fda declines approval of testosterone drug for third time

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In Focus www.thelancet.com/diabetes-endocrinology August 2013 s14 FDA declines approval of testosterone drug for third time In May, the US Food and Drug Administration (FDA) declined, for the third time, approval of Aveed, Endo Pharmaceuticals’ (Malvern, PA, USA) long-acting testosterone undecanoate injection, used for treatment of men with hypogonadism. Testosterone undecanoate is a long-acting depot formulation of testosterone in castor oil and benzyl benzoate. The FDA has concerns about reported side-effects of Aveed, which include anaphylaxis and pulmonary oil microembolism (POME). The FDA’s decision comes after an advisory committee to the FDA met in April to decide whether or not Aveed was a safe testosterone replacement therapy, in view of reports of severe post-injection reactions. The vote was split evenly, with nine members voting for approval and nine voting against. Symptoms of male hypogonadism can include erectile dysfunction, infertility, a decrease in beard and body hair growth, and a decrease in muscle mass. In the USA, there are several approved testosterone replacement products, including orally administered formulations, patches, gels, oral tablets, and two already approved products for intramuscular injection. Aveed allows for a longer interval between treatments, with injections every 10 weeks compared with every 2–4 weeks for available injectable products. In response to the most recent new drug application for Aveed, the FDA issued a complete response letter. According to an Endo Pharmaceuticals press release, although the letter did not request that the company do additional clinical studies, it did state that the company would need to submit an updated Risk Evaluation and Mitigation Strategy—a plan to manage known or potential serious risks associated with a drug or biological product. Specifically, the FDA requested that the company include a medication guide, which is a paper handout that comes with many prescription medicines to address issues specific to particular drugs. Such handouts contain FDA-approved information that can help patients avoid serious adverse events. The FDA also asked Endo Pharmaceuticals to produce an Elements to Assure Safe Use plan, which lists required medical interventions or other actions that health-care professionals need to take before prescribing or dispensing a drug to a patient. “We are encouraged by the feedback received from the FDA in the complete response and appreciate the clarity around the path forward for Aveed”, said Ivan Gergel, executive vice president of research and development and chief scientific officer of Endo Health Solutions (of which Endo Pharmaceuticals is a subsidiary). Aveed is the same formulation as Nebido (Bayer HealthCare Pharmaceuticals), a testosterone undecanoate approved for use in 94 countries, including those in the European Union. The fact that the same product is deemed safe for people in other countries but not in the USA has caused some physicians to question the FDA’s ruling. “The side-effects the FDA reported are very uncommon, and this medication is available throughout the world except in the USA”, said Christina Wang, associate director of the University of California, Los Angeles Clinical and Translational Science Institute. “There have been millions of injections.” Wang said physicians administering the product need to inject it slowly and make sure to not inject it into a vein, so that oil doesn’t escape into the blood. Wang has used this product in small clinical studies in which nurses have injected it under close supervision of doctors and “has never seen a severe allergic reaction”, she said. John Morley, director of endo- crinology and geriatrics at Saint Louis University School of Medicine (MO, USA), also was sceptical of the FDA’s reasons for denying approval for the product. He said many injectable drugs have side-effects. “I’m personally not convinced”, he said. “I follow the literature, and it seems like this product is a reasonable alternative for men who want to use it, as long as all of the side-effects are explained to them.” The FDA denied the company’s new drug application for Aveed in 2008, citing safety concerns, and asked the company to provide additional information about the incidence of serious post injection POME and allergic reactions. The application was denied again in 2009, on the grounds of safety concerns because the Risk Evaluation and Mitigation Strategy that the company provided didn’t go far enough to ensure that the benefits of Aveed outweighed the risks. Morley said there might be other underlying issues. The FDA might be reluctant to approve another testosterone product because such products are commonly being misused. People sometimes take the drug for non-medical reasons, such as attempting to increase sex drive and feel more energetic and young. “The FDA has consistently ruled against many testosterone products”, said Morley. “In the back of the FDA’s mind they think every man is going to be given testosterone”, he said. “But we are talking about this being used in the hands of physicians who understand what they are doing. This is something the average physician could balance and make a reasonable decision about when and how this should be used in a small subset of people who it is appropriate for.” The company will submit a response to the FDA by the end of the third quarter of this year. Leslie Harris O’Hanlon Published Online June 13, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70040-8 Mark Bowden

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Page 1: FDA declines approval of testosterone drug for third time

