浅析仿制药一致性评价程序及内容的相关政策

为了顺利开展仿制药一致性评价工作,国家食品药品监督管理总局出台了大量规范性法规和技术指导原则.本文通过归纳汇总,整理出完整的仿制药一致性评价工作程序和基本内容,为一致性评价工作提供参考.     

Developability assessment of clinical drug products with maximum absorbable doses

Maximum absorbable dose refers to the maximum amount of an orally administered drug that can be absorbed in the gastrointestinal tract. Maximum absorbable dose, or D(abs), has proved to be an important parameter for quantifying the absorption potential of drug candidates. The purpose of this work is to validate the use of D(abs) in a developability assessment context, and to establish appropriate protocol and interpretation criteria for this application. Three methods for calculating D(abs) were compared by assessing how well the methods predicted the absorption limit for a set of real clinical candidates. D(abs) was calculated for these clinical candidates by means of a simple equation and two computer simulation programs, GastroPlus and an program developed at Eli Lilly and Company. Results from single dose escalation studies in Phase I clinical trials were analyzed to identify the maximum absorbable doses for these compounds. Compared to the clinical results, the equation and both simulation programs provide conservative estimates of D(abs), but in general D(abs) from the computer simulations are more accurate, which may find obvious advantage for the simulations in developability assessment. Computer simulations also revealed the complex behavior associated with absorption saturation and suggested in most cases that the D(abs) limit is not likely to be achieved in a typical clinical dose range. On the basis of the validation findings, an approach is proposed for assessing absorption potential, and best practices are discussed for the use of D(abs) estimates to inform clinical formulation development strategies.     

Product selection, bioequivalence, and therapeutic equivalence: the generic drug market

Pharmacists are continually faced with drug product selection decisions. When is a generic drug product equivalent to the innovator product and, thus, a suitable candidate for generic substitution? The FDA policy has been that only drug products that are therapeutic equivalents are candidates for product selection decisions. This paper outlines the regulatory and scientific framework for the FDA's policies and requirements for generic drug products. The history and current status of the Drug Efficacy Study Implementation (DESI) project is described. Originally begun in 1966 as a review of about 3,400 drug products, the review in mid-1983 is more than 90% complete, but its impact has already affected more than 7,000 marketed drug products. The therapeutic equivalence policy and the manner in which decisions on therapeutic equivalence are communicated are reviewed. Regulatory policies for the approval of generic drug products are reviewed and specific litigation challenging the rights of generic drug manufacturers to produce generic "look-alikes" and challenging the FDA's policy that a generic drug product is a new drug requiring an approved New Drug Application for marketing is discussed. The conclusion reached is that the evaluation of regulatory requirements and science is leading to a point where all generic drug products will be known to be safe, effective and therapeutically equivalent, and pharmacists can be optimistic about the quality of products in the generic drug market.     

Practical Bayesian design and analysis for drug and device clinical trials

Perhaps the most valuable contribution of Bayesian methods to health care evaluation involves study design. Drug and medical device clinical trialists are increasingly confronted with data that feature complex correlation structures, and are costly and difficult to obtain. In such settings, Bayesian trial designs are attractive since they can incorporate historical data or information from published literature, thus saving time and expense and minimizing the number of subjects exposed to an inferior treatment. Bayesian designs can also adapt to unexpected changes in the protocol, and allow the investigator to explore the plausibility of various outcome scenarios before any patients are enrolled in the trial. Recently, the FDA Center for Devices has encouraged hierarchical Bayesian statistical approaches which allow for the incorporation of such valuable historical data into the design and analysis of new device trials. The practical application of these methods has only become feasible in the last decade due to advances in computing via Markov chain Monte Carlo (MCMC) methods, especially as implemented in the popular BUGS software package. In this paper we illustrate Bayesian analysis and sample size calculations using BRugs, a function for calling BUGS from R. We provide illustrations in two applied settings where incorporation of available historical information is crucial, one concerning an AIDS drug trial and the other a comparison of left ventricular assist devices (LVADs).     

新药临床试验的中间分析和成组序贯试验

出于对目前新药临床试验的形势要求 ,使试验在技术上能与国际协调会议 (ICH)与GCP相衔接。本文介绍新药临床试验的中间分析和成组序贯试验。应用该方法一般能节约病例数 2 0 %以上 ,因此也节约了时间与费用。本文应用较浅近的方法介绍如何使用中间分析及用绘图法使用成组序贯试验 ,并介绍与固定样本试验法的比较 ,从而使读者能了解其优越性以使在新药临床试验中有较大的获益。     

经口吸入制剂仿制药的药代动力学研究一般考虑

适用于治疗哮喘、慢性阻塞性肺疾病等呼吸系统疾病的经口吸入制剂(OIDPs)药代动力学(PK)行为较复杂,其药物大部分沉积于口腔、鼻咽部、大气道等,仅有少部分药物递送至肺部,沉积的药物可经大气道吸收、吞咽至胃肠道吸收进入体循环,因此与全身作用的药物相比,仅通过PK研究较难评价OIDPs仿制药与参比制剂的生物等效性.近年来...     

