FDA修订帕利哌酮长效注射剂BE指南
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FDA修订帕利哌酮长效注射剂BE指南
笔记 2016-01-06 Lachman CONSULTANTS FDA最近发布修订的BE指南草案概述了其对棕榈酸帕利哌酮生物等效性要求的新思路，代表了对另一个长效产品的BE指南修订，但这次是针对治疗精神分裂症的长效注射剂混悬液。对于该注射混悬液的原始BE指南草案文件发布于2011年8月。 与2011年8月版本的一些显著变化包括在所要求剂量规格方面的变化。在旧版本中，FDA要求申办者使用117mg/0.75mL规格，但允许包括针对不同剂量患者的测试。在新的修订版指南中，FDA建议仅有接受156mg药物的患者可以纳入研究中。新指南还建议申办人应使用平行稳态设计或双周期交叉稳态研究，研究中还应包括批准的两个注射部位。 新指南中，FDA还提出，可能需要超过3个剂量（3个月的注射）以达到稳态。FDA要求药代动力学（PK）数据证明每位患者已达到稳态。此外，FDA要求在体内研究中实施的许多不同测定包括： 在多剂量研究的生物等效性（BE）评估中，应为帕利哌酮递交以下PK数据：
PK参数（AUC和Cmax ）的几何平均比例的90%置信区间应在80-125%。应评估被测产品波动与参照产品波动的可比性。波谷浓度数据应被分析以证实在PK取样之前达到稳态。 参照药品原研商于2013年5月递交了一份请愿书，请求FDA要求高于一般标准生物等效性测试的特定生物等效性测量。请愿书副本请见此处。尽管请愿人的请求并没有完全反映在新的指南草案中，在联邦公报通告中FDA指出，仍在审查请愿中提出的问题，并将考虑在备案卷宗中收到的评议。 这是另外一个FDA针对缓释长效产品修订生物等效性指南的例子，似乎代表着对这类产品较老的生物等效性建议的修订趋势，反映了对这类产品如何建立生物等效性的更大关注，也证明了从过去失误中学习到的教训。 Lachman CONSULTANTS - Bob Pollock先生 OGD Revises Another Bioequivalence Guidance for Long-Acting Product – The Trend Continues FDA recently released a revised draft Guidance outlining its new thinking on the bioequivalence requirements for paliperidone palmitate, representing still another BE guidance revision for a long-acting product, but this time for a long-acting parenteral suspension of this product for schizophrenia. The original draft BE Guidance document for this injectable suspension was issued in August 2011. Some of the prominent changes from the August 2011 version include a change in the dosing strength required. In the old version, FDA asked that the sponsor used the 117mg/0.75mL strength, but permitted the testing to include patients that were on different doses. In the new revised Guidance, FDA suggests that only patients that are receiving 156 mg of drug should be included in the study. The new Guidance also suggests that sponsors should use either a parallel steady state design or a 2-period crossover steady state study and also include both approved sites of injection in the study. In the new Guidance, FDA also notes that more than 3 doses (three months injection) may be required to reach steady state. FDA is asking for pharmacokinetic (PK) data demonstrating that each patient has reached a steady state. In addition, FDA is asking for a number of various measurements to be conducted in the in vivo studies to include: In the evaluation of bioequivalence (BE) of the multiple-dose study, the following PK data should be submitted for paliperidone:
The 90% confidence interval for the ratio of the geometric means of the PK parameters (AUC and Cmax) should be within 80-125%. Fluctuation for the test product should be evaluated for comparability with fluctuation of the reference product. The trough concentration data should also be analyzed to verify that steady state was achieved prior to PK sampling. It should be noted that the innovator of the reference listed drug product submitted a petition in May 2013 asking the FDA to require specific bioequivalence measurements other than those typically associated with standard bioequivalence testing. A copy of that petition can be accessed here. While the requests of the petitioner are not fully reflected in the new draft guidance, in the FR notice announcing its availability (here) FDA noted that it was still reviewing issues raised in the petition and would also consider comments made to the docket. This is another example where the FDA has revised the bioequivalence guidance for extended-release long-acting products and seems to represent a trend in revisiting older bioequivalence recommendations for such products, reflecting either a greater concern for how bioequivalence is established for these products or demonstrating learning over time from some of its past missteps. |