Bioequivalence (BE) l Assessment of bioequivalence l Pharmacodynamic endpoint studies l Clinical endpoint studies l In vitro endpoint studies

                                 

Assessment of bioequivalence

The assessment of BE of different drug products is based on the fundamental assumption that two products are equivalent when the rate and extent of absorption of the test/generic drug does not show a significant difference from the rate and extent of absorption of the reference/brand drug under similar experimental conditions as defined. As per the different regu­latory authorities, BE studies are generally classified as:

1. Pharmacokinetic endpoint studies.  (Already provided details in last blog)

2. Pharmacodynamic endpoint studies.

3. Clinical endpoint studies.

4. In vitro endpoint studies.

 

Pharmacodynamic endpoint studies

Pharmacokinetic studies measure systemic exposure but are generally inappropriate to document local delivery BA and BE. In such cases, BA may be measured, and BE may be established, based on a pharmacodynamic study, providing an appropriate pharmacodynamic endpoint is available.

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

Regulatory authorities request justification from the applicant for the use of pharmacodynamic effects/parameters for the establishment of BE criteria. These studies generally become necessary under two conditions

1) if the drug and/or metabolite(s) in plasma or urine cannot be analyzed quantitatively with sufficient accuracy and sensitivity;

2) if drug concentration measurement cannot be used as surrogate endpoints for the demonstration of efficacy and safety of the particular pharmaceutical product.

The other important specifications for pharmacodynamic studies include

i)               a dose-response relationship should be demonstrated;

ii)        sufficient measurements should be taken to provide an appropriate pharmacodynamic response profile;

iii)            the complete dose-effect curve should remain below the maximum physiological response;

iv)      all pharmacodynamic measurements/methods should be validated for specificity, accuracy, and reproducibility.

Examples of these pharmacodynamic studies include locally acting drug products and oral inhalation drug products, such as metered dose inhalers and dry powder inhalers, and topically applied dermatologic drug products, such as creams and ointments. Bronchodilator drug products, such as albuterol metered dose inhalers, produce relaxation of smooth muscle of the airways.

 

Clinical endpoint studies or comparative clinical trials

In the absence of pharmacokinetic and pharmacodynamic approaches, adequate and well-controlled clinical trials may be used to establish BA/BE. Several international regulatory authorities provide general information about the conduct of clinical studies to establish BE.

In vitro endpoint studies

Biopharmaceutics Classification System (BCS) has categorized drug substances as having either high or low solubility and permeability and drug products as exhibiting rapid dissolution. According to this approach, drug substances may be classified into four primary groups:

1) highly soluble and highly permeable;

2) highly permeable and poorly soluble;

3) highly soluble and poorly permeable;

4) poorly soluble and poorly permeable.

Using this BCS approach, a highly permeable, highly soluble drug substance formulated into a rapidly dissolving drug product may need only in vitro dissolution studies to establish BE. In addition, in vitro approaches to document BE for nonbioproblem drugs approved before 1962 remain acceptable as per FDA regula­tions. Dissolution tests can also be used to reduce the number of in vivo studies in other circumstances, and to i) assess batch-to-batch quality and support batch release; ii) provide process control and quality assurance; and iii) assess the need for further BE studies relative to minor post-approval changes, where they function as a signal of bioinequivalence. The broad spectrum of BA/BE in vitro studies specifications were provided by each regulatory authority.