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BIOEQUIVALENCESTUDIES

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OBJECTIVE

Generic drugs are safe and effective alternatives tobrand name prescriptions

Generic drugs can help both consumers and the

government reduce the cost of prescription drugs BUT Assess the risk of bio-inequivalence If there is a risk of pharmacotherapeutic failure or

diminished clinical safety

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Reference Test

Pharmaceutical EquivalentProducts

Possible Differences

Drug particle size, ..Excipients

Manufacturing process

Equipment

Site of manufacture

Batch size .

Documented Bioequivalence= Therapeutic Equivalence

BIOEQUIVALENCE

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Pharmaceutical equivalent does not necessarilyimply therapeutic equivalence:

- difference excipients

- difference manufacturingprocess

- other variables

drugperformance?

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Therapeutic equivalent does not necessarily implybioequivalence:

- sensitivity

- different formulations (IR/CR)

- different active substance

equivalence?

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NDA VS. ANDA REVIEW PROCESS Original DrugNDA Requirements1. Chemistry2. Manufacturing3. Controls4. Labeling5. Testing6. Animal Studies7. Clinical Studies

(Bioavailability/Bioequivalence)

Generic DrugANDA Requirements1. Chemistry2. Manufacturing3. Controls4. Labeling5. Testing6. Bioequivalence Study

(In Vivo, In vitro)

Note: Generic drug applications are termed "abbreviated" because they are generallynot required to include preclinical (animal) and clinical (human) data to establish safety and effectivenInstead, generic applicants must scientifically demonstrate that their product is bioequivalent(i.e., performs in the same manner as the origina; drug).

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GENERIC DRUG: DEFINITION

Same active ingredient (s) Same route of administration Same dosage form Same strength Same indicationsCompares to reference listed drug (RLD)

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BIOEQUIVALENCE (BE): DEFINITION

the absence of a significant difference in therate and extent to which the active ingredientor active moiety in pharmaceutical equivalents

or pharmaceutical alternatives becomesavailable at the site of drug action whenadministered at the same molar dose under similar conditions in an appropriately designed

study .

CDER U.S. Food & Drug Administration

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BIOEQUIVALENCE

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25 30

Time (hours)

C o n c e n

t r a t i o n

( n g

/ m L )

Test/Generic

Reference/Brand

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Why do we need Bioequivalence studies?

No clinical studies have been performedin patients with the Generic Product tosupport its Efficacy and Safety.With data to support similar in vivoperformance (= Bioequivalence)Efficacy and Safety

data can be extrapolated from theInnovator Product to the GenericProduct.

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WHEN DO WE DO BE STUDIES ?

Clinical Service Form to Final Market Form

Change of formulations (capsules to tablet)

Generic Formulations

Change of Process or manufacturing site (sometimes)

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Bioequivalence

Pharmaceutical equivalents:Medicinal products are pharmaceutical equivalents if they contain thesame amount of the same active substance in the same dosage form

that meet the same or comparable standard.

Pharmaceutical alternatives:

Medicinal products are pharmaceutical alternatives if they contain thesame active moiety but differ in chemical form of that moiety or in the

dosage form or strength.

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PHARMACEUTICAL EQUIVALENTS

Drug products that contain the sametherapeutically active ingredients

Contain the same salt, ester or chemical form, same

dosage form Identical strength, conc. & route of administration Differ in shape, release mechanisms, packaging &

excipients

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PHARMACEUTIC ALTERNATIVES Drug products that contain the same therapeutic

moiety but are:1. Different salts, esters, or complexes (e.g.tetracycline HCl vs. tetracycline phosphate,

erythromycin stearate vs. erythromycin estolate)2. Different dosage forms (e.g. tablet vs. cap,immediate-release vs. controlled-release)3. Different strengths (10 mg vs. 20 mg)

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THERAPEUTIC EQUIVALENTS

Pharmaceutical equivalents that can be expectedto have the same clinical effect and safety profilewhen administered to patients under the same

conditions specified in the labeling

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THERAPEUTIC EQUIVALENTS CRITERIA:

Products are safe & effective Products are pharmaceutical equivalents Meet the compedial or other applicable standards

of strength, quality, purity & identity; meetacceptable in vitro standards Bioequivalent that they do not present a known

potential problem & are shown to meet anappropriated bioequivalence standard

Drug products are adequately labeled Drug products are manufactured in compliance

with CGMP

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TYPES OF BE STUDIES

BE

studies

In vitro In vivo

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IN VIVO

Oral IR productswith systemicaction

Serious indication

Narrowtherapeutic

margin

A < 70%Presystemic E >

70%

Unfavorablephysicochemical

properties

Documented BAproblems

No relevant dataavailable

Non-oral IRproducts

Modified releaseproducts

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IN VITRO BE STUDIES

If none of the previous criteria are applicable,comparative in vitro dissolution studies will suffice.

