, and "are financially harmed when drug companies intentionally raise the prices of their drugs to manipulate the market.”
In part, the lawsuit accused the companies of "the widespread practice of offering trips, consulting opportunities, seminars, gifts, meals and cash payments to medical providers in return for prescribing their products," the press release noted.
"Several of the companies named in my lawsuit," Pappert wrote in a March 19, 2004, Oped, "have already pled guilty to and/or agreed to settle federal charges of having engaged in unlawful marketing and sales practices with respect to certain of their prescription drugs."
"These companies have already paid more than $1 billion in fines and civil penalties to the federal government," he pointed out.
"My pharmaceutical industry lawsuit focuses on the pricing practices, which I believe are clearly illegal," he told Insider. "If we ultimately succeed, it is going to change the way the industry prices pharmaceuticals, and stop the prices from continuing to skyrocket, and reduce prices."
About five months after Pappert went to work for Cephalon, on September 29, 2008, the US Department of Justice announced that the firm would enter a criminal plea to one count of "Distribution of Misbranded Drugs," and pay $425 million to settle federal and state charges and resolve allegations that it marketed three drugs, Provigil, Actiq and Gabitril, for unapproved uses.
Pappert signed off on the agreement as Executive VP and General Counsel of Cephalon.
The government's investigation began in January 2003, when Bruce Boise, a sales representative in Ohio, contacted the FDA about Cephalon's sales practices. Boise agreed to wear a wire to a company sales conference to help the government gather evidence, according to his attorney, Peter Chatfield, in a September 29, 2008 press release by his firm, Phillips & Cohen. In November 2003, another sales rep, Lucia Paccione of Philadelphia, filed the first lawsuit. The complaints remained sealed until the settlement was announced.
"What makes this case unique is that it's the first time, in the absence of substantial kickbacks, that the federal government has used the False Claims Act to go after a pharmaceutical company for marketing drugs for off-label indications for which there were no credible published scientific research supporting these drugs' safety or effectiveness," Chatfield said. "Not only were these uses marketed by Cephalon not approved by the FDA, there was absolutely no literature published in any medical compendia that supported them."
While federally funded healthcare programs "often will pay for off-label use of drugs supported by credible medical research and prescribed based on the medical judgment of physicians, Cephalon's marketing efforts pushed well beyond those constraints," according to the press release.
From 2001 through 2006, "Cephalon improperly promoted Provigil to treat sleepiness, tiredness, decreased activity, lack of energy and fatigue," the DOJ sentencing memorandum reports.
"Cephalon continued its illegal promotional activities after January 2002, when the FDA specifically directed the company to stop promoting Provigil for off-label uses," it states. For instance, in November 2002, a Cephalon manager accompanying a sales representative on calls to physicians, told the sales person: "Your best call of the day was with Dr. [a psychiatrist] ... Informing the physician of the transition that we have made with Provigil from narcolepsy to the variety of areas in which it is currently being used was also effective."
"Cephalon had its sales representatives call on doctors who would not normally
prescribe the defendant’s drugs in the course of the doctors’ practice," DOJ states. In fact, during a February 15, 2007 program, ABC's "20/20," revealed a copy of a sales report that showed allergists, internists, pediatricians and even dentists were prescribing Provigil off-label to people with depression, MS, hyperactivity and cancer.
Celaphon marketed directly to psychiatrists after concluding that they respond to a "lower threshold of scientific proof" than other doctors. "In other words, Cephalon targeted physicians that would least object to their promoting Provigil for uses with little clinical support," says a September 29, 2008 press release by Connecticut's attorney general.
In December 2002, Cephalon sought to expand Provigil’s label to cover excessive sleepiness, without regard to the patient’s underlying medical condition. However, in January 2004, the FDA approved only a narrow expansion for excessive sleepiness associated with obstructive sleep apnea and shift work sleep disorder.
Harvard professor, Dr Charles Czeisler, chief of sleep medicine at Brigham and Women's Hospital, was lead investigator in the shift-worker study, which showed Provigil kept participants awake 1.7 minutes longer than a placebo. In September 2003, Czeisler went before the FDA to lobby for approval to treat shift-workers on behalf of Cephalon.
The FDA formally approved it for shift work disorder on January 23, 2004. Less than four months later, on May 21, 2004, Science Magazine reported that Cephalon was providing $2.75 million to fund an endowed chair at Harvard Medical School to be named after Cephalon's founder and CEO, Frank Baldino, and that Czeisler would hold the chair. Baldino was also on the advisory board of Harvard, Science noted.
Czeisler published a paper in the August 2005, "New England Journal of Medicine," and claimed night-shift workers remained more alert with Provigil. "I would characterize [Provigil] as the treatment of choice with patients with shift-work disorder," he said.
However, in an editorial in the same issue, Dr Robert Basner, director of Columbia University's Cardiopulmonary Sleep and Ventilatory Disorders Center, said the researchers' data showed only slight improvements in workers wakefulness and productivity with Provigil, and the drug seemed to exacerbate insomnia for some patients.
"That's not a very robust endorsement of the drug coming from the investigators themselves," Basner wrote. "This drug is little better than nothing in terms of making them less sleepy during shift work at night.”
For the February 2007 program, "20/20" wanted to find out how well Provigil worked in studies not funded by Cephalon, which led them to the sleep labs of the US Army and research psychologist, Nancy Wesensten, who studies drugs to help soldiers stay awake.
In studying Provigil for the army, Wesensten compared it to caffeine in terms of how well soldiers performed on tests, how alert they were, and side effects. "In our hands, at the dosages we tested, modafinil did not work any better than caffeine," she told 20/20.
Cephalon arranged for "case studies to drive growth for off-label uses such as multiple sclerosis, adult ADD and depression," the DOJ press release charges. And in fact, a literature review, by Dr Jacob Ballon and Dr David Feifel, for an April 2006 paper in the "Journal of Clinical Psychiatry," was conducted on PubMed, with the search term modafinil OR Provigil, and shows a total of 397 articles for on and off-label uses.
"Cephalon employed sales representatives and retained medical professionals to speak to doctors about off-label uses," the press release said. "The company funded continuing medical education programs, through millions of dollars in grants, to promote off-label uses of its drugs."
"Cephalon sent doctors to “consultant” meetings at lavish resorts to hear the company’s off-label message," the DOJ reports. According to a Cephalon document, these meetings "proved incredibly effective in driving prescription growth among the attendees," the memo notes.
"Cephalon trained its sales representatives on techniques to prompt the doctors into
off-label conversations," and "had its sales representatives tell doctors how to document their off-label uses of drugs to get these uses paid by insurers, who often will not pay for off-label uses," the DOJ reports.
The drug maker "also structured its sales quota and bonuses in such a way that sales representatives could only reach their sales goals if they promoted and sold the drugs for off-label uses," the press release notes.
According to the sentencing memo, for over six years, the very top levels of the company knew and approved of these efforts.
Cephalon’s sales reports show the success of the off-label campaigns, with Provigil sales rising from $146 million in 2001, to $691 million in 2006, to more than $850 million in 2007. Sales increased more than a 1,000% from 2000 to 2007, according to Connecticut's attorney general and the government found more than 80% were for off-label use.
It's difficult to see where the off-label marketing has ended because Provigil profits have never fallen. SEC filings show sales of the drug exceeded $988 million in 2008, the year the settlement agreement was signed, roughly $138 million more than 2007.
In 2009, Provigil sales topped the billion dollar mark, and Nuvigil earned $73,391 million. Combined, these two products had an 11% increase in sales over 2008, and made up 51% of Cephalon's total net sales for 2009.
With a doubling of Provigil sales in the first 6 months of 2010, totaling $547,281 million, sales could potentially beat the record set in 2009. In comparison, sales in first 6 months of 2009 were only $515,430 million. Nuvigil had sales of, $75,890 million in the first 6 months of 2010, compared to $16,786 million in the first 6 months of 2009.
Since the launch of Nuvigil on June 1, 2009, Cephalon has been aiming at approvals for additional indications, including people with jet lag and traumatic brain injury, as well as adjunctive therapy for schizophrenia and bipolar disorder, and fatigue associated with cancer treatment. "We expect NUVIGIL to be a much bigger drug than PROVIGIL ever was in a long run," CEO, Baldino, said in a February 11, 2010 Earnings Call.
However, in March 2010, the FDA nixed approval for jet lag, which Cephalon was counting on because it would have allowed sales reps to hit virtually every kind of physician that might treat jet lag, instead of only doctors who treat sleep disorders, according to market analysts.
In the last week of June, Cephalon filed a formal response to the FDA's non-approval. The FDA “classified the response as a class two resubmission requiring a six-month review with a PDUFA date of December 30,” Baldino said in a July 27, Earnings Call.
Also, in June 2010, the results for a study of Nuvigil, in conjunction with antipsychotics, for schizophrenia showed the drug failed to meet its primary endpoint, and in the July 27, Earnings Call, Dr Lesley Russell, Cephalon's Chief Medical Officer, said the company had “decided not to move forward with cancer related to fatigue for NUVIGIL.”
Hammered Again in Court
On the same day that the FDA refused approval of Nuvigil for jet lag, a federal judge refused to dismiss the antitrust lawsuits filed against Cephalon by the Federal Trade Commission and others.
In 2005 and 2006, Cephalon entered into settlements with the generic drug makers, Barr, Mylan, Teva, and Ranbaxy, and agreed to pay the four companies a combined total of more than $200 million, in return for agreements that would keep generic versions of Provigil from coming on the market until April 2012, instead of 2008.
In March 2006, when announcing the settlements, CEO Baldino told the Philadelphia Business Journal: "We were able to get six more years of patent protection. That's $4 billion in sales that no one expected."
Later in 2006, a class of direct purchasers (such as health plans and pharmacies) filed a lawsuit against Cephalon and the generic companies, followed soon after by a class of end-payers of Provigil, and Apotex, another generic firm. They all alleged that Cephalon, and the generic makers were engaged in anticompetitive conduct in violation of the Sherman Antitrust Act.
Pay-For-Delay Deals
The so-called "pay-for-delay" agreements (also known as "reverse payments") are settlements of patent litigation in which a brand-name company pays a potential generic competitor to abandon a patent challenge and delay entering the market with a generic.
Brand-name companies "can delay generic competition that lowers prices by agreeing to pay a generic competitor to hold its competing product off the market for a certain period of time," the FTC explained in a January 2010 report titled, "Pay-for-Delay: How Drug Company Pay-Offs Cost Consumers Billions," which summarized the savings lost to US consumers through such deals during the previous six years.
The FTC found the number of pay-for-delay agreements had increased from none in 2004, to a record 19 in the fiscal year of 2009. On average, these agreements precluded generic entry for 48 months, the agency reports.
Most of the deals reached since 2005 were still in effect, and were protecting at least $20 billion in brand-name sales from generic competition. "These sweetheart deals are being done on the backs of consumers," FTC chairman, Jon Leibowitz, told the New York Times in January 2010. "From the perspective of the Federal Trade Commission, these deals are one of the worst abuses across the board in health care and should be stopped.”
The FTC estimates the agreements currently cost American consumers $3.5 billion a year in higher prescription costs when they miss out on generic prices that can be as much as "90 percent less than brand prices," according to the study.
"Based on a preliminary analysis, already, in the first nine months of FY 2010, there have been more brand-generic settlements involving some sort of compensation - 21 - than in any prior full fiscal year," Leibowitz reported in July 27, 2010 testimony before the House Judiciary Subcommittee on Courts and Competition Policy.
Those settlements protect $9 billion in drug sales from generic competition. "That’s almost an epidemic," he told lawmakers, "and left untreated, these types of settlements will continue to insulate more and more drugs from competition."
The FTC joined the Cephalon antitrust litigation on February 13, 2008, by filing a lawsuit against Cephalon, but not the generics makers, alleging violations of the Federal Trade Commission Act. Cephalon’s anticompetitive scheme "denies patients access to lower-cost, generic versions of Provigil and forces consumers and other purchasers to pay hundreds of millions of dollars a year more for Provigil," the agency stated in a press release the same day.
On March 29, 2010, a federal judge in Philadelphia denied a defense motion to dismiss the FTC’s case (and related cases) against Cephalon. The case is now in the discovery phase, according to the FTC. However, nobody better look for a resolution and cheap generic Provigil anytime soon because Cephalon has every intention of dragging out this litigation as long as possible and is geared up for round two of delay and motion filing.
In a May 4, 2010 Earnings Call, George Pappert, the former champion of lower drug prices for citizens of Pennsylvania, informed listeners that the discovery process "will take us to roughly the middle of 2011."
"And then we will be filing our dispositive motions, our motions for summary judgment," he said. "I believe the court has a schedule set for July of 2011, and then the court will consider those motions at that time."
Being the first batch of motions took years to resolve, generic Provigil will likely enter the market in 2012, exactly as specified in the pay-for-delay deals, and long before the litigation ends. Providing the drug is still allowed to be sold at all that is.
(Evelyn Pringle is an investigative journalist focused on exposing corruption in government and corporate America)
Tuesday, September 21, 2010
The Rise and Fall of Provigil – Part I
Evelyn Pringle
On July 22, 2010, the European Medicines Agency recommended restricting the use of modafinil. Doctors and patients should be advised to use the drug only for the treatment of narcolepsy and all other indications should be withdrawn from market authorization, the press release said.
In addition to the brand-name, Provigil, marketed by Cephalon in the US, modafinil is also sold as Alertec, Modalert, Modavigil, Modiodal, Provake, and Vigil.
A review by the Agency’s Committee for Medicinal Products for Human Use (CHMP), began in May 2009, because of safety concerns relating to psychiatric disorders, such as suicidal thoughts, depression, and psychotic episodes, and life threatening skin reactions, as well as significant off-label use and potential for abuse.
CHMP looked at all the clinical trial data on modafinil for narcolepsy, obstructive sleep apnoea, shift-work sleep disorder and idiopathic hypersomnia, and articles from the published literature. CHMP also reviewed all the side effects reported on modafinil-containing medicines, and convened a group of experts on clinical neurosciences to provide advice, according to a Q&A document on EMA's website.
On the basis of the available data, CHMP concluded that the benefits of modafinil only outweighed the risks in treating narcolepsy and the clinical trials for other disorders did not provide strong evidence to support use of the drug. For other indications, CHMP found the data on effectiveness insufficient to outweigh the risks of skin reactions, psychiatric adverse reactions, and cardiovascular adverse reactions, such as hypertension and irregular heart beat.
CHMP concluded that the product information should carry a recommendation saying modafinil should not be prescribed to children and use of the drug be contraindicated in patients with uncontrolled moderate-to-severe hypertension and cardiac arrhythmias. The recommendations were forwarded to the European Commission for the adoption of a binding decision, the press release said.
Because CHMP noted in its review that modafinil has often been used for conditions not indicated, the drug makers were asked to carry out further studies, including a "drug utilisation study," to look at why family doctors prescribe the drug, according to the Q&A. In addition, data on misuse by university students is currently being collected and will be analyzed once available, the EMA reports.
The Medicines and Healthcare product Regulatory Agency issued a "stop press" notice in the August 2010 edition of "Drug Safety Update," reminding healthcare professionals of the EMA’s recommendations.
US Market
Provigil was approved for narcolepsy in late 1998, which only affects around 200,000 people in the US, according to a July 2010 report by Global Industry Analysts.
US sales began in February 1999. Ten months later, "25% of narcolepsy patients in the country, more than 31,000 people, were taking the drug. It generated $25 million in 1999 sales, and Cephalon's revenue nearly tripled to $45 million," according to an August 1, 2000 report, by Matthew Herper, on Forbes.com.
A November 20, 2002, New York Times article reported that Cephalon CEO, Frank Baldino, himself, was taking Provigil, but would not say what condition he used it for. Provigil is short for "promotes vigilance," according to the Times.
Use of the drug is "expanding rapidly, with more than 80 percent of the prescriptions written to treat the fatigue and sleepiness associated with many other diseases, like depression and multiple sclerosis, or even just sleepiness caused by no disease at all," the article reported in 2002.
At that time, Baldino denied that the drug was or would be abused. "I don't think it's going to happen, because we're careful about how we sell it and doctors are careful how they write prescriptions," he told the Times.
"He added that the growing use of the drug for conditions other than narcolepsy is being driven by physicians, not by Cephalon's marketing," the article said.
Less than eleven months earlier, the FDA had sent a letter warning Cephalon to quit promoting Provigil for off-label uses. The FDA objected to language indicating the drug could be used for symptoms such as sleepiness, tiredness, decreased activity, lack of energy and fatigue. "Provigil is indicated to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy. Provigil is not approved for use as a daytime stimulant," the FDA wrote in January 2002.
The letter requested an immediate end to the dissemination of “all sales aids, journal advertisements, websites and all other promotional materials and activities for Provigil that contain the same or similar violations.”
In 2002, Provigil sold for $5 a pill and some insurers were reluctant to pay that price for narcolepsy because amphetamines were much cheaper, according to the Times.
The treatment of excessive sleepiness associated with sleep apnea and shift work sleep disorder with Provigil were not approved until January 2004. Right before the Summer Olympics in August 2004, the World Anti-Doping Agency added modafinil to the list of banned drugs after a runner in the 2003 World Track and Field Championships tested positive for it.
Provigil Addiction
On March 17, 2009, Harrisburg, Pennsylvania psychiatrist and addiction specialist, Dr Stefan Kruszewski, told USA Today that he was currently treating his third case of Provigil addiction. "I had two doctors back-to-back who were addicted to modafinil," he said, "so I became alarmed." Both were also alcoholics.
The same day, Bloomberg ran the headline, "Narcolepsy Pill Used as Smart Drug May Be Addictive," in reporting a study, by researchers at the National Institute on Drug Abuse, that found Provigil "effects the same brain chemicals as stimulants like Ritalin and amphetamines."
