2014-04-16 Lachman CONSULTANTS
仿制药品办公室（OGD）批准了另一项复杂药品， 2008年11月递交的一项新药简化申请喜获同意。从审批过程的时间长度来说，这项简化新药申请自提交共历经65个月，但在OGD处理和审批的一系列复杂产品中表现另类。因此，Lovaza（GSK）的第一个仿制药可能伴随着Teva公司对ω-3-酸乙酯的简化药品申请#091028在2014年4月7日获准而上市。
鱼油 为什么会有这么多问题？首先是成分确证的问题。仿制药的简化新药申请要求必须含有与所仿制的橙皮书收录的参照药品（RLD）相同的活性成分，仿制药办公室（OGD）首先必须对鱼油当中的成分进行确证。
为了说明不将Vascepa (二十碳五烯酸乙酯)确认为新化学实体，FDA在2014年2月21日的一份致函中声明：“2004年11月10日，早在FDA批准Vascepa （Amarin）七年多之前，FDA批准Lovaza（GSK）的新药申请（NDA 021654）时标示的活性成分为“ω-3 酸乙酯”。相关专论中定义“ω-3-酸乙酯为从鱼油中提取的七种不同ω-3-脂肪酸乙酯组成的混合物”（Lovaza混合物）”,其中二十碳五烯酸（EPA）乙酯及二十二碳六烯酸（DHA）乙酯两种主要成分约占85%。
同样地，Lovaza（GSK）的药品标签中对其成分标示说明如下：“每克LOVAZA胶囊剂含有鱼油来源的Omega-3 脂肪酸乙酯900 mg以上。主要组分为二十碳五烯酸（EPA 约465mg）及二十二碳五烯酸（DHA-约375mg）乙酯。”
Lovaza药品标签的说明书部分标明了EPA乙酯和ＤＨＡ乙酯的成分式，分子量以及结构式，但对混合物的其它组分未作说明。”因此，虽然lovaza的大部分组分都得到详细表征，其它组分并未明确标示。尽管新化学实体（NCE）问题是一个十分值得关注的话题，但FDA是如何做出确定活性成分的判定的呢？且看本文细说。
判定过程实为不易，耗时长久，仿制药品办公室（OGD）经过七年苦工，处理仿制药伊诺肝素（enoxaparin）的成分检验和审批工作，这也反映了OGD目前在这一问题上的深思熟虑，而围绕格拉默（盐酸格拉替雷通用名）的审评，到如今已经历时6年半还未见分晓。OGD在处理Lovaza审评过程中的关键，首先是要明确此产品中其余15%的成分是什么。OGD花时间给相关产业在这个问题上提供指导，还有如何建立产品的生物等效性，与此同时，OGD清楚，必须十分谨慎，保证万全以避免批准仿制药获批之后产生问题。OGD之所以如此谨慎，原因何在？因为一旦出错，如果产品表现不如其所仿制的参照药品，简化新药审批流程的公信力就会遭到质疑。复杂路径合成的以及天然来源产物类的产品最为棘手。在当前的审批办法下，OGD面临的主要问题是新药审批过程中不一定建立复杂产品的详尽表征。
药品在新药审批时必须证明其安全性和有效性，但是新药申请阶段对含有复杂混合物的产品化学组成详尽表征不作要求，只要生产企业能够明确生产工艺流程，建立合适的控制和质量标准，保证每批次产品的一致性和可重现性。完整表征说明的工作通常就留给了之后的寻求产品获批的仿制药竞争者。
总之，新药简化审批过程中，确证复杂产品仿制药与参照药品具有相同的活性成分对OGD批准产品申请至关重要，建立一致性成为ANDA申请者和OGD审评人员团队协力完成的工作。通过频繁的交流沟通以及多个产品的ANDA申请文件，OGD获取了大量有用资料，不断汇总这些信息和数据，逐步建立适当的方法、检测程序、质量标准和工艺，用于检测和确认复杂产品当中的有效成分，以最优的手段建立生物等效性。对复杂产品来说，这项任务十分艰巨，甚至可能是审批过程中所要面临的最大挑战。但一次又一次，OGD似乎都成功了。我们要关注已取得的成果，但别忘了我们还在等着普雷马林仿制药上市，可以说，这项工作永远未完待续！
Lachman CONSULTANTS - Bob Pollock先生 2014-04-11
校译：识林-Kapok 2014-04-16
OMG – Omega -3 ANDA Gets Approved!
