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出自识林

2014-03-18 Lachman CONSULTANTS

前仿制药办公室（OGD）副主任在拟议标签规定问题上支持仿制药生产商协会

面对可能是自Hatch-Waxman法案问世以来，对标签审评流程最有影响的改动，前仿制药办公室副主任Kent Johnson坚信拟议标签规定对患者和药师无益，将只会引起市场混乱。Kent在仿制药办公室任职期间，因推广仿制药与仿制药项目而备受尊重。在最近的评论中，他表达了自己有关实施拟议规定的思考：

1) 开具处方者看到的在线标签说明与在药房给患者的特定产品的标签说明可能没有关联。

2) 处方者不了解按照其处方发药的具体产品的标签者信息。

3) 无论产品大小与类型如何，药房通常有一份基于药店合同以及批发商系统的产品清单（对于具体经销商）。没有药房愿意不断跟进在经修订的标签中获得的信息。成本是药房采购仿制药时考虑的关键因素，而报销通常取决于管理式医疗的最高补贴费用（Maximum Allowable Cost，MAC）。

4) 开具处方者缺乏判断不同标签者的标签信息“一致”或“不同”的有效途径。长期以来同一给定产品的所有标签保持相同的前提十分有效、实用，来自于同一给定产品所有销售者的标签一致的显著优点看上去比其它所有考虑更为重要，任何尝试应遵循这一理念。

5) 在相关并以文件记录情况下，安全信息最具价值。安全性信息与记录散乱的事件混杂后，价值将下降。由于这将扰乱标签修改的一致性，因此应慎重考虑鼓励结合新安全性信息修订标签的计划。

6) 新的安全性考虑可自销售者方便地传递给FDA。FDA应审评这些报告并，判定其质量以及临床重要性。FDA随后将应下达变更所有标签。这将保证不同生产商之间的“一致性”。新安全性信息直接出现于仿制药标签而后再由FDA审评，将导致混乱，难以保证质量，不足以支持变更。

Kent同时指出，当NDA退出市场，橙皮书收录的参照药品（RLD）的认定转移至ANDA持有者时，可能会出现问题。但请记住，当这种情况发生时，没有任何条例或法规将额外责任归咎于ANDA持有人。参照药品仅是随后提交的ANDA在进行生物等效性检测时，所必须依赖的产品。现行规定下，这一监管流程要求FDA（由于其可获得多个ANDA申请者对同一特定药品所提交的全部信息）在获取新信息的情况下，评估标签变更的需要。通常情况是，在仿制药获批时，对该药品的大多数了解已体现在标签说明中。一般的标签变更常根据治疗同类病人的副作用更少的疗法的批准，基于新的风险-获益分析（这似乎是FDA更擅长之事），修订较老产品的警告。

在与我之前在仿制药办公室的同事讨论时，我尚未发现有人支持目前起草的拟议规定。在联邦公告发布这一拟议规定时，他们中的大多数才与我们这些行业人士同时获悉此事。或许人们会认为，多位仿制药标签说明方面的专家一直参与规定起草，或至少征求过建议，从另一方面显示该规定似乎更多出于政治而非科学目的。我们期望清醒的认识占上风，在最终定稿之前对这份拟议规定作出一定的修改，以避免之前提到的意外后果。同行们，让我们正视现实，直面变化，做对公众有益，而非对政客或律师有利的事情。

Lachman CONSULTANTS - Bob Pollock先生 2014-03-10>
校译：识林-Kapok 2014-03-18

Former OGD Deputy Director Sides with GPhA on Proposed Labeling Rule
Written by Bob Pollock • March 10, 2014

Kent Johnson, former Deputy Director of the Office of Generic Drugs (OGD) and perhaps the biggest influence on the labeling review process since the passage of the Hatch-Waxman Act believes that the proposed labeling rule is bad for patients and pharmacists and will only cause confusion in the marketplace. In recent comment to my blog posts (here and here and here), Kent, a well-respected advocate of generic drugs and the generic drug program at OGD, provided his thoughts on the issues associated with implementation of the Proposed Rule as currently written:

1) There would be no correlation between what a prescriber sees in online labeling and the labeling of the specific product given to the patient at the pharmacy.

2) A prescriber has no knowledge of the labeler of the product dispensed pursuant to his/her prescription.

3) A pharmacy, irrespective of size or type, typically has an inventory of product (often specific marketer) based upon pharmacy contracts and wholesaler programs. There would be no pharmacy that would wish to chase a product based upon some information found in revised labeling. Cost of a generic is a key purchasing consideration for a pharmacy, as reimbursement is often determined in by Maximum Allowable Cost (MAC) programs in managed care.

4) There is not a practical way for a prescriber to determine labeling sameness/differences among labelers. The long standing premise that all labeling for a given product is the same is a very useful and practical assumption. THE GREAT ADVANTAGE OF COMMON LABELING FROM ALL MARKETERS OF A GIVEN PRODUCT SEEMS TO OVERRIDE OTHER STATED CONCERNS, AND EVERY ATTEMPT SHOULD BE MADE TO RETAIN THIS CONCEPT.

5) Safety information is most valuable when it is relevant and documented. Safety information becomes less valuable when it is diluted by poorly documented events. There should be great concern for a plan that encourages revising labeling with new safety information, for this will trigger constant labeling changes.

6) New safety concerns can well go from the marketer to FDA. FDA must be the reviewer and determine clinical importance and quality of the report. FDA should then drive down any changes to all labelers. This assures “sameness” among different manufacturers. New safety information going directly into generic labeling to be later reviewed by FDA will lead to confusion and lack of assurance of quality and support for the changes.

Kent also noted that there may be a problem when the NDA leaves the marketplace and the reference listed drug (RLD) designation is shifted to an ANDA holder. But remember, there is nothing in the statue or regulations that ascribe additional responsibilities to an ANDA holder when this occurs. The RLD is merely the product that the subsequently submitted ANDA must rely upon for bioequivalence testing. There is a regulatory process in place under the current rules that require the FDA (since they have access to all of the information submitted by multiple ANDA applicants for a specific drug product) to evaluate the need for label changes when new information becomes available. Also, typically, by the time a generic product is approved, most of what is known about the drug is already covered in the label. Often label changes are made to older products to revise warnings based on new risk-benefit analysis (something the FDA is likely to do best) based on approval of other therapies that may have fewer side effects used to treat the same ailment.

In discussions with my former colleagues at OGD, I have not found one that was in favor of the Proposed Rule as currently drafted. Most of them found out about the Rule at the same time we in the industry did, when the rule was published in the Federal Register. One might think that the experts on generic drug labeling would have been involved in the formation of the Rule or at least asked for their input, another indication that this rule appears to be more politically than scientifically motivated. Let’s hope cooler heads prevail and some revisions are placed into the proposal prior to finalization to avoid the unintended consequences previously written about. Let's be realistic about this, folks, and do something that is good for the public and not the politicians and lawyers.