BIOEQUIVALENCE STUDIES

OBJECTIVE
Generic drugs are safe and effective alternatives to brand 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

BIOEQUIVALENCE
Pharmaceutical Equivalent Products
Reference Possible Differences Drug particle size, .. Excipients Manufacturing process Equipment Site of manufacture Batch size . Test

Documented Bioequivalence = Therapeutic Equivalence

Pharmaceutical equivalent does not necessarily imply therapeutic equivalence:

- difference excipients - difference manufacturing process - other variables

drug performance?

Therapeutic equivalent does not necessarily imply bioequivalence:

- sensitivity - different formulations (IR/CR) - different active substance equivalence?

NDA VS. ANDA REVIEW PROCESS

Original Drug NDA Requirements 1. Chemistry 2. Manufacturing 3. Controls 4. Labeling 5. Testing 6. Animal Studies 7. Clinical Studies (Bioavailability/Bioequiv alence) Generic Drug ANDA Requirements 1. Chemistry 2. Manufacturing 3. Controls 4. Labeling 5. Testing 6. Bioequivalence Study (In Vivo, In vitro)

Note: Generic drug applications are termed "abbreviated" because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectivene Instead, generic applicants must scientifically demonstrate that their product is bioequivalent (i.e., performs in the same manner as the origina; drug).

GENERIC DRUG: DEFINITION

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

BIOEQUIVALENCE (BE): DEFINITION

the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.
CDER U.S. Food & Drug Administration

BIOEQUIVALENCE
90

Concentration (ng/mL)

80 70 60 50 40 30 20 10 0 0 5 10 15 20 Time (hours) 25 30 Test/Generic Reference/Brand

Why do we need Bioequivalence studies?

No clinical studies have been performed in patients with the Generic Product to support its Efficacy and Safety. With data to support similar in vivo performance (= Bioequivalence) Efficacy and Safety data can be extrapolated from the Innovator Product to the Generic Product.

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 (some times)

Bioequivalence
Pharmaceutical equivalents: Medicinal products are pharmaceutical equivalents if they contain the same 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 the same active moiety but differ in chemical form of that moiety or in the dosage form or strength.

PHARMACEUTICAL EQUIVALENTS
Drug products that contain the same therapeutically 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

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)

THERAPEUTIC EQUIVALENTS
Pharmaceutical equivalents that can be expected to have the same clinical effect and safety profile when administered to patients under the same conditions specified in the labeling

THERAPEUTIC EQUIVALENTS CRITERIA:

Products are safe & effective Products are pharmaceutical equivalents Meet the compedial or other applicable standards of strength, quality, purity & identity; meet acceptable in vitro standards Bioequivalent that they do not present a known potential problem & are shown to meet an appropriated bioequivalence standard Drug products are adequately labeled Drug products are manufactured in compliance with CGMP

TYPES OF BE STUDIES

BE studies In vitro In vivo

Serious indication

Narrow therapeutic margin A < 70% Oral IR products with systemic action Presystemic E > 70% Unfavorable physicochemical properties Documented BA problems

IN VIVO

Non-oral IR products

Modified release products

No relevant data available

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 studies under certain circumstances called as biowaivers (exemption)
1. The drug product differ only in strength of the active substance 2. Drug product has been slightly reformulated 3. Certain special requirements 4. Acceptable IVIVC

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

COMPLETELY RANDOMIZED DESIGNS

Treatments are assigned to experimental units completely at random.

Every experimental unit has the same probability of receiving any treatment.
Randomization is performed using a random number table, computer, program, etc.

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

CRD
Advantages Disadvantages

Extremely easy to construct Can accommodate any number of treatments and subjects Easy and simple to analyse

Best suited for relatively few treatments Subjects must be homogenous Variability will inflate random error, making it difficult to detect differences

RANDOMIZED BLOCK DESIGNS

Subjects are sorted into homogenous groups called as blocks on basis of similar backgrounds Treatments are then assigned at random within the blocks Randomization for different blocks are done independent of each other

RBD
Advantages Disadvantages

More precise results because of systematic grouping Accommodate any number of treatments Statistical analysis is simple Variability can be introduced to widen the validity of results

Missing observations within a block require more complex analysis Degree of freedom of experimental error are not as large as with CRD

REPEATED MEASURES, CROSS-OVER AND CARRY-OVER DESIGNS

It is essentially a RBD in which the same subject serves as a block It involves several treatments or a single treatment evaluated at different time points Cross-over or change-over design it involves the administration of 2 or more treatments one after the other in a specified or random order to the same group of patients Carry-over effects potential distortion due to carryover; residual treatments from preceding treatments
Wash-out period is important. 10 half lives.

CROSS-OVER DESIGN

REPEATED MEASURES DESIGN

Advantages Disadvantages

Provide good precision; as all sources of variability are removed Economic. Less subjects needed Can observe same patient at different time intervals rather than different patients

Carryover effect possible Order effect possible depending on order of treatment

LATIN SQUARE DESIGNS

It is a two-factor design i.e. subjects and treatments with one observation in each cell It is useful when 3 or more treatments are to be compared and carry-over effects are balanced Rows represent subjects and columns represent treatments

LSD
Advantages Disadvantages

Minimizes inter-subject variability Minimizes carry-over effects Minimizes variation due to time effects Small-scale experiment

Degrees of freedom of experimental error is large Randomization is more complicated Study takes a long time due to wash-out period If number of formulations to be studied is high, subject drop-out rate is high

BE STUDY PROTOCOL
1 a. b. 2 Title PI Project no. and date Study objective 4 a. b. Study population Subjects Subject selection i) Medical history 6 a. b. c. Ethical considerations Basic principles Institutional review board Informed consent

3
a. b.

Study design
Design Drug product i) Test product ii) Reference product c.

ii) Physical examination

iii) Lab tets Inclusion/ exclusion criteria i) Inclusion criteria ii) Exclusion criteria d. 5 a. b. Restrictions/ prohibitions Clinical procedures Dosage and drug administration Biological sampling schedule

d.
e. 7 8 a. b. 9 10.

Indications for subject withdrawl

Adverse reactions and emergency procedures Facilities Data analysis Analytical validation procedure Statistical treatment of data Drug accountability Appendix

c. d. e. f.

Dosage regimen Sample collection schedule Housing Fasting/ meals schedule

g.

Analytical methods

c.

Activity of subjects

STATISTICAL INTERPRETATION OF BE DATA

Statistical difference between 2 drug products is statistically significant if there is a probability of less than 1 in 20 or 0.05 If p < 0.05 differences between the 2 drug products are not considered statistically significant

ANOVA

Confidence interval approach

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%)