"PET or positron emission tomography scans of the brain activity in 10 healthy volunteers who took the drug showed it boosted the level of dopamine circulating in the part of the brain involved in pleasure, reward and addiction," Bloomberg wrote, in summarizing the study published in the "Journal of the American Medical Association."
The increase of dopamine seen with the medicine is "the signature for drugs that have the potential for producing addiction," Nora Volkow, the lead author and director of the National Institute on Drug Abuse, told Bloomberg.
Physicians prescribing Provigil should "be alert to the possibility that it could produce addiction," she said. Consumers also should be aware the drug "may have more abuse potential than originally believed."
Volkow wanted to add questions about the Provigil to the Institute's annual survey of high school drug use, she told Bloomberg.
The study noted that Provigil was being used off-label by people who want to boost their mental ability. "Modafinil is increasingly being diverted for nonmedical use by healthy individuals with the expectation that it will improve cognitive performance," the authors wrote in the March 18, 2009 Journal.
"The growing use of modafinil in clinical medicine and as a cognitive enhancing agent and the uncertainties surrounding the mechanisms underlying its pharmacological effects highlight the need to better understand its mechanisms of action," they advised.
"Modafinil was developed with an expectation that a medication could have a nondopaminergic target for its wake-promoting effects," they said. "However, the current findings in humans, along with preclinical studies documenting the indispensable role of dopamine in the wake-promoting effects of modafinil, support modafinil’s dopamine-enhancing effects as a mechanism for its therapeutic actions.”
"In addition," they reported, "a recent imaging study in anesthetized monkeys documented significant occupancy of dopamine transporters by intravenously administered modafinil."
They also pointed out that "modafinil was shown to be self-administered in monkeys previously trained to self-administer cocaine."
But the potential for abuse is not the only reason why healthy people should not take modafinil or other so-called "smart drugs," Volkow told USA Today. They can have serious adverse effects, such as brief psychotic episodes, she said, and there is little evidence they improve cognition. Modafinil also significantly increased heart rate and systolic blood pressure, the study found.
In the paper, the authors pointed out that there had been previous "debate surrounding its potential for abuse," and cited two examples. The first, was a March 2006 Letter to the Editor, of the American Journal of Psychiatry, from Dr Kruszewski, in response to an August 2005 paper in the Journal, by Dr Charles O’Brien, that claimed modafinil may decrease cocaine use in some cocaine users and specifically stated: "The medication has not been reported to produce euphoria, and there has been no indication of excessive use or abuse in clinical trials."
As the scientific basis for his comments, O'Brien referenced two studies by his own research group. In his letter, Kruszewski wrote that, "the author's statement does not appear to be supported by his referenced work, nor is it supported by information widely available in the 2004 edition of the Physicians' Desk Reference."
The referenced article may demonstrate that modafinil can, in some cases, blunt cocaine euphoria, he said. "However, it does not say anything about modafinil's intrinsic ability to produce euphoria (or not)."
In fact, the 2004 PDR raises specific concerns about modafinil, saying that it can produce "psychoactive and euphoric effects, alterations in mood, perception, thinking and feelings typical of other CNS stimulants," he wrote.
The PDR also states that "modafinil is reinforcing, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine," Kruszewski noted.
He pointed out that the comment on the lack of euphorigenic effects was also contradicted by the FDA in a January 14, 2002, warning letter sent to Paul Kirsch, the senior director of regulatory affairs at Cephalon, which specifically reiterates the drug's package insert addressing the modafinil's euphorigenic effects and its potential for abuse.
That the euphorigenic side effects or abuse potential may be minimized has current treatment implications because modafinil is increasingly promoted for fatigue and excessive sleepiness unrelated to narcolepsy as well as for cocaine abuse, he warned.
The implications loomed even larger, he said, because Cephalon had submitted a “reformulated” modafinil to the FDA under a new name for the treatment of children and adolescents with attention deficit hyperactivity disorder.
The second example of the debate, was a June 2007 Letter to the Editor, of the Journal of Clinical Psychiatry, from Dr Kruszewski and Dr Steven Klotz, in response to an article published in an August 2006 supplement to the Journal titled, “New Developments in the Treatment of Attention-Deficit/ Hyperactivity Disorder,” by Dr Joseph Biederman, Chief of Pediatric Psychopharmacology at Massachusetts General Hospital and Professor of Psychiatry at Harvard Medical School.
The supplement was underwritten by an educational grant from Cephalon.
In his article, Biederman stated: “The pharmacologic profile and structure of modafinil are notably different from those of stimulants and other agents used to treat ADHD, and modafinil may reduce the core symptoms of ADHD via the same mechanism by which it improves wakefulness—selective activation of the cortex without generalized effects on the central nervous system.”
“This mechanism results in reduced abuse potential and less likelihood of jitteriness, anxiety, or excess locomotor activity than traditional stimulants,” he claimed.
Their concern with Biederman's commentary was that “it appears to seriously misrepresent modafinil’s neuropharmacologic characteristics, contradicting the science-based evaluation of the data by the U.S. FDA and DEA,” Kruszewski and Klotz wrote.
“Dr. Biederman may have misrepresented modafinil’s pharmacologic (stimulant) properties and minimized modafinil’s abuse potential—as described in the authoritative FDA-approved product label,” they told the Editor.
“Dr. Biederman’s misrepresentation of the serious risks posed by this drug, whose target population is children with ADHD, requires reexamination and correction,”they wrote.
In conclusion, they correctly pointed out that if Cephalon “ere to directly mischaracterize modafinil’s pharmacocharacteristics—as Dr. Biederman has—they could be prosecuted under federal law.”
In a June 2007 reply letter, Biederman wrote, the “background research to support the claims of Drs. Kruszewski and Klotz begins and ends with the manufacturer’s package insert.”
“However, the manufacturer’s package insert is neither a standard of care nor the most comprehensive and up-to-date review of the preclinical or clinical science about a molecule,” he said. “Were that so, new knowledge or findings would never be able to be conveyed to the field until the company or the U.S. Food and Drug Administration (FDA) determined to alter the manufacturer’s package insert.”
“Further, the labeling reflects information provided to the FDA at the time of submission of the compound and not necessarily the universe of scientific information available,” he wrote.
"The letter by Drs. Kruszewski and Klotz seriously misrepresents the facts, shows ignorance about the neuropharmacologic characteristics of modafinil, and demonstrates a failure to understand the clinical significance of alternative treatments for ADHD," the hubristic Biederman told the Editor.
"As an independent clinician-researcher and not the agent of the manufacturer, I am compelled to base my teaching on all the information and knowledge available to me," he said.
However, an investigation, the very next year, by the US Senate Finance Committee, led by Iowa Republican Senator, Charles Grassley, found Biederman to be far from independent from Cephalon. For instance, when disclosing plans for a study sponsored by Cephalon in 2001, Biederman claimed he had no financial relationship with the sponsor. But seven years later, in March 2008, Grassley found Cephalon had paid him $13,000 in 2001.
Again in 2005, when Biederman began another trial, sponsored by Cephalon, to run from September 2005 to September 2006, he disclosed no financial relationship with the firm. But in March 2008, Grassley learned that Cephalon had paid him $11,000 for honoraria in 2005, and an additional $24,750 in 2006.
In fact, all total, Biederman had earned about $1.6 million from drug companies between 2000 and 2007, but failed to report about $1.4 million on forms filed with Harvard.
In disclosures at the end of his reply letter, Biederman listed fourteen drug companies, including Cephalon. In December 2008, Mass General announced that Biederman would no longer be participating in several drug company funded trials and would limit his speaking and consulting activities, pending the outcome of an inquiry of his potential conflict of interests and disclosure obligations.
As mentioned by Kruszewski in his letters to the editor, Cephalon had applied for approval of modafinil (in a larger dose formulation called Sparlon), to treat children and adolescents with ADHD, in December 2004.
However, Biederman was out giving talks promoting off-label use with kids long before it came up for approval. On May 26, 2005, in Doctors Guide Dispatch, Bruce Sylvester reported on a May 24th presentation titled, "Modafinil Pediatric Formulation Has Early and Sustained Effect in ADHD," given by Biederman at the annual meeting of the "American Psychiatric Association," on a study funded by Cephalon and led by Biederman, which claimed Sparlon was effective for children aged 6 to 17 with ADHD.
"This study not only shows that this medication is effective and rapid in onset for the treatment of pediatric ADHD," Biederman said in the presentation. "It also gives the clear signal that here we have a medication that can be used by physicians to treat ADHD in children who cannot tolerate amphetamine salts or for whom the clinician simply prefers not to use amphetamine salts."
Another study, in the December 2005, “Pediatrics” journal, with lead investigator Biederman, said Sparlon's effectiveness and safety profile, along with its low potential for abuse, may offer doctors and parents a new option for children with ADHD. At that time, Biederman’s disclosures showed he received research funding from ten drug companies, served on the speaker's bureau of four, and sat on advisory boards of six.
In applying for FDA approval, Cephalon submitted three trials of Sparlon on less than 700 children. According to a report by FDA reviewer Andrew Mosholder, "two kids experienced psychotic or manic episodes; four kids considered suicide; and nine kids engaged in serious "aggression events" in the modafinil trials," Merrill Goozner reported in GoozNews on March 20, 2006.
"That was the equivalent of 20 negative reactions for every 100 patients who take the drug for a year," Goozner said. "Only Adderall and a skin patch had a worse record."
In the end, an FDA Advisory Committee determined that Sparlon was not safe enough to be marketed to kids, by a vote of 12 to 1, in March 2006, and in August 2006, Cephalon reported that the FDA had rejected the drug for children and the company decided to end development of Sparlon.
(Part II will be published tomorrow)
(Evelyn Pringle is an investigative journalist focused on exposing corruption in government and corporate America)
On July 22, 2010, the European Medicines Agency recommended restricting the use of modafinil. Doctors and patients should be advised to use the drug only for the treatment of narcolepsy and all other indications should be withdrawn from market authorization, the press release said.
In addition to the brand-name, Provigil, marketed by Cephalon in the US, modafinil is also sold as Alertec, Modalert, Modavigil, Modiodal, Provake, and Vigil.
A review by the Agency’s Committee for Medicinal Products for Human Use (CHMP), began in May 2009, because of safety concerns relating to psychiatric disorders, such as suicidal thoughts, depression, and psychotic episodes, and life threatening skin reactions, as well as significant off-label use and potential for abuse.
CHMP looked at all the clinical trial data on modafinil for narcolepsy, obstructive sleep apnoea, shift-work sleep disorder and idiopathic hypersomnia, and articles from the published literature. CHMP also reviewed all the side effects reported on modafinil-containing medicines, and convened a group of experts on clinical neurosciences to provide advice, according to a Q&A document on EMA's website.
On the basis of the available data, CHMP concluded that the benefits of modafinil only outweighed the risks in treating narcolepsy and the clinical trials for other disorders did not provide strong evidence to support use of the drug. For other indications, CHMP found the data on effectiveness insufficient to outweigh the risks of skin reactions, psychiatric adverse reactions, and cardiovascular adverse reactions, such as hypertension and irregular heart beat.
CHMP concluded that the product information should carry a recommendation saying modafinil should not be prescribed to children and use of the drug be contraindicated in patients with uncontrolled moderate-to-severe hypertension and cardiac arrhythmias. The recommendations were forwarded to the European Commission for the adoption of a binding decision, the press release said.
Because CHMP noted in its review that modafinil has often been used for conditions not indicated, the drug makers were asked to carry out further studies, including a "drug utilisation study," to look at why family doctors prescribe the drug, according to the Q&A. In addition, data on misuse by university students is currently being collected and will be analyzed once available, the EMA reports.
The Medicines and Healthcare product Regulatory Agency issued a "stop press" notice in the August 2010 edition of "Drug Safety Update," reminding healthcare professionals of the EMA’s recommendations.
US Market
Provigil was approved for narcolepsy in late 1998, which only affects around 200,000 people in the US, according to a July 2010 report by Global Industry Analysts.
US sales began in February 1999. Ten months later, "25% of narcolepsy patients in the country, more than 31,000 people, were taking the drug. It generated $25 million in 1999 sales, and Cephalon's revenue nearly tripled to $45 million," according to an August 1, 2000 report, by Matthew Herper, on Forbes.com.
A November 20, 2002, New York Times article reported that Cephalon CEO, Frank Baldino, himself, was taking Provigil, but would not say what condition he used it for. Provigil is short for "promotes vigilance," according to the Times.
Use of the drug is "expanding rapidly, with more than 80 percent of the prescriptions written to treat the fatigue and sleepiness associated with many other diseases, like depression and multiple sclerosis, or even just sleepiness caused by no disease at all," the article reported in 2002.
At that time, Baldino denied that the drug was or would be abused. "I don't think it's going to happen, because we're careful about how we sell it and doctors are careful how they write prescriptions," he told the Times.
"He added that the growing use of the drug for conditions other than narcolepsy is being driven by physicians, not by Cephalon's marketing," the article said.
Less than eleven months earlier, the FDA had sent a letter warning Cephalon to quit promoting Provigil for off-label uses. The FDA objected to language indicating the drug could be used for symptoms such as sleepiness, tiredness, decreased activity, lack of energy and fatigue. "Provigil is indicated to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy. Provigil is not approved for use as a daytime stimulant," the FDA wrote in January 2002.
The letter requested an immediate end to the dissemination of “all sales aids, journal advertisements, websites and all other promotional materials and activities for Provigil that contain the same or similar violations.”
In 2002, Provigil sold for $5 a pill and some insurers were reluctant to pay that price for narcolepsy because amphetamines were much cheaper, according to the Times.
The treatment of excessive sleepiness associated with sleep apnea and shift work sleep disorder with Provigil were not approved until January 2004. Right before the Summer Olympics in August 2004, the World Anti-Doping Agency added modafinil to the list of banned drugs after a runner in the 2003 World Track and Field Championships tested positive for it.
Provigil Addiction
On March 17, 2009, Harrisburg, Pennsylvania psychiatrist and addiction specialist, Dr Stefan Kruszewski, told USA Today that he was currently treating his third case of Provigil addiction. "I had two doctors back-to-back who were addicted to modafinil," he said, "so I became alarmed." Both were also alcoholics.
The same day, Bloomberg ran the headline, "Narcolepsy Pill Used as Smart Drug May Be Addictive," in reporting a study, by researchers at the National Institute on Drug Abuse, that found Provigil "effects the same brain chemicals as stimulants like Ritalin and amphetamines."
"PET or positron emission tomography scans of the brain activity in 10 healthy volunteers who took the drug showed it boosted the level of dopamine circulating in the part of the brain involved in pleasure, reward and addiction," Bloomberg wrote, in summarizing the study published in the "Journal of the American Medical Association."
The increase of dopamine seen with the medicine is "the signature for drugs that have the potential for producing addiction," Nora Volkow, the lead author and director of the National Institute on Drug Abuse, told Bloomberg.
Physicians prescribing Provigil should "be alert to the possibility that it could produce addiction," she said. Consumers also should be aware the drug "may have more abuse potential than originally believed."
Volkow wanted to add questions about the Provigil to the Institute's annual survey of high school drug use, she told Bloomberg.
The study noted that Provigil was being used off-label by people who want to boost their mental ability. "Modafinil is increasingly being diverted for nonmedical use by healthy individuals with the expectation that it will improve cognitive performance," the authors wrote in the March 18, 2009 Journal.
"The growing use of modafinil in clinical medicine and as a cognitive enhancing agent and the uncertainties surrounding the mechanisms underlying its pharmacological effects highlight the need to better understand its mechanisms of action," they advised.
"Modafinil was developed with an expectation that a medication could have a nondopaminergic target for its wake-promoting effects," they said. "However, the current findings in humans, along with preclinical studies documenting the indispensable role of dopamine in the wake-promoting effects of modafinil, support modafinil’s dopamine-enhancing effects as a mechanism for its therapeutic actions.”
"In addition," they reported, "a recent imaging study in anesthetized monkeys documented significant occupancy of dopamine transporters by intravenously administered modafinil."
They also pointed out that "modafinil was shown to be self-administered in monkeys previously trained to self-administer cocaine."
But the potential for abuse is not the only reason why healthy people should not take modafinil or other so-called "smart drugs," Volkow told USA Today. They can have serious adverse effects, such as brief psychotic episodes, she said, and there is little evidence they improve cognition. Modafinil also significantly increased heart rate and systolic blood pressure, the study found.
In the paper, the authors pointed out that there had been previous "debate surrounding its potential for abuse," and cited two examples. The first, was a March 2006 Letter to the Editor, of the American Journal of Psychiatry, from Dr Kruszewski, in response to an August 2005 paper in the Journal, by Dr Charles O’Brien, that claimed modafinil may decrease cocaine use in some cocaine users and specifically stated: "The medication has not been reported to produce euphoria, and there has been no indication of excessive use or abuse in clinical trials."
As the scientific basis for his comments, O'Brien referenced two studies by his own research group. In his letter, Kruszewski wrote that, "the author's statement does not appear to be supported by his referenced work, nor is it supported by information widely available in the 2004 edition of the Physicians' Desk Reference."
The referenced article may demonstrate that modafinil can, in some cases, blunt cocaine euphoria, he said. "However, it does not say anything about modafinil's intrinsic ability to produce euphoria (or not)."
In fact, the 2004 PDR raises specific concerns about modafinil, saying that it can produce "psychoactive and euphoric effects, alterations in mood, perception, thinking and feelings typical of other CNS stimulants," he wrote.
The PDR also states that "modafinil is reinforcing, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine," Kruszewski noted.
