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6.1 General considerations 6.1.1 Provisions for studies in humans Pharmacokinetic studies, pharmacodynamic studies and clinical studies are all clinical trials and should be carried out in accordance with the provisions and prerequisites for a clinical trial, as outlined in the WHO Guidelines for Good Clinical Practice (GCP) for Trials on Pharmaceutical Products (4).

All research involving human subjects should be conducted in accordance with the ethical principles contained in the current version of the Declaration of Helsinki, including respect for persons, beneficence (maximize benefits and minimize harms and wrongs) and non-maleficence (do no harm).

as defined by the current revision of the International Ethical Guidelines for Biomedical Research Involving Human Subjects issued by the Council for International Organizations of Medical Sciences (CIOMS), or laws and regulations of the country in which the research is conducted, whichever represents the greater protection for subjects.

6.1.2 Justification of human bioequivalence studies Most pharmacokinetic and pharmacodynamic bioequivalence studies are non-therapeutic studies in which no direct clinical benefit accrues to the subject.

It is important for anyone preparing a trial of a medicinal product in humans that the specific aims, problems and risks/benefits of a particular human study be thoroughly considered and that the chosen solutions be scientifically sound and ethically justified. It is assumed that people involved in the planning of a study are familiar with pharmacokinetic theories underlying bioavailability and bioequivalence studies. In the case of multisource products adequate data concerning the pharmacokinetics or pharmacodynamics of the active pharmaceutical ingredient should be available.

Overall design of the bioequivalence study should be based on the knowledge of the pharmacokinetics, pharmacodynamics and therapeutics of the active pharmaceutical ingredient.

Information about manufacturing procedures and data from tests performed on the actual product should establish that the investigational product is of suitable quality.

6.1.3 Selection of investigators

Each investigator should have appropriate expertise, qualifications and competence to undertake the proposed study. Prior to the trial, the investigator(s) and the sponsor should establish an agreement on the protocol, the monitoring, the auditing, standard operating procedures (SOP) and the allocation of trial-related responsibilities. Identity and duties of the individuals who are responsible for the study and safety of the subjects participating in the study must be specified. The logistics and premises of the trial site should comply with requirements for the safe and efficient conduct of the trial.

Working document QAS/04.093/Rev.4 page 12

6.1.4 Study protocol

The bioequivalence study should be carried out in accordance with a protocol agreed upon and signed by the investigator and the sponsor. Any change(s) subsequently required must be similarly agreed on and signed by the investigator and sponsor, and appended as amendments. The protocol and attachments/appendices should state the aim of the study and the procedures to be used, the reasons for proposing the study to be undertaken in humans, the nature and degree of any known risks, assessment methodology, criteria for acceptance of bioequivalence, the groups from which it is proposed that trial subjects be selected and the means for ensuring that they are adequately informed before they give their consent. The investigator is responsible for ensuring that the protocol is strictly followed. The investigator should not make any changes in the study without the agreement of the sponsor, except when necessary to eliminate an apparent immediate hazard or danger to a trial subject.

The protocol and attachments/appendices should be scientifically and ethically appraised by one or, if required, by local laws and regulations, more review bodies (institutional review board, peer review committee, ethics committee, drug regulatory authority, etc.), constituted appropriately for these purposes and independent of the investigator(s) and sponsor.

A signed and dated clinical trial protocol should be presented together with the clinical trial report for the authorities in order to obtain the marketing authorization for the multisource product.

–  –  –

Bioequivalence studies are designed to compare the in vivo performance of a multisource product with that of a comparator product. Pharmacokinetic bioequivalence studies on products designed to deliver the active pharmaceutical ingredient for systemic exposure serve two purposes: (i) they serve as surrogate for clinical proof of equivalence; and (ii) they provide an in vivo measure of pharmaceutical quality. The design of the study should minimize the variability that is not caused by formulation effects and eliminate bias as much as possible. Test conditions should reduce withinand between-subject variability. In general for a pharmacokinetic bioequivalence study involving a multisource and a comparator product, a two-period, single-dose, cross-over study in healthy volunteers will suffice. However, in certain circumstances, an alternate, well-established and statistically appropriate study design should be adopted.

A two-period, two-sequence, single-dose, cross-over, randomized design is the first choice for pharmacokinetic bioequivalence studies. Each subject is given the multisource and the comparator product in randomized order. Administrations of each product should be separated by an adequate washout period. The interval (wash-out period) between dosing of each formulation should be long enough to permit the elimination of essentially all of the previous dose from the body. The wash-out period should be the same for all subjects and normally should be more than five times the terminal half-life of the active pharmaceutical ingredient. Special consideration will need to be given to extending this period if active metabolites with longer half-lives are produced and under other circumstances. If the product has high variability in elimination rate between subjects, the wash-out period can be longer to account for the elimination rate in subjects with lower elimination rates. Just prior to treatment administration at the second study period, blood samples are collected and assayed for concentration of the API or metabolites. The minimum wash-out period should be at least 7 days.

