FDA's decision to review its approval of a generic for Valeant's topical Efudex (fluorouracil) Cream 5% may create a precedent for future approvals of ANDAs for complex small molecule drugs and could set the stage for higher hurdles for eventual approvals of biogenerics.

Legal challenges to FDA's approvals of ANDAs are usually short-lived and vigorously fought by the agency. GlaxoSmithKline sued the agency in 2006 following FDA's approval of Roxane's ANDA for generic Flonase (fluticasone propionate nasal spray) - another generic of a complex dosage form - but that stay lasted only a matter of days (¹ Also see "FDA Approves Generic Of GSK Flonase But Launch Halted By Restraining Order" - Pink Sheet, 27 February, 2006., p. 6).

Earlier, King unsuccessfully challenged FDA's bioequivalence standards for its hypothyroid drug Levoxyl (levothyroxine) (² Also see "FDA Levothyroxine Generic Approvals Upheld In First Court Challenge" - Pink Sheet, 12 July, 2004., p. 9).

So FDA's review of the Efudex generic is an unusual step for the agency, which appears to be backpedaling on its approval for Spear Pharmaceuticals' ANDA April 11 (³ 'The Pink Sheet,' April 21, 2008, p. 17).

The agency issued an "Administrative Reconsideration and Stay of Action" on the ANDA May 14. The decision follows a suit against the agency by Valeant, filed April 25 in the U.S. District Court Central District of California at Santa Ana, resulting in a stay of the proceedings until May 14. The administrative order filed by FDA pushed the decision back to May 30.

"In reviewing its files, the FDA has identified an issue in the Spear ANDA 'concerning whether FDA has required submission of all necessary and appropriate scientific information in support of approval,'" Valeant said.

The administrative order, signed by Jeffrey Shuren, FDA's Associate Commissioner for Policy and Planning, notes that "the Commissioner has concluded that FDA must reconsider the approval of Spear Pharmaceuticals' ANDA.... The Commissioner has concluded that it is in the public interest to do so because there are outstanding questions regarding this approval that the agency must consider."

Recently FDA has shown willingness to give more specific consideration to concerns about generics, which could cause public confidence in generics to sag, even if the agency ends up endorsing them after the review.

Last month, FDA reaffirmed the bioequivalence of Teva's 300 mg Budeprion XL , the generic of GSK's 300 mg Wellbutrin XL , after receiving 78 post-marketing reports of lost efficacy in the first half of 2007 (⁴ 'The Pink Sheet,' April 21, 2008, In Brief).

"This is a very unique situation," Laurie Little, VP-Investor Relations for Valeant, told "The Pink Sheet." Even more so, as Valeant is involved in two lawsuits concerning the issue - one as a plaintiff, and one as a defendant (see chart: " ⁵ Citizen Petition Against ANDA Was An Insider Job, Spear Alleges ").

On the same day as Spear's ANDA was approved, FDA denied a citizen petition by Valeant. The petition, originally filed on Dec. 21, 2004, requested that FDA "refrain from approving any abbreviated new drug application ... for a generic version of Efudex Cream, unless the application contains data from an adequately designed comparative clinical study conducted in patients with superficial basal cell carcinoma," according to agency documents.

Two Indications For One ANDA

The topical cream has two indications: treatment of multiple actinic or solar keratoses; and in the 5 percent strength, treatment of superficial BCC when conventional methods are impractical.

With no patents involved, Little told "The Pink Sheet," Valeant felt that FDA should require generic applicants to complete studies for both indications in order to gain approval.

"We filed this lawsuit, because we feel the approval of Spear's product by the FDA without requiring appropriate clinical testing of its efficacy in the treatment of basal cell carcinoma represents an inappropriate risk to patients," Valeant CEO Mike Pearson said during a May 7 first quarter earnings call.

"Allowing another company to launch an AB-rated product that has only been clinically tested on sun damaged skin, but which will be labeled and used to treat superficial basal cell carcinoma ... is not in the best interest of our patients. And we thought it was prudent to pursue this course of action."

