首页 > 资讯 > FDA仿制药安全性标签变更法律先占性问题引发关注

出自识林

2014-02-03 识林

各位可能注意到了FDA于2013年11月发布了拟议规定，允许仿制药生产商变更产品商标以反映新的安全性信息【仿制药公司雪上加霜，需上报不良反应 识林资讯】。该拟议机制与以往NDA持有人使用的待批变更（CBE-0）补充申请提交相同。自Hatch-Waxman法案生效以来，NDA持有人就不断在做与安全性相关的标签变更，之后为所有仿制药所复制。这有助于保持药品的标签一致，确保某一给定产品的所有生产商都使用相同标签。

作为这一流程的结果，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。这被称为“先占（preemption）”，在患者就受到伤害索赔的产品责任诉讼中，仿制药生产商由于不能变更标签，可不为标签缺陷负责。最近的在美国最高法院审理的产品责任诉讼案之一，就是基于标签先占原则做出了有利于仿制药生产商的判决（PLIVA Inc.诉Mensing）。在判决中，法官论述了先占问题，并有力地阐明，如果不是对更改标签无能为力,那么生产商将要担责。然而，他们也指出FDA目前有权利在标签中注明安全性问题 “如果有意修改，国会和FDA保留修改法律法规的权利。”

FDA提出了对这一先占问题的解决办法，就是仿制药生产商也可以对其标签做安全性的变更。这将会极大地改变现在的局面。这类产品责任诉讼中的很多会导致数以千万计甚至数亿美元计的损害评估。很多仿制药公司无法承担这样的责任，而且他们也不具备能做出与大型品牌药公司所做出的同样类型的安全性评估的地位。他们已经发现很难，某些情况下不可能得到产品责任保险，如果没有先占，可能会发现这是不可能的。对于FDA拟议的变更，仿制药行业感到忧心忡忡，并极力反对这项提议。

1月22日，28位国会议员致函FDA局长Margret Hamburg，向她表达了对于此提案的严重关切。信中写道“我们坚信，这样的规定将会直接与法规冲突，有悖于法律的宗旨和目标，并且使制药行业和医疗消费者成本大增”。这些国会议员对FDA就该拟议规定的信息提出了一些要求。这些信息分类如下。

1. 对于仿制药提交CBE-0补充申请后的时间段，请解释仿制药标签如何“在批准日期之后，与根据Hatch-Waxman法案第505(j)(2)(A)(i)-(v)节所包涵的要求批准的标签一致”
2. 请解释在FDA审议之前将拟定标签变更公布于公开网站上、并逐渐削弱FDA目前作为守门人和变更药品标签的决定性权威的角色这一做法的获益。
3. 请提供所有FDA以外的、参与决定继续推行该拟议规定、或参与起草或审查该决定的、行政部门员工的名单。
4. FDA决定某一不良反应何时应被列入标签的宗旨的政策是什么？在上升到标签变更之前，是否有必要的标准衡量不良反应的现患率和严重程度？
5. FDA及时审评CBE-0申请、建立并更新网站的预期成本是多少，FDA打算利用哪些资源来负担这些开支？FDA将怎样区分这些申请的优先顺序，预计的时间和审评是怎么样的？
6.请详细说明FDA怎样得出预计的成本或每年$4,237到$25,852这一规则？以及如何让估计到将会每年收到来自约15个ANDA持有人的20份CBE-0 补充申请。请解释FDA是如何得出这些估计的。对于生产商准备一份CBE补充申请所花费的时间和成本如何，FDA是否开展过分析？对于生产商制定一个新的监控药品安全性和有效性的流程所需成本如何，FDA是否开展过分析？对于这项拟议规定对药品价格产生的影响，FDA是否开展过分析？请提供所有有关成本-效益分析的文件和通信。
7. 作为新获得的安全性信息结果，仿制药生产商目前可以同FDA一起提出标签变更。请提供与品牌药生产商相比，仿制药生产商有多少次这样的情况，以及使用这一流程时所有造成延期的现阶段原因的统计。请提供所有能表明仿制药生产商现在未提供要求的不良反应事件报告，或以其它方式不能达到上市后监督要求的证据。
8.该拟议规定提到2010年的一项FDA安全性相关药品标签变更的研究，发现从药品首次批准到标签变更平均时间的平均时间为11年。请向相关委员会提交此项研究及所有的支持性文件。还请提供一项标签变更申请后FDA作出决定所用时间的统计数据。
9.请解释先前的批准补充申请流程不能有效地变更仿制药和品牌药标签的原因，以及使用这一流程时所有造成延期的现阶段原因。请提供所有能表明仿制药生产商不会在FDA批准的参照品牌药标签变更时更新他们标签的证据。
10. 作为一个替代方案 ，FDA是否考虑过允许仿制药生产商使用经过改进的CBE流程，这一方式使FDA在产品投入市场之前，有机会评估拟议的标签变更。FDA如何看待使用这一方案相对于CBE-0的利弊？ FDA是否对此种方案开展过成本效益分析？
11. FDA是否考虑过该拟议规定对非处方药（OTC）造成的影响？如果有，请提交相关分析并解释FDA预期如何对OTC药品实施这一拟议规定。