He pointed out that the comment on the lack of euphorigenic effects was also contradicted by the FDA in a January 14, 2002, warning letter sent to Paul Kirsch, the senior director of regulatory affairs at Cephalon, which specifically reiterates the drug's package insert addressing the modafinil's euphorigenic effects and its potential for abuse.
That the euphorigenic side effects or abuse potential may be minimized has current treatment implications because modafinil is increasingly promoted for fatigue and excessive sleepiness unrelated to narcolepsy as well as for cocaine abuse, he warned.
The implications loomed even larger, he said, because Cephalon had submitted a “reformulated” modafinil to the FDA under a new name for the treatment of children and adolescents with attention deficit hyperactivity disorder.
The second example of the debate, was a June 2007 Letter to the Editor, of the Journal of Clinical Psychiatry, from Dr Kruszewski and Dr Steven Klotz, in response to an article published in an August 2006 supplement to the Journal titled, “New Developments in the Treatment of Attention-Deficit/ Hyperactivity Disorder,” by Dr Joseph Biederman, Chief of Pediatric Psychopharmacology at Massachusetts General Hospital and Professor of Psychiatry at Harvard Medical School.
The supplement was underwritten by an educational grant from Cephalon.
In his article, Biederman stated: “The pharmacologic profile and structure of modafinil are notably different from those of stimulants and other agents used to treat ADHD, and modafinil may reduce the core symptoms of ADHD via the same mechanism by which it improves wakefulness—selective activation of the cortex without generalized effects on the central nervous system.”
“This mechanism results in reduced abuse potential and less likelihood of jitteriness, anxiety, or excess locomotor activity than traditional stimulants,” he claimed.
Their concern with Biederman's commentary was that “it appears to seriously misrepresent modafinil’s neuropharmacologic characteristics, contradicting the science-based evaluation of the data by the U.S. FDA and DEA,” Kruszewski and Klotz wrote.
“Dr. Biederman may have misrepresented modafinil’s pharmacologic (stimulant) properties and minimized modafinil’s abuse potential—as described in the authoritative FDA-approved product label,” they told the Editor.
“Dr. Biederman’s misrepresentation of the serious risks posed by this drug, whose target population is children with ADHD, requires reexamination and correction,”they wrote.
In conclusion, they correctly pointed out that if Cephalon “ere to directly mischaracterize modafinil’s pharmacocharacteristics—as Dr. Biederman has—they could be prosecuted under federal law.”
In a June 2007 reply letter, Biederman wrote, the “background research to support the claims of Drs. Kruszewski and Klotz begins and ends with the manufacturer’s package insert.”
“However, the manufacturer’s package insert is neither a standard of care nor the most comprehensive and up-to-date review of the preclinical or clinical science about a molecule,” he said. “Were that so, new knowledge or findings would never be able to be conveyed to the field until the company or the U.S. Food and Drug Administration (FDA) determined to alter the manufacturer’s package insert.”
“Further, the labeling reflects information provided to the FDA at the time of submission of the compound and not necessarily the universe of scientific information available,” he wrote.
"The letter by Drs. Kruszewski and Klotz seriously misrepresents the facts, shows ignorance about the neuropharmacologic characteristics of modafinil, and demonstrates a failure to understand the clinical significance of alternative treatments for ADHD," the hubristic Biederman told the Editor.
"As an independent clinician-researcher and not the agent of the manufacturer, I am compelled to base my teaching on all the information and knowledge available to me," he said.
However, an investigation, the very next year, by the US Senate Finance Committee, led by Iowa Republican Senator, Charles Grassley, found Biederman to be far from independent from Cephalon. For instance, when disclosing plans for a study sponsored by Cephalon in 2001, Biederman claimed he had no financial relationship with the sponsor. But seven years later, in March 2008, Grassley found Cephalon had paid him $13,000 in 2001.
Again in 2005, when Biederman began another trial, sponsored by Cephalon, to run from September 2005 to September 2006, he disclosed no financial relationship with the firm. But in March 2008, Grassley learned that Cephalon had paid him $11,000 for honoraria in 2005, and an additional $24,750 in 2006.
In fact, all total, Biederman had earned about $1.6 million from drug companies between 2000 and 2007, but failed to report about $1.4 million on forms filed with Harvard.
In disclosures at the end of his reply letter, Biederman listed fourteen drug companies, including Cephalon. In December 2008, Mass General announced that Biederman would no longer be participating in several drug company funded trials and would limit his speaking and consulting activities, pending the outcome of an inquiry of his potential conflict of interests and disclosure obligations.
As mentioned by Kruszewski in his letters to the editor, Cephalon had applied for approval of modafinil (in a larger dose formulation called Sparlon), to treat children and adolescents with ADHD, in December 2004.
However, Biederman was out giving talks promoting off-label use with kids long before it came up for approval. On May 26, 2005, in Doctors Guide Dispatch, Bruce Sylvester reported on a May 24th presentation titled, "Modafinil Pediatric Formulation Has Early and Sustained Effect in ADHD," given by Biederman at the annual meeting of the "American Psychiatric Association," on a study funded by Cephalon and led by Biederman, which claimed Sparlon was effective for children aged 6 to 17 with ADHD.
"This study not only shows that this medication is effective and rapid in onset for the treatment of pediatric ADHD," Biederman said in the presentation. "It also gives the clear signal that here we have a medication that can be used by physicians to treat ADHD in children who cannot tolerate amphetamine salts or for whom the clinician simply prefers not to use amphetamine salts."
Another study, in the December 2005, “Pediatrics” journal, with lead investigator Biederman, said Sparlon's effectiveness and safety profile, along with its low potential for abuse, may offer doctors and parents a new option for children with ADHD. At that time, Biederman’s disclosures showed he received research funding from ten drug companies, served on the speaker's bureau of four, and sat on advisory boards of six.
In applying for FDA approval, Cephalon submitted three trials of Sparlon on less than 700 children. According to a report by FDA reviewer Andrew Mosholder, "two kids experienced psychotic or manic episodes; four kids considered suicide; and nine kids engaged in serious "aggression events" in the modafinil trials," Merrill Goozner reported in GoozNews on March 20, 2006.
"That was the equivalent of 20 negative reactions for every 100 patients who take the drug for a year," Goozner said. "Only Adderall and a skin patch had a worse record."
In the end, an FDA Advisory Committee determined that Sparlon was not safe enough to be marketed to kids, by a vote of 12 to 1, in March 2006, and in August 2006, Cephalon reported that the FDA had rejected the drug for children and the company decided to end development of Sparlon.
(Part II will be published tomorrow)
(Evelyn Pringle is an investigative journalist focused on exposing corruption in government and corporate America)
Sunday, August 8, 2010
Glaxo Fights Against Public Paxil Trials
Evelyn Pringle April 8, 2008
Government attorneys appointed by the Bush Administration have been supporting GlaxoSmithKline in a number of courts across the country in an effort to convince the courts that lawsuits filed by victims of Paxil-induced injuries should be dismissed before ever making it to a jury.
In fact, the Administration has spent a massive amount of tax dollars filing amicus briefs on behalf of just about every drug maker involved in litigation in an attempt to get the lawsuits filed by private citizens thrown out of court.
The government claims that, once a drug and the warnings on its label are approved by the FDA, claims alleging injuries caused by a company's failure to warn about a risk not listed on the label are preempted.
The Bush Administration says preemption applies even when a company (1) continues to sell a drug when a risk is known; (2) fails to warn when new risks are discovered; (3) fails to send letters notifying prescribing doctors of a known risk, and (4) fails to disclose a known risk to the FDA during the approval process, or anytime for that matter. In essence, if the FDA doesn’t make the companies warn, they’re off the hook.
If the Administration is successful in obtaining immunity for these drug companies, taxpayers will be left to pay not only the costs of medical care for all persons injured by drugs but also the life-long care for persons disabled by a product.
If Americans realized what was happening, there is no way they would approve of their tax dollars being spent to help the richest industry on the planet deprive fellow citizens of their right to a jury trial.
The typical brief against a plaintiff is filed by an army of government attorneys and will include an Assistant Attorney General, a Deputy Assistant Attorney General, a United States Attorney, an Assistant United States Attorney, two Appellate Attorneys from the Department of Justice, the FDA's Chief Counsel, and the Deputy Chief Counsel, Associate Chief Counsel, and General Counsel for the Department of Health and Human Services.
Glaxo takes things one step further by submitting government amicus briefs that were filed in other cases (not just Paxil cases) and re-files them in virtually every one of the cases filed against the company in order to bolster its preemption arguments.
In O’Neal v GlaxoSmithKline, a case involving the suicide of a 13-year-old Sacramento, California boy, Benjamin Bratt, Glaxo recently used the Bush Administration's preemption policy to argue that the child's family should not be allowed to sue Glaxo for failing to warn about the suicide risk.
Benjamin committed suicide on February 14, 1997 by hanging himself. His parents, Terri O’Neal and Barry Bratt, filed a lawsuit alleging that, despite knowledge of suicide risks associated with Paxil prior to 1997, Glaxo concealed the information, failed to warn doctors, the medical community, and the public and all the while the company promoted the drug as safe and effective for children.
In the lawsuit, the Bratt Family alleged that Glaxo should have warned Benjamin’s doctor about the suicide risk both through the label and through other means, such as promotion, advertising, and “Dear Doctor” letters.
On January 30, 2008, federal judge, Frank Damrell, in the US District Court, Eastern District of California, dismissed the case and ruled that all of the family’s claims were preempted. The Bratt family has asked the court to reconsider the ruling. They believe the judge committed error in essentially holding that a drug that is not safe for adults is nonetheless safe for children until proven otherwise.
The family argues that adult clinical trials conducted by Glaxo as far back as 1989 showed an 8 times increased risk of suicidal behavior for Paxil users compared to patients receiving a placebo, but that Glaxo manipulated the data to obscure the risk, and then published the false data in medical journals and articles throughout the 1990's.
In his ruling, Judge Damrell held that, even if GSK had clinical trial data prior to 1997 that showed an increased risk of suicidality in adults, that data was not sufficient to prove the risk extended to children using Paxil.
The Court held that, because the first clinical trial of Paxil with children did not conclude until 1998, Glaxo could not have known about the suicide risks with kids before that date.
During the January 18, 2008 oral argument on the preemption motion, Judge Damrell himself pointed out that a finding of an increased risk of suicidality in adults would logically apply to children. He specifically stated:
"As a practical matter, if I see there was an association of suicide ideation with anybody and enough of it, the last person I want to see using it is a child. That may not be scientific, but I’m just talking as a grandfather and human being."
However, in his order, Judge Damrell seems to say the exact opposite:
"That later clinical studies ultimately led to a clear signal of pediatric suicidality, and that these studies arguably reflected the initial data in 1989 and 1991 of similar associations among adults, simply does not provide ‘reasonable evidence’ of the association of pediatric suicidality in February 1997."
“It is difficult to reconcile Judge Damrell’s statements during oral argument with his ruling,” says senior trial attorney, Ron Goldman of Baum, Hedlund, Aristei & Goldman, the law firm representing the Bratt family.
Baum Hedlund has roughly 30 lawsuits on file involving Paxil-induced suicides and suicide attempts. Over the past 18 years, the firm has handled more than 3,000 cases involving antidepressants, including Glaxo’s Paxil, Eli Lilly's Prozac and Pfizer's Zoloft.
The first study Glaxo conducted on children was called Study 329. The study was started in 1994, three years prior to Benjamin’s suicide, and was completed in 1998, nine months after his suicide.
Judge Damrell bought Glaxo’s argument that, because Study 329 wasn’t completed until after Ben Bratt’s death, the company could not have warned of a risk in children prior to that. But, during the four years the study was ongoing, Glaxo received numerous reports of suicidal behavior occurring in children taking Paxil.
Coupled with the risk evident from the adult clinical trials since 1989, the Bratt family argues that Glaxo could have and should have warned of the risk for all people taking the drug long before Benjamin ingested Paxil.
Coincidentally, when the study 329 was finally published, the authors stated that, "The adverse-effect profile of paroxetine in this adolescent population was concordant with that reported in studies of adult patients with depression."
The Bratt family argues that, the question of whether reasonable evidence of an association existed between Paxil and suicidality in any population at the time of Benjamin’s death is one for the jury.
The question of what Glaxo knew and when Glaxo knew it is also a question for the jury. Glaxo’s attempt to continue the parade down this rabbit trail is simply an attempt to divert attention away from the core issue here. The decisive question in a preemption context for the Court to determine is, “was GSK ever prohibited by the FDA from issuing a warning” thus creating a direct and positive conflict. The answer is unequivocally “NO.”
Judge Damrell also held that, if Glaxo had warned about a suicide risk for kids prior to 1997, such a warning would have been subject to a misbranding action by the FDA.
According to Mr Goldman, "Under no circumstances, given the regulatory scheme, can a drug be considered ‘misbranded’ if the science supports a truthful warning of the risk of suicidality.”
“Under the law," he says, "it is a drug manufacturer’s duty to warn of risks known or reasonably scientifically knowable.”
“A drug company that fails or refuses to conduct necessary analyses in a scientifically acceptable manner,” he states, “shirks its legal, not to mention ethical and moral, duty to the medical profession and the public.”
According to the US Supreme Court, preemption applies (1) where it is impossible for a private party to comply with both federal and state law; and (2) where the state law stands as an obstacle to the accomplishment and execution of the full purposes and objective of Congress.
“When carefully analyzed, there is absolutely no evidence showing that it would have been ‘impossible’ for Glaxo to warn of this very serious risk, an absolute requirement in cases where conflict preemption is raised,” Mr Goldman contends.
“To the contrary,” he says, “such a warning is in perfect harmony with the FDA regulations and the overarching purpose of the FDA: to promote health and safety in prescription drugs.”
In their brief filed in opposition to summary judgment, the Bratt Family stated: "GSK would like to convince this Court that it is merely a ‘puppet’ when it comes to labeling its multi-billion dollar blockbuster drug, Paxil."
"According to GSK," the brief notes, "it is hapless and at the mercy of the FDA when it comes to the content of Paxil’s label."
Glaxo claims it needed the FDA's prior approval to issue a warning. However, the attorneys in the Paxil cases point out that Glaxo itself changed the label and sent out a Dear Doctor letter warning about the suicide risk in May 2006, with no prior approval from the FDA. The FDA never objected to the letter or the strengthened warning label.
The FDA, in its amicus briefs, has asserted twisted logic in these cases because the FDA cannot force a company to add a warning to a label. On March 1, 2005, the FDA's deputy director for the Office of New Drugs, Dr Sandra Kweder, testified at a hearing before the Senate Committee on Health, Education, Labor and Pensions, that the FDA does not have the authority to require a specific label change and that the agency has to negotiate with the companies about how things should be worded, placement, those kinds of things.
During oral argument in SSRI suicide cases, industry attorneys claim that the reevaluation of the suicide risk of all the pediatric studies on SSRIs occurred after Glaxo “voluntarily” offered up the studies to the FDA.
For instance, on December 10, 2007, during oral argument in a case in a federal court in Philadelphia, a Pfizer attorney, Malcolm Wheeler was asked by the court: “What was the tipping point then for the change in position with respect to adolescents and then later extending that to young adults up to age 24?”
Mr Wheeler replied: “The tipping point was because GlaxoSmithKline voluntarily went forward and informed the FDA of some study results and said here are these results.”
“And what the FDA did as a result of that,” he told the court, “was to conduct a new analysis, pooling the data from nine different drugs, not just SSRIs, but nine different antidepressants, to say when we pool all the data from these various antidepressants, does it indicate any signal that suggests that we ought to do something other than what we've done in the past?”
However, that is a gross misrepresentation of what actually happened. The truth is, according to FDA documents obtained in litigation, that the European Medicines Agency (EMEA) contacted the FDA in mid-2003 to alert officials about the hidden suicide risk in the pediatric Paxil studies.
According to a June 2, 2003, FDA email written by Dr Russell Katz to Dr Andrew Mosholder, the FDA was notified in May 2003, that suicide events were hidden under the term "emotional lability." Dr Katz's email states:
“We have recently become aware of a presumed association between Paxil and suicidality in pediatric patients. We received a call from the EMEA a little over a week ago.
A Dr. Raines told us that the company (GSK) had submitted data that demonstrated that use of Paxil in kids was associated with increased suicidality compared to placebo, and that the company proposed labeling changes.
“I believe she also said that it was in the news, and it was a big issue. Tom and I told her that the company had not informed us of any of this, and we agreed to look into it.”
Dr Katz told Dr Mosholder that the FDA had asked Glaxo to elaborate on the events listed under the term emotional lability and further stated:
“We received this partial response, and almost all of these events related to suicidality. The bottom line is that when data from the controlled trials in depression, OCD, and Social Anxiety are pooled, for “possible suicide related” events occurring during treatment or within 4 days after discontinuation, the rate is 0.14/patient-year on drug, and 0.05/patient-year on placebo, p=0.02.”
“We have some problems with the methodology they used to capture cases, but this is the major finding, and it has us worried,” he wrote.
“We are planning to look at the NDAs for other SSRIs to see whether or not similar events are being hidden by various inappropriate coding maneuvers, but we’d also like to compare the drugs in other meaningful ways if we can,” Dr Katz informed Dr Mosholder.
A report by Harvard psychiatrist, Dr Joseph Glenmullen, retained by Baum Hedlund as an expert witness in the Bratt case shows that Glaxo knew as early as 1989 that patients who received Paxil in clinical trials showed an 8-fold increased risk of suicidality compared to patients who received placebos. Dr Glenmullen’s report was initially filed under seal, however, on January 30, 2008, the majority of the report was unsealed.
In the report, Dr Glenmullen also notes that, when Glaxo coded suicidal behavior in its computerized database, most of the suicides and suicide attempts were coded as "emotional lability," which he says is "a technical term for rapid mood swings, for example from crying to laughing."
