DID - May 20, 2008 Issue

Vol. 7 No. 99

Biovail to Pay $24.6 Million to Settle Charges, Keep Federal Business

Biovail Pharmaceuticals, the U.S. subsidiary of Canada’s Biovail, has agreed to pay $24.6 million to settle criminal charges of improper marketing surrounding its commercial launch of Cardizem LA.

The settlement requires the company to plead guilty to paying thousands of physicians and other healthcare professionals as much as $1,000 each to induce them to prescribe or recommend Cardizem LA (diltiazem HCl) to manage blood pressure and chronic stable angina. The payments were made through the PLACE (Proving LA through Clinical Experience) program, the U.S. attorney for the District of Massachusetts said in announcing the settlement.

Biovail said the agreement eliminates any criminal liability for the company and preserves its ability to conduct business in the U.S., although the government said the investigation is still continuing. Without a settlement, the company risked being excluded from doing business with any health program sponsored by the federal government, which represents a substantial portion of its business, according to Biovail.

Beginning in March 2003, Biovail Pharmaceuticals “paid physicians and other prescribers up to $1,000 for enrolling between 11 and 15 patients in the program, causing patients to fill prescriptions for Cardizem LA. These included prescriptions that were paid for by Medicaid,” the Massachusetts U.S. attorney said.

The first phase of the PLACE program required prescribers to enroll in the program and complete a two-page questionnaire with 10 multiple choice questions that did not usually take more than 10 minutes to complete, for which they received $250, the U.S. attorney said. The second phase offered prescribers as much as $750 more if they enrolled 11–15 patients.

“These payments exceeded the reasonable fair market value of the medical prescribers’ time necessary to enroll these patients and complete the final questionnaire,” the U.S attorney added. “The physicians and other medicine prescribers were told that in order to receive the payment they also had to track the patients’ experience on Cardizem, LA for three regularly scheduled visits. These visits were nothing more than the routine visits and required no additional work for the prescriber.”

Biovail Pharmaceuticals “did not design or implement the PLACE program in a way calculated to provide new or meaningful scientific data about whether Cardizem LA worked better than other available drugs,” the U.S. attorney said.

Following an investigation by the FBI and the HHS Office of Inspector General, the U.S. attorney for the District of Massachusetts pressed charges over what the company and the government described as prior management’s actions (DID, Feb. 4).

The agreement is subject to approval at a court hearing expected to take place between July 31 and Sept. 15. It will not affect current or future Biovail medicines approved for use in the U.S., including the continued marketing of Cardizem LA, according to the company. — Martin Gidron


FDA Appeals Ruling in Risperdal Exclusivity Case

The FDA is appealing a federal court ruling that restored Teva’s 180-day exclusivity for its generic version of the blockbuster antipsychotic Risperdal.

The appeal stems from an April 11 decision by Judge Royce Lambert of the U.S. District Court for the District of Columbia finding that the delisting of the ’952 patent covering Janssen Pharmaceutical’s Risperdal (risperidone) tablets from the Orange Book was unlawful.

Lambert ordered the relisting of the patent and the restoration of Teva’s Paragraph IV certification. He also enjoined the FDA from approving any ANDAs for generic risperidone tablets until the expiration of Teva’s 180-day marketing exclusivity period (DID, April 14).

Teva submitted the ANDA in August 2001. The FDA informed the company Oct. 12, 2001, that the ’952 patent had been delisted from the Orange Book and the agency would not accept the application unless Teva modified it and removed the Paragraph IV certification, Teva said.

The company filed a citizen petition last August asking the FDA to relist the patent and confirm its right to 180-day exclusivity. In the petition, Teva pointed to a 2006 ruling by the U.S. Court of Appeals for the District of Columbia Circuit in Ranbaxy Laboratories v. Leavitt that held the FDA cannot delist a patent after a firm submits a Paragraph IV certification. The agency denied the petition Feb. 26.

After Lambert issued his decision, Canadian drugmaker Apotex asked the court to allow it to intervene as a defendant post-judgment as it did not appear the FDA and Mylan, which earlier had entered the suit as an intervenor-defendant, would appeal, according to court documents. Apotex, which has an ANDA pending for risperidone, says it would be harmed by the market share Teva would get were Lambert’s decision to stand.

Several firms have submitted ANDAs to market the drug and would be precluded from selling their products before June 29, the day listed patents and exclusivities on the brand drug expire. — Elizabeth Jones


FDA Continues Campaign on Unapproved Hydrocodone Producers

A Maryland-based contract manufacturer and distributor entered into a consent decree with the FDA for distributing unapproved prescription cough syrups containing hydrocodone that were manufactured under conditions that did not meet good manufacturing practices (GMP).

