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«WORLD HEALTH ORGANIZATION ORGANISATION MONDIALE DE LA SANTE MULTISOURCE (GENERIC) PHARMACEUTICAL PRODUCTS: GUIDELINES ON REGISTRATION REQUIREMENTS TO ...»

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Gaureault examined the use of partial (truncated) AUC using Monte Carlo simulations and found a high degree of concordance between the bioequivalence decision based on the partial area truncated to 4 times tmax and the area extrapolated to infinity. The evidence suggests that for immediate release formulations it is unnecessary to take blood samples beyond 4 times tmax. (22). There are two Working document QAS/04.093/Rev.4 page 27 important advantages to the use of truncated areas: (i) more blood samples can be clustered around tmax to give greater precision in the estimation of both tmax and Cmax; and (ii) the lack of need for high assay sensitivity in order to define the disposition phase. The applicability of the truncated AUC approach merits particular consideration in the following cases: (i) where low concentrations occur in the terminal portion of the plasma concentration versus time curve, which may not be quantifiable by means of an adequately validated, sensitive analytical method; and (ii) for products of active pharmaceutical ingredients with long half-lives.

7. PHARMACODYNAMIC STUDIES

Studies in healthy volunteers or patients using pharmacodynamic measurements may be used for establishing equivalence between two pharmaceutical products. Pharmacodynamic studies are not recommended for orally administered pharmaceutical products for systemic action when the active pharmaceutical ingredient is absorbed into the systemic circulation and a pharmacokinetic approach can be used to assess systemic exposure and establish bioequivalence. This recommendation arises because variability in pharmacodynamic measures is always greater than that in pharmacokinetic measures. In addition pharmacodynamic measures are often subject to significant placebo effects which add to the variability and complicates experimental design. The result is that often huge numbers of patients would have to be enrolled in pharmacodynamic studies to achieve adequate statistical power. Pharmacodynamic bioequivalence studies may become necessary if quantitative analysis of the active pharmaceutical ingredient and/or metabolite(s) in plasma or urine cannot be made with sufficient accuracy and sensitivity (see section on truncated areas, section 6.11.4).

Furthermore, pharmacodynamic bioequivalence studies in humans are required if measurements of active pharmaceutical ingredient concentrations cannot be used as surrogate endpoints for the demonstration of efficacy and safety of the particular pharmaceutical product. In certain treatment categories, such as pharmaceutical products designed to act locally, there is no realistic alternative than to perform pharmacodynamic bioequivalent studies. Pharmacodynamic bioequivalence studies may be appropriate for pharmaceutical products such as topicals and inhalation dosage forms.

If pharmacodynamic studies are to be used they must be performed as rigorously as bioequivalence studies, and the principles of GCP must be followed (4).

The following requirements must be recognized when planning, conducting and assessing the results of a study intended to demonstrate equivalence by means of measuring pharmacodynamic drug

responses:

• The response which is measured should be a pharmacological or therapeutic effect which is relevant to the claims of efficacy and/or safety.

• The methodology must be validated for precision, accuracy, reproducibility and specificity.

• Neither the test nor the comparator product should produce a maximal response in the course of the study, since it may be impossible to distinguish differences between formulations given in doses which give maximum or near-maximum effects. Investigation of dose-response relationships may be a necessary part of the design.

• The response should be measured quantitatively preferably under double-blind conditions and be recordable in an instrument-produced or instrument-recorded fashion on a repetitive basis to provide a record of the pharmacodynamic events which are substitutes for plasma concentrations.

In those instances where such measurements are not possible, recordings on visual analogue scales may be used. In other instances where the data are limited to qualitative (categorized) measurements appropriate special statistical analysis will be required.

Working document QAS/04.093/Rev.4 page 28

• Non-responders should be excluded from the study by prior screening. The criteria by which responders versus non-responders are identified must be stated in the protocol.

• In instances where an important placebo effect can occur comparison between pharmaceutical products can only be made by a priori consideration of the placebo effect in the study design.

This may be achieved by adding a third phase with placebo treatment in the design of the study.

• The underlying pathology and natural history of the condition must be considered in the study design. There should be knowledge of the reproducibility of baseline conditions.

• A cross-over design can be used. Where this is not appropriate a parallel group study design should be chosen.

Selection basis for the multisource and comparator products should be the same as described in section 6.5.

In studies in which continuous variables could be recorded the time course of the intensity of the drug action can be described in the same way as in a study in which plasma concentrations were measured, and parameters can be derived which describe the area under the effect-time curve, the maximum response and the time when maximum response occurred.





The statistical considerations for the assessment of the outcome of the study are in principle the same as outlined for the pharmacokinetic bioequivalence studies. However, a correction for the potential non-linearity of the relationship between the dose and the area under the effect-time curve should be performed on the basis of the outcome of the dose-ranging study. However, it should be noted that the acceptance range as applied for bioequivalence assessment may not be appropriate in most of the cases but should be justified on a case by case basis and defined in the protocol.