Another claim consistently made by both the Bush Administration attorneys and the attorneys for the SSRI makers, is that the FDA’s failure to make the companies issue warnings somehow means the FDA considered and rejected offers by the companies to add warnings about the suicidality risk.
However, Dr Katz specifically notes in his email that Glaxo never offered to add a warning to the label in the US, even after the FDA became aware of the increased suicide risk and discussed the issue with Glaxo.
“The sponsor has not proposed labeling changes and makes a feeble attempt to dismiss the finding,” he told Dr Mosholder in the email.
In the first SSRI case where preemption was raised (the company lost the argument), Motus v Pfizer, the judge wisely observed that, “although the FDA did not require Pfizer to include suicide-related warnings in Zoloft’s label, FDA has not prohibited Pfizer from doing so” and the “FDA never stated that it would be impermissible to include additional warnings.” Likewise, because Glaxo never sought to add a suicide warning, it is not possible that the FDA considered and a suicide warning.
On June 10, 2003, the UK's Medicines and Healthcare Products Regulatory Agency issued the warning: "It has become clear that the benefits of Seroxat in children for the treatment of depressive illness do not outweigh these risks."
In the June 11, 2003 New York Times, Gardiner Harris reported that Alan Metz, the vice president for clinical development at Glaxo, said the company was not warning American doctors against using the drug with depressed children in the US.
Dr Metz acknowledged that Paxil was not approved for treating children in the US but that many doctors prescribed the drug for children anyway. Mr Harris pointed out that Glaxo had applied for approval from the FDA to sell Paxil to children with obsessive compulsive disorder and the application was pending at that time.
On June 20, 2003, the Times reported that the FDA's reanalysis found that the risk of suicidal thoughts and suicide attempts was 3 times greater among children using Paxil, mostly teenagers, than among children given placebos.
On August 12, 2003, the Times ran a commentary by Richard Friedman, a psychiatrist and director of the psychopharmacology clinic at Weill Medical College of Cornell University, which stated in part:
"What is disturbing about the recent report is that the purported link between Paxil and suicidal thinking comes from an unpublished study sponsored by Paxil's manufacturer, GlaxoSmithKline."
"In fact, GlaxoSmithKline has published only one of its nine studies of Paxil in children and adolescents to date," he reported.
In its preemption motion, Glaxo offered nothing to support the claim that the FDA had considered, much less rejected, a proposal to add a warning about the increased suicide risk for kids. In fact, the studies in question were not submitted to the FDA until 2002, when Glaxo sought approval for new uses of Paxil, meaning it would have been impossible for the FDA to have considered whether a warning was appropriate based on a risk known only to Glaxo.
To support their argument that the FDA had never rejected a Glaxo proposed warning, the Bratt family brief states: "None of the GSK employees in the past 14 years who have, or had, responsibility for communicating with the FDA regarding Paxil could point to any specific, proposed suicide or suicidality language that was rejected by the FDA.
In his report, Dr Glenmullen explains how Glaxo successfully avoided having to include a warning on the label when it obtained FDA approval for Paxil in 1992:
"GlaxoSmithKline's ‘bad’ Paxil data made it look as if patients randomized to Paxil were no more likely to become seriously suicidal when, in fact, the correct data shows patients on Paxil were eight times more likely to commit or attempt suicide."
"One again," he states, "GlaxoSmithKline's ‘bad’ Paxil numbers carried the day: The FDA approved Paxil on December 29, 1992 with no warning to doctors or patients of the significant increased risk of suicidal behavior."
The FDA's Dr David Graham, most famous for exposing the risks associated with Vioxx, says the government's attempts to immunize drug companies must not succeed. In an August 30, 2005 interview with Manette Loudon, the lead investigator for Dr Gary Null, (author of numerous books including “7 Steps To Overcoming Anxiety and Depression”), Dr Graham was asked about his views on attempts to pass tort reform.
"I think it's dangerous and wrong," he stated. "We already have an FDA that's been neutralized by industry and sees industry as its client."
Dr Graham said the agency is not going to protect the average citizen from the consequences of unsafe drugs, so the only alternative is the legal system. "That's the only way we have of getting companies to change their behavior," he said and, "tort reform would remove that threat as well."
"It's basically giving companies immunity because now the people who are injured by the drugs can't recover damages that might actually mean something to industry," he advised.
"I mean $250,000 for damages; they blow that in one ad campaign," he stated. "To them, that's nothing."
"But a lawsuit for multiple millions of dollars has more of an impact," he added.
"Now, is that optimal?" he said. "No."
"But the fact is that since we have a regulatory agency that doesn't regulate and we have a public health agency that doesn't protect the public, we have thousands of people who are being injured by products that the FDA knows are unsafe," he told Ms Loudon.
He pointed out that the FDA knew there was a big problem with Vioxx in mid 2000, and did nothing about it. If the FDA is not going to exercise control over companies, he said, there has to be a system in place "that reins companies in."
In addition to the agency's failure to protect the public against Vioxx, Dr Graham also discussed the FDA's attempts to conceal the increased suicide risks that were found in the reevaluation of the pediatric SSRI studies in early 2004. "The FDA had suppressed a report written by a colleague of mine in drug safety and had prevented him from presenting this information in an advisory committee meeting," he explained.
"That information leaked to the media," Dr Graham continued, "embarrassing the FDA because it had been caught suppressing very important information – that most of the antidepressants don't work for treating children."
He told Ms Loudon that someone in his supervisory chain at the FDA even initiated a criminal investigation to identify the person who had leaked the information to the media.
With the SSRIs, he says, the FDA should have insisted on a signed informed consent form, that said three things: (1) these are the antidepressants available and only Prozac has been shown to work for children; (2) all the other drugs are no better than placebos; and (3) all these drugs appear to have the ability to increase the risk of suicidal behavior.
As a parent, he stated, if I saw that in writing and the doctor was going to write the prescription for some drug other than Prozac, I could say, “Doc, why are you putting my child on a drug that doesn't work in kids.”
According to Dr Graham, the FDA did not want patients to have that information, so it refused to require signed informed consent. And, the companies didn’t want parents to have that information because all of a sudden the lucrative “off-label” use of the drugs would have dried up.
Dr Graham also explained that, if the FDA pulls a drug off the market due to safety issues, it not only hurts the marketing of the drug, but also calls into question why it was approved in the first place.
"Therefore," he said, "you get this culture of cover-up, this culture of suppression, this culture of denial, and this culture that demonstrates above all else that industry is the client and not the American people."
Most Americans do not realize that a preemption decision on whether to throw out a lawsuit largely hinges on the judge assigned to the case. Attorneys James Beck and Mark Herrmann run the “Drug and Device Law” blog and they post their personal views on topics that arise in the defense of pharmaceutical company product liability litigation.
On May 17, 2007, they posted a piece called, "Picking Spots In Preemption Cases.” The bloggers lamented that "two adverse preemption decisions over the last couple of weeks [ ] have us scratching our heads."
The opinions referred to were Barnhill v Teva Pharmaceuticals, No 06-0282, (SD Ala Apr 24, 2007), and Kelly v Wyeth, 2007 WL 1302589 (Mass Super Apr 12, 2007).
In their blog, Mr Beck and Mr Herrmann discuss the importance of filing preemption motions with judges who are already known to be unsympathetic to private plaintiffs who sue drug companies.
"With respect to Kelly," they state, "the most salient point for us is why a preemption motion was brought at all in a state trial court in Massachusetts – a known pro-plaintiff jurisdiction."
"There’s certainly no history of success with preemption motions in prescription medical product cases in Massachusetts," they point out.
"Part of preemption strategy is choosing the jurisdictions in which such motions would have a reasonable likelihood of success," they explain.
"In plain English, you gotta pick your spots," the attorneys advise.
"If defendants go running helter skelter into courts filing preemption motions no matter how hostile the jurisdiction – well, the result is going to be decisions like Kelly," they warn.
"That doesn’t do the filing defendant any good," they state. "Nor does it do anyone else defending prescription drug cases any good."
On the other hand, in the September 2007 paper, "The Truth about Torts: Using Agency Preemption to Undercut Consumer Health and Safety," legal scholars, William Funk, Sidney Shapiro, David Vladeck and Karen Sokol, of the Center for Progressive Reform, discuss the importance of jury trials, and the tort system in general.
“It is less susceptible to disproportionate influence by large companies and trade associations than the federal regulatory system," they note and explain:
“When agencies respond to such influence by failing to regulate, or by adopting inappropriately weak regulations, the tort system becomes the primary legal vehicle for consumers to obtain protection from dangerous products and services.”
"Because tort decisions are made by juries, and because plaintiffs’ lawyers have the necessary skill and incentives to seek appropriate levels of protection for consumers and patients, the civil justice system puts individual consumers on the same footing as large corporations," according to the paper.
"Unlike the regulatory system," the authors explain, "the civil justice system makes it possible for members of the general public to be directly involved in governing."
"This is a crucial distinction," they note, "since individuals normally lack the same incentives as politically appointed government officials to resolve regulatory problems in favor of regulated entities."
They also note that, "although corporate interests expend significant resources in an attempt to populate the judiciary with industry-friendly judges in states where judges are elected, there is simply no way to ‘capture’ all the judges throughout the country’s numerous state and federal, trial and appellate courts."
"Moreover, even where judges are elected, citizens serving on juries are responsible for making decisions about liability," the paper concludes.
(Written as part of the SSRI Antidepressant Litigation Monthly Round-Up, Sponsored by Baum, Hedlund, Aristei & Goldmans’ Pharmaceutical Antidepressant Litigation Department)
Government attorneys appointed by the Bush Administration have been supporting GlaxoSmithKline in a number of courts across the country in an effort to convince the courts that lawsuits filed by victims of Paxil-induced injuries should be dismissed before ever making it to a jury.
In fact, the Administration has spent a massive amount of tax dollars filing amicus briefs on behalf of just about every drug maker involved in litigation in an attempt to get the lawsuits filed by private citizens thrown out of court.
The government claims that, once a drug and the warnings on its label are approved by the FDA, claims alleging injuries caused by a company's failure to warn about a risk not listed on the label are preempted.
The Bush Administration says preemption applies even when a company (1) continues to sell a drug when a risk is known; (2) fails to warn when new risks are discovered; (3) fails to send letters notifying prescribing doctors of a known risk, and (4) fails to disclose a known risk to the FDA during the approval process, or anytime for that matter. In essence, if the FDA doesn’t make the companies warn, they’re off the hook.
If the Administration is successful in obtaining immunity for these drug companies, taxpayers will be left to pay not only the costs of medical care for all persons injured by drugs but also the life-long care for persons disabled by a product.
If Americans realized what was happening, there is no way they would approve of their tax dollars being spent to help the richest industry on the planet deprive fellow citizens of their right to a jury trial.
The typical brief against a plaintiff is filed by an army of government attorneys and will include an Assistant Attorney General, a Deputy Assistant Attorney General, a United States Attorney, an Assistant United States Attorney, two Appellate Attorneys from the Department of Justice, the FDA's Chief Counsel, and the Deputy Chief Counsel, Associate Chief Counsel, and General Counsel for the Department of Health and Human Services.
Glaxo takes things one step further by submitting government amicus briefs that were filed in other cases (not just Paxil cases) and re-files them in virtually every one of the cases filed against the company in order to bolster its preemption arguments.
In O’Neal v GlaxoSmithKline, a case involving the suicide of a 13-year-old Sacramento, California boy, Benjamin Bratt, Glaxo recently used the Bush Administration's preemption policy to argue that the child's family should not be allowed to sue Glaxo for failing to warn about the suicide risk.
Benjamin committed suicide on February 14, 1997 by hanging himself. His parents, Terri O’Neal and Barry Bratt, filed a lawsuit alleging that, despite knowledge of suicide risks associated with Paxil prior to 1997, Glaxo concealed the information, failed to warn doctors, the medical community, and the public and all the while the company promoted the drug as safe and effective for children.
In the lawsuit, the Bratt Family alleged that Glaxo should have warned Benjamin’s doctor about the suicide risk both through the label and through other means, such as promotion, advertising, and “Dear Doctor” letters.
On January 30, 2008, federal judge, Frank Damrell, in the US District Court, Eastern District of California, dismissed the case and ruled that all of the family’s claims were preempted. The Bratt family has asked the court to reconsider the ruling. They believe the judge committed error in essentially holding that a drug that is not safe for adults is nonetheless safe for children until proven otherwise.
The family argues that adult clinical trials conducted by Glaxo as far back as 1989 showed an 8 times increased risk of suicidal behavior for Paxil users compared to patients receiving a placebo, but that Glaxo manipulated the data to obscure the risk, and then published the false data in medical journals and articles throughout the 1990's.
In his ruling, Judge Damrell held that, even if GSK had clinical trial data prior to 1997 that showed an increased risk of suicidality in adults, that data was not sufficient to prove the risk extended to children using Paxil.
The Court held that, because the first clinical trial of Paxil with children did not conclude until 1998, Glaxo could not have known about the suicide risks with kids before that date.
During the January 18, 2008 oral argument on the preemption motion, Judge Damrell himself pointed out that a finding of an increased risk of suicidality in adults would logically apply to children. He specifically stated:
"As a practical matter, if I see there was an association of suicide ideation with anybody and enough of it, the last person I want to see using it is a child. That may not be scientific, but I’m just talking as a grandfather and human being."
However, in his order, Judge Damrell seems to say the exact opposite:
"That later clinical studies ultimately led to a clear signal of pediatric suicidality, and that these studies arguably reflected the initial data in 1989 and 1991 of similar associations among adults, simply does not provide ‘reasonable evidence’ of the association of pediatric suicidality in February 1997."
“It is difficult to reconcile Judge Damrell’s statements during oral argument with his ruling,” says senior trial attorney, Ron Goldman of Baum, Hedlund, Aristei & Goldman, the law firm representing the Bratt family.
Baum Hedlund has roughly 30 lawsuits on file involving Paxil-induced suicides and suicide attempts. Over the past 18 years, the firm has handled more than 3,000 cases involving antidepressants, including Glaxo’s Paxil, Eli Lilly's Prozac and Pfizer's Zoloft.
The first study Glaxo conducted on children was called Study 329. The study was started in 1994, three years prior to Benjamin’s suicide, and was completed in 1998, nine months after his suicide.
Judge Damrell bought Glaxo’s argument that, because Study 329 wasn’t completed until after Ben Bratt’s death, the company could not have warned of a risk in children prior to that. But, during the four years the study was ongoing, Glaxo received numerous reports of suicidal behavior occurring in children taking Paxil.
Coupled with the risk evident from the adult clinical trials since 1989, the Bratt family argues that Glaxo could have and should have warned of the risk for all people taking the drug long before Benjamin ingested Paxil.
Coincidentally, when the study 329 was finally published, the authors stated that, "The adverse-effect profile of paroxetine in this adolescent population was concordant with that reported in studies of adult patients with depression."
The Bratt family argues that, the question of whether reasonable evidence of an association existed between Paxil and suicidality in any population at the time of Benjamin’s death is one for the jury.
The question of what Glaxo knew and when Glaxo knew it is also a question for the jury. Glaxo’s attempt to continue the parade down this rabbit trail is simply an attempt to divert attention away from the core issue here. The decisive question in a preemption context for the Court to determine is, “was GSK ever prohibited by the FDA from issuing a warning” thus creating a direct and positive conflict. The answer is unequivocally “NO.”
Judge Damrell also held that, if Glaxo had warned about a suicide risk for kids prior to 1997, such a warning would have been subject to a misbranding action by the FDA.
According to Mr Goldman, "Under no circumstances, given the regulatory scheme, can a drug be considered ‘misbranded’ if the science supports a truthful warning of the risk of suicidality.”
“Under the law," he says, "it is a drug manufacturer’s duty to warn of risks known or reasonably scientifically knowable.”
“A drug company that fails or refuses to conduct necessary analyses in a scientifically acceptable manner,” he states, “shirks its legal, not to mention ethical and moral, duty to the medical profession and the public.”
According to the US Supreme Court, preemption applies (1) where it is impossible for a private party to comply with both federal and state law; and (2) where the state law stands as an obstacle to the accomplishment and execution of the full purposes and objective of Congress.
“When carefully analyzed, there is absolutely no evidence showing that it would have been ‘impossible’ for Glaxo to warn of this very serious risk, an absolute requirement in cases where conflict preemption is raised,” Mr Goldman contends.
“To the contrary,” he says, “such a warning is in perfect harmony with the FDA regulations and the overarching purpose of the FDA: to promote health and safety in prescription drugs.”
In their brief filed in opposition to summary judgment, the Bratt Family stated: "GSK would like to convince this Court that it is merely a ‘puppet’ when it comes to labeling its multi-billion dollar blockbuster drug, Paxil."
"According to GSK," the brief notes, "it is hapless and at the mercy of the FDA when it comes to the content of Paxil’s label."
Glaxo claims it needed the FDA's prior approval to issue a warning. However, the attorneys in the Paxil cases point out that Glaxo itself changed the label and sent out a Dear Doctor letter warning about the suicide risk in May 2006, with no prior approval from the FDA. The FDA never objected to the letter or the strengthened warning label.
The FDA, in its amicus briefs, has asserted twisted logic in these cases because the FDA cannot force a company to add a warning to a label. On March 1, 2005, the FDA's deputy director for the Office of New Drugs, Dr Sandra Kweder, testified at a hearing before the Senate Committee on Health, Education, Labor and Pensions, that the FDA does not have the authority to require a specific label change and that the agency has to negotiate with the companies about how things should be worded, placement, those kinds of things.
During oral argument in SSRI suicide cases, industry attorneys claim that the reevaluation of the suicide risk of all the pediatric studies on SSRIs occurred after Glaxo “voluntarily” offered up the studies to the FDA.
