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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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The number of subjects to be used in the study should be estimated by considering the standards that must be passed. It should be calculated by appropriate methods (see statistical analysis and acceptance criteria below). The number of recruited subjects should always be justified with the sample size calculation provided in the study protocol. A minimum of 12 subjects is required.

6.3.2 Drop-outs and withdrawals

Sponsors should enter a sufficient number of subjects in the study to allow for possible drop-outs or withdrawals. Because replacement of subjects during the study could complicate the statistical model and analysis, drop-outs generally should not be replaced. Reasons for withdrawal (e.g. adverse drug reaction, personal reasons) must be reported.

Sponsors who wish to replace drop-outs during the study or consider an add-on design should indicate this intention in the protocol.

It is more appropriate to recruit into the study more subjects than the sample size calculation requires.

These subjects are designated as extras. The protocol should state whether samples from extra subjects will be assayed if not required for statistical analysis.

If the bioequivalence study was performed with the appropriate size but bioequivalence cannot be demonstrated because of a result of a larger than expected random variation or a relative difference, an add-on subject study can be performed using not less than half the number of subjects in the initial study. Combining is acceptable only in the case when the same protocol was used and preparations from the same batches were used. Add-on designs must be carried out strictly according to the study protocol and SOPs, and must be given appropriate statistical treatment, including consideration of consumer risk.

6.3.3 Selection of subjects

Pharmacokinetic bioequivalence studies should generally be performed with healthy volunteers.

Clear criteria for inclusion/exclusion should be stated in the study protocol. If the pharmaceutical product is intended for use in both genders, the sponsor may wish to include both, males and females in the study. The risk to women will need to be considered on an individual basis, and if necessary, they should be warned of any possible dangers to the foetus if they should become pregnant. The investigators should ensure that female volunteers are not pregnant or likely to become pregnant during the study. Confirmation should be obtained by urine tests just before the first and last doses of the study.

Generally subjects should be between the ages of 18-55 years, and of weight within the normal range according to accepted life tables. The subjects should be without known history of alcohol or drug abuse problems and should preferably be non-smokers.

The suitability of the volunteers should be screened using standard laboratory tests, a medical history, and a physical examination. If necessary, special medical investigations may be carried out before and during studies depending on the pharmacology of the individual active pharmaceutical ingredient being investigated, e.g. an electrocardiogram if the active pharmaceutical ingredient has a cardiac effect. Ability to understand and comply with the study protocol has to be assessed. Subjects who are being or have been previously treated for any gastrointestinal problems, or convulsive, depressive, or hepatic disorders, and in whom there is a risk of a recurrence during the study period, should be excluded.

Working document QAS/04.093/Rev.4 page 16 In case the aim of the bioequivalence study is to address specific questions (e.g. bioequivalence in a special population) the selection criteria have to be adjusted accordingly.

6.3.4 Monitoring the health of subjects during the study During the study the health of volunteers should be monitored so that onset of side effects, toxicity, or any intercurrent disease may be recorded, and appropriate measures taken. The incidence, severity, and duration of adverse reactions and side effects observed during the study must be reported. The probability that an adverse effect is drug-induced is to be judged by the investigator.

Health monitoring before, during and after the study must be carried out under the supervision of a qualified medical practitioner licensed in the jurisdiction in which the study is conducted.

6.3.5 Considerations for genetic phenotyping Phenotyping for metabolizing activity can be of importance for studies with high clearance drugs that are metabolized by enzymes that are subject to genetic polymorphism, e.g. propranolol. Slow metabolizers will in these cases have a higher bioavailability of the parent drug, while the bioavailability of possible active metabolites will be lower. Phenotyping of subjects can be considered for studies with drugs that show phenotype-linked metabolism and for which a parallel group design is to be used, because it allows fast and slow metabolizers to be evenly distributed in the two groups of subjects.

Phenotyping could also be important for safety reasons, determination of sampling times and washout periods in cross-over design studies.

6.4 Study standardization Standardization of study conditions is important to minimize the magnitude of variability other than in the pharmaceutical products. Standardization should concern exercise, diet, fluid intake, posture, restriction of the intake of alcohol, caffeine, certain fruit juices, and concomitant medicines in the time period before and during the study.





Volunteers should not take any other medicine, including alcoholic beverages and over-the-counter (OTC) medicines, for an appropriate interval before – as well as during – the study. In the event of emergency, the use of any medicine must be reported (dose and time of administration).

Physical activity and posture should be standardized as much as possible to limit effects on gastrointestinal blood flow and motility. The same pattern of posture and activity should be maintained for each study day. The time of day for study drug administration should be specified.