8. CLINICAL TRIALS

In some instances (see example (e) under "In vivo studies" above) plasma concentration time-profile data are not suitable to assess equivalence between two formulations. Whereas in some of the cases pharmacodynamic bioequivalence studies can be an appropriate tool for establishing equivalence, in other instances this type of study cannot be performed because of lack of meaningful pharmacodynamic parameters which can be measured and a comparative clinical trial has to be performed in order to demonstrate equivalence between two formulations. In the cases when equivalence can be assessed by a pharmacokinetic bioequivalence study, the pharmacokinetic bioequivalence study is preferred because comparative clinical trial is less sensitive. Huge numbers of subjects are required to achieve statistical power. For example, 8600 patients were calculated to give adequate power to detect a 20% improvement in response to the study drug compared with placebo (23). Similarly it was calculated that 2600 myocardial infarct patients were required to show a 16% risk reduction. Comparison of two formulations of the same active pharmaceutical ingredient based on such endpoints would require even greater numbers of subjects (24) If a clinical bioequivalence study is considered as being undertaken to prove equivalence, the same statistical principles apply as for the pharmacokinetic bioequivalence studies. The number of patients to be included in the study will depend on the variability of the target parameters and the acceptance range, and is usually much higher than the number of subjects in pharmacokinetic bioequivalence studies.

–  –  –

The methodology issues for establishing equivalence between pharmaceutical products by means of a clinical trial in patients with a therapeutic endpoint have not yet been discussed as extensively as for pharmacokinetic bioequivalence trials. However, important items can be identified which need to be

defined in the protocol:

• The target parameters which usually represent relevant clinical endpoints from which the intensity and the onset, if applicable and relevant, of the response are to be derived.

• The size of the acceptance range has to be defined case by case, taking into consideration the specific clinical conditions. These include, among others, the natural course of the disease, the efficacy of available treatments and the chosen target parameter. In contrast to pharmacokinetic bioequivalence studies (where a conventional acceptance range is applied) the size of the acceptance range in clinical trials cannot be based on a general consensus for all the therapeutic classes and indications.

• The presently used statistical method is the confidence interval approach. The main concern is to rule out that the test product is inferior to the comparator pharmaceutical product by more than the specified amount. Hence a one-sided confidence interval (for efficacy and/or safety) may be appropriate. The confidence intervals can be derived from either parametric or nonparametric methods.

• Where appropriate a placebo leg should be included in the design.

In some cases it is relevant to include safety endpoints in the final comparative assessments.

• Selection basis for the multisource and comparator products should be the same as described in section 6.5.

9. IN VITRO TESTING

Over the past three decades dissolution testing has evolved into a powerful tool for characterizing the quality of oral pharmaceutical products. The dissolution test, at first exclusively a quality control test, is now emerging into a surrogate equivalence test for certain categories of orally administered pharmaceutical products. For these products (typically solid oral dosage forms containing APIs with suitable properties) a comparative in vitro dissolution profile similarity can be used to document equivalence of a multisource with a comparator product (see Section 6.5 for selection of comparator products).

It should be noted that the dissolution tests recommended in The International Pharmacopoeia (25) for quality control have been designed to be compatible with the biowaiver dissolution tests, they may not yet fulfil all requirements for evaluating equivalence of multisource products with comparator products. Dissolution tests for quality control purposes in other pharmacopoeia in general do not correspond to the test conditions required for evaluating bioequivalence of multisource products and should not be applied for this purpose.

9.1 In vitro testing and the Biopharmaceutics Classification System (BCS) 9.1.1 Biopharmaceutics Classification System (BCS) The Biopharmaceutics Classification System (BCS) is based on aqueous solubility and intestinal permeability of the drug substance. It classifies the active pharmaceutical ingredient (API) into one of four classes:

Working document QAS/04.093/Rev.4 page 30 Class 1- High Solubility, High Permeability Class 2 - Low Solubility, High Permeability Class 3 - High Solubility, Low Permeability Class 4 - Low Solubility, Low Permeability Combining the dissolution of the drug product with these two properties of the API, the three major factors that govern the rate and extent of drug absorption from immediate release solid dosage forms are taken into account ( 26). With respect to dissolution properties, immediate release dosage forms can be categorized as having “very rapid”, “rapid”, or “not rapid” dissolution characteristics.

On the basis of scientific principles of solubility and permeability and dissolution characteristics of the dosage form, the BCS approach provides an opportunity to waive in vivo pharmacokinetic bioequivalence testing for certain categories of immediate release drug products (27). Oral drug products not eligible for a so-called “biowaiver” based on the BCS approach are described under Section 5.1.a.

9.1.1.1 High solubility



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