Adequacy of wash-out period can be estimated from the pre-dose concentration of the API and should be less than 5% of Cmax.

Working document QAS/04.093/Rev.4 page 13 It is not foreseen that blood samples be collected for more than 72 hours.

6.2.1 Alternative study designs in patients For active pharmaceutical ingredients that are very potent or too toxic to administer in the usual dose to healthy volunteers it is recommended that the study be conducted at a lower strength. If the pharmacokinetics are not proportional or if the active pharmaceutical ingredient has solubility issues, it will not be appropriate to extrapolate the bioequivalence results of the lower strength to higher strengths. For these APIs and for those that show unacceptable pharmacological effects in volunteers (e.g. serious adverse events, or where the active pharmaceutical ingredient is toxic or particularly potent, or the trial necessitates a high dose) may require multiple-dose, steady-state, cross-over studies in patients or a parallel group design study in patients. The alternative study design should be justified by the sponsor. In this situation, the sponsor should attempt to enter patients whose disease process is stable for the duration of the pharmacokinetic bioequivalence study.

6.2.2 Considerations for drugs with long elimination half-lives

A single dose cross-over pharmacokinetic bioequivalence study of an oral product of a long elimination half-life drug can be conducted provided an adequate wash-out period is used. If the cross-over study is problematic, a pharmacokinetic bioequivalence study with a parallel design can be used. For either a cross-over or a parallel design study, sample collection time should be adequate to ensure completion of gastrointestinal transit (approximately 2 to 3 days) of the pharmaceutical product and absorption of the active pharmaceutical ingredient. Blood sampling up to 72 hours should be carried out, unless shorter periods can be justified. The number of subjects should be derived from statistical calculations but generally more subjects are needed for parallel study design compared with cross-over study design.

6.2.3 Considerations for multiple dose studies

In certain situations multiple dose studies may be considered appropriate. Multiple dose studies in patients are most useful in cases where the medicine is considered to be too potent and/or too toxic to be administered to healthy volunteers, even in single doses (see also 6.2.1). In this case, a multiple dose cross-over study in patients may be performed without interrupting therapy. Evaluation of such studies can be based either on pharmacokinetic or pharmacodynamic endpoints, although it is likely that pharmacodynamic endpoints would require much larger number of patients than pharmacokinetic end points.

In multiple dose studies the dosage regimen should follow the usual dosage recommendations.

Other situations in which multiple dose studies may be appropriate are as follows:

- drugs that exhibit non-linear kinetics at steady state (e.g. saturable metabolism, active secretion);

- cases where the assay sensitivity is too low to adequately characterize pharmacokinetic profile after single dose;

- extended-release dosage forms with tendency to accumulation (in addition to singledose study);

In steady-state studies the wash-out of the previous treatment last dose can overlap with the build-up of the second treatment, provided the build-up period is sufficiently long (at least three times the Working document QAS/04.093/Rev.4 page 14 terminal half-life). Appropriate dosage administration and sampling should be carried out to document the attainment of steady state.

6.2.4 Considerations for modified release products Modified release products include extended release products and delayed release products. Extended release products are also known as controlled release, prolonged release and sustained release products.

Bioavailability data must be obtained for all modified-release products. A single dose, non-replicate cross-over, fasting study comparing the highest strength of the multisource and the comparator product should be performed. Single dose studies are preferred to multiple dose studies as single dose studies are considered more sensitive to measure the release of active pharmaceutical ingredient from the pharmaceutical product into the systemic circulation. Multiple dose studies may need to be considered for extended-release dosage forms with tendency to accumulation (in addition to singledose study).

The comparator product in this study should be a pharmaceutically equivalent modified release product, which is already marketed. The pharmacokinetic bioequivalence criteria for modified release products are basically the same as for conventional release dosage forms.

Co-administration of food with oral pharmaceutical products may influence drug bioavailability and in certain cases also pharmacokinetic bioequivalence. In addition to physiological changes in the gastro-intestinal tract, food can affect the release of the active pharmaceutical ingredient from the formulation. A concern with modified release products is the possibility that food may trigger a sudden and abrupt release of the active pharmaceutical ingredient leading to “dose dumping”. This would most likely be manifested as a spike in plasma concentration time profile. Therefore, a pharmacokinetic bioequivalence study under fed conditions is generally required for orally administered modified release pharmaceutical products. Absence of either fed or fasting study should be justified by the applicant. A fed pharmacokinetic bioequivalence trial should be conducted after the administration of an appropriate standardized meal at a specified time (usually not more than 30 min.) before taking the medicine (see also Section 6.4.). The most appropriate meal would be one of high lipid content in accordance with local diet and customs. The caloric breakdown and composition of the test meal should be provided in the study report.

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