Written by Bob Pollock • April 11, 2014
OGD approved another “complex” drug product and brings a happy closure to an ANDA submitted in November 2008. By no means a record in terms of length of approval, this ANDA has been percolating for 65 months since submission and represents another in a string of complex products that OGD has tackled and approved. Thus, the first generic for Lovaza will likely hit the market soon as Teva’s ANDA # 091028 for Omega-3 – Acid Ethyl Esters gained approval on April 7, 2014.
Fish oil – why such a problem? First there is the problem of characterization. Because an ANDA must have the same active ingredient as the reference listed drug (RLD) it relies upon for approval, OGD first must know what is actually in the fish oil. In describing its denial of New Chemical Entity (NCE) status for Vascepa (Icosapent Ethyl) in a February 21, 2014 letter FDA noted: “On November 10, 2004, more than 7 years prior to FDA's approval of Vascepa, FDA approved NDA 021654 for Lovaza, which lists "Omega-3 acid ethyl esters" as its active ingredient. The relevant monograph defines "Omega-3 acid ethyl esters" as a mixture containing, among other things, seven distinct omega-3 fatty acid ethyl esters obtained from fish oil (the Lovaza mixture). Two of the seven omega-3 acid ethyl esters, the ethyl esters of EPA and docosahexaenoic acid (DHA), make up approximately 85% of the Lovaza mixture. Similarly Lovaza's labeling describes its composition as follows: "Each 1 gram capsule of LOVAZA contains at least 900 mg of the ethyl esters of omega 3 fatty acids sourced from fish oils. These are predominantly a combination of ethyl esters of eicosapentaenoic acid (EPA- approximately 465 mg) and docosahexaenoic acid (DHA - approximately 375 mg)." The "Description" section of the Lovaza labeling further gives the empirical formulas, molecular weights and structural formulas of EPA ethyl ester and DHA ethyl ester, respectively, without referring to any other component of the Lovaza mixture.” Thus, while much of the Lovaza contents are well characterized, there are other components that are not. And while the NCE issue is certainly a blog-worthy topic, the concept of how the FDA arrives at its decision on what the active ingredient actually is really the story here.
This decision is never easy and usually lengthy as evidenced by OGD’s 7 year struggle to come to grips with the composition and approval of a generic enoxaparin and is also reflected in OGD’s current deliberations, now at 6.5 years and counting, surrounding their review of glatiramer (the generic for Copaxone). The key for OGD in the Lovaza situation was first to define what is in the other 15% of the Lovaza product. While OGD took their time in terms of providing guidance to the industry on this issue, as well as how to establish bioequivalence of the product, OGD knows they have to get it right to avoid any potential problems once they approve an ANDA. Why? Because if OGD gets it wrong and the product does not preform the way the RLD does, then the credibility of the ANDA approval process gets called into question. Complex synthetic and naturally occurring products give the Agency the most problems. And the problem OGD faces with the current approval approach is that full characterization for these complex products are not necessarily established during the NDA approval process.
Drug products subject to NDAs must demonstrate they are safe and effective, but often the work to characterize products with complex mixture is not always necessary at the NDA stage, as long as the firm can define the manufacturing process, establish appropriate controls and specifications to assure that each batch manufactured will produce a consistent and reproducible product. The job of full characterization is, thus, often left to prospective generic competitors seeking to gain approval of the product.
Anyway, I think you can see that the process of establishing that an ANDA for a complex product has the “same” active ingredient as the RLD is essential for OGD to be able to approve the product, and the job of establishing sameness becomes a team effort between the ANDA applicants and the OGD reviewers. There is a lot of back and forth and OGD learns much from multiple ANDA submissions for the product as it pieces information and data together to establish the appropriate methods, tests procedures, specifications and techniques to measure and define the “active ingredient” and the best methods to establish bioequivalence. For complex products, this task is difficult and represents perhaps the biggest challenge to the approval process. But time and time again OGD seems to succeed. Keep your eyes on the prize, but remember we are still waiting for a Premarin generic so the work, so to speak, is never really done!