Tuesday, September 21, 2010

The Rise and Fall of Provigil - Part II

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)

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)