首页 > 资讯 > FDA发布阿片类仿制产品滥用遏制指南草案

出自识林

2016-03-26 Lachman CONSULTANTS

3月25日FDA发布《行业指南草案 –仿制固体口服阿片类药品的滥用遏制评价一般原则》，随着指南草案的发布关于滥用遏制仿制产品的一些问题变得更加清晰。指南草案描述了仿制药申请人在寻求参照药品（RLD）在标签中具有滥用遏制属性描述的阿片类产品的批准时应开展的实验类型（可比性体外研究，以及在某些情况下，可适当进行相关的药代动力学或其它研究）。推荐的研究被设计用来确保仿制产品的滥用遏制不低于RLD。

指南草案继续指出，“如果RLD的标签描述滥用遏制属性，ANDA申请人应评估其产品，以表明产品对所有潜在滥用途径的滥用遏制不低于RLD。”这项声明表明仿制药的滥用遏制属性必须至少与提交批准的RLD一样好。仿制药能有额外的属性吗？这是个尚未解决的有趣问题。FDA指出“销售滥用遏制比RLD低的仿制阿片类药品会导致阿片类药物滥用者优先寻求和滥用仿制药。”根据这一说法，FDA暗示，任何较低滥用遏制的仿制药不能被视为治疗等效，因此无法通过505(j) ANDA过程获批。

“该指南关注仿制固体口服阿片类药品包含物理或化学屏障、激动剂/拮抗剂、厌恶剂或两种或更多技术组合研发和评价的一般原则。”虽然新批准的NDA可能包含有其它技术，FDA指出，ANDA申请人应审查RLD标签，以确定在标签上是否有滥用遏制信息，但对一些通过NDA工艺包含在其产品内的某些滥用遏制属性但尚未将这类语言纳入其标签的NDA产品，ANDA申请人被指示评估关于NDA产品的公开文献，以确定完成哪些研究，以及什么特征被纳入进NDA产品以告知仿制药在其提交中应包含什么研究。这意味着，如果具有一些滥用遏制属性的NDA已获批，但FDA尚未同意任何具体标签以指出这些属性，ANDA申请人仍应研发相一致的产品，并证明所包含的滥用遏制属性不低于具体作为其申请的基础所参照的RLD NDA。这与指南中的规定有些不一致，指南中指出“如果产品标签没有描述任何滥用遏制属性，本指南中的研究建议不不适用。”

FDA在文件中概述正推荐一种分级方式来检测，FDA解释如下：“该基于层级的方法允许分级检测，由产品在体外研究的简单而温和的处理开始（1级），发展至更具破坏性的机械和化学处理，直到参照产品的滥用遏制被击败或损害，或检测样品显示出比参照产品的滥用遏制低。”

FDA指出，申请人应评估参照产品所有给药途径的滥用遏制属性，并采用分级方法，然而，FDA明确指出，试验配方和参照产品不必相同。FDA还指出，申请人应解决篡改技术、时间和篡改可用资源，以及在鉴别研究中，建议申请人使用一个控制产品。在该类可比性研究中，仿制药的表现应不差于RLD。FDA在指南文件的附录中提供了评价可比性实验的统计学参数。

指南文件进一步给出了通过给药途径滥用的细分，并给出了建议实验和FDA关于这些可比性研究的期望。检测应针对所有提出的检测产品和参照产品的规格，除非有证据表明参照产品规格是所有剂量成正比的。

关于药物代谢动力学（PK）实验，FDA给出了以下例子：“当评估通过口服摄入的目标所提议产品的滥用可能性时，如果，在尝试了附录3中建议的溶出度研究后，潜在申请人认为实验表征其仿制药产品相关的滥用遏制过于敏感，产品可在PK研究中被进一步评估。在这种情况下，潜在申请人应寻求FDA关于PK研究设计的建议。”关于pK研究提供了其它指南。另外，如果在检测产品中的厌恶剂与参照产品使用的不同，企业可能必须开展产品的可比性相似pK研究。FDA建议，如果这类研究是必要的，申请人可在继续研究之前寻求FDA的建议。

该文件的其余部分讨论了方法学和统计学评估。对于那些在该领域的企业，应仔细阅读文件，如有疑问或不一致之处应向FDA提出。另外，请记住，这是一份指南草案，虽然提供了FDA当前的观点，但这些观点和我们看到的其它复杂产品的观点一样会随着时间的推移而发生变化。

Lachman CONSULTANTS - Bob Pollock先生
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Generics Draft Abuse-Deterrent Guidance Issues
By Bob Pollock | March 25, 2016

Here is something the generic industry has been waiting for. The questions about what and how a generic abuse-deterrent product has become somewhat more clear with the issuance today of the Draft Guidance for Industry – General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products (here) .The Guidance document describes the types of tests (comparative in vitro studies and, in some cases, relevant pharmacokinetic or other studies that may be appropriate) that a generic applicant should undertake when seeking approval for a Reference Listed Drug (RLD) opioid product that has abuse-deterrent properties described in its labeling. The studies recommended are designed to assure that the generic product is no less abuse-deterrent than the RLD.