For instance, on December 10, 2007, during oral argument in a case in a federal court in Philadelphia, a Pfizer attorney, Malcolm Wheeler was asked by the court: “What was the tipping point then for the change in position with respect to adolescents and then later extending that to young adults up to age 24?”
Mr Wheeler replied: “The tipping point was because GlaxoSmithKline voluntarily went forward and informed the FDA of some study results and said here are these results.”
“And what the FDA did as a result of that,” he told the court, “was to conduct a new analysis, pooling the data from nine different drugs, not just SSRIs, but nine different antidepressants, to say when we pool all the data from these various antidepressants, does it indicate any signal that suggests that we ought to do something other than what we've done in the past?”
However, that is a gross misrepresentation of what actually happened. The truth is, according to FDA documents obtained in litigation, that the European Medicines Agency (EMEA) contacted the FDA in mid-2003 to alert officials about the hidden suicide risk in the pediatric Paxil studies.
According to a June 2, 2003, FDA email written by Dr Russell Katz to Dr Andrew Mosholder, the FDA was notified in May 2003, that suicide events were hidden under the term "emotional lability." Dr Katz's email states:
“We have recently become aware of a presumed association between Paxil and suicidality in pediatric patients. We received a call from the EMEA a little over a week ago.
A Dr. Raines told us that the company (GSK) had submitted data that demonstrated that use of Paxil in kids was associated with increased suicidality compared to placebo, and that the company proposed labeling changes.
“I believe she also said that it was in the news, and it was a big issue. Tom and I told her that the company had not informed us of any of this, and we agreed to look into it.”
Dr Katz told Dr Mosholder that the FDA had asked Glaxo to elaborate on the events listed under the term emotional lability and further stated:
“We received this partial response, and almost all of these events related to suicidality. The bottom line is that when data from the controlled trials in depression, OCD, and Social Anxiety are pooled, for “possible suicide related” events occurring during treatment or within 4 days after discontinuation, the rate is 0.14/patient-year on drug, and 0.05/patient-year on placebo, p=0.02.”
“We have some problems with the methodology they used to capture cases, but this is the major finding, and it has us worried,” he wrote.
“We are planning to look at the NDAs for other SSRIs to see whether or not similar events are being hidden by various inappropriate coding maneuvers, but we’d also like to compare the drugs in other meaningful ways if we can,” Dr Katz informed Dr Mosholder.
A report by Harvard psychiatrist, Dr Joseph Glenmullen, retained by Baum Hedlund as an expert witness in the Bratt case shows that Glaxo knew as early as 1989 that patients who received Paxil in clinical trials showed an 8-fold increased risk of suicidality compared to patients who received placebos. Dr Glenmullen’s report was initially filed under seal, however, on January 30, 2008, the majority of the report was unsealed.
In the report, Dr Glenmullen also notes that, when Glaxo coded suicidal behavior in its computerized database, most of the suicides and suicide attempts were coded as "emotional lability," which he says is "a technical term for rapid mood swings, for example from crying to laughing."
Another claim consistently made by both the Bush Administration attorneys and the attorneys for the SSRI makers, is that the FDA’s failure to make the companies issue warnings somehow means the FDA considered and rejected offers by the companies to add warnings about the suicidality risk.
However, Dr Katz specifically notes in his email that Glaxo never offered to add a warning to the label in the US, even after the FDA became aware of the increased suicide risk and discussed the issue with Glaxo.
“The sponsor has not proposed labeling changes and makes a feeble attempt to dismiss the finding,” he told Dr Mosholder in the email.
In the first SSRI case where preemption was raised (the company lost the argument), Motus v Pfizer, the judge wisely observed that, “although the FDA did not require Pfizer to include suicide-related warnings in Zoloft’s label, FDA has not prohibited Pfizer from doing so” and the “FDA never stated that it would be impermissible to include additional warnings.” Likewise, because Glaxo never sought to add a suicide warning, it is not possible that the FDA considered and a suicide warning.
On June 10, 2003, the UK's Medicines and Healthcare Products Regulatory Agency issued the warning: "It has become clear that the benefits of Seroxat in children for the treatment of depressive illness do not outweigh these risks."
In the June 11, 2003 New York Times, Gardiner Harris reported that Alan Metz, the vice president for clinical development at Glaxo, said the company was not warning American doctors against using the drug with depressed children in the US.
Dr Metz acknowledged that Paxil was not approved for treating children in the US but that many doctors prescribed the drug for children anyway. Mr Harris pointed out that Glaxo had applied for approval from the FDA to sell Paxil to children with obsessive compulsive disorder and the application was pending at that time.
On June 20, 2003, the Times reported that the FDA's reanalysis found that the risk of suicidal thoughts and suicide attempts was 3 times greater among children using Paxil, mostly teenagers, than among children given placebos.
On August 12, 2003, the Times ran a commentary by Richard Friedman, a psychiatrist and director of the psychopharmacology clinic at Weill Medical College of Cornell University, which stated in part:
"What is disturbing about the recent report is that the purported link between Paxil and suicidal thinking comes from an unpublished study sponsored by Paxil's manufacturer, GlaxoSmithKline."
"In fact, GlaxoSmithKline has published only one of its nine studies of Paxil in children and adolescents to date," he reported.
In its preemption motion, Glaxo offered nothing to support the claim that the FDA had considered, much less rejected, a proposal to add a warning about the increased suicide risk for kids. In fact, the studies in question were not submitted to the FDA until 2002, when Glaxo sought approval for new uses of Paxil, meaning it would have been impossible for the FDA to have considered whether a warning was appropriate based on a risk known only to Glaxo.
To support their argument that the FDA had never rejected a Glaxo proposed warning, the Bratt family brief states: "None of the GSK employees in the past 14 years who have, or had, responsibility for communicating with the FDA regarding Paxil could point to any specific, proposed suicide or suicidality language that was rejected by the FDA.
In his report, Dr Glenmullen explains how Glaxo successfully avoided having to include a warning on the label when it obtained FDA approval for Paxil in 1992:
"GlaxoSmithKline's ‘bad’ Paxil data made it look as if patients randomized to Paxil were no more likely to become seriously suicidal when, in fact, the correct data shows patients on Paxil were eight times more likely to commit or attempt suicide."
"One again," he states, "GlaxoSmithKline's ‘bad’ Paxil numbers carried the day: The FDA approved Paxil on December 29, 1992 with no warning to doctors or patients of the significant increased risk of suicidal behavior."
The FDA's Dr David Graham, most famous for exposing the risks associated with Vioxx, says the government's attempts to immunize drug companies must not succeed. In an August 30, 2005 interview with Manette Loudon, the lead investigator for Dr Gary Null, (author of numerous books including “7 Steps To Overcoming Anxiety and Depression”), Dr Graham was asked about his views on attempts to pass tort reform.
"I think it's dangerous and wrong," he stated. "We already have an FDA that's been neutralized by industry and sees industry as its client."
Dr Graham said the agency is not going to protect the average citizen from the consequences of unsafe drugs, so the only alternative is the legal system. "That's the only way we have of getting companies to change their behavior," he said and, "tort reform would remove that threat as well."
"It's basically giving companies immunity because now the people who are injured by the drugs can't recover damages that might actually mean something to industry," he advised.
"I mean $250,000 for damages; they blow that in one ad campaign," he stated. "To them, that's nothing."
"But a lawsuit for multiple millions of dollars has more of an impact," he added.
"Now, is that optimal?" he said. "No."
"But the fact is that since we have a regulatory agency that doesn't regulate and we have a public health agency that doesn't protect the public, we have thousands of people who are being injured by products that the FDA knows are unsafe," he told Ms Loudon.
He pointed out that the FDA knew there was a big problem with Vioxx in mid 2000, and did nothing about it. If the FDA is not going to exercise control over companies, he said, there has to be a system in place "that reins companies in."
In addition to the agency's failure to protect the public against Vioxx, Dr Graham also discussed the FDA's attempts to conceal the increased suicide risks that were found in the reevaluation of the pediatric SSRI studies in early 2004. "The FDA had suppressed a report written by a colleague of mine in drug safety and had prevented him from presenting this information in an advisory committee meeting," he explained.
"That information leaked to the media," Dr Graham continued, "embarrassing the FDA because it had been caught suppressing very important information – that most of the antidepressants don't work for treating children."
He told Ms Loudon that someone in his supervisory chain at the FDA even initiated a criminal investigation to identify the person who had leaked the information to the media.
With the SSRIs, he says, the FDA should have insisted on a signed informed consent form, that said three things: (1) these are the antidepressants available and only Prozac has been shown to work for children; (2) all the other drugs are no better than placebos; and (3) all these drugs appear to have the ability to increase the risk of suicidal behavior.
As a parent, he stated, if I saw that in writing and the doctor was going to write the prescription for some drug other than Prozac, I could say, “Doc, why are you putting my child on a drug that doesn't work in kids.”
According to Dr Graham, the FDA did not want patients to have that information, so it refused to require signed informed consent. And, the companies didn’t want parents to have that information because all of a sudden the lucrative “off-label” use of the drugs would have dried up.
Dr Graham also explained that, if the FDA pulls a drug off the market due to safety issues, it not only hurts the marketing of the drug, but also calls into question why it was approved in the first place.
"Therefore," he said, "you get this culture of cover-up, this culture of suppression, this culture of denial, and this culture that demonstrates above all else that industry is the client and not the American people."
Most Americans do not realize that a preemption decision on whether to throw out a lawsuit largely hinges on the judge assigned to the case. Attorneys James Beck and Mark Herrmann run the “Drug and Device Law” blog and they post their personal views on topics that arise in the defense of pharmaceutical company product liability litigation.
On May 17, 2007, they posted a piece called, "Picking Spots In Preemption Cases.” The bloggers lamented that "two adverse preemption decisions over the last couple of weeks [ ] have us scratching our heads."
The opinions referred to were Barnhill v Teva Pharmaceuticals, No 06-0282, (SD Ala Apr 24, 2007), and Kelly v Wyeth, 2007 WL 1302589 (Mass Super Apr 12, 2007).
In their blog, Mr Beck and Mr Herrmann discuss the importance of filing preemption motions with judges who are already known to be unsympathetic to private plaintiffs who sue drug companies.
"With respect to Kelly," they state, "the most salient point for us is why a preemption motion was brought at all in a state trial court in Massachusetts – a known pro-plaintiff jurisdiction."
"There’s certainly no history of success with preemption motions in prescription medical product cases in Massachusetts," they point out.
"Part of preemption strategy is choosing the jurisdictions in which such motions would have a reasonable likelihood of success," they explain.
"In plain English, you gotta pick your spots," the attorneys advise.
"If defendants go running helter skelter into courts filing preemption motions no matter how hostile the jurisdiction – well, the result is going to be decisions like Kelly," they warn.
"That doesn’t do the filing defendant any good," they state. "Nor does it do anyone else defending prescription drug cases any good."
On the other hand, in the September 2007 paper, "The Truth about Torts: Using Agency Preemption to Undercut Consumer Health and Safety," legal scholars, William Funk, Sidney Shapiro, David Vladeck and Karen Sokol, of the Center for Progressive Reform, discuss the importance of jury trials, and the tort system in general.
“It is less susceptible to disproportionate influence by large companies and trade associations than the federal regulatory system," they note and explain:
“When agencies respond to such influence by failing to regulate, or by adopting inappropriately weak regulations, the tort system becomes the primary legal vehicle for consumers to obtain protection from dangerous products and services.”
"Because tort decisions are made by juries, and because plaintiffs’ lawyers have the necessary skill and incentives to seek appropriate levels of protection for consumers and patients, the civil justice system puts individual consumers on the same footing as large corporations," according to the paper.
"Unlike the regulatory system," the authors explain, "the civil justice system makes it possible for members of the general public to be directly involved in governing."
"This is a crucial distinction," they note, "since individuals normally lack the same incentives as politically appointed government officials to resolve regulatory problems in favor of regulated entities."
They also note that, "although corporate interests expend significant resources in an attempt to populate the judiciary with industry-friendly judges in states where judges are elected, there is simply no way to ‘capture’ all the judges throughout the country’s numerous state and federal, trial and appellate courts."
"Moreover, even where judges are elected, citizens serving on juries are responsible for making decisions about liability," the paper concludes.
(Written as part of the SSRI Antidepressant Litigation Monthly Round-Up, Sponsored by Baum, Hedlund, Aristei & Goldmans’ Pharmaceutical Antidepressant Litigation Department)
Lawmakers Catch Glaxo Hiding Paxil Suicide Risks - Again (Part I)
Evelyn Pringle February 12, 2008
GlaxoSmithKline recently received greetings from a Congressional Committee, asking the company to explain the findings in a report unsealed last month in a lawsuit which shows that Glaxo knew as early as 1989 that Paxil increased the risk of suicidal behavior in patients by more than 8-fold compared to patients who received a placebo.
In a February 6, 2008 letter, Senator Charles Grassley (R-Iowa), ranking member of the Senate Finance Committee, is asking Glaxo to explain why the American public was never adequately informed of this risk until May 2006 in a "Dear Healthcare Professional" letter which reported a "higher frequency of suicidal behavior" associated with Paxil as compared to placebo.
The report showing the 8-fold suicide risk, by Harvard instructor and psychiatrist Joseph Glenmullen, was unsealed on January 18, 2008, by a federal judge in a US District Court in Sacramento, California in the Paxil suicide case of O'Neal v SmithKline Beecham d/b/a GlaxoSmithKline, filed by the surviving family members of 13-year-old Benjamin Bratt.
Dr Glenmullen was retained as an expert in the case by the California-based Baum, Hedlund, Aristei & Goldman law firm.
On January 30, 2008, the court dismissed the lawsuit on the basis of the Bush Administration's new preemption policy, largely unknown to most Americans, which says that once the FDA approves a drug and its label, citizens may not sue a company for failing to warn about a risk not listed on the label, even in cases like this where the plaintiff can prove that the company knew about the risk and intentionally concealed it.
SSRI's are antidepressants known as selective serotonin reuptake inhibitors and include Paxil, Eli Lilly's Prozac, Zoloft by Pfizer and Celexa and Lexapro marketed by Forest Labs. Wyeth's Effexor, Lilly's Cymbalta and Glaxo's Wellbutrin are not considered SSRI's, but they also carry a warning about an increased risk of suicidality in young people.
Two SSRI suicide cases are now awaiting a joint decision from the Third Circuit Court of Appeals for which oral arguments took place in December 2007.
In the case of Colacicco v Apotex, the US District Court for the Eastern District of Pennsylvania was the first to dismiss a failure-to-warn claim based on the new preemption policy, and in McNellis v Pfizer, the US District Court for the District of New Jersey found no preemption.
Also unbeknownst to most Americans, the Bush Administration is instructing judges to dismiss the lawsuits against the SSRI makers in amicus briefs filed by the government's top attorneys, who also attend hearings when necessary to argue on behalf of the SSRI makers during oral arguments on motions to dismiss.
In fact, in regard to requiring a warning about suicide, during oral arguments in the Third Circuit, Bush Administration attorney Sharon Swingle told the court that the FDA "had again and again and again made an expert determination that the warning was not appropriate."
She maintained that the claims were preempted because the SSRI makers were not allowed to add warnings to the label under any circumstances without prior approval from the FDA.
At one point, the court asked an attorney for an SSRI maker, "assume for the moment that you had reasonable evidence of an association between your product and a serious hazard or a serious possibility of an enhanced suicide risk."
Under federal regulations, "what would be your obligation?"
The attorney stated, "our obligation would be to take that information to the FDA, advise the FDA of the information."
"It then would be the FDA's determination whether that represented a substantial relationship," he told the court.
"So if you had evidence internally that there's an enhanced risk of suicide, you would go to the FDA," the court said, and asked, "And how long would that take?"
"I do not know the answer to that, your Honor," the attorney said, and the court asked, "Could it take months?"
"I imagine it would depend on the seriousness --," the attorney stated.
"But isn't there a significant possibility that additional people then might have the same consequence that happened here with McNellis, or with Colacicco and McNellis's father?" the court asked.
The attorney said, "on the basis of the information that was available we would take it per FDA directive to the FDA and they would make the determination whether the label should be changed."
"Other people could then," the court continued, "possibly have an enhanced risk of suicide and other people may commit suicide as a result of taking your product?"
"We would be bound by law to comply with the FDA, then to comply with its directives," the attorney replied.
"Are they requiring that you go through them first rather than act on your own?" the court asked.
"That's exactly correct, your Honor, because there is the bigger issue of the --" the attorney stated.
However, at the end of the hearing, Pennsylvania attorney Derek Braslow proved beyond any doubt that the claims made by the Bush Administration attorney and the attorneys for the drug makers were blatant lies, when he informed the court that Glaxo had "independently, strengthened their warning in May 2004 to warn about increased suicidality and worsening depression in everyone, not just children."
"There was specifically in bold letters a new warning with respect to increased suicidality and worsening depression in May 2004," he stated.
"Glaxo changed the label on their own without FDA approval," Mr Braslow told the court.
Glaxo did it again in May 2006, he said, when they sent out a "Dear Healthcare Professional" letter and warned about the increased risk of suicidality and suicidal behaviors with Paxil in persons of all ages.
During oral arguments in the O'Neal case on January 21, 2008, Glaxo's preemption argument was presented by King & Spalding attorney Mark Brown, who just happens to be a former Associate Chief Counsel for the FDA from the first Bush Administration.
The family intends to ask the court to reconsider the ruling in the O'Neal case, according to a statement by Baum Hedlund.
