Bio-Equivalence : Module 3

STUDY PROTOCOL & DESIGN

The most common study design for pharmacokinetic bioequivalence study involving a multisource (generic) and a comparator product is open label, two-period, single-dose, cross-over study in healthy volunteers. Each subject is given the multisource and the comparator product in randomized order. An adequate wash-out period should follow the administration of each product. The interval (wash-out period) between doses of each formulation should be long enough to permit the elimination of essentially the entire previous dose from the body. The wash-out period should be the same for all subjects and should normally be more than five times the terminal half-life of the API. Just prior to administration of treatment during the second study period, blood samples are collected and assayed to determine the concentration of the API or metabolites. The adequacy of the wash-out period can be estimated from the pre-dose concentration of the API and should be less than 5% of Cmax.

A bioequivalence study should be carried out in accordance with a protocol agreed upon and signed by the investigator and the sponsor. The protocol and its attachments and/or 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. Any change(s) required must be agreed on and signed by the investigator and sponsor, and appended as amendments, 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 (e.g. institutional review board, peer review committee, ethics committee, drug regulatory authority), constituted appropriately for these purposes and independent of the investigator(s) and sponsor.

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

  • Selection of comparator Product: The selection of the comparator product is usually made at the national level by the drug regulatory authority. FDA reference listed drug products (RLDP) from orange book is important souce for this information.

             http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm

  • Selection of sampling time points: 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.

There is other possible study design depending on the release profile of drug which is not scope of this short course.

Dr. Manoj Karwa


P.S

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