Clinical trials are not required to demonstrate bioequivalence of generic lidocaine patches to Endo Pharmaceuticals Inc.’s reference drug Lidoderm, FDA said.

In an Aug. 22 citizen’s petition response that paved the way for approval of ANDA first-filer Allergan PLC’s lidocaine patch 5%, FDA rejected Endo’s arguments that Lidoderm is a topical dermatological drug product for which pharmacokinetic studies are often inappropriate.

FDA’s response is premised on the view that Lidoderm is a topical pain relief product, not a dermatological product intended to treat skin disease.

Rather, FDA said Lidoderm was a topical pain relief product not intended to treat a disease of the skin. The product’s active ingredient penetrates beneath the skin surface, making pharmacokinetic bioequivalence studies feasible, the agency said.

“We are disappointed in FDA’s decision to deny the citizen’s petition and approve a generic version of Lidoderm,” Endo said in a statement. “The company believes that the approval of a generic version of Lidoderm without requiring clinical endpoint studies is inadequate to establish the safety and efficacy of this locally-acting topical medication.”

The 43-page FDA response caps an almost six-year regulatory battle by Endo to keep generics of its top-selling product at bay. Endo’s efforts have extended beyond the regulatory realm: the company was reported to be involved in an unsuccessful bid to include in the recently enacted FDA Safety and Innovation Act provisions regarding generic approval standards for locally acting products Also see "User Fee Conference Cmte. Could Be Relatively Messy After Clean Floor Votes" - Pink Sheet, 4 June, 2012..

Despite FDA’s resounding rejection of the citizen’s petition and approval of the first Lidoderm generic, Endo does have the benefit of a grace period before it is expected to face competition: Watson’s generic is not scheduled to launch until September 2013 pursuant to a patent settlement with Endo.

However, whether another generic will be ready for approval before Watson’s launch and whether Watson is entitled to 180 days of marketing exclusivity on the lidocaine patch remains to be seen (see related story, Also see "Watson’s Generic Lidoderm Approval Leaves Questions About Exclusivity" - Pink Sheet, 3 September, 2012.).

Bioequivalence Recommendations Draw Objections

In a citizen’s petition first filed in December 2006 but subsequently amended in August 2007 and March 2012, Endo urged FDA to require that ANDAs referencing Lidoderm establish bioequivalence through clinical trials.

Endo’s original petition challenged FDA recommendations in an October 2006 advice letter stating that two studies would suffice to support a demonstration of bioequivalence – a single-dose, fasting, pharmacokinetic study using up to three topical patches in healthy subjects, and a skin irritation/sensitization study Also see "Endo To Submit Response To FDA On Lidoderm Bioequivalence Recommendation" - Pink Sheet, 18 October, 2006.. These recommendations were subsequently incorporated into a draft bioequivalence guidance posted on the agency’s website in May 2007.

Endo argued that ANDA filers should be required to conduct clinical endpoint studies in patients with post-herpetic neuralgia, Lidoderm’s indicated population, to demonstrate bioequivalence. Furthermore, ANDA applicants should be required to show their product produces the same local analgesic effect as Lidoderm without causing a complete sensory block, and the only way to adequately do this is through a clinical trial, Endo said.

The company also asserted that FDA’s recommendations in the draft guidance represented a substantive change in the agency’s interpretation of its regulations and were inconsistent with previous agency statements on bioequivalence for topical products.

FDA’s response, signed by Center for Drug Evaluation and Research Director Janet Woodcock, acknowledged that for topical dermatological products, pharmacokinetic measurements in blood, plasma and urine often are not feasible because the drug works at the upper layers of the skin and is not systemically absorbed.

Nevertheless, the response states that Endo’s arguments and the many requested actions outlined in its citizen’s petition are based “on the erroneous premise that Lidoderm is a topical dermatological product (i.e., intended to treat a disease of the skin itself) for which pharmacokinetic bioequivalence studies are often not feasible due to a lack of systemic absorption. Lidoderm is a topical pain relief product, however, and not a dermatological product.”

