July 2010 Archives

July 30, 2010

Patent Use Code Misuse Challenge Will Not Be Reheard by Federal Circuit

by Andrew S. Wasson

444221_93338615.jpgOver the clamorous arguments of the generic pharmaceutical industry, on July 29, the Federal Circuit refused to review en banc its April 2010 decision in Novdisk A/S v. Caraco Pharm. Labs. Ltd., where it nixed a district court injunction compelling Novo Nordisk to modify a patent use code narrative relating to the drug Prandin® (repaglinide). Judges Gajarsa and Dyk entered spirited dissents, potentially setting the stage for legislative remedy or Supreme Court review.

Caraco, its parent company Sun Pharmaceutical Industries, and six other amicus curiae from the generics industry, requested that the Federal Circuit rehear the case en banc. Caraco and Sun argued that the original decision misconstrued the language of the Hatch-Waxman Act and failed to read the statutory language in the context of the full provision itself and with other provisions of the Act, such as subsection viii. Continuing the thread of Judge Dyk's dissent in the original opinion, the request also argued that the ruling failed to give the appropriate deference to FDA in its interpretation of "patent information."

Despite these arguments, the Federal Circuit refused to rehear the case, with Judges Gajarsa and Dyk dissenting. Writing the dissent, Judge Gajarsa stated that the April opinion "eviscerates Section viii" and that "[w]ith the majority's blessing, pioneering drug manufacturers now have every incentive to follow Novo's lead and draft exceedingly broad use codes thereby insulating themselves from generic competition and rendering Section viii a dead letter." Judge Gajarsa stated that it was an "untenable and absurd result" that even though the Orange Book patent would admittedly not cover Caraco's proposed carved-out labeling, Caraco would be effectively blocked from marketing until that patent's expiration in 2018. In addition, Judge Gajarsa argued that the opinion "effectively invalidates" he FDA's effort to define patent information broadly.

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July 29, 2010

Biosimilar Biological Act Update 08/10

by and Scot B. Pittman

dna.jpgPassage of the Biologics Price Competition and Innovation Act of 2009 ("the Act"), part of the larger Health Care Bill, has provided for the abbreviated approval of so called "biosimilar" biological products. While there has been much talk surrounding its passage, there has been little action as we wait to see how implementation of the Act will unfold. FDA has been relatively quietly about its policy for biosimilars. Their current implementation plan can be found here. According to the plan, FDA has created the Biosimilar Implementation Committee (BIC) which is chaired by Dr. Janet Woodcock, Director of the Center for Drug Evaluation and Research (CDER) and Dr. Karen Midthun, Acting Director for the Center for Biologics Evaluation and Research (CBER). Furthermore, two Biosimilar Review Committees, a CDER one chaired by Dr. John Jenkins and CBER one chaired by Dr. Robert Yetter, have been formed to review product-specific issues.

Coincidentally, FDA's initial implementation play came a day after an American Conference Institute's conference on Follow-On Biologics on June 21-22, which addressed the lead up to an abbreviated biologics pathway and what to expect now that one exists. At the conference, Frommer Lawrence & Haug LLP Partners Brian J. Malkin and Charles J. Raubicheck gave presentations on Defining Biosimilars: Proving (or Disproving) Interchangeability and Biosimilarity and Developing Alternative Pathways for Getting Biosimilars on the Market, respectively.

Players in the follow-on biologics industry have been somewhat hesitant to act while waiting for further FDA guidance. Late last year Teva chose to forgo waiting for an abbreviated pathway and sought approval of a biosimilar Neupogen (filgrastim) drug under the traditional BLA pathway, which it filed before the new law was signed. (Teva Press Release, Feb. 2, 2010). Merck appears to be the first company that is going to test the new pathway as it is reportedly seeking approval of a biosimilar granulocyte colony-stimulating factor that references Amgen's Neupogen (filgrastim) and further plans for have five biosimilar projects in full swing by 2012. (The Pink Sheet, July 5, 2010).

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July 28, 2010

Enoxaparin Petition Answered - FDA Requires Similar Ring Structure But Denies Other Requests

by and Scot B. Pittman

On July 23, 2010, FDA finally issued its response to a citizen petition filed by Aventis Pharmaceuticals Inc. ("Aventis"), a subsidiary of Aventis SA (now part of Sanofi-Aventis) more than seven years earlier regarding abbreviated new drug application (ANDA) for generic versions of Lovenox® (enoxaparin sodium injection) ("enoxaparin"). Aventis filed its citizen petition on February 19, 2003, requesting that FDA withhold generic approvals, until such time as enoxaparin had been fully characterized, for any ANDA referencing Lovenox® that did not use an equivalent manufacturing process or did not show proof of equivalent safety and efficacy through clinical trials. Furthermore, Aventis requested that FDA require any generic drug referencing Lovenox® to have a 1, 6 anhydro ring structure at the reducing ends of between 15 percent and 25 percent of its polysaccharide chains.

FDA's response granted the petition in part, with respect to the request that generic enoxaparin contain the 1, 6 anhydro ring structure at the reducing of between 15 percent and 25 percent of its polysaccharide, but denied all other requests. FDA identified the main argument of the Citizen Petition as whether an ANDA applicant for enoxaparin could demonstrate its product had the same active ingredient as Lovenox®.

