1. Bioequivalence Studies Anoop Agarwal

2. Basic Assumptions
Drug effect depends upon drug concentration at the site of action
Drug concentration at the site is determined by rate and extent of absorption, and rate and extent of disposition
Formulations which produce similar blood levels will have similar pharmacological effects

3. BioEquivalence
Two formulations which produce similar blood levels are said to be bioequivalent
Bioequivalent products can be substituted for each other
Switch from one to another would not affect the therapy of the patient.

4. BIOAVAILABILITY
The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.
For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action
21 CFR 320.1

5. ABSOLUTE BIOAVAILABILITY
Comparison of the bioavailability of a particular dosage form with that following intravenous administration (100%)‏
e.g. oral solution vs IV
RELATIVE BIOAVAILABILITY
Availability of a drug product as compared to another dosage form or product of same drug given in the same dose.
Determine effect of formulation differences on drug absorption
e.g. Tablets vs oral solutions

6. BIOAVAILABILITY
DATA OBTAINED FROM A BIOAVAILABILITY STUDY IS USED TO DETERMINE :
The amount of drug absorbed from a dosage form.
The rate of absorption of the drug.
The duration of the drug’s presence in the body fluids.
The relationship between blood levels and therapeutic effectiveness or toxic effects of the drug.
A direct measurement of the concentration of the drug at the receptor site.

7. PHARMACEUTICAL EQUIVALENTS
Pharmaceutical Equivalents mean drug products that contain identical amounts of the same active drug ingredient (the same salt or ester of the same drug), in same dosage forms, but do not necessarily contain the same excipients, and that meet the same compendial or other applicable standard of identity, strength, quality and purity, including potency and where applicable, content uniformity, disintegration time and/or dissolution rate and generally be labeled for the same indications.

8. BIOEQUIVALENCE
The absence of a significant difference in the rate at and extent to which the active ingredients in the pharmaceutical equivalence become available at the site of drug action in the body when administered under similar experimental conditions in an appropriately designed study

9. PHARMACEUTICAL EQUIVALENCE DOES NOT IMPLY BIOEQUIVALENCE
Differences in the excipients and/ or
manufacturing process
can lead to faster or slower dissolution and absorption

10. Equivalence If the active ingredient has been shown to be
SAFE and EFFECTIVE, after it is absorbed into the blood stream
Achieves same concentration of active ingredients at the same rate from two different formulations
It will produce the similar therapeutic effect

11. THERAPEUTIC EQUIVALENCE
FDA considers two products to be ‘Therapeutic Equivalents’ if they
Have same and established potential for safety and efficacy
Are pharmaceutical equivalents
Are Bioequivalent

12. THERAPEUTIC EQUIVALENCE
Are in compliance with compendial standards for strength, quality, purity and identity
Are adequately labelled
Are manufactured as per GMP

13. BIOEQUIVALENCE
In practice, demonstration of bioequivalence is generally the most appropriate method of substantiating therapeutic equivalence between medicinal products which are pharmaceutical equivalents

14. WHY BA/ BE STUDIES ARE DONE?
Comparison of different dosage forms
Changes in formulation
Changes in manufacturing
Generic Drug Approval (ANDA)‏

15. GENERIC DRUG PRODUCT
A generic product is a product manufactured by firms other than the innovator
More appropriately generic product is “interchangeable multi-source pharmaceutical product”

16. WHY BA / BE?
Several therapeutic misadventures in the past related to differences in bioavailability (digoxin, phenytoin)‏
Need for testing performance of the dosage form in delivering active substance to the site of action
Concept of known and reproducible bioavailability

17. GUIDELINES AND REGULATIONS
Became effective on July 1, CFR (Code of Federal Regulations) Part 320
In 1984, the FDA was authorized to approve generic drug products (ANDA) under the Drug Price Competition and Patent Term Restoration Act

18. In June, 1992, the first book on statistical design and analysis of bioavailability and bioequivalence
October 1997, the U.S. FDA circulated a draft guidance entitled “In Vivo Bioequivalence Studies Based on Population and Individual Bioequivalence Approaches” for comments

19. This new guidance requires the sponsors to provide evidence of individual bioequivalence for approval of generic drugs.
For New Drugs, BE needs to be done when scale up of operations is undertaken for marketing.

20. HOW TO ASSESS? Plasma Drug Concentration Urinary Drug Excretion
The time for peak plasma concentration (tmax)‏
The peak plasma drug concentration (Cmax)‏
The area under the plasma drug concentration versus time curve (AUC)‏
Urinary Drug Excretion
The cumulative amount of drug excreted in the urine (Du)‏
The rate of drug excretion in the urine (dDu/dt)‏
The time for maximum urinary excretion (t)‏

21. Measuring drug concentration in urine is applicable for those drugs that are not extensively metabolized prior to urine elimination.
As a rule of thumb only such drugs where 20% of the dose is excreted unchanged in urine after an IV dose

22. BIOEQUIVALENCE
For most oral tablets or capsule dosage forms, BE is demonstrated in vivo by comparing the rate and extent of absorption of generic product with those of the innovator product

23. WAIVER
Under certain circumstances, the BA/BE requirement is waived as in case of
Injectables
Ophthalmic solutions
Antacids
Topical applications
as in such cases dissolution concerns are not relevant

24. BE A MUST!!!! Drugs with Narrow Therapeutic Index NTI.ppt
Drugs with critical dose critical dose drug.ppt
Poorly Soluble Drugs
Slowly Soluble Drugs
Drugs Administered as high dose
Poorly absorbed Drugs
Drugs Unstable in GIT

25. EXAMPLES Levothyroxine, Insulin Inherent Levels
Fexofenadine, Momentasone
Pharmakodyamic
Celiprolol.HCl
Non linear kinetics
Salbutamol, Paracetamol
Rapid absorption
Bisoprolol, Amlodipine
Long half life
Warfarin, Theophylline
Narrow range
EXAMPLES
CATEGORY

26. BE A MUST!!!!
Small changes in BE may lead to significant changes in efficacy or safety of the product

27. BIOEQUIVALENCE STUDY DESIGN

28. GENERAL DESIGN Two phases CLINICAL PHASE ANALYTICAL PHASE
Screening for selection
Drug Administration
Blood/urine sample collection
Centrifugation
Method Validation
Sample Analysis
Statistical Analysis

29. STUDY CONDUCT STUDY DESIGN INVESTIGATOR SELECTION
REGULATORY/EC APPROVAL

30. STUDY CONDUCT METHOD VALIDATION OBTAINING REF DRUG CLINICAL PHASE
ANALYTICAL PHASE
STATISTICAL PHASE

31. GENERAL DESIGN Single Dose multiple dose study.ppt
Crossover CROSSOVER DESIGN.ppt
Normal and healthy volunteers
Minimum 12 (ideally 24)‏
Fasting state at least 10 hours before administration and 2 – 4 hours after administration

32. GENERAL DESIGN
No medicine one week prior to or no medicine except the study drug during the study
Blood sample/ or urine sample collection at different timepoints over a period of time
Measurement of the concentration of drug present in the samples

33. CLINICAL PHASE Volunteer Admission Physical Examination
Icard (bed number) and assignment of randomization code
Gowning Area/wash room
Entry to CPU
0 hr sampling
Drug Administration
Hand and mouth check
Food (at specified time)‏
Sampling at specified intervals
monitoring of vital signs, ADR, activities
Last sampling
Discharge
Follow-up
Screening

34. BIOLOGICAL SAMPLE
SAMPLING AREA CENTRIFUGATION STORAGE AREA TRANSPORTATION ANALYTICAL AREA ANALYSIS (BENCH TOP)‏