In his report, Dr Glenmullen sums up the inadequacy of the system, including the FDA, that allowed Glaxo to keep this vital information hidden from prescribing doctors and patients for nearly 2 decades and states, in part:
"One of the most sobering aspects of the story of Paxil-induced suicidality is that GlaxoSmithKline was not forthcoming with its data demonstrating the risk and regulatory agencies like the FDA did not take the initiative to get to the bottom of and expose the true risk."
"Rather, the impetus came from attorneys and medical experts surprised by what they found in GlaxoSmithKline's confidential documents, which only came to light through litigation."
"The GlaxoSmithKline documents that have so-far made it into the public record have in turn been critical to educating patients, the public, and the media about the true risk. The media - particularly the BBC in England - played a crucial role in turning the tide in the history of Paxil-induced suicidality."
According to Dr Glenmullen, "it was the diligent efforts of plaintiff's attorneys that forced GlaxoSmithKline to divulge the inaccurate counting method to the FDA."
Another leading expert on pharmacology, Dr Peter Breggin, warns that an 8-fold increased risk of suicidality in controlled clinical trials could mean 80-fold in actual practice. "We can't determine exactly how much greater the risk will be in clinical practice but it will be astronomically greater," he advises.
In actual practice, he explains, many patients are already suicidal when they start taking the drug, increasingly the likelihood that the drug can push them over the edge.
Despite the warnings to watch patients closely, Dr Breggin says, busy doctors do not monitor patients properly. He explains that they are almost never evaluated for suicidality and are often given multiple drugs at the same time, by doctors who know little about their adverse effects on the mind.
Glaxo is facing lawsuits from surviving family members of Paxil suicide victims all over the country and is attempting to use preemption to avoid public trials for good reason. The first case to go before a jury in Wyoming in 2001, involved a man who shot his wife, daughter and infant granddaughter before shooting himself after being on Paxil for just a matter of days.
The trial resulted in a verdict against Glaxo for $6.4 million after the jury weighed the expert testimony of famed pharmacologist Dr David Healy, who presented a summary of Glaxo's hidden suicide data on Paxil, against the testimony of the industry-funded SSRI defender Dr John Mann, whose name appears on many of the studies issued over the years, some as late as 2007, that steadfastly proclaim that SSRI's are not linked to suicide and should be prescribed to children.
In addition to Dr Healy's revelations about hidden data showing that Glaxo was aware of the increased risk, Dr Mann's credibility was likely weighed against the fact that he had received over $30 million in research funding from drug companies between the early 1990's and the trial in 2001, which was brought out during his testimony by Houston attorney Andy Vickery.
Mr Vickery also established that, roughly 10 years and $30 million earlier, Dr Mann had published a paper stating that SSRI's could increase suicidality in a small subset of patients.
In his report, Dr Glenmullen states that, since Glaxo had the original data in 1989 that showed a greater than eightfold increased risk, it should have warned doctors and patients about the risk "a decade-and-a-half ago when Paxil was first approved by the FDA."
The report includes portions of an April 29, 1991 report, written by Glaxo psychiatrist Dr Geoffrey Dunbar, sent to the FDA in response to a specific request for information on suicidality in which Glaxo openly lies in stating: "analyses of our prospective, clinical trials for depression show that patients who were randomized to Paxil therapy were at no greater risk for suicidal ideation or behavior than were patients randomized to placebo or other active control therapies."
Dr Glenmullen notes the importance of the date that this false data was submitted because the FDA had scheduled a hearing with a nine-member advisory panel for September 20, 1991, to discuss concerns raised a year earlier about the possibility of Prozac making patients suicidal. Paxil was not approved for use in the US until December 2002.
In his report, Dr Glenmullen points out that 5 of the 9 members on the advisory panel had conflicts of interest with drug makers and that 2 psychiatrists, Dr David Dunner of the University of Washington in Seattle and Dr Stuart Montgomery from England, had done research on Prozac for Eli Lilly, and later played crucial roles in Glaxo's publishing of what he calls "bad" suicide numbers in the Paxil story.
Dr Glenmullen's report includes portions of a September 19, 1991, memo distributed to over 20 senior staff the day before the hearing with a "Statement to be used to respond to inquiries re Paxil/Suicide," which claims explicitly that during GlaxoSmithKline's studies: "the incidence of suicide was lower among patients receiving Paxil than among those receiving placebo."
This was the statement the company ordered employees to make, even though 5 patients on Paxil committed suicide while no patients in the placebo group did. In addition, Dr Glenmullen points out that, up to 1989, seriously suicidal patients were excluded from Glaxo's studies, and therefore "anyone who became seriously suicidal during the studies only became so after being given Paxil or a placebo."
Yet the actual numbers show that there were 40 suicide attempts in the clinical trials by patients taking Paxil compared to 1 suicide attempt in the placebo groups.
Despite the poor quality of the data available to the advisory committee, and despite the many conflicts of interest of its members, one third of the members still voted for a warning in 1991, Dr Glenmullen points out.
Three months later, in December 1991, Dr Dunner, together with Glaxo psychiatrist Dr Dunbar, presented Glaxo's Paxil data with the "bad" numbers at a meeting of the American College of Neuropsychopharmacology (ACNP) in Puerto Rico.
During the presentation, the doctors told the ACNP: "Suicide and suicide attempts occurred less frequently with Paxil than with either placebo or active control," according to the Glenmullen report.
The ACNP's members are considered prominent academic psychiatrists who specialize in pharmacology, and the group has issued a number of position papers over the years which consistently denied a link between SSRI's and suicidality.
Dr Mann led an ACNP task force which included Dr Fred Goodwin, Dr Charles O'Brien and Dr Robinson, which supposedly reviewed all the clinical trial data on SSRI's and issued a consensus statement with the position that SSRI's did not increase the risk of suicidal behavior, which was published in the journal Neuropsychopharmacology in 1993.
In March 1995, Dr Dunner, Dr Montgomery and Dr Dunbar published the paper, "Reduction of suicidal thoughts with paroxetine in comparison with reference antidepressants and placebo," in the European journal Neuropsychopharmacology. This paper included a table with the "bad" numbers and claimed that other antidepressants were more likely to increase the risk of suicide than Paxil.
The paper specifically states: "Consistent reduction in suicides, attempted suicides, and suicidal thoughts, and protection against emergent suicidal thoughts suggest that Paxil has advantages in treating the potentially suicidal patients."
On July 5, 1995, Glaxo's marketing department issued a memo urging its sales force to use the Dunner-Dunbar paper to reassure doctors who were concerned over Paxil-related suicide that there was no need for concern.
The fact is, documents obtained in litigation prove that the FDA has known about the suicide risks of SSRI's for roughly 23 years. Two years before Prozac was approved, in May 1985, the FDA's chief investigator, Dr Richard Kapit, wrote: "Unlike traditional tricyclic antidepressants Fluoxetine's profile of adverse side effects more closely resembles that of a stimulant drug than one that causes sedation."
"It is Fluoxetine's particular profile of adverse side-effects which may perhaps, in the future give rise to the greatest clinical liabilities in the use of this medication to treat depression," he noted.
Dr Kapit's review described data from 46 clinical trials with a total of 1,427 patients and under the section, "Catastrophic and Serious Events," he listed 52 cases of "egregiously abnormal laboratory reports which were the reason for early termination," and "additional adverse event reports not reported by the company were revealed on microfiche."
"In most cases," he wrote, "these adverse events involved the onset of an unreported psychotic episode."
There were ten reports of psychotic episodes including 2 reports of completed suicides, 13 attempted suicides, 4 seizures, and 4 reports of movement disorders. In 1985, Dr Kapit recommended "labeling warning the physician that such signs and symptoms of depression may be exacerbated by this drug".
When Prozac was approved, no such warning was issued.
Two weeks after the FDA advisory panel met in February 2004 to review the data on SSRI's to determine whether they were linked to suicide, Dr Healy sent a report to Peter Pitts, Associate Commissioner for External Relations, at the FDA, in response to an invitation by Dr Robert Temple for a submission of the details of studies referred to in the course of a presentation at the meeting.
"A great number of the patient testimonies in the course of the Feb 2nd hearing were from individuals who became suicidal on an SSRI when their underlying disorder was Lyme Disease, migraine or a condition such as social phobia," Dr Healy pointed out.
He also noted that this had been the case in the 1991 hearings, when it was framed by FDA's Dr Temple as follows:
"The discussion we heard earlier showed that people who commit suicide are highly likely to have a diagnosis of depression, which means that somebody identified them as in a high-risk category. But there were still a significant number of people who committed suicide without having that sort of diagnosis and I guess I would like some advice or discussion on who those people were."
"The anecdotes that one hears that are most evocative to me anyway are not the ones where people who have a 20-year history of suicidal ideation and then finally do it - that is not too surprising - it is where they assert that there has never been anything in their minds like that before and yet now they have suddenly become excessively concerned with suicide and may even do it."
Dr Healy's analysis submitted to the FDA included the data from the pediatric trials on suicidality and hostility, including some that were concealed for years. To distinguish the difference between suicide caused by SSRI's verses suicide caused by the underlying depression, he separated the data on children who were treated for depression and children who were treated for obsessive compulsive disorder or social phobia.
The analysis found that SSRI's can cause some children who are not depressed to become suicidal when taking the drugs for other conditions. From a pool of 931 depressed patients taking SSRI's versus 811 depressed patients taking placebo, Dr Healy determined that there were 52 suicidal acts by patients on SSRI's versus 18 in the placebo group.
In a pool of 638 patients taking SSRI's for other disorders versus 562 patients taking a placebo, there were 10 suicidal acts in the SSRI group versus 1 in the placebo group.
When these data sets were combined, there were 62 episodes of suicidality in the 1,569 patients on SSRI's versus only 19 episodes in the 1,373 patients on a placebo.
In his submission to the FDA, Dr Healy also explained that he had conducted his own trial on Zoloft in 2000 with 20 "healthy volunteers," meaning they had no mental disorder when entering the trial, and two of the Zoloft patients became suicidal. This type of study provides the strongest evidence of drug-induced suicidality because it's impossible for drug companies to claim that a patient became suicidal as a result of the underlying depression.
Seven years ago, during the Wyoming jury trial involving the tragic Paxil-induced murder-suicide, the man's physician testified that he may not have prescribed Paxil if a warning regarding homicide and suicide had been added to the drug's label.
In his report released last month, Dr Glenmullen offers the following heart-wrenching conclusion to the court: "It is my opinion to a reasonable degree of medical probability that if GlaxoSmithKline had provided a warning all these years, Benjamin Bratt would still be alive today."
On April 24, 2004, the Lancet medical journal published an editorial entitled, "Depressing Research," with the following comments that surely ring doubly true today for the Bratt family, as well as all the other families whose children committed suicide while on SSRI's:
"It is hard to imagine the anguish experienced by the parents, relatives, and friends of a child who has taken his or her own life. That such an event could be precipitated by a supposedly beneficial drug is a catastrophe. The idea of that drug's use being based on the selective reporting of favourable research should be unimaginable."
GlaxoSmithKline recently received greetings from a Congressional Committee, asking the company to explain the findings in a report unsealed last month in a lawsuit which shows that Glaxo knew as early as 1989 that Paxil increased the risk of suicidal behavior in patients by more than 8-fold compared to patients who received a placebo.
In a February 6, 2008 letter, Senator Charles Grassley (R-Iowa), ranking member of the Senate Finance Committee, is asking Glaxo to explain why the American public was never adequately informed of this risk until May 2006 in a "Dear Healthcare Professional" letter which reported a "higher frequency of suicidal behavior" associated with Paxil as compared to placebo.
The report showing the 8-fold suicide risk, by Harvard instructor and psychiatrist Joseph Glenmullen, was unsealed on January 18, 2008, by a federal judge in a US District Court in Sacramento, California in the Paxil suicide case of O'Neal v SmithKline Beecham d/b/a GlaxoSmithKline, filed by the surviving family members of 13-year-old Benjamin Bratt.
Dr Glenmullen was retained as an expert in the case by the California-based Baum, Hedlund, Aristei & Goldman law firm.
On January 30, 2008, the court dismissed the lawsuit on the basis of the Bush Administration's new preemption policy, largely unknown to most Americans, which says that once the FDA approves a drug and its label, citizens may not sue a company for failing to warn about a risk not listed on the label, even in cases like this where the plaintiff can prove that the company knew about the risk and intentionally concealed it.
SSRI's are antidepressants known as selective serotonin reuptake inhibitors and include Paxil, Eli Lilly's Prozac, Zoloft by Pfizer and Celexa and Lexapro marketed by Forest Labs. Wyeth's Effexor, Lilly's Cymbalta and Glaxo's Wellbutrin are not considered SSRI's, but they also carry a warning about an increased risk of suicidality in young people.
Two SSRI suicide cases are now awaiting a joint decision from the Third Circuit Court of Appeals for which oral arguments took place in December 2007.
In the case of Colacicco v Apotex, the US District Court for the Eastern District of Pennsylvania was the first to dismiss a failure-to-warn claim based on the new preemption policy, and in McNellis v Pfizer, the US District Court for the District of New Jersey found no preemption.
Also unbeknownst to most Americans, the Bush Administration is instructing judges to dismiss the lawsuits against the SSRI makers in amicus briefs filed by the government's top attorneys, who also attend hearings when necessary to argue on behalf of the SSRI makers during oral arguments on motions to dismiss.
In fact, in regard to requiring a warning about suicide, during oral arguments in the Third Circuit, Bush Administration attorney Sharon Swingle told the court that the FDA "had again and again and again made an expert determination that the warning was not appropriate."
She maintained that the claims were preempted because the SSRI makers were not allowed to add warnings to the label under any circumstances without prior approval from the FDA.
At one point, the court asked an attorney for an SSRI maker, "assume for the moment that you had reasonable evidence of an association between your product and a serious hazard or a serious possibility of an enhanced suicide risk."
Under federal regulations, "what would be your obligation?"
The attorney stated, "our obligation would be to take that information to the FDA, advise the FDA of the information."
"It then would be the FDA's determination whether that represented a substantial relationship," he told the court.
"So if you had evidence internally that there's an enhanced risk of suicide, you would go to the FDA," the court said, and asked, "And how long would that take?"
"I do not know the answer to that, your Honor," the attorney said, and the court asked, "Could it take months?"
"I imagine it would depend on the seriousness --," the attorney stated.
"But isn't there a significant possibility that additional people then might have the same consequence that happened here with McNellis, or with Colacicco and McNellis's father?" the court asked.
The attorney said, "on the basis of the information that was available we would take it per FDA directive to the FDA and they would make the determination whether the label should be changed."
"Other people could then," the court continued, "possibly have an enhanced risk of suicide and other people may commit suicide as a result of taking your product?"
"We would be bound by law to comply with the FDA, then to comply with its directives," the attorney replied.
"Are they requiring that you go through them first rather than act on your own?" the court asked.
"That's exactly correct, your Honor, because there is the bigger issue of the --" the attorney stated.
However, at the end of the hearing, Pennsylvania attorney Derek Braslow proved beyond any doubt that the claims made by the Bush Administration attorney and the attorneys for the drug makers were blatant lies, when he informed the court that Glaxo had "independently, strengthened their warning in May 2004 to warn about increased suicidality and worsening depression in everyone, not just children."
"There was specifically in bold letters a new warning with respect to increased suicidality and worsening depression in May 2004," he stated.
"Glaxo changed the label on their own without FDA approval," Mr Braslow told the court.
Glaxo did it again in May 2006, he said, when they sent out a "Dear Healthcare Professional" letter and warned about the increased risk of suicidality and suicidal behaviors with Paxil in persons of all ages.
During oral arguments in the O'Neal case on January 21, 2008, Glaxo's preemption argument was presented by King & Spalding attorney Mark Brown, who just happens to be a former Associate Chief Counsel for the FDA from the first Bush Administration.
The family intends to ask the court to reconsider the ruling in the O'Neal case, according to a statement by Baum Hedlund.
In his report, Dr Glenmullen sums up the inadequacy of the system, including the FDA, that allowed Glaxo to keep this vital information hidden from prescribing doctors and patients for nearly 2 decades and states, in part:
"One of the most sobering aspects of the story of Paxil-induced suicidality is that GlaxoSmithKline was not forthcoming with its data demonstrating the risk and regulatory agencies like the FDA did not take the initiative to get to the bottom of and expose the true risk."
"Rather, the impetus came from attorneys and medical experts surprised by what they found in GlaxoSmithKline's confidential documents, which only came to light through litigation."
"The GlaxoSmithKline documents that have so-far made it into the public record have in turn been critical to educating patients, the public, and the media about the true risk. The media - particularly the BBC in England - played a crucial role in turning the tide in the history of Paxil-induced suicidality."
According to Dr Glenmullen, "it was the diligent efforts of plaintiff's attorneys that forced GlaxoSmithKline to divulge the inaccurate counting method to the FDA."
Another leading expert on pharmacology, Dr Peter Breggin, warns that an 8-fold increased risk of suicidality in controlled clinical trials could mean 80-fold in actual practice. "We can't determine exactly how much greater the risk will be in clinical practice but it will be astronomically greater," he advises.
In actual practice, he explains, many patients are already suicidal when they start taking the drug, increasingly the likelihood that the drug can push them over the edge.
Despite the warnings to watch patients closely, Dr Breggin says, busy doctors do not monitor patients properly. He explains that they are almost never evaluated for suicidality and are often given multiple drugs at the same time, by doctors who know little about their adverse effects on the mind.
Glaxo is facing lawsuits from surviving family members of Paxil suicide victims all over the country and is attempting to use preemption to avoid public trials for good reason. The first case to go before a jury in Wyoming in 2001, involved a man who shot his wife, daughter and infant granddaughter before shooting himself after being on Paxil for just a matter of days.