FDA应在2014年2月5日前回复该函。

这对于美国仿制药行业来说是一个暗藏危机的经济问题。如果律师或律师事务所同意以部分最终赔偿金（通常为30%或更多）接下案子，诉讼可以酬金的形式开展，这样的事实，意味着任何人都可以就产品责任起诉。陪审团倾向于同情受到伤害的原告，屡次做出有利于原告的判决并判予巨额赔偿金。尽管生产药品公司并不开具处方，但因为他们比其它直接参与开具处方者更有钱，他们仍会因“产品缺陷”而吃官司。

我们只能期盼这一拟议变更不会生效，或者即使生效，也被法院以有悖于现行法律而取消。如果这些情况发生，国会将不得不介入，或者就如我们所知的，仿制药行业的生存将受到严重威胁。

北京大学药物信息与工程研究中心 - Garth Boehm 博士 2014-01-25
校译：识林-Kapok 2014-02-02

Many of you may be aware of FDA's proposed rule published in November 2013 to allow generic manufacturers to change labelling of their products to reflect new safety information. The proposed mechanism is the same as that used by the NDA holders, submission of a CBE-0 supplement. Ever since Hatch-Waxman came into being, safety related label changes have been made by the NDA holder and then copied by all generics. This served to keep drug labels consistent ensuring that all manufacturers of a given product had the same label.

As a consequence of this procedure, generic manufacturers were not (ultimately) held liable for safety issues not being labeled or not being adequately labeled. This was called “preemption” and in product liability suits by patients claiming injury, generic manufacturers could not be found liable due to labeling deficiencies as they could not change the label. One of the most recent product liability cases that went to the US Supreme Court was decided in favor of the generic manufacturer on the basis of labeling preemption (PLIVA Inc v's Mensing). In this decision the Justices addressed the preemption issue and effectively stated that absent the inability to change the labeling, the manufacturer would have been liable. However they also pointed out that FDA currently has the power to address safety issues in labeling “Congress and the FDA retain the authority to change the law and regulations if they so desire”.

FDA has proposed as it's solution to preemption that generic manufacturers can make safety changes to their label. This would be a huge change to the current situation. Many of these product liability suits result in damage assessments of tens of millions or even hundreds of millions of dollars. Many generic companies cannot afford this liability and are not in a position to make the same kinds of safety assessments that can be made by large brand companies. They already find it difficult, and in some cases impossible to get product liability insurance, and without preemption they would likely find it impossible. The generic industry is very concerned about FDA's proposed change and has objected vigorously to the proposal.

