Warner-Lambert's 1995 guilty plea related to good manufacturing practices compliance is an important factor in the Neurontin off-label promotion case settled by Pfizer on May 13.

The ¹ criminal complaint filed against Warner-Lambert (now owned by Pfizer) by the Boston U.S. Attorney's Office cites Warner-Lambert's prior conviction of distributing misbranded and unapproved new drugs in outlining the off-label charges.

Pfizer is paying $430 mil. - the largest settlement for an off-label promotion case - to resolve charges related to marketing practices for Neurontin (see ² Also see "Rx Comparative Studies Will Be Funded By Neurontin Settlement" - Pink Sheet, 17 May, 2004.).

Pfizer also entered into a corporate integrity agreement under which it agrees to comply with FDA promotional regulations and report off-label use trends (see ³ Also see "Pfizer To Monitor Off-Label Drug Use Under Neurontin Settlement" - Pink Sheet, 17 May, 2004.).

The Neurontin complaint offers a new twist on the enduring repercussions of FDA compliance problems - in this case, the settlement comes more than a decade after Warner-Lambert's Puerto Rican manufacturing operations were disrupted by GMP violations.

Warner-Lambert pled guilty in 1995 to charges arising from the GMP case and paid a $10 mil. fine to settle criminal charges (⁴ Also see "WARNER-LAMBERT FAJARDO, P.R. PLANT TO BE TAKEN OFF FDA INTEGRITY POLICY SOON, FIRM SAYS; FAILURE TO REPORT DILANTIN TEST FAILURES PROMPTS GUILTY PLEA" - Pink Sheet, 4 December, 1995., p. 3).

Although GMP issues are a distinct regulatory area from promotional policies, in both cases the company faced the same fundamental charge: violating the FD&C Act by introducing unapproved new drugs into commerce.

The timing of the two cases also played an important role in the case. The off-label promotion conduct cited in the Boston U.S. Attorney's complaint covers the period of April 1995 to August 1996 - essentially overlapping with the final resolution of the GMP charges.

The Boston U.S. Attorney cited the prior GMP conviction in listing the two counts against Warner-Lambert in the charging documents for the off-label promotion case.

"After previously having been convicted of violating the FD&C Act," Warner-Lambert distributed Neurontin intended for unapproved uses, causing the drug to be misbranded, the criminal complaint states.

The prior conviction may also have helped strengthen the prosecutors' hand in settlement negotiations. Off-label promotion remains a gray area under First Amendment case law.

The Boston prosecutors, however, believe the Neurontin case demonstrates that off-label promotion can be prosecuted either if it is "untruthful," accompanied by kickbacks, or found to encourage prescribing of indications not reimbursed by Medicaid (⁵ Also see "Neurontin Ruling Is Guide For DoJ Off-Label Promotion Cases – Prosecutor" - Pink Sheet, 13 October, 2003., p. 15).

According to the complaint, Neurontin was promoted for a number of unapproved uses: bipolar disorder, amyotrophic lateral sclerosis, attention deficit disorder, migraine, drug/alcohol withdrawal seizures and restless leg syndrome, among others.

At the time, Neurontin was indicated only as adjunctive therapy for epilepsy-related seizures.

The complaint states that Warner-Lambert did not seek NDA approval for the unapproved uses during the time period at issue in an attempt to reserve an expanded label for the follow-on product pregabalin. (A post-herpetic neuralgia indication cleared FDA in 2002.)

In the meantime, the company "conducted evaluations of the market potential for certain of the Unapproved Uses for Neurontin, including, but not limited to: post-herpetic neuralgia, pain diabetic neuralgia, anxiety disorder, social phobias and bipolar disorder."

For example, in April or May 1995, Warner-Lambert performed a marketing assessment of potential psychiatric indications for Neurontin. The assessment included the financial implications for two scenarios: "with or without FDA approval," the complaint says.

The charging document outlines the specific tactics used to promote Neurontin. Practices adopted during sales calls and physician conferences "were part of a widespread, coordinated national effort to implement an off-label marketing plan," DoJ declared.

Warner-Lambert encouraged sales representatives "to provide one-on-one sales pitches to physicians about off-label uses of Neurontin without prior inquiry by doctors."

For example, an October 1995 memo to senior members of the company's Epilepsy Disease Team reported that the "main message of certain sales pitches...given by 10 of 50 Warner-Lambert sales representatives for whom data was available in a two-month period, was for off-label use of Neurontin."

In 1996, a sales rep created a marketing document, "Neurontin Can Do/Can't Do" stating that reps could mention that approximately 35% of Neurontin use is non-seizure, and advocated for "lunch programs" on Neurontin and pain, the criminal complaint says.

Warner-Lambert also used medical liaisons to promote Neurontin for pain indications. The medical liaisons "represented themselves (often falsely) as scientific experts in a particular disease," DoJ said.

In a May 1996 voicemail message, a Warner-Lambert medical director told the medical liaisons "any time you're called out just make sure that your main focus" is Neurontin. "We want to sell Neurontin on pain. All right? And monotherapy and everything that we can talk about."

Off-label pain promotion also took place through Warner-Lambert consultants and advisory boards, during which physicians made detailed presentations about unapproved uses, the complaint says.

Physicians were paid to attend "consultants meetings," in which they "received a fee for attending expensive dinners or conferences during which presentations about off-label uses of Neurontin were made," DoJ said. "There was little or no significant consulting provided by the physicians."

The company also sponsored "independent medical education events on off-label Neurontin uses with extensive input from Warner-Lambert regarding topics, speakers, content and participants."

"Warner-Lambert misled the medical community beforehand about the content, as well as the lack of independence from the company's influence, of many of these educational events," DoJ said.

"In at least one instance, when unfavorable remarks were proposed by a speaker, Warner-Lambert offset the negative impact by 'planting' people in the audience to ask questions highlighting the benefits of the drug."

Warner-Lambert GMP Conviction Plays Role In Neurontin Case

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