Regulatory requirements-BA/BE Studies

Bioavailability & Bioequivalence studies

General Considerations forOrally

Administered Drugs

KIREETI BHEEMAVARAPU MSc (IPSc), MSc (Chemistry)

CONTENTS

• Background

• Methods to document BA & BE

• Comparison of BA measures in BE studies

• Documentation of BA & BE

• Special Topics

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1

2

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Duration of action

Therapeutic range

Minimum effective concentration

Maximum safe concentration

Elimination phaseAbsorption

phaseA

vera

ge s

erum

con

cntr

atio

n (m

cg/m

l)

Time after drug administration (h)

Cmax

SERUM CONC. vs TIME

BACKGROUND

• Bioavailability is defined in § 320.1 as:

“ 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.”

PHARMACO-KINETIC PERSPECTIVE

• Estimate of the relative fraction of the dose in systemic circulation (vs Solution, suspension or Intravenous)

• ADME information

• Nutrients effect on absorption

• Dose proportionality

• Linearity of Pharmacokinetics

REGULATORY OBJECTIVE

• The performance of the formulations used in the clinical trials provide evidence of safety and efficacy (21 CFR 320.25(d)(1)).

• Focus on using relative BA (referred to as product quality BA) and, in particular, BE studies as a means to document product quality.

• In vivo performance in terms of BA/BE, can be considered to be one aspect of product quality that provides a link to the performance of the drug product used in clinical trials and to the database containing evidence of safety and efficacy.

BIO-EQUIVALENCE

“ 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”

BIO-EQUIVALENT??

• INDs/ NDAs

• ANDAs

• Post Approval Changes

REQUIRED FOR

BE for INDs/NDAs

To establish links between:

(1) early and late clinical trial formulations;

(2) formulations used in clinical trial and stability

studies, if different;

(3) clinical trial formulations and to-be-

marketed drug product; and

(4) any other appropriate comparisons

POSSIBLE OUTCOMES

Note: *

CASE (1)

CASE (2)

Note: *

CASE (3)

REGULATORY CONCERN

Case (1) :

Test product generates plasma levels that are substantially above those of the reference product

Concern: Not therapeutic failure, but the adequacy of the safety database from the test product

REGUATORY CONCERN

Case (2) :

The test product has levels that are substantially

below those of the reference product

Concern: Therapeutic Efficacy

Case (3):

Variability of the test product

Concern: Ensuring safety & Efficacy

Contd..

• Individual dose response Curves

• Population dose response Curves

• Concentration dose response curves

“ Burden is on the sponsor to demonstrate the adequacy of the clinical trial dose-response or concentration-response data to provide evidence of therapeutic equivalence.”

For Case (3) the FDA needs :

ANDA

Purpose:

“To demonstrate BE between a pharmaceutically equivalent generic drug product and the corresponding reference listed drug (21 CFR 314.94 (a)(7)).”

BE + Pharmaceutical equivalence Therapeutic equivalence

POST APPROVAL CHANGES

• Immediate release dosage forms

• Modified release dosage forms

“ Requirements of in vitro dissolution & in vivo BE studies depend on the type (level 1,2,3) –Ref: corresponding detailed guidance from FDA”

METHODS TO DOCUMENT BA & BE

§ 320.24 - Invitro & in vivo methods used to measure product quality and establish BE

1) Pharmaco-kinetic study

2) Pharmacodynamic Study

3)Comparative clinical studies

4)In-vitro studies

Comparison of BA measures inBE studies

FDA’s Approach:

(1) a criterion to allow the comparison,

(2) a confidence interval for the criterion, and

(3) a BE limit

DOCUMENTATION OF BA & BE

• An in vivo study is generally recommended for all solid oral dosage forms approved after 1962 and for bioproblem drug products approved before 1962.

BIO WAIVER

§ 320.22(d)(2):

1) the drug product is in the same dosage form, but in a different strength;

2) this different strength is proportionally similar in its active and inactive ingredients to the strength of the product for which the same manufacturer has conducted an appropriate in vivo study; and

3) the new strength meets an appropriate in vitro dissolution test.

PROPORTIONALLY SIMILAR1) All active and inactive ingredients are in exactly the same proportion between different strengths if not,2) ratios of inactive ingredients to total weight of the

dosage form are within the limits defined by the SUPAC-IR and SUPAC-MR guidance up to and including Level II

3) For high potency drug substances, where the amount of the active drug substance in the dosage form is relatively low, the total weight of the dosage form remains nearly the same for all strengths (± 10 % of the total weight of the strength on which a biostudy was performed)

DOSAGE FORMSSolutions:

• For oral solutions, elixirs, syrups, tinctures, or other solubilized forms, in vivo BA and/or BE can be waived (21 CFR 320.22(b)(3)(i)).

• Generally, in vivo BE studies are waived for solutions on

“ release of the drug substance from the drug product is self-evident and that the solutions do not contain any excipient that significantly affects drug absorption” (exceptions - Sorbitol, Mannitol)

Contd....

Suspensions:

• BA BE for immediate release solid orals

• Both Invivo & invitro studies are recommended.

Capsules & Tablets (Immediate release):• Single dose fasting study –Focus on release of

DS into Systemic circulation) &

• Invitro dissolution profiles on all strengths of each product.

• ANDAs: BE Test vs RL product (strength-Orange book)

DIFFERENCE FACTOR

The difference factor (f 1) calculates the percent (%) difference between the two curves at each time point and is a mea-surement of the relative error between the two curves:

SIMILARITY FACTOR (f2)

n = number of time points

R(t) = mean % API dissolved of reference productat time point x

T(t) = mean % API dissolved of test product at time point x

Range : 0-100

PRE-APPROVAL BIOWAIVERS In vivo BE demonstration of one or more lower

strengths can be waived based on dissolution tests and an in vivo study on the highest strength when

“ drug product is in the same dosage form, but in a different strength, and is proportionally similar in its active and inactive ingredients to the strength on which BA or BE testing has been conducted”

Contd...