FDA concluded that enoxaparin had been adequately characterized to approve generic enoxaparin derived from natural sources. FDA stated that the following five criteria would be adequate to demonstrate sameness in the active ingredients of generic enoxaparin and Lovenox®: (1) the physical and chemical characteristics of enoxaparin, (2) the nature of the source material and the method used to break up the polysaccharide chains into smaller fragments, (3) the nature and arrangement of components that constitute enoxaparin, (4) certain laboratory measurements of anticoagulant activity, and (5) certain aspects of the drug's effect in humans. This information would be sufficient to demonstrate sameness of the enoxaparin active ingredient, including with respect to the 1, 6 anhydro ring structure. FDA also noted that a complete characterization of all the different polysaccharides of enoxaparin was not required to show sameness. The agency further discussed that an ANDA applicant did not need to show that it used identical or equivalent manufacturing processes to those used by Aventis. Finally, FDA stated that ANDA applicants are not required to provide clinical trial data to establish safety and efficacy.

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July 27, 2010

Opioid REMS for ER/LA Dosage Forms Stumbles on Prescriber Training Issue

by Fitz Beckwith Collings

Thumbnail image for Pills with empty bottle.jpgIn light of the increasing prevalence of opioid abuse, FDA proposed the creation of a Risk Evaluation and Management Strategy (REMS) for extended-release (ER) and long-acting (LA) opioids in February 2009. On July 22-23, 2010, an FDA advisory panel consisting of both the Anesthetic and Life Support Drugs and Drug Safety Committee and the Risk Management Advisory Committee convened to consider four major REMS questions and conduct a simple up-down vote on FDA's proposed REMS. The advisory panel heard presentations regarding the nature of opioid abuse and misuse; efforts to address the abuse/misuse problem; the content of FDA's REMS proposal; metrics for REMS evaluation; the safe use initiative; and patient and prescriber training programs designed to prevent abuse and misuse.

FDA presented data from the National Survey on Drug Use and Health showing that the proportion of patients using ER/LA opioid pain killers for non-medical use has doubled in the last ten years. The data also indicated that a vast majority of non-medical ER/LA opioid users obtained the product either directly from their doctor or from friends and relatives who obtained the product directly from their doctor. Despite the apparent disconnect between prescribers and patients, the training component of FDA's proposed REMS mandated only sponsor-developed patient education materials for voluntary use by prescribers.

The proposed REMS did not include features like enrollment of individual prescribers into a REMS program or real-time electronic verification of prescriber training at the pharmacy level. FDA noted the potential high cost of such programs, but acknowledged the possibility of piggy-backing such features onto the DEA registration system, a step which would require legislation. Presenters from the industry working group (IWG) agreed that FDA's voluntary prescriber and patient educational programs were necessary REMS components. IWG also highlighted educational problem areas, such as the lack of time prescribers spend discussing the possibility of a fatal overdose with patients and the lack of patient awareness about what to do in the event of an overdose. Like FDA, however, IWG did not express support for mandatory prescriber training.

Twenty-five members of the 35-member advisory panel voted to reject FDA's proposed REMS. (The Pink Sheet, July 23, 2010). The panel specifically cited concerns over the lack of mandatory prescriber training. (The Pink Sheet, July 23, 2010). Going forward, the extent of patient and prescriber educational programs on the use and abuse of opioids remains a key unresolved issue that FDA will need to address. Legislation may be required in order to reconcile the potentially prohibitive cost of such programs with the need to close the prescriber-patient communication gap.

July 26, 2010

Tighter GMPs Petition Denied

by Charles J. Raubicheck

On July 21, FDA denied a citizen petition by the drug manufacturer Kremers Urban ("Kremers") (through its law firm Foley & Lardner) that asked the agency to impose more stringent good manufacturing practices (GMP) requirements for: (i) production of highly potent drugs, and (ii) possible cross-contamination during manufacturing operations.

FDA asserted that existing GMP standards, in the Federal Food Drug and Cosmetic Act and related regulations and guidances, are adequate to address these issues, particularly those standards governing specifications and process validation.

The agency rejected the petition's call for new drug application and abbreviated new drug application disapprovals, draft guidances, and advisory committee review.

July 23, 2010

Menthol Cigarette Ban? FDA's TPSAC Continues to Hear the Evidence

by

cigarrettes.jpgOn July 15-16, FDA's Tobacco Products Scientific Advisory Committee (TPSAC) revisited the effect of menthol in cigarettes as part of its charge under the Tobacco Control Act. For this meeting, TPSAC requested from members of the tobacco industry reports on: (1) characterization of menthol in cigarettes, (2) clinical effects of menthol in cigarettes, (3) biomarkers of disease risk for menthol cigarette smokers, (4) marketing data on menthol cigarettes, and (5) population effects of menthol cigarettes.

Industry representatives provided a largely uniform picture that menthol has been used for a long time in cigarette products, does not play a unique role in smoking or cessation, and does not require further restrictions. Menthol cigarettes currently account for about 30% of all cigarette sales in the U.S. Despite Caucasians representing 58% of all menthol product sales, a majority (approximately 75%) of African Americans prefer menthol cigarettes to nonmenthol varieties.

During the process of asking "clarifying questions" to the industry representatives, several voting members of the TPSAC appeared to reveal their bias toward banning or limiting the amount of menthol in cigarettes. TPSAC's Jack E. Henningfield, Ph.D., Vice President, Research and Health Policy, Pinney Associates, for instance, was highly critical of industry's "taste" preference surveys for menthol products, believing them to be euphemisms for addiction. Henningfield and Patricia Nez Henderson, M.P.H., M.D., Vice President, Black Hills Center for American Indian Health, both asked industry what would happen if menthol were banned, with Henningfield going as far as saying that banning menthol would be an "important public health step." In addition, various members of the TPSAC asked industry to explain why more African Americans preferred menthol, suggesting that a combination of marketing, product discounting, and a genetic susceptibility to menthol for African Americans was being exploited.

Near the end of the meeting, the TPSAC focused on identifying additional clarifying questions, including a request for more brand/subbrand data and chemosensory data to determine why menthol appeals more to African Americans. TPSAC must issue its report on menthol to FDA by March 23, 2011.