The trial resulted in a verdict against Glaxo for $6.4 million after the jury weighed the expert testimony of famed pharmacologist Dr David Healy, who presented a summary of Glaxo's hidden suicide data on Paxil, against the testimony of the industry-funded SSRI defender Dr John Mann, whose name appears on many of the studies issued over the years, some as late as 2007, that steadfastly proclaim that SSRI's are not linked to suicide and should be prescribed to children.
In addition to Dr Healy's revelations about hidden data showing that Glaxo was aware of the increased risk, Dr Mann's credibility was likely weighed against the fact that he had received over $30 million in research funding from drug companies between the early 1990's and the trial in 2001, which was brought out during his testimony by Houston attorney Andy Vickery.
Mr Vickery also established that, roughly 10 years and $30 million earlier, Dr Mann had published a paper stating that SSRI's could increase suicidality in a small subset of patients.
In his report, Dr Glenmullen states that, since Glaxo had the original data in 1989 that showed a greater than eightfold increased risk, it should have warned doctors and patients about the risk "a decade-and-a-half ago when Paxil was first approved by the FDA."
The report includes portions of an April 29, 1991 report, written by Glaxo psychiatrist Dr Geoffrey Dunbar, sent to the FDA in response to a specific request for information on suicidality in which Glaxo openly lies in stating: "analyses of our prospective, clinical trials for depression show that patients who were randomized to Paxil therapy were at no greater risk for suicidal ideation or behavior than were patients randomized to placebo or other active control therapies."
Dr Glenmullen notes the importance of the date that this false data was submitted because the FDA had scheduled a hearing with a nine-member advisory panel for September 20, 1991, to discuss concerns raised a year earlier about the possibility of Prozac making patients suicidal. Paxil was not approved for use in the US until December 2002.
In his report, Dr Glenmullen points out that 5 of the 9 members on the advisory panel had conflicts of interest with drug makers and that 2 psychiatrists, Dr David Dunner of the University of Washington in Seattle and Dr Stuart Montgomery from England, had done research on Prozac for Eli Lilly, and later played crucial roles in Glaxo's publishing of what he calls "bad" suicide numbers in the Paxil story.
Dr Glenmullen's report includes portions of a September 19, 1991, memo distributed to over 20 senior staff the day before the hearing with a "Statement to be used to respond to inquiries re Paxil/Suicide," which claims explicitly that during GlaxoSmithKline's studies: "the incidence of suicide was lower among patients receiving Paxil than among those receiving placebo."
This was the statement the company ordered employees to make, even though 5 patients on Paxil committed suicide while no patients in the placebo group did. In addition, Dr Glenmullen points out that, up to 1989, seriously suicidal patients were excluded from Glaxo's studies, and therefore "anyone who became seriously suicidal during the studies only became so after being given Paxil or a placebo."
Yet the actual numbers show that there were 40 suicide attempts in the clinical trials by patients taking Paxil compared to 1 suicide attempt in the placebo groups.
Despite the poor quality of the data available to the advisory committee, and despite the many conflicts of interest of its members, one third of the members still voted for a warning in 1991, Dr Glenmullen points out.
Three months later, in December 1991, Dr Dunner, together with Glaxo psychiatrist Dr Dunbar, presented Glaxo's Paxil data with the "bad" numbers at a meeting of the American College of Neuropsychopharmacology (ACNP) in Puerto Rico.
During the presentation, the doctors told the ACNP: "Suicide and suicide attempts occurred less frequently with Paxil than with either placebo or active control," according to the Glenmullen report.
The ACNP's members are considered prominent academic psychiatrists who specialize in pharmacology, and the group has issued a number of position papers over the years which consistently denied a link between SSRI's and suicidality.
Dr Mann led an ACNP task force which included Dr Fred Goodwin, Dr Charles O'Brien and Dr Robinson, which supposedly reviewed all the clinical trial data on SSRI's and issued a consensus statement with the position that SSRI's did not increase the risk of suicidal behavior, which was published in the journal Neuropsychopharmacology in 1993.
In March 1995, Dr Dunner, Dr Montgomery and Dr Dunbar published the paper, "Reduction of suicidal thoughts with paroxetine in comparison with reference antidepressants and placebo," in the European journal Neuropsychopharmacology. This paper included a table with the "bad" numbers and claimed that other antidepressants were more likely to increase the risk of suicide than Paxil.
The paper specifically states: "Consistent reduction in suicides, attempted suicides, and suicidal thoughts, and protection against emergent suicidal thoughts suggest that Paxil has advantages in treating the potentially suicidal patients."
On July 5, 1995, Glaxo's marketing department issued a memo urging its sales force to use the Dunner-Dunbar paper to reassure doctors who were concerned over Paxil-related suicide that there was no need for concern.
The fact is, documents obtained in litigation prove that the FDA has known about the suicide risks of SSRI's for roughly 23 years. Two years before Prozac was approved, in May 1985, the FDA's chief investigator, Dr Richard Kapit, wrote: "Unlike traditional tricyclic antidepressants Fluoxetine's profile of adverse side effects more closely resembles that of a stimulant drug than one that causes sedation."
"It is Fluoxetine's particular profile of adverse side-effects which may perhaps, in the future give rise to the greatest clinical liabilities in the use of this medication to treat depression," he noted.
Dr Kapit's review described data from 46 clinical trials with a total of 1,427 patients and under the section, "Catastrophic and Serious Events," he listed 52 cases of "egregiously abnormal laboratory reports which were the reason for early termination," and "additional adverse event reports not reported by the company were revealed on microfiche."
"In most cases," he wrote, "these adverse events involved the onset of an unreported psychotic episode."
There were ten reports of psychotic episodes including 2 reports of completed suicides, 13 attempted suicides, 4 seizures, and 4 reports of movement disorders. In 1985, Dr Kapit recommended "labeling warning the physician that such signs and symptoms of depression may be exacerbated by this drug".
When Prozac was approved, no such warning was issued.
Two weeks after the FDA advisory panel met in February 2004 to review the data on SSRI's to determine whether they were linked to suicide, Dr Healy sent a report to Peter Pitts, Associate Commissioner for External Relations, at the FDA, in response to an invitation by Dr Robert Temple for a submission of the details of studies referred to in the course of a presentation at the meeting.
"A great number of the patient testimonies in the course of the Feb 2nd hearing were from individuals who became suicidal on an SSRI when their underlying disorder was Lyme Disease, migraine or a condition such as social phobia," Dr Healy pointed out.
He also noted that this had been the case in the 1991 hearings, when it was framed by FDA's Dr Temple as follows:
"The discussion we heard earlier showed that people who commit suicide are highly likely to have a diagnosis of depression, which means that somebody identified them as in a high-risk category. But there were still a significant number of people who committed suicide without having that sort of diagnosis and I guess I would like some advice or discussion on who those people were."
"The anecdotes that one hears that are most evocative to me anyway are not the ones where people who have a 20-year history of suicidal ideation and then finally do it - that is not too surprising - it is where they assert that there has never been anything in their minds like that before and yet now they have suddenly become excessively concerned with suicide and may even do it."
Dr Healy's analysis submitted to the FDA included the data from the pediatric trials on suicidality and hostility, including some that were concealed for years. To distinguish the difference between suicide caused by SSRI's verses suicide caused by the underlying depression, he separated the data on children who were treated for depression and children who were treated for obsessive compulsive disorder or social phobia.
The analysis found that SSRI's can cause some children who are not depressed to become suicidal when taking the drugs for other conditions. From a pool of 931 depressed patients taking SSRI's versus 811 depressed patients taking placebo, Dr Healy determined that there were 52 suicidal acts by patients on SSRI's versus 18 in the placebo group.
In a pool of 638 patients taking SSRI's for other disorders versus 562 patients taking a placebo, there were 10 suicidal acts in the SSRI group versus 1 in the placebo group.
When these data sets were combined, there were 62 episodes of suicidality in the 1,569 patients on SSRI's versus only 19 episodes in the 1,373 patients on a placebo.
In his submission to the FDA, Dr Healy also explained that he had conducted his own trial on Zoloft in 2000 with 20 "healthy volunteers," meaning they had no mental disorder when entering the trial, and two of the Zoloft patients became suicidal. This type of study provides the strongest evidence of drug-induced suicidality because it's impossible for drug companies to claim that a patient became suicidal as a result of the underlying depression.
Seven years ago, during the Wyoming jury trial involving the tragic Paxil-induced murder-suicide, the man's physician testified that he may not have prescribed Paxil if a warning regarding homicide and suicide had been added to the drug's label.
In his report released last month, Dr Glenmullen offers the following heart-wrenching conclusion to the court: "It is my opinion to a reasonable degree of medical probability that if GlaxoSmithKline had provided a warning all these years, Benjamin Bratt would still be alive today."
On April 24, 2004, the Lancet medical journal published an editorial entitled, "Depressing Research," with the following comments that surely ring doubly true today for the Bratt family, as well as all the other families whose children committed suicide while on SSRI's:
"It is hard to imagine the anguish experienced by the parents, relatives, and friends of a child who has taken his or her own life. That such an event could be precipitated by a supposedly beneficial drug is a catastrophe. The idea of that drug's use being based on the selective reporting of favourable research should be unimaginable."
Lawmakers Catch Glaxo Hiding Paxil Suicide Risks - Again (Part II)
Evelyn Pringle February 13, 2008
Apparently, GlaxoSmithKline is still trying to hide damaging information about Paxil, because 9 pages of a report released from under a court order last month, are not available to the public. However, Senator Charles Grassley has instructed Glaxo to provide him with the full report by February 14, 2008.
In the report, which is dated roughly 6 months ago on June 29, 2007, Harvard Professor, Dr Joseph Glenmullen reveals that Glaxo had clinical trial data since 1989 which showed that Paxil increases the risk of suicide by more than 8-fold compared to patients who received a placebo.
The report was submitted in O'Neal v Glaxo, a lawsuit filed in a California federal court by the surviving family members of Benjamin Bratt who committed suicide at age 13 while on Paxil. The family is represented by the California law firm of Baum, Hedlund, Aristei & Goldman.
On January 30, 2008, the judge dismissed the case on the basis of the new preemption policy of the Bush Administration, but the family intends to ask the court to reconsider the ruling, according to Baum Hedlund.
In his report, Dr Glenmullen also makes a plea for public disclosure of all information that remains sealed under court orders on the basis of Glaxo's claim that the documents contain trade secrets and states:
"Given the importance of GlaxoSmithKline's internal documents, it is unfortunate that so many of the documents cited in this report and the attached Appendix are still confidential."
"Given the stakes for public health and safety, GlaxoSmithKline should not be permitted to claim the documents are proprietary trade secrets."
"All the documents should be made part of the public record so the full story of Paxil-induced suicidality can be told and the additional necessary steps can be taken to fully protect patients and the public."
Dr Glenmullen also mentions a companion report related to children and adolescents and a "Specific Causation Report" in the case of Benjamin Bratt, and Senator Grassley has instructed Glaxo to provide him with a copy of that report as well.
In what can only be viewed as an eerily prophetic comment, in a letter back on September 16, 2004, to the Secretary of Health and Human Services, and the acting FDA Commissioner at the time, Senator Grassley warned: "I intend to keep the FDA's feet to the fire to insure that the American public is knowledgeable about the risks of SSRI's."
SSRI's refer to antidepressants known as selective serotonin reuptake inhibitors that include Paxil, Eli Lilly's Prozac, Zoloft by Pfizer and Celexa and Lexapro marketed by Forest Labs, along with their generic counterparts. Lilly's Cymbalta, Wyeth's Effexor and Glaxo's Wellbutrin are often referred to as SSRI's but they are slightly different chemically. However, the new antidepressants all carry the same warnings about the suicide risks.
Senator Grassley's letter followed the vote by an FDA advisory committee for a black box warning about the increased risk of suicide with kids to be added to the drugs' labels.
His angry tone, and not so subtle threat, was due to the fact that, during the advisory committee meeting, it became apparent that not only Glaxo, but all the SSRI makers, had concealed and misrepresented clinical trial data for years in the published medical literature which clearly indicated that there was an increased risk of suicidality with SSRI use.
In fact, as soon as Glaxo's was asked about the hidden studies by regulators in the UK, Glaxo issued a "Dear Doctor" letter to physicians in England saying Paxil should not be prescribed to children because it "failed" to work any better than a placebo and frequently caused "hostility, agitation, emotional lability (including crying, mood fluctuations, self-harm, suicidal thoughts, and attempted suicides.)"
Glaxo did not issue any such warning to doctors in the US.
The paper that garnered the most wrath from pharmacology experts all over the world was published in the July 2001 issue of the Journal of the American Academy of Child and Adolescent Psychiatry on Paxil study 329, which was conducted from 1993 through to late 1995 or early 1996, according to a leading pharmacology expert, Dr David Healy.
Twenty academics, considered to be the tops in their field, signed off on the study. The main authors of paper on the study were later found to be in constant contact with Glaxo when the media began reporting that the data published was fraudulent, and include Dr Martin Keller, Dr Neil Ryan and Dr Karen Wagner.
In the paper, the authors write: "Of the 11 patients only headache (one patient) was considered to be related to the treatment," and Paxil is "generally well tolerated and effective."
However, when the actual study was analyzed in 2003, it showed suicidal acts by 5 out of 93 children on Paxil compared to no suicidal acts in the 89 children who received placebo.
On January 29, 2007, the BBC's Panorama broadcast, "Secrets of the Drug Trials." Attorney Karen Barth Menzies obtained many of the secret Paxil documents that were quoted during litigation, and she explained how Glaxo found ways "to blow up out of proportion the supposed benefits in Study 329 and downplayed the negative findings."
Glaxo recruited the opinion leaders to put their names on the published 329 study, she said, because they were academics whom everybody looked up to, and the company knew that doctors would be far more likely to prescribe Paxil after listening to these doctors than they would be if approached by Glaxo salespersons.
One letter that was quoted, revealed that these so-called opinion leaders never even wrote a paper. The letter was from a ghost writer to Dr Keller, informing him that all the necessary materials were enclosed for him to submit the study to a journal for publication. The packet even included a cover letter, with instructions telling Dr Keller to: "please re-type on your letterhead. Revise if you wish."
Dr Wagner, along with Dr Graham Emslie, was also responsible for publishing papers on studies that resulted in Prozac's approval for children, and Dr Wagner and Dr Keller were also investigators on Zoloft studies and several of the unpublished Paxil studies.
In the October 4, 1999 Boston Globe, Alison Bass reported that in 1998, as a professor at Brown University, Dr Keller was forced to forfeit "hundreds of thousands of dollars" in state grant money and was paid more than $500,000 in consulting fees in 1998, most of it from companies whose drugs he touted in medical journals and at conferences.
In the report, Ms Bass pointed out that Keller was a valuable resource for the University, and had brought in about $14.4 million in research funding from drug companies and federal agencies since 1993.
According to the report, in 1998, the year Keller published 3 studies with colleagues in the Journal of the American Medical Association and the Journal of Clinical Psychiatry touting the efficacy of Zoloft, he received $218,000 in personal income and more than $3 million in research funding from Zoloft maker Pfizer.
Several ethicists contacted by the Globe said Keller's unusually large consulting fees, a total of $556,000 in 1998 and $444,000 in 1997, constitute the most serious potential conflict they've heard of yet, Ms Bass noted.
Dr Wagner received an onslaught of criticism from experts all over the world when she misrepresented trial data in a paper on Zoloft, claiming it was safe and effective for use with children. On November 29, 2004, Barry Meier wrote, "Contracts Keep Drug Research Out of Reach," in the New York Times, and reported that over the past decade, Dr Wagner from the University of Texas Medical Center in Galveston had led or worked on some 20 studies published in medical journals and had also "attracted a large number of industry-financed studies, including those aimed at testing whether antidepressants approved for use in adults were safe and effective in children and adolescents."
In a financial filing with the university in December 1999, Mr Meier found the same month that a Zoloft trial began recruiting patients, Dr Wagner disclosed that she had received more than $10,000 from Pfizer but she did not provide details.
She also did not respond to written questions about the payments but a lawyer for the school, told Mr Meier that Dr Wagner had told him that Pfizer had paid her $20,500 during the course of the Zoloft trial.
Mr Meier also noted that academic researchers routinely receive speaking and consulting fees from companies whose products they test and at Galveston the financial threshold for such a review is $10,000. But the school lawyer, told Mr Meier that the center had been unable to locate records related to Pfizer's payments to Dr Wagner.
Glaxo's study 329 was successfully used to promote Paxil for children, and sales to kids skyrocketed to $55 million in 2002 alone. It also served as the smoking gun in a lawsuit filed against Glaxo by New York Attorney Elliot Spitzer, charging Glaxo with fraud for promoting the off-label use of Paxil to children while concealing and misrepresenting the data from 5 studies that showed the increased suicide risks and the fact that Paxil did not work with children. Glaxo settled out of court to shut that lawsuit down within 2 months.
In 2003, after reviewing the same fraudulent studies, the UK banned the use of Paxil with children, and the FDA scheduled an advisory committee meeting in February 2004 to review the data on all SSRI's.
In response to the announcements by the regulatory agencies, the American College of Neuropsychopharmacology (ACNP), which designated a Task Force in the early 1990's to review the SSRI trial data, and subsequently published an position paper saying SSRI's were not linked to suicide, appointed a new Task Force in September 2003, to study the matter again.
This Task Force was made up of many of the same authors whose published papers were under attack for being fraudulent and included Dr John Mann, Dr Graham Emslie, Dr Karen Wagner, Dr Neal Ryan, Dr Andrew Leon, Dr Fredrick Goodwin, Dr David Shaffer, Dr Beardslee, Dr Jan Fawcett, Dr Herbert Meltzer and Dr Ross Baldessarini.
Two weeks before the advisory committee meeting, the Task Force issued a report, once again claiming SSRI's did not cause suicide, and began making what many experts condemned as preemptive statements in the media to influence the advisory committee to vote against adding a warning about the risk of suicide to SSRI labels.
