Clinical Trial Terminology for BA/BE Studies

The bioavailability of an active substance from a pharmaceutical product should be known and reproducible.In most cases, it is cumbersome and unnecessary to assess this by clinical studies. Bioavailability and bioequivalence data is therefore required to be furnished with applications for new drugs, as required under Schedule Y, depending on the type of application being submitted.Both bioavailability and bioequivalence focus on the release of a drug substance from its dosage form and subsequent absorption into the systemic circulation.

For this reason, similar approaches to measuring bioavailability should generally be followed in demonstrating bioequivalence.

Bioavailability can be generally documented by a systemic exposure profile obtained by measuring drug and/or metabolite concentration in the systemic circulation over time. The systemic exposure profile determined during clinical trials in the early drug development can serve as a benchmark for subsequent BE studies.


Bioequivalence studies should be conducted for the comparison of two medicinal products containing the same active substance. The studies should provide an objective means of critically assessing the possibility of alternative use of them. Two products marketed by different licensees, containing same active ingredient(s), must be shown to be therapeutically equivalent to one another in order to be considered interchangeable.



BIOAVAILABILITY

Bioavailability refers to the relative amount of drug from an administered dosage form which enters the systemic circulation and the rate at which the drug appears in the systemic circulation.

BIOEQUIVALENCE

Bioequivalence of a drug product is achieved if its extent and rate of absorption are not statistically significantly different from those of the reference product when administered at the same molar dose.

CLINICAL TRIAL

A clinical trial is a systematic study of pharmaceutical products in human subject(s), in order to discover or verify the clinical, pharmacological (including pharmacodynamic / pharmacokinetic), and/or adverse effects, with the object of determining their safety and/or efficacy.

GOOD CLINICAL PRACTICE (GCP) GUIDELINES:

Good Clinical Practice Guidelines issued by Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India.

MODIFIED RELEASE DOSAGE FORMS

Modified-release dosage forms are those for which the drug-release characteristics of time course and/or drug-release location are chosen to accomplish such therapeutic or convenience objectives that are not offered by immediate-(conventional) release dosage forms.

PHARMACEUTICAL EQUIVALENTS

Pharmaceutical equivalents are drug products that contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, in identical dosage forms, but not necessarily containing the
same inactive ingredients.

PHARMACEUTICAL ALTERNATIVES

Pharmaceutical alternatives are drug products that contain the identical therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage form or as the same salt or ester.

PHARMACODYNAMIC EVALUATION

Pharmacodynamic evaluation is measurement of the effect on a pathophysiological process as a function of time, after administration of two different products to serve as a basis for bioequivalence assessment.

PHARMACOKINETICS

Pharmacokinetics deals with the changes of drug concentration in the drug product and changes of concentration of a drug and/or its metabolite(s) in the human or animal body following administration of the drug product, i.e., the changes of drug concentration in the different body fluids and tissues in the dynamic system of liberation, absorption, distribution, body storage, binding, metabolism, and excretion.

NON-LINEAR PHARMACOKINETICS

Nonlinear kinetics or saturation kinetics refers to a change of one or more of the pharmacokinetic parameters during absorption, distribution, metabolism, and excretion by saturation or overloading of processes due to increased dose sizes.

REFERENCE PRODUCT

For purpose of these guidelines, the reference product is a pharmaceutical product which is identified by the Licensing Authority as “Designated Reference Product” and contains the same active ingredient(s) as the new drug. The Designated Reference Product will normally be the global innovator’s product. An applicant seeking approval to market a generic equivalent must refer to the Designated Reference Product to which all generic versions must be shown to be bioequivalent. For subsequent new drug applications in India the Licensing Authority may, however, approve another Indian product as Designated Reference Product.

SUPRA-BIOAVAILABILITY

This is a term used when a test product displays an appreciably larger bioavailability than the reference product.
SUSTAINED RELEASE DOSAGE FORM These are modified release dosage forms where the liberation (drug release) rate constant is smaller than the unrestricted absorption rate constant.

STEADY STATE

Steady state is the state when the plasma concentration of drug at any time point during any dosing interval should be identical to the concentration at the same time during any other dosing interval. The steady state drug concentrations fluctuate (oscillate) between a maximum and a minimum steady state concentration within each of the dosing intervals.

THERAPEUTIC EQUIVALENTS

Therapeutic equivalents are drug products that contain the same active substance or therapeutic moiety and, clinically show the same efficacy and safety.

PHARMACOKINETIC TERMS

Cmax

This is the maximum drug concentration achieved in systemic circulation following drug administration.

Cmin

This is the minimum drug concentration achieved in systemic circulation following multiple dosing at steady state.

Cpd

This is the pre-dose concentrations determined immediately before a dose is given at steady state.

Tmax

It is the time required to achieve maximum drug concentration in systemic circulation.

AUC0-t

Area under the plasma concentration - time curve from 0 h to the last quantifiable concentration to be calculated using the trapezoidal rule

AUC0-∞

Area under the plasma concentration - time curve, from zero to infinity to be calculated as the sum of AUC0-t plus the ratio of the last measurable concentration to the elimination rate constant

AUC0-τ

Area under the plasma concentration - time curve over one dosing interval following single dose for modified release products.

AUC0-τ(ss)
Area under the plasma concentration - time curve over one dosing interval in multiple dose study at steady state.

Kel
Apparent first-order terminal elimination rate constant calculated from a semi-log plot of the plasma concentration versus time curve.

T1/2

Elimination half life of a drug is the time necessary to reduce the drug concentration in the blood, plasma, or serum to one-half after equilibrium is reached.