首页 > 资讯 > FDA发布透皮给药系统ANDA黏附力评估指南草案

出自识林

2016-06-03 Lachman CONSULTANTS

5月31日FDA发布题为《透皮给药系统和局部贴剂简化新药申请的黏附力评估》指南草案。草案文件讨论了申办人证明其拟定产品的黏附力与参照产品（RLD）类似的方法。

显然，对于一个仿制透皮给药系统（TDS）产品与RLD治疗等效，必须具有类似于RLD的黏附力。这是因为被吸收进入全身循环的药物依赖于在贴敷期间持续与皮肤接触的表面积。虽然FDA认为所有透皮系统的脱离程度（部分和全部）取决于环境因素，如“由解剖学运动引起的扭转应变，环境温度或湿度的改变，如日常接触水（例如，日常淋浴），以及与衣物、寝具或其它表面的接触”，产品未能按照拟定的方式如RLD一样黏附在皮肤上，会导致给送较少的药量，因此疗效也较差。

此外，部分或全部脱离倾向较高的仿制产品不仅让患者面临缺乏足够药物治疗的风险，还会使其他照顾者、家庭成员或宠物暴露在药物中的风险增加，因为他们会与脱落的TDS接触。指南草案将取代先前具体产品指南中的建议，并将成为建立仿制产品与RLD具有相同黏附力的标准。FDA提供了相似性试验的标准并讨论了独立的黏附力试验的选择，以及讨论了将黏附力试验和生物等效性试验合并为一个试验的方法。

FDA建议申办人在试验中应入组足够数量的受试者，以提供80%或更高的效能，但没有指定受试者数量。FDA还指出选择合适的TDS大小（最小或最大）取决于试验包括的产品的特性，并建议如果将参照RLD标签作为试验的一部分，试验应包括某些环境因素。此外，药物特性必须被考虑在内，从而为健康志愿者选择安全剂量。指南中还提供了根据RLD标签中标明的总贴敷期需测量指标的不同测量时间点。

关于黏附力研究的有趣之处是，每个人的皮肤是不同的，虽然品牌名贴剂可能贴在一名患者的身上，而仿制药可能脱落，而正好相反的情况可能发生在另一患者身上。因此需要做必要的交叉研究设计以做出正确地对比。

Lachman CONSULTANTS - Bob Pollock先生
编译：识林-椒
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Stick it to Me!
By Bob Pollock | May 31, 2016

Today, the FDA announced the availability of a draft Guidance titled “Assessing Adhesion with Transdermal Delivery Systems and Topical Patches for Abbreviated New Drug Applications” (here). The document discusses the way in which sponsors should document the adhesion of their proposed product with that the of reference listed drug (RLD).

Clearly, for a generic transdermal delivery system (TDS) product to be therapeutically equivalent to the RLD, it must have adherence properties similar to that of the RLD. This is because the drug absorbed into the systemic circulation is dependent on a consistent surface area contact with the skin during the duration of wear. While FDA recognizes that all transdermal systems are subject to degree of detachment (partial and full) depending on environmental factors such as “torsional strains arising from anatomical movements, changes in environmental temperature or humidity such as the daily exposure to water (e.g., during routine showering), and contact with clothing, bedding or other surfaces”, products that fail to behave in a manner that suggests that they will not adhere as well to the skin as the RLD could deliver less drug and thus be less effective.

In addition, a generic product that has a higher propensity for partial of full detachment not only places the patient at risk from lack of adequate drug treatment, but also places other caregivers, family members or pets at increased risk of drug exposure should they come in contact with the detached TDS. The Guidance document is replacing previous recommendation in product-specific guidance and will become the standard for establishing that the adhesion of the generic product is the “same as” that of the RLD. The FDA provides the criteria for similarity testing and discusses options for a standalone adhesion test, as well as discussing methods for combining adhesion testing and bioequivalence testing into a single study.

FDA advises sponsors that a sufficient number of subjects should be enrolled in the study to provide an 80% or higher power but does not specify the number of subjects. FDA also speaks to selecting the appropriate size of the TDS (smallest or largest) depending on the characteristics of the product to include in the study and suggests including certain environmental factors if cited in the RLD labeling as part of testing. In addition, the characteristics of the drug must be taken into account such that a safe dose is selected for healthy volunteers. They also provide guidance on the various time points for measurement of the metrics to be measured which are based on the total wear period stated in the RLD labeling.

The interesting thing about adhesion studies is that everyone’s skin is different and, while a brand name patch may stick on one patient and the generic falls off, the exact opposite may happen with another patient. Thus a crossover study design in essential for the comparison to properly be made.