Drug Industry Daily - April 27, 2010 Issue

Vol. 9 No. 81

FDA to Revise GMPs for Components to Protect Supply Chain

The FDA is revising good manufacturing practice (GMP) regulations for incoming raw materials to help industry secure the pharmaceutical supply chain against economically motivated adulteration.

Revised regulations will significantly improve the control over suppliers, Deb Autor, director of CDER’s Office of Compliance, said Monday at the 2010 PDA/FDA Pharmaceutical Supply Chain Workshop in Bethesda, Md. There is no timeline for the revisions, but they are under way, she told DID.

Controlling the risk of counterfeit, adulterated or misbranded products entering the supply chain “really comes down to each company thinking very hard about what its potential vulnerabilities are and building systems around that,” Autor told the audience. The FDA would like to see industry be more proactive in predicting potential economically motivated adulterants and designing test methods and supply chain controls.

The FDA is finding that companies are failing to adequately control raw materials — particularly physical characteristics such as particle size and hydration — which contribute to the difficulty of reliably producing a dosage form that performs consistently from batch to batch, CDER Director Janet Woodcock said.

The agency is encouraging manufacturers to warn each other about suppliers and materials that pose hazards. Companies also should notify the FDA as soon as a problem is identified that could pose a health risk.

“Folks have been reluctant,” she said. “People’s instinct is to just drop the supplier and not talk about it.” Failing to act could damage the industry’s credibility, she added.

Some companies are already working toward collaboration on supply chain control. Martin VanTrieste, vice president of operations and quality for Amgen, said that Johnson & Johnson unit Janssen-Cilag is encouraging other companies to mimic its Drug Validation Portal, which provides U.S. Customs and Border Protection with electronic images of its product labels and packaging for comparison with incoming shipments.

Similar photos can be used by a drug company’s own employees to help screen incoming raw materials from suppliers, VanTrieste said.

Limited foreign supplier audits have also become a concern, Edwin Rivera-Martinez, chief of the FDA’s International Compliance Branch, said. Sometimes a company official, rather than a trained auditor, is sent to the manufacturing site. That can be a problem because auditors must be familiar with the manufacturing processes for ingredients, Rivera-Martinez said. Even products that meet U.S. Pharmacopeia testing standards may not have been manufactured under GMPs.

Among the solutions suggested by conference participants was auditing suppliers’ control of the chain of ingredients as part of the qualification procedure. Industry also noted more effort is needed to train procurement employees to incorporate quality standards in searches for suppliers.

The FDA is also acting to produce guidelines to promote safe supply chains. A final version of the July 2009 draft guidance on physical-chemical identifiers in solid oral dosage form drug products is one such guidance, Ilisa Bernstein, director of pharmacy affairs in the Office of the Commissioner, Office of Policy, said (DID, July 14, 2009). — April Hollis


FTC: Ending Pay-for-Delay Settlements is Top Priority

The FTC is making its fight against pay-for-delay settlements between brand- and generic-drug makers a top priority this year.

The patent settlements, in which brand companies reward generic-drug makers to delay the introduction of less expensive versions of their medicines, keep generic drugs off the market for an average of 17 months longer than agreements without payments and will cost consumers and taxpayers $35 billion over the next 10 years, the commission says in its annual report.

The FTC also is pursuing actions against drugmakers in federal court cases. In one case, the agency lodged a complaint against Cephalon in 2008, alleging the drugmaker paid four companies to refrain from selling generic versions of its sleep drug Provigil (modafinil) until 2012 (DID, Feb. 15, 2008).

The company entered into seemingly separate transactions worth a total of more than $200 million, the FTC said in 2008 (DID, May 23, 2008). For example, Teva Pharmaceuticals agreed not to launch generic Provigil until April 2012 in exchange for a license agreement relating to its modafinil patents and patent applications worth up to $125 million in Provigil royalties. Cephalon also agreed to buy modafinil active pharmaceutical ingredient from Teva at prices higher than what it had been paying, the commission alleged at the time.

The case is still pending in the U.S. District Court for the Eastern District of Pennsylvania, the FTC says.

In a separate case, the commission obtained $2.1 million from Bristol-Myers Squibb (BMS) for failing to inform the FTC of agreements reached with Canadian drugmaker Apotex regarding potential generic competition for blockbuster drug Plavix, the commission says in the report. The commission charged that, as part of a patent settlement with Apotex, BMS promised that it would not compete with Apotex during the first 180 days that Apotex marketed its generic version of the drug.

The agency suffered a defeat, however, in a case in which it claimed reverse payment, or pay-for-delay, settlements Solvay Pharmaceuticals made with Watson Pharmaceuticals, Par Pharmaceutical and Paddock Laboratories for the marketing of generic AndroGel (testosterone) violated federal antitrust laws.

The U.S. District Court for the Northern District of Georgia dismissed the case in February, saying patent litigation is too complex and the results too uncertain to assert such a claim (DID, Feb. 25).

The agency had also hoped that a ban on the agreements would be included in healthcare overhaul legislation signed into law earlier this year, but the provision failed to be included in the final bill. Sen. Herb Kohl (D-Wis.), however, has indicated that he will fight for his pay-for-delay bill Preserve Access to Affordable Generics Act, S. 369, to be considered as an individual piece of legislation by the full Senate or piggyback on another bill (DID, March 23).

