首页 > 资讯 > FDA发布针对多动症治疗药品的生物等效性指南

出自识林

2014-11-11 识林

专注达®( Concerta®，杨森公司 ) 于2000年8月1日首次获批，用于治疗儿童注意力缺乏多动障碍。专注达®并非首个缓释哌甲酯片，却是这类药品在商业上首屈一指的成功者。由于哌甲酯是一个老药（同活性成分首次获批早于1982年），专注达®在橙皮书上所列的专利，主要是保护其处方的专利。对于希望分一杯羹的仿制药公司而言，设法规避专利处方并赢得第IV段专利挑战官司，确是其梦寐以求的制胜法宝。正因为如此，专注达®上市不久，就进入到很多仿制药公司的产品研发名录。2005年7月19日，就有企业提交了首份第IV段产品申请，当年末，好几份包含段IV声明申请也争相而至。

四个哌甲酯长效药品及持有人如下：

专注达®控释片( Concerta®，TABLET，EXTENDED RELEASE) (JANSSEN 杨森公司，盐酸哌甲酯控释片，54 mg、36 mg、 27 mg和18 mg)

利他林®缓释片（Ritalin SR®，TABLET，EXTENDED RELEASE）（NOVARTIS ，Discontinued，已停产）

利他林®长效胶囊（Ritalin LA®，CAPSULE，EXTENDED RELEASE）（NOVARTIS ）

Metadate CD 控释胶囊®(Metadate CD®，CAPSULE, EXTENDED RELEASE）（LANNETT CO INC）

专注达®是渗透泵片剂，在片剂外有一层速释药物包衣。因此，专注达®含有速释组分和缓释组分。专注达®原创药生产商（杨森公司）声称，服用这种药品时，首先提供一个负荷剂量（loading dose），接下来是一段延迟期，在延迟期内，由制剂中的缓释部分维持治疗血药浓度，这一血药浓度通过代谢清除下降消耗殆尽，因此，入睡时血药浓度低，不会干扰睡眠。此外，血药浓度曲线几乎不受进食干扰，这意味着药品可以在早餐前后服用， 可以一整天提供负荷剂量和维持剂量。这种一天服药一次的药品，解决了上学所面临的难题。哌甲酯是一类苯丙胺衍生物，因此在美国被归类于第二类管制（CII类）药物，标准的速释片需每4小时服用一次，要求服用速释片的儿童在上学期间服药。缓释片消除了上学所面临的难题，也方便了那些不愿在同学面前服药的儿童。由于在那个时代特点独特，年销售额达到10亿美元，很快获得回报，专注达®肯定被看好。

2004年，杨森公司（代表旗下的McNeil消费品保健部门）向FDA发出一份公民请愿（2004-P-0151），宣称：
“McNeil公司支持FDA仿制药办公室批准治疗等效的药品。只要FDA能够确保仿制药产品表现出于专注达®相当的总体药代动力学特性，并认定临床等效，McNeil公司对考虑专注达®的仿制药产品并无异议。”

尽管随着时间的推移，但这一份请愿书一直被认为详尽阐述了原创药厂家相信应该是必需的内容。这么多年来，就像其它提交的申请一样，这一请愿书一直被FDA束之高阁。

2010年4月召集了药学和临床药理学咨询委员会会议，旨在解决一些生物等效性相关问题。其中的问题之一，是将部分曲线下面积（partial AUC, pAUC）用于具有“复杂药代动力学特征”的药品的仿制药申请评价。在这次会议上，FDA给出了几个示例产品数据。在这些产品中，最为显眼的是两个哌甲酯缓释药品，Metadate CD ®和专注达®。FDA给出了哌甲酯药代动力学行为和针对这两个药品开展模拟的大量背景数据。FDA建议运用部分曲线下面积（pAUC）更好地定义所提出的仿制药与橙皮书收录的参照药品的曲线的等效性。

这次咨询委员会会议之后，2011年11月FDA发布了针对利他林长效胶囊®（Ritalin LA®）的具体产品生物等效性指南草案。这份指南草案建议，针对来自于空腹条件下的常规单剂量双向交叉设计研究的数据，开展AUC_0-3和AUC_3-t生物等效性评价；针对来自于进食条件下的常规单剂量双向交叉设计研究的数据，开展AUC_0-4和AUC_4-t生物等效性评价。这一计划就是我认为用来处理这些“复杂药代动力学特性”的方式，仿制药品需与释药曲线的早期部分等效（达到参照的最大血药浓度达峰时间（Tmax），或者在这一案例中，达到参照药品的速释释药部分完成）。为了重申这一点，在33个月之后的2012年9月，本质上完全相同的 Metadate CD®具体产品生物等效性指南草案，使用完全相同的部分曲线下面积（pAUC）。这似乎建立了针对使用速释负荷剂量再跟随缓释“维持”剂量的缓释哌甲酯药品的框架。对于空腹条件，使用AUC_0-3和AUC_3-t，而对于进食条件，使用AUC_0-4和AUC_4-t。到2012年9月之时，针对所有3种使用速释负荷剂量的缓释哌甲酯药品的生物等效性指南草案均已到位。

