Top CDER officials moderated the primary reviewers' inclination to delay approval of Pfizer's Lyrica (pregabalin) until more data on dermatologic and visual effects better characterized the drug's risks, review documents show.

Visual and dermatologic adverse events were only one of the contentious issues in the review of Lyrica, but the issues were sufficiently perplexing for the review team to seek input of senior FDA officials.

The input came in the form of a regulatory briefing, a meeting called when the review team requests center-level input. Regulatory briefings are relatively uncommon and, not surprisingly, tend to be called for high-profile dilemmas. Regulatory briefings were held, for example, for Elidel , Vioxx , Palladone and pediatric antidepressants.

The Lyrica regulatory briefing on March 19, 2004, was chaired by CDER Acting Director Steven Galson. Other panelists included Office of New Drugs Director John Jenkins, Associate Director for Medical Policy Robert Temple, Office of Drug Evaluation IV Director Edward Cox, ODE IV and V Associate Director for Pharm/Tox Abigail Jacobs, and Office of Pharmaceutical Sciences Associate Director for Medical Affairs Solomon Sobel.

At the regulatory briefing, the Division of Anesthetic, Critical Care & Addiction Drug Products proposed "that the dermatologic and ophthalmic effects of pregabalin should be better characterized prior to drug approval in order to establish that the risk/benefit ratio is favorable in the diabetic population." Both clinical and pharmacology/toxicology reviewers had recommended against approval of Lyrica based on the vision and skin issues.

Visual changes also could be addressed with labeling and a Phase IV study, the panel said. The recommendations dovetailed with the ophthalmology consult provided by Division of Anti-Inflammatory, Analgesic & Ophthalmologic Drug Products Deputy Director Wiley Chambers.

Chambers told the briefing that "in his opinion, this was also a labeling issue." Phase IV trials could resolve questions left outstanding by the poor design of Pfizer's vision testing, which Chambers said was "conducted in such a way that it was not sensitive to minor changes, rendering the evaluation the equivalent of a 'large, simple trial,'" the minutes report.

The "overall recommendation" of the briefing was that "based upon the efficacy of pregabalin, the seriousness of the disease, and lack of treatment options, the division should consider approving the drug for a limited population with appropriate labeling to address the safety concerns and Phase IV commitments."

The review team's unease over interpretation of the safety data apparently persisted: a week after the regulatory briefing, the team consulted with the European Medicines Agency "to discuss key safety issues with the EMEA reviewers who had recently recommended the drug for marketing," according to minutes of a March 24, 2004 teleconference.

In addition to the toxicity data addressed by the regulatory briefing, the EMEA teleconference discussed abuse potential.

EMEA "reviewed the application with respect to a broader claim of neuropathic pain," the minutes note. In the U.S., a 2002 advisory committee spurred a shift from broad NP claims to programs targeting specific types of neuropathic pain.

EMEA handled vision concerns with Periodic Safety Update Reports, a less intensive mechanism than the Phase IV study recommended by Chambers and the regulatory briefing panel. "EMEA did not recommend a post-marketing study due to the lack of a pattern in the current, extensive database," minutes report.

One of the biggest differences between the agencies was interpretation of the animal carcinogenicity data that resulted in an FDA clinical hold on Lyrica studies prior to NDA submission.

While FDA ultimately concluded that the carcinogenicity data could be handled in labeling, the agency felt that Pfizer's contention that mouse hemangiosarcomas were not relevant to humans was not well supported. EMEA, however, felt Pfizer's mechanistic studies supported the company's claim that the hemangiosarcomas were species-specific.

EMEA and FDA agreed during the teleconference that dermatopathy should not preclude approval. Review documents indicate that the FDA position emerged out of internal disagreement, as both the primary and secondary pharm/tox reviewers found the preclinical dermatopathy finding warranted non-approval.

A similar dynamic played out on the medical review side, with agreement by the primary and secondary reviewers against approval being overruled.

Addiction Drugs Team Leader Celia Winchell considered the regulatory briefing's conclusion of approvability in her June 3, 2004, supervisory review, but nonetheless supported Kashoki's recommendation against approval. At the regulatory briefing, CDER management "concluded that it may be possible to define a population for whom the benefits of pregabalin outweigh the risks," Winchell noted in her review.

The CDER panel had recommended limiting Lyrica to refractory patients. "However, it is not clear that the efficacy of the product can be assured in this population," Winchell responded. "In fact, patients refractory to Neurontin (commonly used off-label) were specifically excluded from trial participation."

"Exploration of the data available did not reveal any obvious way to limit the population," Winchell stated.

"The animal carcinogenicity and dermatopathy, along with the ophthalmologic effects of pregabalin, taken together with the vulnerabilities of the diabetic population, call into question the risk/benefit ratio for the overall DPN population," Winchell wrote.

Division Director Bob Rappaport disagreed, and recommended approval. In a June 28, 2004 summary review, he explained that while the toxicity concerns "are relevant, I do not find the data regarding most of these toxicities to be compelling."

ODE II Director Robert Meyer concurred with Rappaport in his July 28, 2004 sign-off memo. "None" of the unresolved issues "are of sufficient import to preclude approval at this point," he said.

FDA cleared Lyrica for the management of postherpetic neuralgia and neuropathic pain associated with diabetic peripheral neuropathy on Dec. 30, 2004 (¹ Also see "Pfizer Lyrica Launch Awaits Controlled Substance Scheduling" - Pink Sheet, 10 January, 2005., p. 5).

[Editors' note: Additional analysis of FDA's review of Lyrica appears in the August issue of FDC Reports' Pharmaceutical Approvals Monthly. For a sample copy, contact customer service at 800-332-2181.]

Lyrica Reviewer Concerns On Vision, Skin Led To Consults With Top FDA Staff

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