2 Basic AssumptionsDrug effect depends upon drug concentration at the site of actionDrug concentration at the site is determined by rate and extent of absorption, and rate and extent of dispositionFormulations which produce similar blood levels will have similar pharmacological effects
3 BioEquivalenceTwo formulations which produce similar blood levels are said to be bioequivalentBioequivalent products can be substituted for each otherSwitch from one to another would not affect the therapy of the patient.
4 BIOAVAILABILITYThe 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 action21 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 IVRELATIVE BIOAVAILABILITYAvailability 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 absorptione.g. Tablets vs oral solutions
6 BIOAVAILABILITYDATA 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 BIOEQUIVALENCEThe 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/ ormanufacturing processcan 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 streamAchieves same concentration of active ingredients at the same rate from two different formulationsIt will produce the similar therapeutic effect
11 THERAPEUTIC EQUIVALENCE FDA considers two products to be ‘Therapeutic Equivalents’ if theyHave same and established potential for safety and efficacyAre pharmaceutical equivalentsAre Bioequivalent
12 THERAPEUTIC EQUIVALENCE Are in compliance with compendial standards for strength, quality, purity and identityAre adequately labelledAre manufactured as per GMP
13 BIOEQUIVALENCEIn 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 formsChanges in formulationChanges in manufacturingGeneric Drug Approval (ANDA)
15 GENERIC DRUG PRODUCTA generic product is a product manufactured by firms other than the innovatorMore 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 actionConcept of known and reproducible bioavailability
17 GUIDELINES AND REGULATIONS Became effective on July 1, CFR (Code of Federal Regulations) Part 320In 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 bioequivalenceOctober 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 ExcretionThe 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 BIOEQUIVALENCEFor 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 WAIVERUnder certain circumstances, the BA/BE requirement is waived as in case ofInjectablesOphthalmic solutionsAntacidsTopical applicationsas 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.pptPoorly Soluble DrugsSlowly Soluble DrugsDrugs Administered as high dosePoorly absorbed DrugsDrugs Unstable in GIT
28 GENERAL DESIGN Two phases CLINICAL PHASE ANALYTICAL PHASE Screening for selectionDrug AdministrationBlood/urine sample collectionCentrifugationMethod ValidationSample AnalysisStatistical Analysis
29 STUDY CONDUCT STUDY DESIGN INVESTIGATOR SELECTION REGULATORY/EC APPROVAL
30 STUDY CONDUCT METHOD VALIDATION OBTAINING REF DRUG CLINICAL PHASE ANALYTICAL PHASESTATISTICAL PHASE
31 GENERAL DESIGN Single Dose multiple dose study.ppt Crossover CROSSOVER DESIGN.pptNormal and healthy volunteersMinimum 12 (ideally 24)Fasting state at least 10 hours before administration and 2 – 4 hours after administration
32 GENERAL DESIGNNo medicine one week prior to or no medicine except the study drug during the studyBlood sample/ or urine sample collection at different timepoints over a period of timeMeasurement of the concentration of drug present in the samples
33 CLINICAL PHASE Volunteer Admission Physical Examination Icard (bed number) and assignment of randomization codeGowning Area/wash roomEntry to CPU0 hr samplingDrug AdministrationHand and mouth checkFood (at specified time)Sampling at specified intervalsmonitoring of vital signs, ADR, activitiesLast samplingDischargeFollow-upScreening
34 BIOLOGICAL SAMPLESAMPLING AREA CENTRIFUGATION STORAGE AREA TRANSPORTATION ANALYTICAL AREA ANALYSIS (BENCH TOP)