Biowaiver for Higher strength for NDA is based on :

(1) clinical safety and/or efficacy studies including data on the dose and the desirability of the higher strength,

(2) linear elimination kinetics over the therapeutic dose range,

(3) the higher strength being proportionally similar to the lower strength, &

(4) the same dissolution procedures being used for both strengths and similar dissolution results obtained

Contd....

DISSOULTION NOT DEPENDENT ON STRENGTH • Dissolution profile from one medium are

enough to support waivers or profiles from three media (PH 1.2, 4.5 & 6.8) are needed

• F2 test is used to compare profilesdifferent strengths of the product

• F2 ≥ 50 – no further in vivo studies are needed.

• Not suitable for rapidly dissolving drug prod-ucts (e.g., > 85% dissolved in 15 minutes or less).

Contd.....

“Invivo studies are NOT required for high-est strength” for an ANDA if :

1) Linear elimination kinetics has been shown over the therapeutic dose range

2) The higher strengths of the test and reference products are proportionally similar to their corresponding lower strength.

3) Comparative dissolution testing on the higher strength of the test and reference products is submitted and found to be appropriate

POST APPROVAL: NDAs & ANDAs

• SUPAC –IR provides specific guidance.

• Eg: Looking at level 2 change BCS class II (LS/HP): In vitro dissolution (pH 1-7.4) Multiple profiles – f2 ≥ 50 BCS class IV (LS/LP):In vivo – AUC & Cmax: 80-125% (90% CI )

MODIFIED RELASE PRODUCTS

• Delayed release products

• Extended (controlled) release products

NDAs : BA –BE

§ 320.25(f)- BA requirements• Purpose: The drug product meets the controlled-

release claims made for it.• The BA profile established for the drug product rules

out the occurrence of any dose dumping.• The product’s steady-state performance is equivalent

to a currently marketed noncontrolled release or controlled-release drug product that contains the same active drug ingredient or therapeutic moiety of approved NDA

• The drug product’s formulation provides consistent pharmacokinetic performance between individual dosage units

TYPE OF STUDIES

• A single-dose, fasting study on all strengths of tablets and capsules and highest strength of beaded capsules

• A single-dose, food-effect study on the highest strength

• A steady-state study on the highest strength• BE studies : “substantial changes in the

components or composition and/or method of manufacture for an extended-release drug product occur between the to be-marketed NDA dosage form and the clinical trial material”

ANDAs: BE Studies

(1) a single-dose, nonreplicate, fasting study comparing the highest strength of the test and reference listed drug product and

(2) a food-effect, non replicate study comparing the highest strength of the test and reference product

Tablets:

When “Proportionality” applies:

• In Vivo study for the highest strength

• Waiver for lower strengths with comparison

of dissolution with higher strengths • “Similar” dissolution profiles ( f2 ≥ 50 ) in three

dissolution media (pH 1.2, 4.8 & 6.8)

Post Approval Changes :

• SUPAC- MR guidance applies

• Invitro – Prechange vs Post change product

BIO WAIVERS (BE) : NDAs &ANDAs

Beaded Capsules:

• Strength – no. of beads

• BE study – for Highest Strength is sufficient.

• Bio Waiver for lower strengths based on dissolution profiles

• F2 ≥ 50

MISC. DOSAGE FORMS

1) Rapidly dissolving drug products –buccal & sublingual usage:

2) Both in vivo BA & /BE and in vitro dissolution:

WHY?

SPECIAL TOPICSFOOD - EFFECT studies:

1) Influence of Co-administation of food with oral dosage forms

2) BA studies – focus on effect of food drug release

3) BE demostration – comparable BA (test vsref.) when coadministered with food

4) Single dose, two period, two sequence corssover study.

MOIETIES MEASURED

• Parent drug vs metabolities

• BA Studies- Concentration & Activity

• BE studies –Parent drug preferred. WHY?

Except :

=>Low Parent drug levels –Analysis problems

2) Pre-systemic Metabolism

Contd...

Enantiomers vs Racemates:“BA studies: Individual enantiomers

BE Studies: Measurement of racemate”

Individual enantiomers are preferred when :

• Enantiomers exhibit different PK /PD characteristics,

• Primary efficacy and safety activity re-

sides with the minor enantiomer, &

• Nonlinear absorption is present for at least one of the enantiomers

Contd.....

COMPLEX MIXTURES AS “ACTIVE”

• Some or all of the APIs can’t be characterized with regard to chemical structure /activity

• Case by Case basis

• BA and BE studies be based on a small number of markers of rate and extent of absorption

• Possibility of pharmacodynamic or clinical approach

LONG HALF LIFE DRUGS

• Adequate characterization of half life

• Non-replicate single dose cross over

• Parallel study when cross over is not feasible

• Sample collection time – gastro-intestinal transit (2-3 days )

• Truncated Curve: AUC 0-72 hr

• Intra subject variability issue.

FIRST POINT Cmax

• First point of concentration time curve –reflects Cmax

• Early sampling times ? insufficient sampling?

Better sampling approach :

• Initial 5-15 min after administration

• Additional 2-3 samples in the first hour

NTI DRUGS

Note : *

BE STUDIES

BE LIMITS FOR GENERIC NTI DRUGS

REFERENCES

1) www.FDA.gov

2) * - Taken from the work of LAWRENCE YU, Acting Director – Office of Pharmaceutical science FDA.