FDA Warning Letter

[Released by FDA: 1/3/02. Posted by FDA: 1/14/02]

Paul M. Kirsch
Senior Director, Regulatory Affairs
Cephalon Inc.
145 Brandywine Parkway
West Chester, PA 19380-4245

RE: NDA # 20-717
Provigil (modafinil) Tablets
MACMIS ID # 10183

Dear Mr. Kirsch:

This letter objects to Cephalon Inc's (Cephalon) dissemination of false or misleading promotional materials¹ for Provigil (modafanil) Tablets. As a part of its routine monitoring and surveillance program, the Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed these materials for Provigil and has concluded that they are false, lacking in fair balance, or otherwise misleading in violation of the Federal Food, Drug, and Cosmetic Act (Act), and applicable regulations. Our specific objections follow:

Promotion of Unapproved Uses

Promotional materials are false, lacking in fair balance, or otherwise misleading if they contain representations or suggestions that a drug is better, more safe, more effective, or useful in a broader range of conditions or patients than has been demonstrated by substantial evidence. Provigil is indicated in a select group of patients. Specifically, the "Indications and Usage" section of the approved product labeling (PI) for Provigil States, "Provigil is indicated to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy."

The claims contained in your promotional materials suggest that Provigil is safe and effective for a variety of unapproved uses. For example, your journal advertisements² prominently present the following misleading claims under the header "Consider PROVIGIL to improve wakefulness:"

"When patients complain of FATIGUE or TIREDNESS"
"When patients present with SLEEPINESS"
"When patients complain of SLEEPINESS"
"When patients present with FATIGUE or TIREDNESS"
"When patients complain of feeling FATIGUED or TIRED"
"When patients present with sleepiness and Decreased ACTIVITY"
"When patients complain of sleepiness and Decreased ACTIVITY"
"When patients present with Lack of ENERGY"
"When patients complain of Lack of ENERGY"

The claims are misleading because Provigil is not approved to treat such symptoms as sleepiness, tiredness, decreased activity, lack of energy, and fatigue. Therefore, the claims promote Provigil for unapproved uses.

Similarly, your sales aids³ prominently present the claim "[a] wake-promoting alternative for your psychiatry practice..." on the front cover, followed by the claim "PROVIGIL: A prescription for daytime wakefulness," on the inside front cover. These claims are misleading because they suggest that Provigil is a safe and effective treatment for anyone with daytime sleepiness. 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. Furthermore, presenting the indication for Provigil in small print at the bottom of the sales aids and journal advertisements does not correct the overwhelming misleading impression that Provigil can be used to improve wakefulness in all patients presenting with symptoms of daytime sleepiness, characteristic of generalized sleep disorders, whether or not they have narcolepsy.

The Provigil website⁴ also prominently presents the claim, "Provigil, a prescription for daytime wakefulness," along with a questionnaire with the headline, "Do you suffer from excessive daytime sleepiness?" Thus, the Provigil website is misleading because, like your sales aids and journal advertisements, the website does not adequately communicate the indication for Provigil. Additionally, the website promotes Provigil for unapproved uses by suggesting that Provigil is useful for anyone with excessive daytime sleepiness.

Minimization of CNS Effects and Abuse Potential

Your promotional materials⁵ present claims that "Provigil promotes wakefulness without widespread CNS stimulation in preclinical models" and "Low abuse potential" to suggest that Provigil does not have CNS properties that may lead to abuse and are common to other scheduled stimulants or stimulant-like drugs. The claim is misleading because it is inconsistent with the Pl. The PI states, "[t]he abuse potential of modafanil (200, 400, and 800mg) was assessed relative to methylphenidate (45 and 90mg) in an inpatient study in individuals experienced with drugs of abuse. Results from this clinical study demonstrated that modafanil produced psychoactive and euphoric effects and feelings consistent with other scheduled CNS stimulants (methylphenidate)." Furthermore, presenting data from pre-clinical models is not considered substantial evidence to support efficacy claims.

Misleading Mechanism of Action Claims

Claims contained in your promotional materials⁶ suggest that the mechanism of action of Provigil is understood. For example, your sales aids, journal advertisements, and Provigil website present the following misleading claims:

"PROVIGIL works differently from stimulants in preclinical models."
"PROVIGIL promotes wakefulness without widespread CNS stimulation."
"PROVIGIL acts selectively in areas of the brain to regulate normal wakefulness."
"Unlike stimulants, PROVIGTL is not mediated by a dopaminergic mechanism."
"The highly selective CNS activity of PROVIGIL is distinct from amphetamine and methylphenidate in pre-clinical models."