Relevance of equivalence assessment of topical products based on the dermatopharmacokinetics approach

Common procedures to test bioequivalence of oral products, measuring the rate and extent of the obtained plasma levels, do not apply to drug products for topical use, which provide limited systemic absorption. Nowadays, clinical trials are still the goldenrule for the development of a generic topical product but, unfortunately, not many techniques are helpful for the specific investigation of in vivo topical absorption.Additionally, during early stages of pharmaceutical development, experimental procedures for demonstrating the quality by design of topical formulations are lacking.In some cases, the dermatopharmacokinetic characterization in healthy volunteers of the topical drug penetration by skin stripping has resulted to be a promising option. Recently, some authors have focused special efforts to enlighten all the capabilities of this approach.This short review tries to describe and discuss some aspects under optimization of dermatopharmacokinetics as is the influence of the formulation on drug performance, the parameter calculation and the experimental procedure for minimizing variability. All those aspects are nowadays in continuous improvement trying to define the place of dermatopharmacokinetics as a putative technique for avoiding clinical trials in topical generics development.     

中美两国批准仿制药情况比较分析

采用文献检索法和统计分析方法,通过对FDA近5年批准的仿制药和我国对应产品批准数据的比较分析,得出我国仿制药在某些种类产品及新剂型、新给药系统开发上与美国仍有较大差距,尚有很大的发展空间。     

Sample size re-estimation for adaptive sequential design in clinical trials

There is considerable interest in methods that use accumulated data to modify trial sample size. However, sample size re-estimation in group sequential designs has been controversial. We describe a method for sample size re-estimation at the penultimate stage of a group sequential design that achieves specified power against an alternative hypothesis corresponding to the current point estimate of the treatment effect.     

Harmonization of regulatory approaches for evaluating therapeutic equivalence and interchangeability of multisource drug products: workshop summary report

Regulatory approaches for evaluating therapeutic equivalence of multisource (or generic) drug products vary among different countries and/or regions. Harmonization of these approaches may decrease the number of in vivo bioequivalence studies and avoid unnecessary drug exposure to humans. Global harmonization for regulatory requirements may be promoted by a better understanding of factors underlying product performance and expectations from different regulatory authorities. This workshop provided an opportunity for pharmaceutical scientists from academia, industry and regulatory agencies to have open discussions on current regulatory issues and industry practices, facilitating harmonization of regulatory approaches for establishing therapeutic equivalence and interchangeability of multisource drug products.     

Practical,regulatory and clinical considerations for development of inhalation drug products

The formulation and device collectively constitute an inhalation drug product. Development of inhaled drugs must consider the compatibility between formulation and device in order to achieve the intended pharmaceutical performance and usability of the product to improve patient compliance with treatment instruction. From the points of formulation, device and patient use, this article summarizes the inhalation drugs, including pressurized metered dose inhaler (pMDI), dry powder inhaler (DPI), and nebulizer that are currently available in the US and UK markets. It also discusses the practical considerations for the development of inhalers and provides an update on the corresponding regulations of the FDA (U.S. Food and Drug Administration) and the EMA (European Medicines Agency).     

On the assessment of similarity for dissolution profiles of two drug products

The assessment of similarity between dissolution profiles of two drug products is considered. After reviewing some existing approaches, we propose a statistical method of assessing local and global similarities based on a time series model for the ratio of the dissolution results from two drug products and a polynominal model for the mean of the ratio. An example is presented for illustration.     

Pilot trial for the assessment of relative bioavailability in generic drug product development: statistical power

In developing generic drug products, pilot trials are used for identifying successful test formulations to enter pivotal trials. In this study, we derive the power function based on the log-normal distribution and evaluate the effects of potential influential factors-the true test-reference ratio, intrasubject variability, and sample sizes-on the statistical power of a pilot trial to identify successful test formulations, defined as the probability that the test-reference ratio estimate from a pilot trial falls within a predetermined acceptance range when the true ratio is acceptable. Of these influential factors, the test-reference ratio exhibits the largest impact on the statistical power of a pilot trial, followed by intrasubject variability, sample sizes of pivotal trials, and sample sizes of pilot trials. The sample sizes that are used in pilot trials (8-12 subjects) may be sufficient for test products with low intrasubject variability and true ratio close to 1 and may fall short otherwise.     

Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products of agomelatine in Chinese subjects

The aim of this study was to apply the reference-scaled average bioequivalence (RSABE) approach to evaluate the bioequivalence of 2 formulations of agomelatine, and to investigate the pharmacokinetic properties of agomelatine in Chinese healthy male subjects. This was performed in a single-dose, randomized-sequence, open-label, four-way crossover study with a one-day washout period between doses. Healthy Chinese males were randomly assigned to receive 25 mg of either the test or reference formulation. The formulations were considered bioequivalent if 90% confidence intervals (CIs) for the log-transformed ratios and ratio of geometric means (GMR) of AUC and C_max of agomelatine were within the predetermined bioequivalence range based on RSABE method. Results showed that both of the 90% CIs for the log-transformed ratios of AUC and C_max of 7-desmethyl-agomelatine and 3-hydroxy-agomelatine were within the predetermined bioequivalence range. The 90% CIs for natural log-transformed ratios of C_max, AUC_0–t and AUC_0–∞ of agomelatine (104.42–139.86, 101.33–123.83 and 97.90–117.94) were within the RSABE acceptance limits, and 3-hydroxy-agomelatine (105.55–123.03, 101.95–109.10 and 101.72–108.70) and 7-desmethyl-agomelatine (104.50–125.23, 102.36–111.50 and 101.62–110.64) were within the FDA bioequivalence definition intervals (0.80–1.25 for AUC and 0.75–1.33 for C_max). The RSABE approach was successful in evaluating the bioequivalence of these two formulations.KEY WORDS: Reference-scaled average bioequivalence, Agomelatine, 3-Hydroxy-agomelatine, 7-Desmethyl-agomelatine, Chinese subjects, High variability, Generic drug     

肿瘤药物临床试验中成组序贯设计的统计学考虑

成组序贯设计因其拥有较少的病例样本数和较早终止试验的可能性成为肿瘤药物临床试验设计方法的较好选择。如何科学有效地设计和应用成组序贯设计,本文通过Monte Carlo试验模拟,探讨肿瘤药物临床试验中成组序贯设计的期中分析次数、实施时间以及α消耗函数选取等问题,为读者系统指明如何去规划一次成组序贯试验以及如何确定其最优的试验参数。模拟结果表明,成组序贯设计以时间点2∶1∶1折半划分的三次期中分析为好,其期望样本含量仅为420.53。Lan-Demets的五种α消耗函数中,1.5次幂和2次幂的α消耗函数拥有最小期望样本含量约393例,相对于O＇Brien-Fleming设计和Po-cock设计在整体上更显优势。     

Practical experience with the design and analysis of a three-armed equivalence study

Objective: While there is a lot of experience with the design, conduct and interpretation of bioequivalence studies, the methodology of trials concerning therapeutic equivalence is still at an early stage of development. Two-armed equivalence studies involve special problems of interpretation, which can be partly solved by the introduction of a third (placebo) arm. We describe a trial in which the therapeutic equivalence of horse chestnut seed extract (HCSE) and compression treatment was to be demonstrated in patients with chronic venous insufficiency (CVI). Compression is regarded as the standard therapy in this field. However, the efficacy of compression in terms of the variable of primary interest, namely oedema reduction, has never been demonstrated according to current methodological rules. Thus, the `standard' had to be established in the trial itself. This can be achieved by demonstration of relevant superiority in comparison with placebo. Methods: Two hypotheses had to be tested: (1) the relevant superiority of compression compared with placebo as a precondition for (2) the at most irrelevant inferiority of HCSE in comparison with compression (`equivalence'). For both corresponding statistical tests, the irrelevance criterion – formulated as standardized difference – was set to 0.5. Results: Therapeutic equivalence could not be demonstrated following this design, because compression failed to be relevantly superior compared with placebo, even though HCSE was shown to be at most irrelevantly inferior compared with compression. Explorative analyses show that it is not possible to reject simultaneously both null hypotheses with the obtained data when using equal irrelevance limits for both tests. Conclusion: Although the primary objective of the trial could not be achieved, the results were encouraging. Thus, a new study was planned and started based on the observed data. The concept of a shifted null hypothesis may be applied to `routine' clinical trials too; using `no difference' as the null hypothesis in a trial does not seem to be meaningful when in fact an at least relevant difference is required. Received: 16 March 1998 / Accepted in revised form: 9 June 1998     

对进口化学药品在国内进行临床研究的要求

自2002—12—01国家药品监督管理局颁布实施《药品注册管理办法》(试行)后，“已在国外上市销售但尚未在中国境内上市销售”的进口化学药品如何进行国内临床研究，是许多申报者面临的问题。因此，本文对进口化学药品在国内进行临床研究的要求叙述如下。