DID - May 14, 2008 Issue

Vol. 7 No. 95

Firm Settles With Justice for Manipulating Manufacturing Data

Leiner Health Products agreed to forfeit $10 million and plead guilty to one count of wire fraud under a proposed settlement with the Justice Department concerning charges that the firm manipulated stability data at its OTC production facility.

Justice alleges that the manipulation occurred in December 2006 at Leiner’s Fort Hill, S.C., plant. The company said it has revamped its entire quality control operation and the facility has been discontinued.

According to a motion submitted by Leiner to the U.S. Bankruptcy Court for the District of Delaware, the settlement would resolve charges that the firm “gave the false appearance that certain drugs had passed stability testing and allowed nonconforming drugs to be shipped to customers.”

The company, which is in Chapter 11 bankruptcy proceedings because the quality control problems have affected sales, is asking the court to let it enter into the plea agreement.

The data manipulation charges were detailed in an August 2007 warning letter citing Leiner’s OTC drug manufacturing operations at Fort Hill. The letter, issued by the FDA’s Atlanta District Office, resulted from a Jan. 22 through March 16, 2007, inspection of the site.

The letter cited the company for “extensive manipulation of data with no explanation regarding why the manipulation was conducted. This manipulation would include changing integration parameters or re-labeling peaks such that previously resolved peaks would not be integrated and included in the calculation for impurities.”

In response to the FDA Form 483 observations, the firm suspended production and distribution of OTC drug products.

The U.S. District Court for the District of South Carolina issued a search warrant for the Fort Hill facility Sept. 5, 2007, as requested by the FDA. Justice subsequently copied electronic servers containing all email accounts and electronic documents maintained by staff at the site. The seized data included “numerous manufacturing, production, distribution, laboratory testing and personnel records,” according to court filings.

Under the terms of the settlement, Justice will recommend that the firm forfeit $10 million. The U.S. District Court for the District of South Carolina has the final say in how much restitution will be paid upon sentencing.

Justice reserves the right to prosecute any individual “in connection with the conduct encompassed by [the] plea agreement, and [Leiner] would agree to cooperate,” according to the plea deal.

Although the FDA informed Leiner last October that it could resume distribution of OTC products upon verification by a third party, the Justice investigation remained unresolved, making Leiner’s customers reluctant to do business with the firm, according to court filings.

The issues with Leiner’s OTC operations spilled over into the firm’s vitamins, minerals and nutritional supplements (VMS) business.

“The impact of the OTC issues on the VMS business has been significant, including lost market share in the amount of $50 million, lost profits in the amount of $10 million and pricing adjustments in the amount of $40 million as a result of competitors’ efforts to displace [Leiner’s] products,” the company says in court documents.

“In light of this commercial reality, [Leiner] expedited its efforts to bring the … investigation to a conclusion,” court documents state. The firm filed for bankruptcy in March.

Leiner told DID it expects bankruptcy proceedings to be completed June 11. The company will be auctioned off roughly at the same time. The firm derived 25 percent of its sales from its OTC business, primarily from subsidiaries in Canada. The VMS portion of the business accounted for the vast majority of its sales.   — Christopher Hollis


Study: Beta-Blockers Can Pose Risk for Patients After Surgery

Patients taking beta-blockers after noncardiac surgery have a higher risk of death or stroke than those given placebo, according to the authors of an article published in an upcoming edition of The Lancet.

Because of the risk of cardiovascular complications during noncardiac surgery, patients often are given beta-blockers to reduce catecholamine levels. Prior studies of whether such drugs are effective yielded mixed results, and researchers from the PeriOperative ISchemic Evaluation study group, headed by P.J. Devereaux of Ontario-based McMaster University, wanted to see whether the products prevent cardiovascular complications.

The researchers evaluated 8,351 patients with or at risk of developing artherosclerotic disease who were undergoing noncardiac surgery. Roughly half received AstraZeneca’s beta-blocker Toprol XL (metoprolol succinate) while 4,177 took placebo. Treatment started two to four hours prior to surgery and continued for 30 days.

Although fewer patients experienced a heart attack or cardiac arrest while taking the drug, 129 subjects died in the Toprol group compared with 97 in the placebo group. Additionally, 41 patients taking the drug had a stroke compared with 19 taking placebo, according to the article.

In the conclusion, the study authors write, “In view of the large numbers of individuals undergoing surgery and the high risk of cardiovascular complications, more large trials are needed” to evaluate the drug.

In response to the article, James Hainer, medical science director at AstraZeneca, said, “It is the anticipation of AstraZeneca that this large trial will be considered by the expert groups that prepare guidelines and recommendations for perioperative management of patients undergoing general surgery.”

Watson Pharmaceuticals recently said it expects to launch a generic version of Toprol XL now that the FDA has lifted a warning letter, which had blocked approval of the drug, for the firm’s manufacturing facility in Davie, Fla. Last year, Watson transferred its 180-day exclusivity rights for 50-mg generic Toprol-XL extended-release tablets to Sandoz in exchange for a share of the profits (DID, May 5).

Sales of the drug were $1.4 billion in 2007, down 22 percent from 2006, according to AstraZeneca. — Elizabeth Jones


Indian Clinical Trials Industry Booming, Experts Say

The clinical trials industry in India has taken off since 2005 as trials have become standardized, predictable and quickly approvable, experts said at an RxTrials Institute audioconference Tuesday.

