首页 > 资讯 > 布洛芬口腔崩解片无法作为ANDA提交

出自识林

2015-01-24 Lachman CONSULTANTS

2015年1月13日，FDA拒绝了要求将100mg布洛芬咀嚼片剂型变更为同规格口腔崩解片的ANDA适应性请愿（请见此处）。大家都知道，ANDA产品必须与参照药品（RLD）具有相同的剂型、规格、活性成分和给药途径，除非对于变更批准了ANDA适应性请愿（也称505(j)(2)(C)请愿）。你可以仅申请对规格、剂型、给药途径的变更，或组合产品活性成分变更（只要提出活性成分是相同治疗类别，并且RLD成分和提议成分之间存在已知的等效剂量关系。）如果FDA认定你提出的变更不会引起安全性或有效性问题，请愿将会获批。如果FDA认定需要临床安全性和/或有效性研究以保证提议变更产品的安全性和有效性，那么请愿将会被拒绝。 2012年得克萨斯州奥斯汀诺贝尔实验室向FDA申请，要求允许口腔崩解剂型的布洛芬作为ANDA提交。FDA拒绝了这一要求，指出： “目前没有已获批的布洛芬口腔崩解片。因此，没有安全性数据，尤其是关于这种剂型保持与口腔黏膜长时间接触的局部（口腔）安全性或耐受性。”

因为对于剂型变更的决议认为需要安全性研究，FDA不需要评估由变更请求触发的是否符合《儿科研究平安法案》（PREA）的规定。（记住— PREA要求对药品的某些变更或新NDA需要在儿科患者中研究药品。至于考虑到ANDA适应性请愿，在要求变更剂型、给药途径或活性成分时，必须解决PREA，但并不适用于规格变更。）

FDA关于口腔崩解片的指南指出，出于口腔崩解考虑，产品必须在30秒内在口腔内溶解。通常设计口腔崩解产品，以便在没有水的情况下待溶解后吞咽。有趣的是，FDA选择提出安全性问题，而布洛芬不仅有咀嚼片剂型（不知道需要花费多长时间咀嚼并吞咽这样的产品），还有必须在口中停留一段时间的悬浮剂型，有人认为，由于悬浮液的黏度，一定会存在残留。总之，FDA一定有其原因，除非申请者提交复议，FDA的决议将成立。对于包括请愿中所提安全问题信息的口腔崩解产品，企业始终还有提交505(b)(2)申请的选择。

我们已经看到，不仅需要更长的时间获得请愿书审查和采取相应行动（Lachman有一些请愿等待FDA行动已经超过6、7年的时间），而且请愿决议似乎变得越来越保守。其实我以为这份请愿会顺利通过。这恰好向大家显示了，即使是我，30年前FDA ANDA适应性请愿委员会的首席主席，也被FDA今天的行为迷惑了。

Lachman CONSULTANTS - Bob Pollock先生 2015-01-14
编译：识林-椒 2015-01-24
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FDA Says Orally Disintegrating Ibuprofen is a No Go for an ANDA
Written by Bob Pollock • January 14, 2015

On January 13, 2015, FDA denied an ANDA suitability petition requesting a change in dosage form from Ibuprofen Chewable Tablets, 100 mg to an Orally Disintegrating Tablet of the same strength (here). As you know, an ANDA product must be the same as the reference listed drug (RLD) in dosage form, strength, active ingredients, and route of administration, unless an ANDA suitability petition (also referred to as a 505(j)(2)(C)) petition) is approved for the change. You may only petition for a change in strength, dosage form, route of administration, or change in active ingredient in a combination product (as long as the proposed active ingredient is of the same therapeutic category and there is a known equipotent dosage relationship between the RLD ingredient and the proposed ingredient). If the Agency determines that the change you propose does not pose questions of safety or efficacy, then the petition must be approved. A petition must be denied if FDA determines that clinical safety and/or efficacy studies must be required to assure the safety and efficacy of the proposed changed product.

Nobel Laboratories of Austin, Texas petitioned the FDA in November 2012 asking that an orally disintegrating form of ibuprofen be permitted to be submitted as an ANDA. FDA denied the request and stated that:

“There are no currently approved ibuprofen orally disintegrating tablets. Therefore, there are no safety data especially regarding local (oral) safety or tolerability for this formulation that remains in prolonged contact with the buccal mucosa.”

Because the decision on the change in dosage form found that safety studies were needed, FDA did not need to evaluate the issue of whether the provisions of the Pediatric Research Equity Act (PREA) would be triggered by the request. (Remember- PREA requires the study of drug products in pediatric patients for certain changes in drug products or new NDAs. As far as ANDA suitability petitions are concerned, PREA must be addressed in requests to change dosage form route of administration or ingredient, but it is not applicable to proposed changes in strength.)

The FDA has Guidance on orally disintegrating tablets that states that, in order to be considered orally disintegrating, the product must dissolve in the mouth within 30 seconds. Orally disintegrating products are typically designed so they may be taken without water and usually swallowed as they dissolve. It is interesting that FDA chose to raise a safety issue when ibuprofen is available not only in a chewable tablet form (don’t know how long it takes to chew up and swallow such a product), but the product is also available in a suspension dosage form, which must reside in the mouth for some period of time, and one would assume that, due to the suspension's viscosity, there must be some residue left behind. Anyway, FDA must have its reasons, and the Agency's decision will stand unless the petitioner files a petition for reconsideration. The firm also always has the option of submitting a 505(b)(2) application for the proposed orally disintegrating product that includes information on the safety question raised in the petition.

We have seen that, not only is it taking longer to get a petition reviewed and acted upon (Lachman has some petitions awaiting FDA action for more than 6 or 7 years), but the decision making on petitions appears to be getting more conservative. I actually thought this petition would sail through the process. Just goes to show you that even I, the first chairman of FDA's ANDA Suitability Petition Committee some 30 years ago, can get fooled by some of FDA's actions today.