In vitro studies can be used instead of in vivo studiesunder certain circumstances called as biowaivers(exemption)1. The drug product differ only in strength of the active

substance2. Drug product has been slightly reformulated3. Certain special requirements4. Acceptable IVIVC

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BE EXPERIMENTAL STUDY DESIGN

4 types of designs

1. Completely randomised designs

2. Randomised block designs

3. Repeated measures, cross-over and carry-over designs

4. Latin square designs

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COMPLETELY RANDOMIZED DESIGNS

Treatments are assigned to experimental unitscompletely at random.

Every experimental unit has the same probability ofreceiving any treatment.

Randomization is performed using a randomnumber table, computer, program, etc.

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EXAMPLE OF RANDOMIZATION

Given you have 4 treatments (A, B, C, and D) and 5replicates, how many experimental units would you

have?

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CRD

Advantages

Extremely easy toconstruct

Can accommodateany number oftreatments andsubjects

Easy and simple toanalyse

Disadvantages

Best suited for relativelyfew treatments

Subjects must behomogenous

Variability will inflaterandom error, making itdifficult to detectdifferences

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RANDOMIZED BLOCK DESIGNS

Subjects are sorted into homogenous groups calledas blocks on basis of similar backgrounds

Treatments are then assigned at random within theblocks

Randomization for different blocks are done

independent of each other

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RBD

Advantages More precise results

because of systematicgrouping

Accommodate anynumber of treatments

Statistical analysis is

simple Variability can be

introduced to widenthe validity of results

Disadvantages

Missing observationswithin a block requiremore complex analysis

Degree of freedom ofexperimental error arenot as large as withCRD

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REPEATED MEASURES, CROSS-OVERAND CARRY-OVER DESIGNS

It is essentially a RBD in which the same subjectserves as a block

It involves several treatments or a single treatmentevaluated at different time points

Cross-over or change-over design it involves theadministration of 2 or more treatments one after theother in a specified or random order to the samegroup of patients

Carry-over effects

potential distortion due tocarryover; residual treatments from precedingtreatments

Wash-out period is important. 10 half lives.

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CROSS-OVER DESIGN

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REPEATED MEASURES DESIGN

Advantages

Provide good precision;as all sources ofvariability are removed

Economic. Less subjectsneeded

Can observe samepatient at differenttime intervals rather than different patients

Disadvantages

Carryover effectpossible

Order effect possibledepending on order oftreatment

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LATIN SQUARE DESIGNS

It is a two-factor design i.e. subjects and treatmentswith one observation in each cell

It is useful when 3 or more treatments are to becompared and carry-over effects are balanced

Rows represent subjects and columns represent

treatments

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LSD

Advantages

Minimizes inter-subjectvariability

Minimizes carry-over effects

Minimizes variation dueto time effects

Small-scale experiment

Disadvantages Degrees of freedom of

experimental error islarge

Randomization is morecomplicated

Study takes a long time

due to wash-out period If number of

formulations to bestudied is high, subjectdrop-out rate is high

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BE STUDY PROTOCOL1 Title 4 Study population 6 Ethical considerations

a. PI a. Subjects a. Basic principles

b. Project no. and date b. Subject selection b. Institutional review board

2 Study objective i) Medical history c. Informed consent

3 Study design ii) Physical examination d. Indications for subjectwithdrawl

a. Design iii) Lab tets e. Adverse reactions andemergency procedures

b. Drug product c. Inclusion/ exclusion criteria 7 Facilities

i) Test product i) Inclusion criteria 8 Data analysis

ii) Reference product ii) Exclusion criteria a. Analytical validationprocedure

c. Dosage regimen d. Restrictions/ prohibitions b. Statistical treatment ofdata

d. Sample collection schedule 5 Clinical procedures 9 Drug accountability

e. Housing a. Dosage and drug administration 10. Appendix

f. Fasting/ meals schedule b. Biological sampling schedule

g. Analytical methods c. Activity of subjects

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STATISTICAL INTERPRETATION OF BEDATA

Statistical difference between 2 drugproducts is statistically significant if there is aprobability of less than 1 in 20 or 0.05

If p < 0.05 differences between the 2 drugproducts are not considered statisticallysignificant

ANOVA

Called as two one-sided test procedure Students t test distribution of data 90%

confidence limits are estimated (BE intervals) 90% CI means 2 drug products must be

within + 20% (i.e. 80 120%)

Confidenceinterval

approach