Generic-Drug Testing Goes Widespread in U.S. FDA Effort

Generic drugs that make up almost 80 percent of U.S. prescriptions are being tested in the first widespread safety and quality evaluation run by the Food and Drug Administration.

The $20 million effort, coming as concerns grow over the quality of products from abroad, started in September without any public notice. At least a dozen academic centers are involved in a testing program that will run through 2017, agency officials confirmed. The research this year will focus on heart drugs, ADHD treatments, immunosuppressants, anti-seizure medicines, and antidepressants. Results aren’t yet available.

Testing of generic drugs previously has been done only on an occasional basis in the U.S. The program, testing medicines made domestically and overseas, reflects a new emphasis by the FDA on the quality of copycat drugs. The agency has banned the import of treatments made at four India-based plants over the last nine months, and the FDA chief visited that country last week to talk with government officials and companies there.

While the agency long wanted to test generics, “we didn’t have money for that,” said Kathleen Uhl, acting director of the FDA’s Office of Generic Drugs, in an interview at the Generic Pharmaceutical Association annual meeting in Orlando. Before this year, “there was a very small research program -- $2 or $3 million each year.”

New fees collected from the generics industry to fund FDA reviews, approved by Congress in 2012, enabled the agency to put more broad-based testing into action, Uhl said.

Lipitor Study

The FDA is reviewing a 2013 study by a Boston-based researcher that found widespread impurities in copies of Pfizer Inc. (PFE)’s Lipitor cholesterol pill made outside of the U.S., said Christopher Kelly, an FDA spokesman. Kelly wouldn’t say when the agency may complete the review.

As late as this week, the agency said generics generally meet “rigorous standards” for quality, purity and potency, though it acknowledged reports that some people may experience an undesired effect when switching from some brand-name drugs to generic versions. The FDA didn’t specify which medicines and said it doesn’t have the authority to require post-market studies by generics manufacturers.

The new program by academic centers wasn’t publicized because “it took us a bit of time to compile all of the various awards into one list,” said Sandy Walsh, an FDA spokeswoman. “We plan to post it soon.”

Duke, Johns Hopkins

Among the academic centers to receive grants are Duke University in Durham, North Carolina,Johns Hopkins University in Baltimore, Brigham & Women’s Hospital in Boston and the universities of Florida, Michigan and Maryland. Researchers are studying how absorption, inactive ingredients and packaging affect generic efficacy, according to a partial list of grantees provided by the FDA.

Other, more limited, testing efforts also exist. The U.S. Pharmacopeial Convention, based in Rockville, Maryland, has a program used mainly by companies in India and China to ensure ingredients are made properly and that test product purity, John Atwater, director for verification services at the non-profit organization, said in an interview.

Companies pay $20,000 plus travel expenses for a manufacturing review and $10,000 for three years of testing, though consumers have no way of knowing which drugmakers take advantage of the programs, he said.

“The demand for the program is not as great as we would like it to be,” Atwater said. Small and mid-sized companies looking to set themselves apart are the most likely to participate in the voluntary program, he said.

Medical Professionals

Medical professionals have become increasingly vocal about their concerns about the quality of drugs made overseas.

Harry Lever, a Cleveland Clinic cardiologist, has said he will tell lawmakers in the Feb. 26 congressional briefing that generic medicines made by India-based companies for heart failure often don’t work the way they should, opening questions about the FDA’s ability to keep track of that country’s growing copycat-drug business.

“It’s like taking a platoon to fight a huge army,” Lever said in a Feb. 10 telephone interview about FDA’s inspection efforts in India.

Tony Mauro, the North American president of Mylan Inc., the largest U.S. generic-drug manufacturer, said problems with quality has a negative effect on all generic-drug makers, no matter where they’re located.

“The industry as a whole always suffers when there’s challenges from a quality perspective because this whole industry’s foundation is about sameness of the brand,” Mauro said in an interview at the generics association meeting.

Wellbutrin XL Study

The FDA’s new widespread testing program follows a 2012 agency finding that copies of Wellbutrin XL, an antidepressant, didn’t work as well as the original. The agency’s research led Teva Pharmaceutical Industries (TEVA) Ltd. to withdraw its version from the market in 2012.

The Lipitor study being reviewed by the FDA was done by Preston Mason at Brigham & Women’s Hospital.

The research found that some copies of the cholesterol drug produced overseas were rendered ineffective as a result of manufacturing impurities. Mason is now in the process of testing generic products sent to him by Cleveland Clinic’s Lever. Lever and Mason have each declined in interviews to specify which medicine until results are final in a few weeks.

Mason is also set to testify at next week’s congressional briefing.

The Wellbutrin XL result “triggered pretty substantial changes and requests for additional studies or requests to withdraw their products from the market,” The FDA’s Uhl said. “What will the research that’s going to be conducted do? I think we’re going to have to wait and see.”

Further Understanding

The first testing grants, awarded at the end of the 2013 fiscal year in September, focused on further understanding why generic Wellbutrin XL, also called bupropion, didn’t work well in patients. They also are weighing the effectiveness of the active ingredient in inhaled drugs such as GlaxoSmithKline Plc (GSK)’s Advair to fight asthma and a deadly lung condition often caused by smoking, according to an e-mail listing some of the contracts from Walsh, the FDA spokeswoman.

Advair faces generic competition as the agency works with companies seeking to copy the complicated drug.

The FDA has banned drug sales in the U.S. from Indian facilities belonging to Ranbaxy Laboratories (RBXY) Ltd. and Wockhardt Ltd. (WPL), both based in India. FDA Commissioner Margaret Hamburg visited India Feb. 10-18 to discuss quality concerns.

Recall Need

Ranbaxy, based in Gurgaon, India, was allowed by the FDA to sell the first generic copies of Lipitor in 2011. Wockhardt, based in Mumbai, controlled about 26 percent of the U.S. market for the generic version of the Toprol-XL, known as metoprolol, to treat high blood pressure and heart failure prior to a ban on its Chikalthana plant that makes the pill, according to Needham & Co.

Hamburg said the FDA didn’t see the need to recall the medicines sold at four banned plants in India.

“Our goal is to prevent problems from occurring when we see situations that may represent an imminent problem,” Hamburg said yesterday on a conference call about her trip to India. “We monitor adverse event reports very carefully and use that information for our decision-making.”

The FDA also is creating a new Office of Pharmaceutical Quality to improve the agency’s scrutiny of brand name, generic and over-the-counter drugs, Bloomberg News reported on Feb. 14. The agency is talking with the industry to develop data that may signal which manufacturing plants are straying from standards and need inspection, said Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research.

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