Medicines are usually given after overnight fasting for at least 10 hours. However, alcohol-free and xanthine-free clear fluids are permissible during the night prior to the study. On the morning of the study no water is allowed for one hour before drug administration. The dose should be taken with water of a standard volume (usually 150-250 ml). Two hours after drug administration water is permitted ad libitum. A standard meal is usually provided 4 hours after drug administration. All meals should be standardized and of similar composition and quantity during each study period.

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labelling states that the pharmaceutical product should be taken with food then a fed study should be used to assess bioequivalence.

Fed studies are also required in bioequivalence studies of modified release formulations. The objective is to select a meal that will challenge the robustness of the new multisource formulation to prandial effects on bioavailability. The test meal should be selected based on local custom and diet and should be completed within 20 min. Drugs should be administered according to the dosing regimen, within 30 min. after the meal has been completed.

6. 5 Investigational product 6.5.1 Multisource pharmaceutical product The multisource pharmaceutical product used in the bioequivalence studies for registration purposes should be identical to the projected commercial pharmaceutical product. Therefore, not only the composition and quality characteristics (including stability) but also the manufacturing methods (including equipment and procedures) should be the same as those to be used in the future routine production runs. Test products must be manufactured under GMP regulations. Batch control results of the test product, the lot numbers of both test and comparator products and the expiration date for the comparator product should be stated.

Samples ideally should be taken from batches of industrial scale. When this is not feasible pilot or small-scale production batches may be used provided that they are not smaller than 10% of expected full production batches, or 100 000 units whichever is higher (unless otherwise justified), and are produced with the similar equipment, machinery and process as that planned for commercial production batches. If the product is subjected to further scale-up, this should be properly validated.

It is recommended that potency and in vitro dissolution characteristics of the multisource and the comparator pharmaceutical products be ascertained prior to performance of an equivalence study.

Content of the active pharmaceutical ingredient(s) of the comparator product should be close to the label claim, and the difference between two products should preferably not be more than +/-5%.

6.5.2 Choice of comparator product

The innovator pharmaceutical product is usually the most logical comparator product for a multisource pharmaceutical product because its quality, safety and efficacy should have been well assessed and documented in premarketing studies and post-marketing monitoring schemes.

For some pharmaceutical products an innovator product cannot be identified; in some cases an innovator product is not available on the market. A generic pharmaceutical product should not be used as a comparator as long as an innovator pharmaceutical product is available, because this could lead to progressively less reliable similarity of future multisource products and to a lack of interchangeability with the innovator.

The selection of the comparator product is usually made at the national level by the drug regulatory authority. A national drug regulatory authority has in principle options which are listed in order of

preference:

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A product approved based on comparison with a non domestic comparator product may not be interchangeable with currently marketed domestic products.

In the context of regional harmonization efforts, there may be advantages to choose a list regional comparator products for which quality, safety and efficacy has been established, in order to increase access to medicines WHO has initiated a list of comparator products ("WHO comparator product") for equivalence assessment of interchangeable multisource products which provides recommendations for choosing comparator product in cases where the innovator product is not available (2).

The choice of comparator product should be justified by the applicant. The country of origin of the comparator product should be reported together with lot number and expiry date.

6.6 Study conduct 6.6.1 Selection of dose In bioequivalence studies the molar equivalent dose of multisource and comparator product should be used.

Generally the marketed strength with the greatest sensitivity to bioequivalence assessment should be administered as a single unit. This will usually be the highest marketed strength. A higher dose may be employed when analytical difficulties exist. In this case the total single dose should not exceed the maximal daily dose of the dosage regimen.

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6.6.2 Sampling times Blood samples should be taken at a frequency sufficient for assessing Cmax, AUC and other parameters. Sampling points should include a pre-dose sample, at least 1-2 points before Cmax, 2 points around Cmax and 3-4 points during the elimination phase. Consequently at least seven sampling points will be necessary for estimation of the required pharmacokinetic parameters. For most medicines the number of necessary samples can be higher because of between-subject differences in absorption and elimination rate to enable accurate determination of the maximum concentration of the active pharmaceutical ingredient in the blood (Cmax) and terminal elimination rate constant in all subjects. Generally, sampling should continue for long enough to ensure that 80% of the AUC (0 infinity) can be accrued, but it is not necessary to sample more than 72 hours. An alternative approach is to use the truncated AUC approach, which curtails the numbers of samples required to define the elimination phase and allows more samples to be devoted to the elucidation of Cmax (see Section 6.11.4). The exact timing for sample collection depends on the nature of the active pharmaceutical ingredient and the input function from the administered dosage form.



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