Topical lidocaine has several characteristics that distinguish it from most other topical drug products and provide support for the conclusion that bioequivalence may be demonstrated through plasma concentration measurements, the response states.

Lidocaine can be measured in plasma following its application to the skin. The drug is expected to pass through the stratum corneum to reach its site of action, a characteristic that sets lidocaine apart from topical drugs that do not penetrate the stratum corneum or upper layers of the skin. Furthermore, lidocaine is expected to enter the bloodstream through capillaries that are present in dermal tissue beneath the stratum corneum, and it is expected to be present in plasma at a concentration proportional to its presence at the site of action when applied topically to skin for the treatment of post-herpetic neuralgia.

“Based upon these considerations … we conclude that the pharmacokinetic studies and skin testing described in the Draft Lidocaine Patch BE Guidance together are the most sensitive, accurate and reproducible method for detecting differences in bioavailability between Lidoderm and a proposed generic product (and therefore for demonstrating bioequivalence) and that comparative clinical endpoint studies, which you urge us to require, would be less sensitive, accurate and reproducible,” the response states.

The agency said the methodology recommended in the draft guidance ”is grounded in FDA’s scientific conclusion that when two lidocaine patches with the same drug concentration and the same area and time of application produce equivalent plasma concentration-time profiles, the local delivery of the drug from the formulation to the topical site of action will be equivalent.”

Clinical endpoint studies are not appropriate because “the nature of lidocaine permits a more precise evaluation of bioavailability through the pharmacokinetic methods and skin testing described,” FDA said.

Comparative clinical endpoint trials would be less sensitive than pharmacokinetic studies at detecting differences between lidocaine patch formulations, the agency maintained.

“In particular, in vivo clinical endpoint studies measure formulation differences indirectly rather than directly, include confounding variables such as different severities of disease, may have variability in the definition of the instrument used to measure efficacy … and may have difficulty in assessing dose response,” the response states. “They also often require approximately 500 subjects to demonstrate bioequivalence. While sometimes appropriate, they are not here, where the nature of lidocaine permits a more precise evaluation of bioavailability through the pharmacokinetic methods and skin testing described” in the draft guidance.

The agency rejected Endo’s request that it convene a joint meeting of the Dermatologic and Ophthalmic Drugs Advisory Committee and the Advisory Committee for Pharmaceutical Science and Clinical Pharmacology to discuss development of appropriate methods for demonstrating bioequivalence for drug products with patch dosage forms and local routes of administration.

“We have determined that bioequivalence testing methodology for lidocaine topical patches is not sufficiently controversial or of such significant public interest that it would be highly beneficial for FDA to obtain the advice of an advisory committee,” the response states. “Nor do we find that this subject requires special expertise that an advisory committee could provide.”

A Special Focus On Cetero Studies

Endo’s petition also sought to capitalize on the troubles surrounding Cetero Research, a contract research organization that has been accused by FDA of falsifying bioanalytical and bioequivalence study data.

Watson has said one of the studies supporting its lidocaine patch ANDA was conducted by Cetero but the issue was addressed to FDA’s satisfaction.

Endo requested that FDA not review or approve any product referencing Lidoderm unless the agency verified that all bioavailability and bioequivalence studies were submitted, and that the agency review all studies conducted by Cetero between April 2005 and August 2009 supporting such applications.

FDA said it was denying Endo’s request to make “wholesale determinations about all lidocaine patch product ANDAs or 505(b)(2) applications that contain data from Cetero.”

“If an applicant is relying on studies conducted by Cetero Research during the stated 2005-2009 time frame, those studies would need to be repeated or audited as we have specified,” the agency said. “Any bioequivalence studies conducted by Cetero that are not relied upon to support approval would be reviewed in the same way we review such studies generally. During the review of such studies, if we determine the summary results indicate that a review of the full study report is needed, FDA would perform an evaluation of the integrity of the data in the full study report. We will determine on a case-by-case basis whether any Cetero studies not relied upon for approval require special scrutiny or confirmation.”

Clinical Trials Not Required For Lidoderm Generics, FDA Tells Endo

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