A survey of publicly available data on the NIH’s ClinicalTrials.gov registry shows the number of trials under way in India has risen from 50 in 2002 to 560 today, a total that does not include non-U.S./IND studies or investigator-initiated research, Dan McDonald, vice president of business development of Excel Life Sciences, said.

“Until 2005, India was best known as a generic powerhouse. It had poor intellectual property laws and long start-up times, so it was not considered a clinical trials destination,” McDonald said.

The FDA has conducted eight site inspections in India since 2005, half of which resulted in a finding of “voluntary action indicated” while the other half were deemed “no action indicated.” Another six FDA inspections are planned this year, Excel’s President Vijay Kumar said.

Trial approvals from regulators are accomplished quickly because they now comply with FDA standards or those of the HHS Office for Human Research Protections (OHRP). Global clinical trials typically receive approval for Indian sites from the country’s Drugs Controller General in four to six weeks, Kumar said. Sponsors can obtain provisional institutional review board approval to get a trial moving before the Ministry of Health gives the green light.

Mumbai has 14 OHRP-registered IRBs, New Delhi has 13, Bangalore and Chennai have 11 each, Hyderabad has eight and Pune has four, Kumar said.

The number of clinical investigators available is fairly evenly distributed among these and other major Indian cities, McDonald said.

One advantage of doing a clinical trial in India is the country’s well-credentialed base of physicians, many of whom are computer literate and fluent in English. “Soon there will be 1,000 qualified investigators in India,” McDonald said.

India has a growing market for patent-protected therapies and fast and cost-effective studies, MacDonald said. It also has a growing infrastructure for marketing and supplies and a large patient population that is “treatment-naïve” — has not received any healthcare for a range of diseases — he said.

For example, “the overall incidence of heart disease in India has doubled in the past 20 years, and by 2010 it is projected that 60 percent of the world’s cardiac patients will be in India. There are 35.5 million cases of diabetes in India, which is very rapidly becoming the diabetes capital of the world,” McDonald said.

Perhaps the strongest advantage of the Indian clinical research enterprise is its human capital. “Indian investigators are very excited about doing international clinical trials and publishing journal articles in India and internationally. There is an enthusiasm you might not see in some of the more mature markets,” McDonald said. — Martin Gidron


Cipher Files Revised NDA for Opioid Pain Drug

Cipher Pharmaceuticals has submitted a revised NDA for CIP-Tramadol ER, an opioid pain reliever, after receiving an approvable letter for the drug a year ago.

The revised NDA includes data from additional pharmacokinetic studies comparing the company’s drug with opioid Ultram ER (tramadol HCl) marketed by Ortho-McNeil and for which Biovail is the patent holder, Cipher President Larry Andrews told DID.

Last December, Cipher appealed the FDA’s approvable letter, which said an additional clinical trial was needed for the drug. The FDA defended its letter but later told the company a new analysis could be an alternative to a new trial. In February, Cipher said the FDA asked it to do additional statistical sensitivity analysis of existing clinical data on CIP-Tramadol ER (tramadol HCl) (DID, Feb. 12).

After considering feedback from the FDA appeal process and the results of the additional analysis, Cipher concluded that submitting the revised NDA was the fastest path to final regulatory approval, it said.

CIP-Tramadol ER is a biphasic, extended-release formulation of tramadol, which is used to manage moderate to moderately severe pain. Tramadol is a synthetic opioid molecule developed to have the analgesic efficacy of the opioid family of drugs without the well-known side effects, including addiction, Cipher said.

The treatment is enabled by oral, controlled-release beads, an extended-release drug delivery technology licensed from Galephar Pharmaceutical Research.

Cipher said it expects the FDA to complete its review by October, but the NDA submission could trigger patent infringement litigation from Biovail for its Ultram ER formulation and a stay of up to 30 months under the Hatch-Waxman Act, the company said.

Earlier this year, Labopharm said the FDA rejected its appeal of an approvable letter for another formulation of tramadol. The agency suggested the firm do additional statistical analysis of existing data (DID, Jan. 25). — April Astor


Supreme Court Rebuffs Apotex

The U.S. Supreme Court will not hear Canadian drugmaker Apotex’s appeal over the launch of its generic version of Abbott’s antiseizure drug Depakote.

Apotex originally filed an ANDA with a Paragraph IV certification seeking approval to market a generic version of Depakote (divalproex sodium) in 1997. Abbott subsequently brought a suit in the U.S. District Court for the Northern District of Illinois alleging the drugmaker had infringed on the ’731 and ’326 patents, both of which expire this year.

The Illinois court granted Abbott’s motion for summary judgment and upheld the validity of Abbott’s patents. Apotex appealed the decision. In August 2002, the U.S. Court of Appeals for the Federal Circuit upheld the district court’s decision on the validity of the patents but sent the case back to the lower court for trial on a narrow issue of infringement, according to court documents (DID, March 17, 2004).

Apotex had designed a generic version of the epilepsy drug around the patents and entered into an agreement with NuPharm, which submitted an ANDA for the new product. The district court granted Abbott’s motion to extend the injunction to NuPharm, but the appeals court found that the original injunction could not be rewritten. — Elizabeth Jones

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