The pharmaceutical company, Cephalon Inc, is going through the motions of legitimizing the sale of Sparlon for the treatment of ADHD even though its active ingredient, modafinil, has been heavily promoted and sold under the name Provigil, for off-label treatment of ADHD by Cephalon for years.
Last October, the FDA sent an "approvable" letter to Cephalon for the pediatric use of Sparlon pending a March 23, 2006, meeting of the Psychopharmacologic Drugs Advisory Committee to review the drug's approval.
Modafinil-based Provigil is currently only approved for narcolepsy, sleep apnea and shift work sleep disorder, according to the FDA. However, it is estimated that half of all Provigil prescriptions are written for off-label use.
"Doctors now prescribe it to treat everything from attention deficit hyperactivity disorder (ADHD) to fatigue associated with multiple sclerosis and depression," according to the November 1, 2004 Business Week Online.
Cephalon gets nearly half of its $1.2 billion in annual sales from modafinil. Its original patent ran out in December 2005. However, in a sweetheart deal, Cephalon agreed to pay 4 generic drug makers, including Mylan Laboratories and Teva Pharmaceutical, over $200 million to postpone marketing generic versions of the medication until October 2011, GoozNews reported on March 17, 2006.
In addition, the Cephalon will get a 6-month extension of that agreement if it wins a pediatric approval for the drug, according to documents filed with the Securities and Exchange Commission.
With Sparlon's application to FDA approval, Cephalon claimed 3 studies involving more than 600 children aged 6 to 17, found the drug to be more effective than a placebo.
Which says what? What does it mean to be more effective than a placebo? The question is, how many trials did it take to get the drug to win out over a placebo three times?
Each of the Sparlon studies lasted only 9 weeks and the most common side effects listed were mild insomnia, headaches and loss of appetite. Sparlon was "generally well-tolerated," Cephalon reported.
What does "generally well-tolerated," mean? Tolerated better than what? A placebo?
One study of 248 patients was published in December 2005 issue of Pediatrics, and said Sparlon's effectiveness and safety profile, along with its low potential for abuse, may offer doctors and parents a new option for children and adolescents with ADHD.
However, because the study only lasted 9 weeks, the authors said they did not know if "the initial benefits will be sustained over longer periods of time," and called for more research to assess the "longer-term efficacy and safety."
Dr DuBose Ravenel, MD, who will testify on behalf of the International Center for the Study of Psychiatry and Psychology at the advisory committee hearing on March 23, makes the point that although "48% of drug treated subjects at final follow-up were "much" or "very much" improved clinically, 52% were not."
"This is a substantially lower response rate than has been reported for traditional stimulants," the doctor notes.
Dr Dubose Ravenel is a pediatrician with 25 years experience in private practice with a heavy emphasis upon behavioral issues, including diagnosing and managing ADHD.
In addition, she notes, with regard to potential conflicts of interest, itemized conflicts for each of the Pediatric study's authors are numerous.
For instance, "Dr. Biederman received research support from 10 companies, serves on speakers' bureaus for 4 companies, and is on advisory boards of 6 companies," Dr Dubose Ravenel reveals.
"Dr. Kratochvil," she advises, "has received research support from, served as a consultant for, and/or served on speakers' bureaus for 10 pharmaceutical companies."
Other authors have numerous listed conflicts as well she notes.
"In light of recent widely publicized articles showing widespread deceptive practices engaged in by pharmaceutical companies in designing, selective reporting, and interpreting studies," she says, "the large number of pharmaceutical company ties with the authors of the study do not lend confidence to the reader even beyond the aforementioned concerns."
Initial marketing of modafinil, Dr Dubose Ravenel concludes, "as a drug for treating ADHD reveals inaccurate and exaggerated claims concerning efficacy, safety, and the mechanism of action by which the drug works."
