安非他酮缓释片仿制药故事继续
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安非他酮缓释片仿制药故事继续
笔记 2013-04-01 Lachman CONSULTANTS The Continuing Saga of Generic Bupropion – Is the End Near? Bupropion Hydrochloride Extended-Release Tablets 300 mg have been in the news ever since the Office of Generic Drugs (OGD) approved the first generic version for Impax Laboratories on December 15, 2006. That product was the subject of many reports of lack of effect when the switch was made from the innovator's 300 mg product. The peculiar issue associated with this product approval relates to the strength upon which the original bioequivalence study was conducted to support approval of the generic products. The innovator product was approved in both a 150 mg and 300 mg strength. However, at the time of generic application submissions, the OGD was worried about the use of a 300 mg dose in normal healthy volunteers due to the potential for first-dose seizures as outlined in the labeling. Because at the time OGD considered this a possible safety issue, they permitted the generic applicants to conduct bioequivalence testing on the 150 mg strength and permitted the firm to “waive” the 300 mg in vivo requirement. (OGD typically requires bioequivalence testing on the highest dose of the approved reference listed drug (RLD) unless there is a potential safety issue with a higher strength.) The Agency has been addressing the reports of problems with this product for quite a while and, based on a bioequivalence study the FDA commissioned, it was determined that the Impax 300 mg tablet was not bioequivalent to the RLD.  On October 31, 2012, the law firm of Covington and Burling submitted a Citizen Petition, FDA-2012-P-1091 (here), on behalf of the Valeant Pharmaceuticals (the RLD and NDA holder) requesting that the Agency take certain steps relative to approved and pending generic applications, including 1) withdrawal of the approved generic ANDAs (there were 5 at the time of the issuance of the petition action letter; ;2) require bioequivalence studies to measure the three main metabolites of bupropion and apply a 90% confidence interval to each metabolite; 3) require Tmax as a bioequivalence metric; 4) require generic firms to conduct a pharmacovigilance analysis on any lack of effect complaints on their product; and finally 5) they requested that the Agency convene a public advisory committee on the issues. The Petition was granted in part and denied in part. The FDA outlined its reasoning relative to the already approved products (described in detail below) and refused to take regulatory action against the products until the results of the requested bioequivalence studies are conducted, indicating that they have a high degree of confidence in the other approved 300 mg generic products. "We agree that the four generic 300 mg bupropion HCl ER products remaining on the market were approved using the same bioequivalence standards as Budeprion XL and were originally granted waivers of in vivo BE testing on the 300 mg strength. However, FDA has asked these sponsors (Anchen, Actavis, Watson, and Mylan) to conduct additional studies to confirm the bioequivalence of their 300 mg bupropion HCl ER tablets, and to submit the results to FDA. The Agency also believes that the bioequivalence issues with the Impax/Teva 300 mg product may have been the result of that product's particular formulation and thus limited to that product. We expect that the additional bioequivalence studies that we have asked Anchen, Actavis, Watson, and Mylan to perform will be sufficient to determine whether each of those products is bioequivalent to Wellbutrin XL 300 mg. Based on the information available to us, we do not believe it is necessary to withdraw approval of these products prior to completing our review of the results of the confirmatory BE studies. Once our review of the study data is complete, FDA will take any appropriate regulatory action." FDA did agree that it was important to measure and evaluate the three major metabolites of bupropion and report those values; however, only the parent compound, bupropion, would be subject to the confidence interval approach. In addition, FDA denied the firm's request to apply Tmax as a bioequivalence criteria and noted that the product is a chronically administered medication and the impact of Tmax, even if there were a difference of several hours, is not considered meaningful to efficacy. Further, FDA denied a request for additional analysis of lack of effect reports as manufacturers of the specific products are often not identified. FDA did note that firms are responsible to report these events, and thus, the Agency would have the required information available to it. FDA also denied the petitioner's request to convene a public advisory committee to discuss the issues. While some have pointed to this incident in an attempt to question the generic drug review and approval process, there are very few examples of generic products that have been withdrawn for bioequivalence issues after approval. As a matter of fact, I can think of only three since the approval of the Hatch-Waxman Amendments in 1984. Considering that OGD approves an average of about 450 ANDAs a year, and with generics accounting for 80% of all prescriptions dispensed, that is a pretty stellar record. 原文请见 The Continuing Saga of Generic Bupropion – Is the End Near? |