The consent decree bars Scientific Laboratories from manufacturing and distributing any drug until it is approved. The company, which operates out of Columbia, Md., produces and distributes several prescription cough and cold products, including DC Tann HC Suspension and Nazarin HC liquid, both containing hydrocodone bitartrate.

“The FDA will not allow a company to put the public’s health at risk,” CDER Director Janet Woodcock said regarding the decree. “These unapproved new drugs have not undergone FDA review for safety and efficacy and may pose potential health risks.”

The decree also stipulates that the company must bring its production operation into GMP compliance. The company can be shut down if future Food, Drug & Cosmetic Act violations occur.

Last year, the FDA said it would start cracking down on companies marketing approximately 200 unapproved cough suppressants containing hydrocodone because the agency had received a number of adverse event reports for such products, including death due to overdosing (DID, Oct. 1, 2007).

According to a complaint to enjoin the company filed in the U.S. District Court for the District of Maryland, an FDA inspection last August revealed numerous GMP violations at the firm’s production facility, including an inadequate quality control unit, failure to use sound sampling procedures to test drug components and in-process materials, failure to ensure that drugs are free of objectionable microorganisms and failure to maintain written procedures and records of equipment cleaning.

The firm’s manufacturing operations were cited in a warning letter issued in November 2005, which can be accessed at www.fda.gov/foi/warning_letters/archive/g5980d.pdf. — Christopher Hollis


Product Mix-Up Leads to Recall, Health Risk

Medicis is recalling two lots of antibiotic Solodyn due to a product mix-up — patients may receive Azasan instead of the acne treatment, exposing them to a medication that can cause myelosuppression and infection.

Solodyn (minocycline HCl), an extended-release tetracycline antibiotic, is approved for the treatment of inflamed acne lesions in patients age 12 and older. Azasan (azathioprine) is indicated to prevent rejection of kidney transplants and to treat rheumatoid arthritis. The mix-up occurred during production operations in February, Medicis said in its announcement.

Contract manufacturer AAIPharma makes both Solodyn for Medicis and Azasan for Salix Pharmaceuticals, according to the contracting companies.

The side effects of the two drugs are not similar. Physician labeling for Azasan has a boxed warning for an increased risk of neoplasia, the development of tumors or cancer. The drug is mutagenic in animals and humans and carries a warning for severe blood disorders and serious infections. It also can cause severe bone marrow suppression.

Physician labeling for Solodyn carrries warnings for serious liver injury, drug-induced autoimmune syndromes, skin reactions, dizziness or vertigo, sensitivity to sunlight and hyperpigmentation. The drug should not be used by pregnant woman.

Solodyn is becoming an increasingly important product for Medicis. In February, the firm reported $140 million in revenue for the fourth quarter of 2007, an increase of 40 percent from the same period during the prior year. The increase primarily was due to strength in Medicis’ acne franchise, which includes Solodyn.

The company recently filed a citizen petition with the FDA over bioequivalence requirements for generic versions of the drug (DID, March 28). Solodyn’s active ingredient has been generic for several years but at different doses than Medicis’ brand drug.

Defending the drug against generic competition is a main focus of the firm, Medicis has said. It is involved in patent litigation with Impax Laboratories over the drug in the U.S. District Court for the Northern District of California in which the court ruled last April that Medicis’ ’838 patent was valid.

Because the drug contains an antibiotic component approved before the FDA Modernization Act of 1997 became law, Solodyn does not have protection under the Hatch-Waxman Act, according to the company. So if the company were to sue over patent infringement of its drug, it could not receive a 30-month stay against the generic approval. — Christopher Hollis.


Clinical Investigator Cited for Informed Consent, Enrollment Violations

A clinical investigator was warned by the FDA for testing subjects without their informed consent, enrolling subjects who did not meet required criteria, and failing to perform required tests and procedures.

Nasim Golzar was cited for her conduct in three separate clinical trials testing drugs for community-acquired pneumonia, acute sinusitis and acute exacerbation of chronic bronchitis. The warning letter was based on an FDA investigation conducted July 24 to Aug. 22, 2007.

The FDA said Golzar did not acquire proper informed consent for seven subjects in one trial. The letter said blood was drawn without a signed informed consent in four cases, and there was no date or time on the consent forms in three other cases, making it impossible to know if subjects underwent study procedures before giving consent. Golzar told the agency she acquired verbal informed consent from subjects in one of the trials, but the FDA said that was inadequate.

The agency’s warning letter said Golzar enrolled 11 subjects who did not meet criteria for the acute sinusitis trial. Although the protocol required patients to have a clinical diagnosis of the condition based on radiographic and clinical criteria, X-rays for 10 subjects failed to demonstrate they had the disease, according to the letter. Another subject was enrolled despite having taken the antibiotic doxycycline for more than 24 hours within seven days of enrolling, and nine subjects did not have required paranasal X-rays done, the letter said.