The draft Guidance goes on to say that “if the RLD’s labeling describes abuse-deterrent properties, the ANDA applicant should evaluate its product to show that it is no less abuse-deterrent than the RLD with respect to all potential routes of abuse.” This statement demonstrated that the abuse-deterrent properties of the generic must be at least as good as those of the RLD for approval. Could the generic have additional properties? That is an interesting question that has not yet been answered. FDA states that “[m]arketing a generic opioid drug product that is less abuse-deterrent than the RLD could lead opioid abusers to preferentially seek out and abuse generics.” By this statement, FDA implies that a generic that is any less abuse-deterrent cannot be considered as therapeutically equivalent, and thus, could not be approved through the 505(j) ANDA process.

“This guidance focuses on the general principles for developing and evaluating the abuse deterrence of generic solid oral opioid drug products formulated to incorporate physical or chemical barriers, agonist/antagonists, aversive agents, or combinations of two or more of these technologies.” While there may be other technologies that newly approved NDAs may incorporate, FDA notes that, in such cases, FDA will likely issue product-specific guidance for those newer technologies. FDA notes that the ANDA applicant should review the RLD labeling to determine if there are any abuse-deterrent information in the labeling, but for some NDA products that have incorporated certain abuse-deterrent properties into their product through the NDA process but have not yet been able to incorporate such language into their labeling, the ANDA applicant is instructed to evaluate the public literature regarding the NDA product to determine what tests were done and what characteristics were incorporated into the NDA product to inform what test the generic should incorporate into its submission. This implies that if an NDA has been approved with some abuse-deterrent properties but the Agency has not yet agreed on any specific labeling to call out these properties, the ANDA applicant should still develop a product that is consistent with and demonstrates no less of the incorporated abuse-deterrent properties than the specific RLD NDA they reference as the basis of their application. This is somewhat of an inconsistency as the Guidance states that “[i]f the labeling for the R product does not describe any abuse-deterrent properties, the testing recommendations in this guidance are not applicable.”

FDA is recommending a tiered approach to testing outlined in the document, which FDA explains as follows: “This tier-based approach allows for hierarchical testing, starting with simple and gentle manipulations of the product in in vitro studies (Tier 1) and progressing to more destructive mechanical and chemical manipulations until R[eference] product’s abuse deterrence is defeated or compromised, or T[est] product is shown to be less abuse-deterrent than R product.”

The Agency notes that the applicant should assess the reference product’s abuse-deterrent properties for all routes of administration and employ the tiered approach, however, FDA makes it clear that the formulations of the test and reference product do not have to be the same. FDA also notes that the applicant should address tampering skills, time, and tampering resources available and, in discriminating studies, the application is suggested to also use a control product. The generic should perform no worse than the RLD in such comparative studies. The Agency provides statistical parameters for evaluation of comparative tests in appendices to the Guidance document.

The document is further broken down by routes of abuse and guidance is given for the proposed testing and FDA expectations regarding those comparisons. Testing should be conducted against all proposed strengths of the test and reference product, unless there is evidence that the reference product strengths are all dose proportional.

In regard to pharmacokinetic (pK) testing, FDA gives the following example: “when evaluating the potential to abuse the proposed product by ingestion, if, after attempting the dissolution study recommended in Appendix 3, the potential applicant believes the testing is overly sensitive to characterize its generic drug product with respect to abuse deterrence, the product may be evaluated further in a PK study. In such cases, the potential applicant should seek the Agency’s input on the PK study design before conducting the study.” Other Guidance on the conduct of pK studies are provided. Also, if the aversion ingredient in the test product differs from that used in the reference product, firms may have to perform a comparative liking pK study of the products. FDA suggests that, if such a study is deemed necessary, the applicant seeks FDA’s advice before proceeding.

The remainder of the document discusses methodology and statistical evaluation. For those firms that are in this space, the document should be read carefully and questions or inconsistencies should be raised with the Agency. Also, remember, this is a draft Guidance and, although it provides a view of current Agency thinking, that thinking as we have seen with other complex products has changed over time.