回到专注达®的话题上，2012年7月19日，在杨森公司提交公民请愿8年零4个月之后，FDA对这一请愿做出回应，同时做出回应的还有优时比公司（UCB, INC）涉及Metadate CD ®的公民请愿(FDA-2004-P-0290)，对请愿所涉问题，部分认可，部分否定。回应冗长而详细，但在本质上，同意对于诸如专注达®和Metadate CD ®这样的缓释哌甲酯类产品，应要求应用部分曲线下面积（pAUC）证明“生物等效性和真正的治疗等效性”。由于与治疗效果和/或耐受性相关，该回应并未认可诸如查准率-查全率曲线下面积（AUC_pR）之类的其它方法用于血药浓度-时间曲线的早期部分。这份由Janet Woodcock签署的回应，宣称根据详细模拟，FDA认为，空腹条件下3小时或4小时部分曲线下面积对释药速率差异敏感，而之后的曲线下面积，例如6小时曲线下面积，对这样的差异的并不更加敏感，甚至敏感度下降。2005年提交了数份仿制药申请。对几家仿制药申请人提起了多桩第IV段专利侵权诉讼。有两种仿制药等效药品获批，即2012年12月28日Mallinckrodt公司（ANDA 202608）和2013年7月9日获批的Kudco（爱尔兰）公司（ANDA 091695）的产品。外界看来，Mallinckrodt公司如何成为首家提交申请的公司，一直有些神秘，2010年12月30日才提交的仿制药申请，却成为首个获批者。于是，在对公民请愿做出回应6个月之后，专注达®的仿制药版获批。因此，在2012年底的时候，哌甲酯缓释药品的仿制药生物等效性似乎告一段落。

然而，2014年11月5日，在最初的针对专注达®的生物等效性指南草案发布两年多之后，FDA宣布发布经修订的针对专注达®的生物等效性指南。这份新指南与FDA之前确定的针对缓释哌甲酯药品的立场有显著差异，大大增加了证明生物等效性的难度。之前的指南要求单剂量空腹和进食研究、常规双向研究以及下述的置信期间。

新指南要求如下述：
1. 以完全可重复研究方式开展空腹和进食单剂量研究。
2. 符合下述置信期间。

3. “为确保专注达®与仿制药之间的可互换性，除了根据之前部分确定的药代动力学指标确定平均生物等效性之外，建议对每一个药代动力学指标开展处方对受试者（subject-by-formulation）影响的检测。”

指南草案继续解释了如何计算处方影响受试者值和运用限度。

因此，大家需要开展完全可重复单剂量研究，成本大致翻番，并需要通过10个平均生物等效性指标、10个处方影响受试者指标，来证明相互替代的生物等效性。这将耗费大量时间和财力，是相当不容易做到的。

北京大学药物信息与工程研究中心 - Garth Boehm博士 2014-11-10
校译：识林-Kapok 2014-11-11
修订：识林-葳 2015-05-28

OGD Issues Individual Bioequivalence Guidance for Concerta®
Written by Garth Boehm November 10, 2014

Concerta® was first approved August 1, 2000. It was not the first extended-release methylphenidate, but it would prove to be the most commercially successful one. Since methylphenidate was an old drug (first approved prior to Jan 1, 1982), Concerta® was protected by Orange Book listed patents that primarily claimed the formulation. This is the “holy grail” for generic companies who see big money in formulating around patented formulations and winning para IV patent challenge cases. Not long after Concerta® launched it was on many generic company development lists. The first to file para IV product was filed on July 19, 2005. By the end of 2005 there were apparently several para IV filings.

Concerta®(Methylphenidate Extended-release Tablets, 54 mg, 36 mg, 27 mg, and 18 mg) is one of at least four different versions of extended-release methylphenidate intended to treat ADHD primarily in children (the others are Ritalin SR®, Ritalin LA®, and Metadate CD®).

Concerta® itself is an osmotic pump tablet with an immediate-release layer of drug coated on the outside of the tablet. So the product had an immediate-release component and an extended-release component. The Innovator (Janssen) claimed that the product provided a loading dose when first taken which was followed by a lag then the extended-release part of the dose maintained therapeutic drug levels until exhausted when the levels dropped through elimination so that by bedtime the drug levels were low and would not interfere with sleep. In addition, the blood level profile was almost unaffected by food which meant the dose could be taken either before or after breakfast and still provide the “all day” profile of the loading and sustaining dose. This once a day dosing solved a big problem for schools. Methylphenidate is an amphetamine derivative and so is scheduled CII in the US, the standard IR tablet has to be dosed every 4 hours which required children taking this drug to be dosed while at school. The ER products eliminated this substantial problem for schools (and for children who now didn't have to take doses in front of their schoolmates. Concerta in particular must have worked well because it quickly became a billion dollar drug back when they were not as common as they are now.