On January 22nd, 28 Congressmen sent a Letter to the Commissioner of the FDA, Margret Hamburg expressing “grave concern” about the proposal. The letter goes on to say “We strongly believe that such a rule would conflict directly with the statute, thwart the law's purposes and objectives, and impose significant costs on the drug industry and healthcare consumers”. The Congressmen then make a number of demands for information from FDA concerning the proposed rule. The information sort is as follows.

1. For the period of time after a generic drug has submitted a CBE-0 supplement, please explain how the generic drug's label will be “the same as the labeling approved for the requirements included in sections 505(j)(2)(A)(i)-(v) of the Hatch-Waxman Act extend beyond the date of approval?
2. Please explain the benefit of having proposed label changes published on a public website before FDA consideration, undermining FDA's current role as the gatekeeper and deciding authority for changes to a drug's label.
3. Please provide the names of any executive branch employees outside the FDA who were involved in the decision to proceed with this proposed rule or who participated in drafting or reviewing it.
4. What is FDA's policy on when an adverse event needs to be listed on the label? Are there standards around the prevalence or severity of the adverse event that are necessary before it rises to a labeling change?
5. What is the expected cost to the FDA to review the CBE-0 submissions in a timely manner and establish and update the website, and from where does the FDA propose drawing resources to meet these costs? How will the agency prioritize submissions and what is the estimated time or review?
6. Please describe in detail how FDA arrived at the estimated cost or the rule of $4,237 to $25,852 per year and estimates it will receive 20 CBE-0 supplements annually from approximately 15 ANDA holders. Please explain how the agency derived these estimates. Did FDA conduct any analysis of how long it takes a manufacturer to prepare a CBE supplement and how much it costs? Did FDA conduct any analysis of what it will cost manufacturers to institute new procedures for monitoring safety and effectiveness of drugs? Did FDA conduct any analysis of the effect the proposed rule will have on drug prices? Please provide all documents and communications regarding the cost-benefit analysis.
7. Generic drug manufacturers can currently propose labeling changes with FDA as a result of newly acquired safety information. Please provide statistics for how many times this is done in comparison to brand name manufacturers and the current causes of any delay when using that process. Please provide any evidence that would indicate generic drug manufacturers are not submitting required adverse event reports or otherwise not meeting their post-market surveillance requirements[.]
8. The proposed rule notes a 2010 study of FDA safety-related drug labeling changes that found the median time from initial approval of the drug product to label change was 11 years. Please provide this study and all supporting documentation to the Committee(s). Please also provide statistics showing how long it takes FDA to make a decision once a label change is suggested.
9. Please explain why the prior approval supplement process alone cannot be used effectively to change generic and brand drug labels, and the current causes of any delay when using that process. Please provide any evidence that would indicate generic drug manufacturers are not updating their label upon FDA approval of a change to the label of the reference brand drug.
10. As an alternative approach, did the FDA consider permitting generic drug manufacturers to use a modified CBE process by which the agency has an opportunity to assess a proposed labeling change before introducing it into the market? What does the agency believe would be the pros and cons of using this approach as opposed to the CBE-0? Did the agency conduct a cost benefit analysis of such an approach?
11. Did the agency consider the impact the proposed rule would have on over-the-counter (OTC) drugs? If so, please submit any such analysis and explain how FDA envisions the proposed regulation applying to OTC drugs.

FDA has until February 5, 2014 to respond to the letter.

This is potentially a very serious economic issue for the US generic industry. The fact that litigation can be pursued on a contingency basis, where a lawyer or law firm agrees to take on the case for a portion of the eventual damages (often 30% or more) mean that anyone can bring such a product liability case. Juries tend to be sympathetic to the injured plaintiff and many times find in favor of the plaintiff and award huge damages. Although companies that manufacture drug products do not prescribe them, they are sued based on a “defective product” theory because they have more money than other people directly involved in the prescribing.

We can only hope that this proposed change does not go into effect, or if it does that it is stuck down by the courts as against the current law. If neither of these things happens, then Congress will have to step in or the existence generic industry as we know it will be seriously threatened.