首页 > 资讯 > REMS改善安全性的意向外后果

出自识林

2014-12-15 识林

REMS代表风险评估与减轻策略。FDA这一通知和管理药品安全信息问题的系统由来已久。该问题的一个方面就是使用药品具体策略以改善具有潜在安全问题的药品安全使用，包括毒性反应、严重副作用、对胎儿的影响，以及其它安全问题。REMS继2007年9月FDA修正案（FDAAA）通过后的几个单独的安全策略后应运而生。自那时起，REMS已经成为FDA药品安全计划的重要组成部分。

REMS有5个要素。然而，我想重点强调的只有其中一个要素，该要素描述如下：
保证安全使用措施（EASU）- 建立严格控制的系统或要求，以强制实施适当的药物使用。EASU的例子包括医师认证要求以开处方，中央注册系统的患者登记，仅限于某些专业药房的药品配送等。

EASU的目的是防止具有潜在严重安全问题而无必要”安全措施”的药品不当或失控处方。虽然这是一个值得称赞的目标，但是（很可能）存在一个意向外后果—阻止仿制药公司获得具有REMS中EASU的品牌产品的样品。品牌药公司拒绝出售品牌产品给仿制药公司，因为他们不符合EASU的要求。现实中并不存在这样的风险，只是使用EASU阻止仿制药公司研发和提交与品牌产品的仿制等效。对品牌药样品的一些需求是做体外测试，如溶出度研究，一些是生物等效性研究或可能的临床等效性研究。在某些情况下，对于体内研究已发布指南。

仿制药行业关于REMS阻碍获得品牌产品问题的抱怨长久而强烈。到目前为止，并没有什么措施移除这一限制。但FDA最近发布了新的题为《如何从FDA获得生物等效性研究方案包含可与参照药品适用REMS相若的安全保护措施声明函》的指南草案。

该指南的标题比平常的指南更具描述性，而且一目了然。正如标题所说，指南告诉仿制药申请人如何从FDA获得实际上符合EASU要求的声明函。这封函件的目的是消除品牌药公司不向仿制药公司（以仿制等效研发为目的）出售品牌产品的最后一个（而且是非常脆弱的）借口。虽然这并不能保证品牌公司出售RLD，但为压制品牌公司拒绝出售产品提供了一个非常强大的依据。最后，如果该指南无法改变这种垄断行为，可能需要立法修正。让我们拭目以待在未来一年左右的时间里将发生什么。

北京大学药物信息与工程研究中心 - Garth Boehm博士 2014-12-14
校译：识林-椒 2014-12-15

REMS and ANDAs – An “Unintended” Consequence of Improved Safety
Written by Garth Boehm December 14, 2014 REMS stand for Risk Evaluation and Mitigation Strategies. FDA has a long history of systems for informing on and managing drug safety issues. One aspect of this issue is the use of drug product specific strategies aimed at improving safe use of drugs with potential safety issues. These can include toxicity, serious side effects, effects on a fetus, and other safety issues. REMS came into being following several previous versions of individual safety strategies (broadly referred to as Medication Guides) in September 2007 following the passage of the FDA Amendments Act (FDAAA). Since that time, REMS have become an important part of FDA's drug safety programs.

A REMS has five elements. I want to focus, however, on only one of those elements. This element is described as follows.
Elements to Assure Safe Use (EASU) – These are strictly controlled systems or requirements put into place to enforce the appropriate use of a drug. Examples of EASUs include physician certification requirements in order to prescribe the drug, patient enrollment in a central registry, distribution of the drug restricted to certain specialty pharmacies, etc.

The intention of EASU is to prevent inappropriate or uncontrolled prescribing of a drug product with potentially serious safety issues without the necessary “safety elements” being in place. While this is a laudable goal, it has had a (presumably) unintended consequence of preventing generic companies from obtaining samples of brand products which have a REMS with an EASU included. Brand companies refuse to sell brand product to generic companies because they do not meet the requirements of the EASU. In reality there is no risk here, the issue is using the EASU to prevent generic companies developing and filing generic equivalents to the brand product. Some of the requirement for brand samples is for in vitro testing, such as dissolution studies, and some is required for bioequivalence studies or possible clinical equivalence studies. In some instances there is already posted guidance on the required in vivo studies.

The generic industry has complained long and loudly about the issues getting hold of brand product where REMS is blocking access to product. So far nothing has happened to remove this block. However FDA very recently issued new draft guidance entitled:
“How to Obtain a Letter from FDA Stating that Bioequivalence Study Protocols Contain Safety Protections Comparable to Applicable REMS for RLD”

This guidance title is a little more descriptive than usual for a guidance, and is self-explanatory. As the title says, the guidance tells generic sponsors how to get a letter from FDA stating, in effect, that they comply with the EASU requirements. The purpose of this letter is to remove the last (and very flimsy) excuse for a brand company not selling brand product to a generic company for the purpose of developing a generic equivalent. While this will not guarantee that the brand company will sell the RLD, it should provide a very strong basis to press a case against brand companies that refuse to sell product. Ultimately, if this guidance does not change this anti-trust behavior, a legislative fix may be required. We will have to see what happens in these instances over the next year or so.

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