In March 2004 Janssen (on behalf of McNeil Consumer) filed a Citizen's Petition with FDA (2004-P-0151) which says, in part, that:
“McNeil supports the FDA's Office of Generic Drugs in the approval of therapeutically equivalent drug products. McNeil has no objection to the consideration of a generic version of CONCERTA as long as FDA ensures that the generic version exhibits an overall pharmacokinetic profile comparable to CONCERTA, and can be found to be clinically equivalent.”

This petition, which was added to over time, went on to specify what the Innovator believed should be required. The petition languished at FDA, as did the filed generic applications, for many years.

At April 2010, there was a meeting of the Advisory Committee on Pharmaceutical Science and Clinical Pharmacology which was convened to address several bioequivalence related issues. One of these issues was the use of partial AUCs for evaluation of ANDAs for products with “complex pharmacokinetic profiles”. At this meeting FDA presented data on some example products. Prominent among these were two extended-release methylphenidate products, Metadate CD® and Concerta®. FDA presented a lot of background data on methylphenidate PK behavior and on numerous simulations that they had performed for these two products. They recommended the use of partial AUCs to better define equivalence of a proposed generic product profile to the RLD profile. The AC was in favor of using partial AUCs.

After the AC meeting, they issued a draft Individual Bioequivalence Guidance for Ritalin LA® . This draft guidance recommends doing AUC_0-3 and AUC_3-t for data from a conventional single dose two-way cross-over study under fasting conditions and AUC_0-4 and AUC_4-t for data from a conventional single dose two-way cross-over study under fed conditions. This is the scheme that I thought was the way that these “complex PK profiles” would be handled, the generic product would have to be bioequivalent to the early part of the release profile (either up to the reference Tmax, or as in this case up to the completion of an IR release portion from the reference product). To reiterate this, in September 2012 (33 months later) essentially the same guidance, using exactly the same partial AUCs was issued for Metadate CD® and for Concerta®. So it seemed that this established a framework for extended-release methylphenidate products with immediate-release loading doses followed by an extended-release “maintenance” dose. For fasting conditions AUC_0-3 and AUC_3-t and for fed conditions AUC_0-4 and AUC_4-t. By September 2012 draft Bioequivalence Guidance for all three extended-release methylphenidate products that used an immediate-release loading dose was in place.

To return to Concerta®, on July 19, 2012, 8 years and 4 months after Janssen filed their Citizens Petition, FDA responded to this petition, and to one by UCB concerning Metadate CD®, together and granted in part and denied in part the Petitions. The response is lengthy and detailed, but in essence it agrees that partial AUCs should be required for demonstrating “bioequivalence and true therapeutic equivalence” for MR methylphenidate products “such as Concerta and Metadate CD”. It goes on, however, to deny that other measures such as AUC_pR should be used in the early part of the time concentration curve because this is related to therapeutic effect and/or tolerance. The response, signed by Janet Woodcock, states that following extensive simulations, FDA believes that partial AUCs of 3 hours or 4 hours under fed conditions are sensitive to drug release rate differences and that later partial AUCs, such as 6 hours are no more or even less sensitive to such differences. Several ANDAs had been filed in 2005. There are several Para IV patent infringement suits filed against several generic sponsors. There are also two approved generic equivalents approved, Mallinckrodt approved December 28, 2012 and Kudco (Ireland) approved July 9, 2013. How Mallinckrodt became “First-to-file” is a bit of a mystery, the ANDA was filed on December 30, 2010, however first approved they were. So about 6 months after the Citizens Petition response, generic Concerta® approval was granted. So at the end of 2012 it seemed that the chapter on what constitutes generic bioequivalence for extended-release methylphenidate products was closed.

However, on November 5, 2014, over two years after the original draft bioequivalence guidance for Concerta®, FDA announced the release of revised bioequivalence guidance for Concerta®. This new draft guidance is very significantly different from FDA's previously established position on extended-release methylphenidate products. The previous guidance called for single dose fasting and fed studies, conventional two-way studies and confidence intervals as follows.

The new draft guidance calls for the following. 1. Both fasting and fed single dose studies to be conducted as full replicate studies. 2. Meet the following confidence intervals.

3.“To ensure the switchability between Concerta® and generic products, a subject-by-formulation test for each PK metric is recommended in addition to the establishment of average bioequivalence based on PK metrics identified in the previous section”

The draft guidance goes on to explain how to calculate the subject-by-formulation values and what limits to apply.

So you are now required to do fully replicated single dose studies, which will approximately double the cost, and to pass ten average bioequivalence metrics and ten subject-by-formulation metrics for a grand total of 20 ways to fail this demonstration of “switchable bioequivalence”.

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