And come to find out, it seems Sparlon is not so "well-tolerated" after all. Last week the FDA announced that an analysis provided by Cephalon as part of its response to the FDA's "approvable" letter found 4 suicidal events, 2 events of psychosis/mania and 9 aggression events in the double blind clinical studies of Sparlon, in a summary report for the Pediatric Advisory Committee.
In addition, two events of psychosis/mania and 14 aggression events were seen in open-label studies of modafinil for ADHD, the FDA said. These rates are compared to 5 aggression events and no suicidal or psychosis/mania events in placebo patients from the double-blind trials.
"There were more events in all categories among modafinil treatment patients compared to placebo, but the exposure to modafinil was greater," the FDA said.
"It will be noted, however, that the frequency of these events during double-blind treatment was higher than during open-label treatment," the FDA said.
The FDA summary also pointed out that "two additional probable cases of aggression during double-blind treatment, in study 207", were found by the agency's Psychiatry Products Division.
A March 3, 2006, memorandum to various FDA's divisions on drug safety, from FDA official Andrew Mosholder, noted that psychosis/mania events occurred during double-blind treatment with every ADHD drug studied except Adderall XR.
"With respect to psychosis and mania events," the memorandum wrote, "although the numbers of such events with drug treatment were small, the complete absence of such events with placebo treatment was notable."
The memorandum also noted that suicidal events were found to be more frequent with modafinil treatment than with placebo.
At a hearing last month on February 9, 2006, Dr Mosholder, told the FDA's Drug Safety Advisory Committee that modafinil, marketed as Provigil, is a stimulant. He said "modafinil is a different type of stimulant, marketed for excessive sleepiness associated with various sleep disorders."
"It too may have some cardiovascular effects," Dr Mosholder told the panel. "There was a finding that use of antihypertensives during the clinical trials was more frequent than on placebo, which suggests that there are some cardiovascular effects there as well."
Promoters of modafinil contend it can be useful in the treatment of cocaine addiction. In the August 2005, American Journal of Psychiatry, Charles O'Brien, MD, PhD, claims modafinil, the active ingredient in Sparlon, may decrease cocaine use in some cocaine users and specifically states:
"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, Dr O'Brien references his own group's work
According to Psychiatrist, Dr Stefan P Kruszewski, MD, "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, Dr Kruszewski says, may demonstrate that modafinil can, in some cases, blunt cocaine euphoria. However, it does not say anything about modafinil's intrinsic ability to produce euphoria (or not), he says.
"Separately," Dr Kruszewski advises in the March 2006, American Journal of Psychiatry, "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."
"The PDR also states that "modafinil is reinforcing, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine," he adds.
In addition, says Dr Kruszewski, the comment about the lack of euphorigenic effects is contradicted by the FDA in a January 14, 2002, warning letter sent to Paul Kirsch, the senior director of regulatory affairs at Cephalon, that 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, Dr Kruszewski says in the Journal.
Sparlon's approval is set to be reviewed by the Psychopharmacologic Drugs Advisory Committee on March 23, 2006.
Last month, Allen Jones, testifying as a representative of the Alliance for Human Research Protection, told the advisory panel: "Most of you have had past or current relationships with the drug industry."
As it turn out, conflicts of interest exist on this month's advisory panel as well. Wayne Goodman, the chairman of the Psychopharmacologic Drugs Advisory Committee that will consider Sparlon's approval heads the psychiatry department at the University of Florida, that receives hundreds of thousands of dollars a year in research grants from 2 of Cephalon's competitors in the field of ADHD drugs.
Another member of the Committee, Andrew Leon of Cornell University, disclosed he owns less than $25,000 in stock in a Cephalon competitor, according to GoozNews on March 18, 2006.
The Pediatric Advisory Committee is meeting on March 22, 2006, the day before the Sparlon hearing, to focus on neuropsychiatric adverse event reports and clinical trial data from approved ADHD medications, and will also receive an update on cardiovascular adverse events possibly related to ADHD medications, according to the FDA web site.
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