首页 > 资讯 > 资讯公开 > FDA推迟对标签拟议规定的决定

出自识林

2015-12-08 Lachman CONSULTANTS

FDA将推迟对《已获批药品和生物制品标签说明变更补充申请拟议规定》的决定直到2016年7月。2013年11月13日FDA发布标签拟议规定征询各界意见，之后各方争论不休，我们陆续报道了各利益攸关方对该拟议规定的意见。明年7月之时，FDA将会对该拟议规定做出何种决定，我们拭目以待。

那么FDA通过拟议标签规定真正想做的是什么？有两个主要问题。第一点是相当直接和合理的，即让仿制药公司在更改标签增加新安全性信息方面更加积极主动。第二点在我看来等同于，撤销美国最高法院于2010年10月的裁决，即仿制药产品的标签安全性信息只需与品牌参比药品一致，不必单方面增加新的安全性信息（Pliva公司诉Mensing案，最高法院基于标签先占（preemption）原则，即仿制药生产商并不（最终）为标签未列出或标签未充分标明的安全性问题负责，做出了有利于仿制药生产商的判决。），给予原告起诉仿制药产品不更改标签造成伤害的优势 。第一个原因当然是为了公众健康，而且直接在FDA职责管辖范围下。第二个原因，在我看来，不论是提供直接还是间接的获益，都不在FDA法规之中。FDA并不能立法，也不能通过监管权力更改法律。

拟议规定将允许仿制药生产商单方面改变自己的标签，添加任何自己认为必要的新安全性信息。恐怕对于相同的仿制产品会存在多种不同版本的警告，这取决于由哪家企业销售仿制药。这可能会导致市场混乱，削弱Hatch-Waxman法案确保仿制药与所仿制的创新产品相同的目标。Hatch-Waxman法案中规定“同一性”和现行书面法规要求仿制药标签与品牌产品相同。仿制药公司通过上市后监测和报告不良反应进入FDA安全性数据库。FDA接收来自品牌药NDA持有人和所有生物等效产品的所有信息，因此FDA是拥有做出最终标签变更决定所需的所有必要信息的唯一机构。

FDA认为，因为80%以上的处方药为仿制药版本，当获悉新的安全性问题时，仿制药申办人应通过更改标签扮演更积极的角色。然而，仅看到单一的异常不良反应，并不总是意味着该药实际上导致该不良反应，或者标签应该更改。针对这类变更需要有一个由FDA评估的流程。此外，FDA显然认为一些仿制药公司可能在不良反应报告方面没有承担自己的责任；然而，FDA有审查企业履行不良反应报告要求的合规计划，我们没有看到有很多FDA发布的警告信或483引用这方面的异乎寻常的不符合项。

拟议规定中，FDA还解释指出，当NDA产品不再销售时，其关联产品的不良反应报告情况以及持有人做出标签变更的积极性与之前存在差距。然而，我们必须记住现行法规规定，在NDA停止销售的情况下，FDA有责任并且被要求启动仿制药产品的标签变更。此外，目前立法赋予FDA权力，如果FDA有安全性方面的担心的情况下，FDA甚至有权要求品牌药生产商修改标签，即使持有人不同意。

我担心按照目前的拟议规定，即使在没有确凿证据证明不良反应与药品相关的情况下，也可能会迫使持有人采取行动修改标签，以努力践行防守型标签来规避责任。PhRMA和GPhA支持的替代方法更加可行【两大团体对FDA标签拟议的替代建议】，并且提供系统的方法在确保FDA适当的安全性审查的同时保持标签同一性。我希望的是FDA推迟8个月公布最终规定，表明了FDA在得到对其原拟议规定的诸多意见后，已经开始考虑与其拟议规定不同的其它方式来加强对仿制药标签安全性内容的监管。

Lachman CONSULTANTS - Bob Pollock先生
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Delay in Proposed Labeling Rule – Is FDA Listening to the Industry?
By Bob Pollock | December 7, 2015

You all know my position on this issue based on multiple posts (here, here, here, here, here, here, here, here, here, and here) (wow-you get the idea – there is a lot to be said and a lot riding on this Proposed Rule). The news is that the FDA is postponing its decision on its Proposed Labeling Rule until July 2016. Mark that month on your calendar because it will mark the time where either FDA adopts a modified position or the legal process will likely be initiated by many in the generic industry.

So what is it that FDA really wants to do by this Proposed Labeling Rule? There are two major issues. One is rather direct and reasonable; that is, to make generic companies more proactive in changing their label to add new safety information. The second, as I see it, is to undo the Mensing decision and give plaintiffs the leverage they need to sue for injury from generic products for not changing their labeling. The first reason is certainly in the interest of public health and directly under the purview of the Agency responsibilities. The second, however, is really not a change of the FDA and, in my opinion, has no place in an FDA Rule whether providing a direct or indirect benefit. It is important to remember that the FDA can’t make law, nor can they change law through its regulatory authority.

The Proposed Rule would allow generic drug makers to unilaterally change their labels to add whatever new safety information they deem necessary. Fear is that there can be multiple different versions of warnings on the same generic product, depending on what firm sells the drug. This can cause confusion in the marketplace and undermine the Hatch-Waxman goal of assuring that generic drugs are the same as the innovator product they copy. The sameness provisions of the Hatch-Waxman Act and the regulations as currently written requires the generic label to be the same as the brand name product. Generic companies feed into the safety database of the Agency by their postmarking surveillance and reporting of adverse events. The Agency receives all of the information from the brand name NDA holder and all of the generic equivalent products, so they are the only entity that has all of the information necessary to make any final label change decisions.

The Agency argues that, because over 80% of all prescriptions filled are for generic versions of the medication, generic sponsors should take a more active role by changing their label when they learn of a new safety issue. However, seeing a single unusual adverse event here and there does not always mean that the drug actually caused the event or that the label should be changed. There is a process in place now for such changes to be evaluated by the Agency. In addition, it is clear that FDA thinks that some generic companies may not be living up to their responsibilities in adverse event reporting; however, FDA has a compliance program that reviews firms performance towards fulfilling that requirement and we don’t see many Warning Letters or FDA Form 483 citing egregious nonconformance being issued by the FDA.

In the Proposed Rule, the Agency also explained that, when the NDA product is no longer being marketed, a gap arises in the reporting, as well as the proactive ability for a sponsor to make a label change. However, we must remember the current regulations provide that, in the case where an NDA is discontinued from marketing, the FDA has the responsibility and is required to initiate label changes for generic products. In addition, the current legislation gives the FDA authority to require even brand name manufacturers to revise labeling if the FDA has a safety concern, even if the sponsor disagrees.

I am worried that the Rule as currently proposed may force sponsors to take an action to revise their label, even if there is no solid evidence that the event is drug-related in an effort to practice defensive labeling to avoid liability. There have been alternate approaches put forward that have the endorsement of both PhRMA and GPhA that are more workable and will provide a systematic approach to maintain label sameness while assuring appropriate safety review by the Agency. Let’s hope the 8-month time delay for finalization of the publication of the Rule, whether repurposed or final, signals a willingness of the FDA to adopt an alternate approach from its original Proposed Rule and takes into account the numerous comments and suggestions the FDA has received.