On January 21, 2007, WebMd's headline on the internet stated: "Group Finds No Suicide-Antidepressant Link".
"Our conclusion is that when you look at the SSRI's as a group, there is evidence they are effective for treating depression in children and adolescents," Dr Mann told WebMD.
"Instead of being a risk for suicidal behavior, they are potentially therapeutic," he stated.
In fact, the $30-million Dr Mann, who admitted under oath in a jury trial that it was possible that he got over $30 million in research funding from drug companies over a 10-year period, said the group found strong evidence that SSRI's help depressed kids and that suicide rates started going down when SSRI's became available.
He claimed that a 14-year study showed a decline in suicide rates in kids. "Across 15 countries there has been a 33% decline in suicide rates amongst youths," he told WebMD.
"Doctors must go on treating depression, and SSRI's appear to be a reasonable choice," he stated.
The FDA even allowed Task Force members Dr Andrew Leon and Dr Neil Ryan to participate as voting members of the February 2, 2004 advisory panel.
The day after a September 2004 advisory committee finally voted to add a black box warning to the SSRI labels, on September 14, 2004, Senator Grassley issued a press release stating that the FDA "needs to learn an important lesson from what's developed this year on the matter of kids and antidepressants."
"Transparency in government is the best policy," he noted. "Parents and doctors should not be left in the dark, and especially when information that's available could be a matter of life and death."
"Given the scientific findings," he added, "it's obvious that the strongest label warning for this class of drugs is critically important for the health and safety of young Americans."
"These measures are especially critical," he said, "since I also understand from previously released studies and from the Advisory Committee's own deliberations that only one of the nine antidepressant drugs has been proven to provide any benefit to children and adolescents."
"In fact," he pointed out, "in almost all cases, the FDA's own data demonstrates that these drugs actually perform no better than do placebos."
In a September 16, 2004, letter, Senator Grassley asked the FDA to "very quickly and fully consider" the recommendations for the black box and med guides, "before the lives of more children are needlessly lost because parents and others lack adequate, readily understandable information when they most need it."
He also brought up the issue of informed consent and said he was curious about the FDA's rationale for not requiring doctors to provide a clear, informed consent document that parents must read, understand and sign before accepting a prescription, as the FDA had done with the drug Lotronex, due to a 1 in 300 risk of ischemic colitis in patients.
In the case of antidepressants, Senator Grassley pointed out, "a suicide-related event involving Prozac (fluoxetine) is about 1 in 15 according to the TADS study, and about 1 in 30 for all SSRI's, according to FDA's own study."
The letter said that the informed consent form should at least include the following points: (1) Only Prozac has been shown to be effective in treating depression in children and adolescents, and is the only drug approved for this; (2) All others have been shown to be no different than a placebo, and their use in the treatment of children and adolescents is not an approved use; (3) All antidepressants increase the risk of suicidality, and (4) The risk of a suicide event (planned or actually attempted) is one for every 15 to 30 children and adolescents taking the antidepressant.
Senator Grassley also asked what the FDA planned to do about educating doctors and the public about the risk-benefits of antidepressants, especially in children. Obviously, the short answer to that question more than three years later is, not a thing.
In fact, in the January 17, 2008, Wall Street Journal, David Armstrong and Keith Winstein reported that, "the effectiveness of a dozen popular antidepressants has been exaggerated by selective publication of favorable results, according to a review of unpublished data submitted to the Food and Drug Administration."
"As a result," they wrote, "doctors and patients are getting a distorted view of how well blockbuster antidepressants like Wyeth's Effexor and Pfizer Inc.'s Zoloft really work," in discussing research led by Erick Turner, a psychiatrist at Oregon Health & Science University, published in a study in New England Journal of Medicine.
They also point out that sales of antidepressants total about $21 billion a year.
In all the studies, old and new, which promote the off-label sale of SSRI's for children with claims that the drugs work and do not cause suicide, almost without fail, the same names appear as investigators and authors. A complete listing includes Dr John Mann, Dr Martin Keller, Dr Graham Emslie, Dr Frederick Goodwin, Dr Karen Wagner, Dr Neal Ryan, Dr Charles Nemeroff, Dr David Dunner, Dr Andrew Leon, Dr John March, Dr David Shaffer, Dr John Rush, Dr Mark Olfson and Dr Robert Gibbons.
This time around, in addition to going after Glaxo for concealing and misrepresenting the data that showed an 8-fold increased risk of suicide, somebody needs to take the bull by the horns and see to it that these industry-funded quacks get thrown in the slammer.
It's also more than apparent that a few FDA officials belong there as well.
Apparently, GlaxoSmithKline is still trying to hide damaging information about Paxil, because 9 pages of a report released from under a court order last month, are not available to the public. However, Senator Charles Grassley has instructed Glaxo to provide him with the full report by February 14, 2008.
In the report, which is dated roughly 6 months ago on June 29, 2007, Harvard Professor, Dr Joseph Glenmullen reveals that Glaxo had clinical trial data since 1989 which showed that Paxil increases the risk of suicide by more than 8-fold compared to patients who received a placebo.
The report was submitted in O'Neal v Glaxo, a lawsuit filed in a California federal court by the surviving family members of Benjamin Bratt who committed suicide at age 13 while on Paxil. The family is represented by the California law firm of Baum, Hedlund, Aristei & Goldman.
On January 30, 2008, the judge dismissed the case on the basis of the new preemption policy of the Bush Administration, but the family intends to ask the court to reconsider the ruling, according to Baum Hedlund.
In his report, Dr Glenmullen also makes a plea for public disclosure of all information that remains sealed under court orders on the basis of Glaxo's claim that the documents contain trade secrets and states:
"Given the importance of GlaxoSmithKline's internal documents, it is unfortunate that so many of the documents cited in this report and the attached Appendix are still confidential."
"Given the stakes for public health and safety, GlaxoSmithKline should not be permitted to claim the documents are proprietary trade secrets."
"All the documents should be made part of the public record so the full story of Paxil-induced suicidality can be told and the additional necessary steps can be taken to fully protect patients and the public."
Dr Glenmullen also mentions a companion report related to children and adolescents and a "Specific Causation Report" in the case of Benjamin Bratt, and Senator Grassley has instructed Glaxo to provide him with a copy of that report as well.
In what can only be viewed as an eerily prophetic comment, in a letter back on September 16, 2004, to the Secretary of Health and Human Services, and the acting FDA Commissioner at the time, Senator Grassley warned: "I intend to keep the FDA's feet to the fire to insure that the American public is knowledgeable about the risks of SSRI's."
SSRI's refer to antidepressants known as selective serotonin reuptake inhibitors that include Paxil, Eli Lilly's Prozac, Zoloft by Pfizer and Celexa and Lexapro marketed by Forest Labs, along with their generic counterparts. Lilly's Cymbalta, Wyeth's Effexor and Glaxo's Wellbutrin are often referred to as SSRI's but they are slightly different chemically. However, the new antidepressants all carry the same warnings about the suicide risks.
Senator Grassley's letter followed the vote by an FDA advisory committee for a black box warning about the increased risk of suicide with kids to be added to the drugs' labels.
His angry tone, and not so subtle threat, was due to the fact that, during the advisory committee meeting, it became apparent that not only Glaxo, but all the SSRI makers, had concealed and misrepresented clinical trial data for years in the published medical literature which clearly indicated that there was an increased risk of suicidality with SSRI use.
In fact, as soon as Glaxo's was asked about the hidden studies by regulators in the UK, Glaxo issued a "Dear Doctor" letter to physicians in England saying Paxil should not be prescribed to children because it "failed" to work any better than a placebo and frequently caused "hostility, agitation, emotional lability (including crying, mood fluctuations, self-harm, suicidal thoughts, and attempted suicides.)"
Glaxo did not issue any such warning to doctors in the US.
The paper that garnered the most wrath from pharmacology experts all over the world was published in the July 2001 issue of the Journal of the American Academy of Child and Adolescent Psychiatry on Paxil study 329, which was conducted from 1993 through to late 1995 or early 1996, according to a leading pharmacology expert, Dr David Healy.
Twenty academics, considered to be the tops in their field, signed off on the study. The main authors of paper on the study were later found to be in constant contact with Glaxo when the media began reporting that the data published was fraudulent, and include Dr Martin Keller, Dr Neil Ryan and Dr Karen Wagner.
In the paper, the authors write: "Of the 11 patients only headache (one patient) was considered to be related to the treatment," and Paxil is "generally well tolerated and effective."
However, when the actual study was analyzed in 2003, it showed suicidal acts by 5 out of 93 children on Paxil compared to no suicidal acts in the 89 children who received placebo.
On January 29, 2007, the BBC's Panorama broadcast, "Secrets of the Drug Trials." Attorney Karen Barth Menzies obtained many of the secret Paxil documents that were quoted during litigation, and she explained how Glaxo found ways "to blow up out of proportion the supposed benefits in Study 329 and downplayed the negative findings."
Glaxo recruited the opinion leaders to put their names on the published 329 study, she said, because they were academics whom everybody looked up to, and the company knew that doctors would be far more likely to prescribe Paxil after listening to these doctors than they would be if approached by Glaxo salespersons.
One letter that was quoted, revealed that these so-called opinion leaders never even wrote a paper. The letter was from a ghost writer to Dr Keller, informing him that all the necessary materials were enclosed for him to submit the study to a journal for publication. The packet even included a cover letter, with instructions telling Dr Keller to: "please re-type on your letterhead. Revise if you wish."
Dr Wagner, along with Dr Graham Emslie, was also responsible for publishing papers on studies that resulted in Prozac's approval for children, and Dr Wagner and Dr Keller were also investigators on Zoloft studies and several of the unpublished Paxil studies.
In the October 4, 1999 Boston Globe, Alison Bass reported that in 1998, as a professor at Brown University, Dr Keller was forced to forfeit "hundreds of thousands of dollars" in state grant money and was paid more than $500,000 in consulting fees in 1998, most of it from companies whose drugs he touted in medical journals and at conferences.
In the report, Ms Bass pointed out that Keller was a valuable resource for the University, and had brought in about $14.4 million in research funding from drug companies and federal agencies since 1993.
According to the report, in 1998, the year Keller published 3 studies with colleagues in the Journal of the American Medical Association and the Journal of Clinical Psychiatry touting the efficacy of Zoloft, he received $218,000 in personal income and more than $3 million in research funding from Zoloft maker Pfizer.
Several ethicists contacted by the Globe said Keller's unusually large consulting fees, a total of $556,000 in 1998 and $444,000 in 1997, constitute the most serious potential conflict they've heard of yet, Ms Bass noted.
Dr Wagner received an onslaught of criticism from experts all over the world when she misrepresented trial data in a paper on Zoloft, claiming it was safe and effective for use with children. On November 29, 2004, Barry Meier wrote, "Contracts Keep Drug Research Out of Reach," in the New York Times, and reported that over the past decade, Dr Wagner from the University of Texas Medical Center in Galveston had led or worked on some 20 studies published in medical journals and had also "attracted a large number of industry-financed studies, including those aimed at testing whether antidepressants approved for use in adults were safe and effective in children and adolescents."
In a financial filing with the university in December 1999, Mr Meier found the same month that a Zoloft trial began recruiting patients, Dr Wagner disclosed that she had received more than $10,000 from Pfizer but she did not provide details.
She also did not respond to written questions about the payments but a lawyer for the school, told Mr Meier that Dr Wagner had told him that Pfizer had paid her $20,500 during the course of the Zoloft trial.
Mr Meier also noted that academic researchers routinely receive speaking and consulting fees from companies whose products they test and at Galveston the financial threshold for such a review is $10,000. But the school lawyer, told Mr Meier that the center had been unable to locate records related to Pfizer's payments to Dr Wagner.
Glaxo's study 329 was successfully used to promote Paxil for children, and sales to kids skyrocketed to $55 million in 2002 alone. It also served as the smoking gun in a lawsuit filed against Glaxo by New York Attorney Elliot Spitzer, charging Glaxo with fraud for promoting the off-label use of Paxil to children while concealing and misrepresenting the data from 5 studies that showed the increased suicide risks and the fact that Paxil did not work with children. Glaxo settled out of court to shut that lawsuit down within 2 months.
In 2003, after reviewing the same fraudulent studies, the UK banned the use of Paxil with children, and the FDA scheduled an advisory committee meeting in February 2004 to review the data on all SSRI's.
In response to the announcements by the regulatory agencies, the American College of Neuropsychopharmacology (ACNP), which designated a Task Force in the early 1990's to review the SSRI trial data, and subsequently published an position paper saying SSRI's were not linked to suicide, appointed a new Task Force in September 2003, to study the matter again.
This Task Force was made up of many of the same authors whose published papers were under attack for being fraudulent and included Dr John Mann, Dr Graham Emslie, Dr Karen Wagner, Dr Neal Ryan, Dr Andrew Leon, Dr Fredrick Goodwin, Dr David Shaffer, Dr Beardslee, Dr Jan Fawcett, Dr Herbert Meltzer and Dr Ross Baldessarini.
Two weeks before the advisory committee meeting, the Task Force issued a report, once again claiming SSRI's did not cause suicide, and began making what many experts condemned as preemptive statements in the media to influence the advisory committee to vote against adding a warning about the risk of suicide to SSRI labels.
On January 21, 2007, WebMd's headline on the internet stated: "Group Finds No Suicide-Antidepressant Link".
"Our conclusion is that when you look at the SSRI's as a group, there is evidence they are effective for treating depression in children and adolescents," Dr Mann told WebMD.
"Instead of being a risk for suicidal behavior, they are potentially therapeutic," he stated.
In fact, the $30-million Dr Mann, who admitted under oath in a jury trial that it was possible that he got over $30 million in research funding from drug companies over a 10-year period, said the group found strong evidence that SSRI's help depressed kids and that suicide rates started going down when SSRI's became available.
He claimed that a 14-year study showed a decline in suicide rates in kids. "Across 15 countries there has been a 33% decline in suicide rates amongst youths," he told WebMD.
"Doctors must go on treating depression, and SSRI's appear to be a reasonable choice," he stated.
The FDA even allowed Task Force members Dr Andrew Leon and Dr Neil Ryan to participate as voting members of the February 2, 2004 advisory panel.
The day after a September 2004 advisory committee finally voted to add a black box warning to the SSRI labels, on September 14, 2004, Senator Grassley issued a press release stating that the FDA "needs to learn an important lesson from what's developed this year on the matter of kids and antidepressants."
"Transparency in government is the best policy," he noted. "Parents and doctors should not be left in the dark, and especially when information that's available could be a matter of life and death."
"Given the scientific findings," he added, "it's obvious that the strongest label warning for this class of drugs is critically important for the health and safety of young Americans."
"These measures are especially critical," he said, "since I also understand from previously released studies and from the Advisory Committee's own deliberations that only one of the nine antidepressant drugs has been proven to provide any benefit to children and adolescents."
"In fact," he pointed out, "in almost all cases, the FDA's own data demonstrates that these drugs actually perform no better than do placebos."
In a September 16, 2004, letter, Senator Grassley asked the FDA to "very quickly and fully consider" the recommendations for the black box and med guides, "before the lives of more children are needlessly lost because parents and others lack adequate, readily understandable information when they most need it."
He also brought up the issue of informed consent and said he was curious about the FDA's rationale for not requiring doctors to provide a clear, informed consent document that parents must read, understand and sign before accepting a prescription, as the FDA had done with the drug Lotronex, due to a 1 in 300 risk of ischemic colitis in patients.
In the case of antidepressants, Senator Grassley pointed out, "a suicide-related event involving Prozac (fluoxetine) is about 1 in 15 according to the TADS study, and about 1 in 30 for all SSRI's, according to FDA's own study."
The letter said that the informed consent form should at least include the following points: (1) Only Prozac has been shown to be effective in treating depression in children and adolescents, and is the only drug approved for this; (2) All others have been shown to be no different than a placebo, and their use in the treatment of children and adolescents is not an approved use; (3) All antidepressants increase the risk of suicidality, and (4) The risk of a suicide event (planned or actually attempted) is one for every 15 to 30 children and adolescents taking the antidepressant.
Senator Grassley also asked what the FDA planned to do about educating doctors and the public about the risk-benefits of antidepressants, especially in children. Obviously, the short answer to that question more than three years later is, not a thing.
In fact, in the January 17, 2008, Wall Street Journal, David Armstrong and Keith Winstein reported that, "the effectiveness of a dozen popular antidepressants has been exaggerated by selective publication of favorable results, according to a review of unpublished data submitted to the Food and Drug Administration."
"As a result," they wrote, "doctors and patients are getting a distorted view of how well blockbuster antidepressants like Wyeth's Effexor and Pfizer Inc.'s Zoloft really work," in discussing research led by Erick Turner, a psychiatrist at Oregon Health & Science University, published in a study in New England Journal of Medicine.
They also point out that sales of antidepressants total about $21 billion a year.
In all the studies, old and new, which promote the off-label sale of SSRI's for children with claims that the drugs work and do not cause suicide, almost without fail, the same names appear as investigators and authors. A complete listing includes Dr John Mann, Dr Martin Keller, Dr Graham Emslie, Dr Frederick Goodwin, Dr Karen Wagner, Dr Neal Ryan, Dr Charles Nemeroff, Dr David Dunner, Dr Andrew Leon, Dr John March, Dr David Shaffer, Dr John Rush, Dr Mark Olfson and Dr Robert Gibbons.
This time around, in addition to going after Glaxo for concealing and misrepresenting the data that showed an 8-fold increased risk of suicide, somebody needs to take the bull by the horns and see to it that these industry-funded quacks get thrown in the slammer.
It's also more than apparent that a few FDA officials belong there as well.
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