The FTC annual report can be found at www.ftc.gov/os/2010/04/2010ChairmansReport_screen.pdf. — David Belian


Genentech Gets Untitled Letter for Consumer-Directed Herceptin Video

The FDA has issued an untitled letter to Genentech for a patient video that overstates the efficacy of its breast cancer drug Herceptin and minimizes its risks.

The consumer-directed video fails to present information about risks associated with the chemotherapy drug with the same prominence as seen in the presentation on the drug’s effectiveness, according to the letter dated March 26 from the FDA’s Division of Drug Marketing, Advertising and Communications.

Most of the 5 ½-minute video is a lively multimedia presentation with a dramatic announcer’s voice and testimonials from Herceptin patients, breast cancer awareness advocates, television news reports and an oncology nurse, according to the letter. But the presentation of serious risks associated with Herceptin (trastuzumab) is relegated to a running telescript with no audio that rolls for 30 seconds before the start of the video, the letter says.

The only risk information in the main part of the video is found in two patient testimonials and omits discussion of the drug’s boxed warnings regarding cardiomyopathy, pulmonary toxicity and infusion reactions, the letter adds.

Patient testimonials in the video also imply the drug improves long-term survival. For example, one woman says the drug allows her to enjoy her son’s life “as he grows up.” However, clinical trials for Herceptin plus chemotherapy as first-line therapy in patients with metastatic breast cancer showed a median increase in survival of 4.8 months.

Genentech has formally responded to the letter and removed the video from the Herceptin website, Genentech spokeswoman Krysta Pellegrino told DID Monday. The company also is looking at other Herceptin promotional materials, as well as promotional material for other products, to ensure they are in compliance with FDA guidance in the letter, she added.

The untitled letter can be found at www.fdanews.com/ext/files/Herceptin.pdf. — Owen Skoler


Glenmark Wins Approval for Generic Progestin-Only Contraceptive

Glenmark Generics has received FDA approval of a generic formulation of Watson Laboratories’ Nor-QD oral contraceptive.

The company will begin distributing the progestin-only oral contraceptive in 0.35-mg tablets immediately, Glenmark said Monday. Its generic norethindrone will be sold under the name Heather.

The approval marks the first time an India-based company has won approval for a hormone product, Glenmark spokesman Jason D’Souza told DID Monday. The FDA approval also is the first for a Glenmark product manufactured at its Goa, India, hormone facility, according to the company.

The U.S. market size for the approved product is $38 million, D’Souza said. The company has another six hormone products awaiting FDA approval, he added. — Owen Skoler


Nycomed, Merck Sign Commercialization Pact for COPD Drug Candidate

Nycomed will collaborate with Merck to market the investigational chronic obstructive pulmonary disease (COPD) treatment Daxas in Canada, France, Germany, Italy, Spain and Portugal.

Nycomed will make and distribute its Daxas (roflumilast), the companies said Monday. The drugmaker will receive an undisclosed upfront fee and is eligible for milestone payments based on regulatory and commercialization events.

Marketing applications for Daxas were filed with the European Medicines Agency (EMA) and Health Canada last year. The EMA’s Committee for Medicinal Products for Human Use recommended approval of the drug last week. If approved, Daxas, a once-a-day oral tablet, will be the first oral anti-inflammatory treatment for COPD patients, Nycomed and Merck said.

In the UK, Merck will have exclusive commercialization rights, and Nycomed will supply the finished product and have an option to co-promote the drug.

In the U.S., Nycomed’s NDA for Daxas was acquired by Forest Research Institute, but the drug failed to muster the votes for a recommendation from an FDA panel this month (DID, April 8). The Pulmonary-Allergy Drugs Advisory Committee suggested Forest conduct clinical trials comparing Daxas with existing COPD treatments, such as inhaled corticosteroids, to obtain more data. — David Belian


China Counts More Than 600,000 Adverse Drug Events in 2009

China’s State Food and Drug Administration (SFDA) has published its first annual report on adverse drug reaction (ADR) monitoring, noting more than 600,000 reports of ADRs last year.

Fifty-five percent of the ADR reports were associated with anti-infective drugs. The SFDA issued six ADR information bulletins for adverse events related to acyclovir; clindamycin injection; cefoperazone sodium and sulbactam sodium, a broad-spectrum antibacterial agent; levofloxacin injection; and several traditional medications. Another 8 percent of the reports involved cardiovascular drugs.

The SFDA suspended sales by two Chinese companies of an herbal product widely used to treat inflammatory conditions and withdrew marketing authorization for bulk fenfluramine HCl drugs and formulations and another traditional medicine. The agency also requested modifications to 10 package inserts because of changes in the drugs’ specifications.

Injectable drugs for all conditions accounted for almost 60 percent of ADR reports, 37 percent involved oral preparations and 4 percent were listed as “other.” The annual report also includes medication safety tips and a Q&A on adverse drug event reporting.

Drug companies contributed just over 12 percent of the reports, though the proportion is rising, SFDA says. Hospitals and other medical institutions were responsible for about 85 percent of ADR reports last year and 3 percent were made by individuals, the SFDA says.

In the U.S., the FDA logged 353,318 reports related to drugs and biologics in its adverse events reporting system in the first three quarters of last year. — Meg Bryant

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Reporters: David Belian, April Hollis, Owen Skoler, Virgil Dickson

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