The claims are presented with pictures that illustrate selective sites of action in the brain where Provigil is purported to have activity based on animal studies. Moreover, the claims and pictures are presented in comparison to amphetamine and methylphenidate. These presentations are misleading because they imply that the mechanism of action of Provigil is fully understood when such is not the case. The PI specifically states that "the precise mechanism(s) of action through which modafanil promotes wakefulness is unknown." Additionally, it is misleading to make claims based on data from animal studies to suggest clinical significance when, in fact, no clinical significance has been demonstrated. Furthermore, placement of statements in small pint that "the relationship of these findings in animals to the effects of Provigil in humans has not been established" or "the precise mechanism of action is unknown" does not correct the overwhelming misleading impression presented by the claims and pictures.

Misleading Switch Protocol

Your sales aids⁷ and Provigil website⁸ state or suggest that patients should be switched from traditional stimulants (e.g., methylphenidate) to Provigil, along with other claims such as "switching to Provigil is easy" and "switch to Provigil for all the right reasons." Additionally, a protocol for switching from methylphenidate to Provigil is provided in the promotional materials. The claims and switch protocol are misleading because they imply that the efficacy of Provigil and methylphenidate, for example, are equivalent when such has not been demonstrated by substantial evidence.

Unsubstantiated Superiority Claims

Your sales aids⁹ present claims that patients dissatisfied with stimulants and patients seeking a well tolerated agent are candidates for Provigil. Your sales aids also claim that patients should be switched to Provigil because Provigil has more selective activity in the brain and improves sleep latency compared to traditional stimulants. These claims are misleading because they suggest that Provigil is superior to other agents when such has not been demonstrated by substantial evidence i.e., head-to-head clinical studies. In fact, data used to support the unproved sleep latency claim was derived from a post-hoc analysis of sleep latency. Data from post-hoc analyses are not adequate evidence to support superiority or comparative efficacy claims.

Additionally, your sales aid¹⁰ presents the misleading claim "Provigil significantly improved daytime wakefulness in patients unsatisfactorily treated with traditional stimulants" followed by a graph entitled "Provigil improved wakefulness." The claim and accompanying graph are misleading because they suggest superiority for Provigil versus dextroamphetamine, methylphenidate, and pemoline, when such has not been demonstrated by substantial evidence.

Requested Action

We request that you immediately cease the dissemination of sales aids, journal advertisements, websites and all other promotional materials and activities for Provigil that contain the same or similar violations outlined in this letter. Your written response to the above request should be received no later than January 17, 2002. Your response should include a list of all promotional materials that are discontinued and the date that they were discontinued. If you have any questions or comments, please contact James Rogers, Pharm.D., by facsimile at (301) 594-6771, or at the Food and Drug Administration, Division of Drug Marketing, Advertising, and Communications, HFD-42, Rm 17-1320, 5600 Fishers Lane, Rockville, MD 20857. We remind you that only written communications are considered official.

In all future correspondence regarding this particular matter, please refer to MACMIS ID # 10183 in addition to the NDA number.

Sincerely,

James R. Rogers, Pharm.D.
Regulatory Review Officer
Division of Drug Marketing,
Advertising, and Communications

____________________________________________

1 The promotional materials include, but are not limited to the following sales aids (PR0214, PR0215, PR0212, PR0227, PR0221, PRO197, PRO198 and PR0164), journal advertisements (PR0230, PR0231, PR0228, PR0229, PR0225, PR0224, PR0223, and PR0222), and Provigil website (http://www.provigil.com) PR0264.

2 PR0222, PR0223, PR0224, PR0225, PR0228, PR0229, PR0230, and PR0231

3 PRO 197, PRO 198, PR0214, and PR0215

4 PR0264, http://provigil.com/patient/ess/default.asp

5 PR0222, PR0223, PR0224, PR0225, PR0228, PR0229, PR0230, and PR0231

6 PRO197, PRO198, PR0212, PR0214, PR0215, PR0222, PR0223, PR0224, PR0225, PR0228, PR0229, PR0230, PR0231, and PR0264, http://www.provigil.com/patient/ess/default.asp

7 PRO 197, PRO 198, PR0212, PR0214, and PR0215

8 PR0264, http://www.provigil.com/physician/mate,rials/dosing.asp

9 PRO 164, and PR0212

10 PRO 164

Refs
modafanil/Provigil
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