In Focus

www.thelancet.com/diabetes-endocrinology August 2013 s14

FDA declines approval of testosterone drug for third timeIn May, the US Food and Drug Administration (FDA) declined, for the third time, approval of Aveed, Endo Pharmaceuticals’ (Malvern, PA, USA) long-acting testosterone undecanoate injection, used for treatment of men with hypogonadism. Testosterone unde can oate is a long-acting depot formulation of testosterone in castor oil and benzyl benzoate. The FDA has concerns about reported side-eff ects of Aveed, which include anaphylaxis and pulmonary oil microembolism (POME). The FDA’s decision comes after an advisory committee to the FDA met in April to decide whether or not Aveed was a safe testosterone replacement therapy, in view of reports of severe post-injection reactions. The vote was split evenly, with nine members voting for approval and nine voting against.

Symptoms of male hypogonadism can include erectile dysfunction, infertility, a decrease in beard and body hair growth, and a decrease in muscle mass. In the USA, there are several approved testosterone replacement products, including orally administered formulations, patches, gels, oral tablets, and two already approved products for intramuscular injection. Aveed allows for a longer interval between treatments, with injections every 10 weeks compared with every 2–4 weeks for available injectable products.

In response to the most recent new drug application for Aveed, the FDA issued a complete response letter. According to an Endo Pharmaceuticals press release, although the letter did not request that the company do additional clinical studies, it did state that the company would need to submit an updated Risk Evaluation and Mitigation Strategy—a plan to manage known or potential serious risks associated with a drug or biological product. Specifi cally, the FDA requested that the company include a medication guide, which is a

paper handout that comes with many prescription medicines to address issues specifi c to particular drugs. Such handouts contain FDA-approved information that can help patients avoid serious adverse events. The FDA also asked Endo Pharmaceuticals to produce an Elements to Assure Safe Use plan, which lists required medical interventions or other actions that health-care professionals need to take before prescribing or dispensing a drug to a patient.

“We are encouraged by the feedback received from the FDA in the complete response and appreciate the clarity around the path forward for Aveed”, said Ivan Gergel, executive vice president of research and development and chief scientifi c offi cer of Endo Health Solutions (of which Endo Pharmaceuticals is a subsidiary).

Aveed is the same formulation as Nebido (Bayer HealthCare Pharmaceuticals), a testosterone undecanoate approved for use in 94 countries, including those in the European Union. The fact that the same product is deemed safe for people in other countries but not in the USA has caused some physicians to question the FDA’s ruling.

“The side-eff ects the FDA reported are very uncommon, and this medication is available throughout the world except in the USA”, said Christina Wang, associate director of the University of California, Los Angeles Clinical and Translational Science Institute. “There have been millions of injections.”

Wang said physicians administering the product need to inject it slowly and make sure to not inject it into a vein, so that oil doesn’t escape into the blood. Wang has used this product in small clinical studies in which nurses have injected it under close supervision of doctors and “has never seen a severe allergic reaction”, she said.

John Morley, director of endo-crinology and geriatrics at Saint

Louis University School of Medicine (MO, USA), also was sceptical of the FDA’s reasons for denying approval for the product. He said many injectable drugs have side-eff ects. “I’m personally not convinced”, he said. “I follow the literature, and it seems like this product is a reasonable alternative for men who want to use it, as long as all of the side-eff ects are explained to them.”

The FDA denied the company’s new drug application for Aveed in 2008, citing safety concerns, and asked the company to provide additional information about the incidence of serious post injection POME and allergic reactions. The application was denied again in 2009, on the grounds of safety concerns because the Risk Evaluation and Mitigation Strategy that the company provided didn’t go far enough to ensure that the benefi ts of Aveed outweighed the risks.

Morley said there might be other underlying issues. The FDA might be reluctant to approve another testosterone product because such products are commonly being misused. People sometimes take the drug for non-medical reasons, such as attempting to increase sex drive and feel more energetic and young.

“The FDA has consistently ruled against many testosterone products”, said Morley. “In the back of the FDA’s mind they think every man is going to be given testosterone”, he said. “But we are talking about this being used in the hands of physicians who understand what they are doing. This is something the average physician could balance and make a reasonable decision about when and how this should be used in a small subset of people who it is appropriate for.”

The company will submit a response to the FDA by the end of the third quarter of this year.

Leslie Harris O’Hanlon

Published OnlineJune 13, 2013http://dx.doi.org/10.1016/S2213-8587(13)70040-8

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