In the April 11 letter informing Valeant of its decision to deny the citizen petition, CDER Director Janet Woodcock wrote that for generic topical corticosteroid drug products, "FDA has determined that it is not necessary to test for bioequivalence in every clinical indication."

Woodcock notes that "Although clinical bioequivalence studies are not necessarily required for locally acting topical formulations, in the absence of pharmacodynamic endpoints, it has generally been FDA's policy to use clinical studies to evaluate bioequivalence (except for solutions)."

According to court documents, Spear conducted a single comparative trial, in line with FDA requirements, on the actinic keratosis indication.

Valeant argued that sponsors should conduct a study in patients with sBCC because the site of action "is deeper within the epidermis [than where AK are located], and a comparative clinical trial that shows equivalence to the [sBCC site] may be sufficient to demonstrate, by implication, equivalence to the [AK site]."

FDA conducted a "thorough review of the medical literature related to AK and sBCC," Woodcock wrote, and concluded that contrary to Valeant's claim, the site of action on AK and sBCC is not different.

The physiological nature of the conditions was such that a drug that penetrated the skin to treat AK would also be able to treat sBCC, Woodcock added.

"We conclude that a single clinical study in AK would be sufficient to demonstrate that a generic topical [5-fluorouracil] product is bioequivalent to Efudex Cream for both the AK and sBCC indications."

Carving Out A Future

The Efudex case is not a traditional "carve out" case for FDA - in which a generic seeks to come to market with only a partial label - since the patents covering Efudex expired 20 years ago. But if it concedes the point that both indications need separate studies, the agency may consider putting the generic on the market labeled only for actinic keratosis.

Carve-outs are a well established practice for FDA, but the agency is now facing a petition from Victor Raczkowski, the former director of its drug safety office, asking it to block generics of Solvay's synthetic cannabinoid Marinol (dronabinol).

Solvay's petition, the first to be affected by the FDA Amendments Act of 2007 provisions intended to curb petitions designed to delay generic approvals, argued that allowing ANDAs to carve out certain still-protected indications create the risk of overdose (⁶ Also see "Generic Labeling “Carve-Outs” For Marinol Challenged On Safety Grounds" - Pink Sheet, 3 December, 2007., p. 22).

Given the current climate, such a safety argument could carry more weight at the agency.

FDA may also face a similar dilemma with Cobalt's proposed generic for AstraZeneca's Crestor (rosuvastatin), which would carve out the indication for primary hypercholesterolemia (⁷ Also see "AstraZeneca Aims To Grow Seroquel XR With Added Indications, Not Switches" - Pink Sheet, 5 November, 2007., p. 3).

Beyond small-molecule drugs, any decision on what indications generics can carry and what studies they have to do for them could create a precedent for how such questions would be handled by any eventual system for the approval of follow-on biologics.

Some of the legislative proposals would mandate separate tests for each indication of a follow-on, but even if such a requirement does not become law, FDA might be inclined to ask for it anyway. Such a decision would like be based on what the agency thought was necessary to demonstrate comparability - and the outcome of the Efudex case.

As of April 11, the agency had concluded that science justified a more limited scientific approach in that case. In the denial of Valeant's petition, Woodcock rejected the argument that the sBCC indication was most difficult to treat.

"The ideal clinical endpoint bioequivalence study should be conducted in the indication, which will be the most sensitive in discriminating formulation differences," she wrote.

"The optimal indication is generally one with the least variability in the disease state and expected course of disease and for which the recommended treatment is the same for all patients. This is often, but not necessarily, the most difficult-to-treat condition."

"Furthermore, the shortest duration of treatment for which a significant treatment effect is expected is likely to be the most discriminatory, since extending the duration of therapy may result in a higher probability of success for all study groups and less ability to differentiate between products."

According to information from the Efudex product label, Woodcock concluded, "the sBCC indication may not be the indication that is most sensitive in discriminating formulation differences between 5-FU products."

- Becky Jungbauer (r.jungbauer@elsevier.com)

Is FDA Less Confident In ANDAs? Stay On Efudex Generic May Set Precedent

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