Golzar told the FDA that “the patients all had clinical signs and symptoms highly suggestive of acute bacterial sinusitis and would have been treated with antibiotics regardless of the study,” according to the FDA’s letter, which rejected her response as inadequate. Moreover, two subjects in the study were prematurely withdrawn but did not have their sputum collected or have post-alternate antibiotic chest X-rays taken as required by the protocol, the letter said.

In another of the studies, Golzar was cited for not performing such procedures as a pregnancy test, base line urinalysis and obtaining a complete medical history. Two subjects were enrolled although their sputum samples should have disqualified them, and a third was enrolled despite being unable to produce a sputum sample. Golzar’s response that patients coming into the office with an acute infection needed to be treated quickly was rejected by the agency.

Unsatisfactory Recordkeeping

Golzar also was cited for not maintaining adequate and accurate case histories in the acute sinusitis trial. For example, the clinical signs and symptoms she reported in the electronic case report forms for 17 of 30 subjects could not be verified against source documents, the letter said. She also signed and dated a change to a subject’s case report form, indicating the patient had moderate and not mild wheezing, which did not match the source document’s record.

The warning letter also cited her for not maintaining adequate drug disposition records, citing a log entry that said a subject had returned 15 tablets of the study drug while the electronic case report form indicated that 12 tablets had been returned. In addition, the letter said Golzar made a protocol amendment but was unable to document that she had promptly reported it to the institutional review board or that the board had approved it.

Golzar did not respond to a request for comment by press time. The warning letter, which was sent Feb. 13 and posted to the FDA website May 15, can be viewed at www.fda.gov/cder/warn/2008/golzar.pdf. — Martin Gidron


Cobalt Drops Suit Against FDA

Cobalt has voluntarily dismissed a lawsuit in which it had asked a court to restore its marketing exclusivity for a generic version of Bayer Pharmaceutical’s diabetes drug Precose.

In a one-paragraph document, the company said it was dismissing the case against the FDA without prejudice. Cobalt had brought the suit May 8 in the U.S. District Court for the District of Columbia, alleging the agency had unlawfully forfeited the company’s 180-day marketing exclusivity for a generic version of Precose (acarbose).

Cobalt had maintained that it was the first company to file an ANDA with a Paragraph IV certification on the drug’s ’769 patent, which has been delisted from the Orange Book. However, the FDA informed Cobalt May 7 that it had forfeited its right to generic exclusivity.

Cobalt said in court documents the FDA acknowledged its actions had delayed the company’s ability to market the product, but the agency said Cobalt had forfeited its exclusivity because it failed to obtain final approval and launch within 30 months of its 2005 ANDA submission.

Cobalt asked the court to enjoin the agency from approving all other ANDAs for the drug “until natural expiration of Cobalt’s statutory right to exclusivity for its acarbose ANDA.” It also requested that the FDA stay or withdraw approval for other acarbose ANDAs, including one from Boehringer Ingelheim’s subsidiary Roxane, which the agency had approved May 7. Finally, it asked the court to order the FDA to recall any acarbose product made by Roxane on the market.

The court declined to issue a temporary restraining order against Roxane, finding that under the language of the Food, Drug and Cosmetic Act, Cobalt was unlikely to prevail in the case and Roxane would suffer “significant competitive injury,” Zuckerman Spaeder, the law firm representing Roxane, said.

According to IMS data, Precose had sales of approximately $35 million for the period ending Jan. 1, Roxane said. — Elizabeth Jones


InterMune IPF Treatment Receives Fast-Track Designation

InterMune has received fast-track designation from the FDA for idiopathic pulmonary fibrosis (IPF) treatment pirfenidone.

Currently, there are no approved medications for IPF, a fatal disease characterized by lung scarring and inflammation, InterMune Chairman and CEO Dan Welch said.

InterMune is holding a webcast and conference call Tuesday to discuss its Phase III CAPACITY program for pirfenidone, including data from a trial of the drug in Japan by Shionogi & Co., which holds a license for the drug in Japan, Korea and Taiwan.

InterMune previously said it would begin an open-label, rollover study this August to evaluate the long-term safety of pirfenidone in IPF patients who complete one of the two concurrent Phase III CAPACITY studies.

In 2007, InterMune purchased pirfenidone patent rights previously licensed from Marnac and KDL GmbH. That agreement did not affect the rights to pirfenidone in Japan, Korea and Taiwan, which are licensed to Shionogi & Co.

InterMune’s previous president, Scott Harkonen, was indicted March 18 for alleged illegal marketing of Actimmune for IPF (DID, March 20). The court has set a Sept. 15 date in USA v. Harkonen for review of discovery. — April Astor

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