be criteria

8/12/2019 BE Criteria

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Bioequivalence Guidance Summary

Bioequivalence Guidance SummaryEnter Drug Name Here

Regulatory Body

Study Design

Drug Characteristics

Click here to check the FDA Guidance for Industry: Individual Product Bioequivalence Recommendations

Standards for BioequivalenceUnless otherwise indicated by a specific guidance, this guidance recommends that the traditional BE limit of 80 to 125 percent for non-narrow therapeutic ra

unchanged for the bioavailability measures (AUC and Cmax) of narrow therapeutic range drugs. (1)

*90%CI of ln-Cmax, ln-AUCt, ln-AUCinf within 80.00-125.00%. Additional PK Parameters: AUC0-t, AUC0-∞, Cmax, Tmax, λz , and t1/2+ (1)

Sampling Scheme CriteriaWe recommend that blood samples be drawn at appropriate times to describe the absorption, distribution, and elimination phases of the drug. For most dru

recommend that 12 to 18 samples, including a predose sample, be collected per subject per dose. This sampling can continue for at least three or more term

the drug. The exact timing for sample collection depends on the nature of the drug and the input from the administered dosage form. The sample collection

such a way that the maximum concentration of the drug in the blood (Cmax) and terminal elimination rate constant (λz) can be estimated accurately. At leas

samples can be obtained during the terminal log-linear phase to obtain an accurate estimate of λz from linear regression. (1) An adequate washout period (e

half lives of the moieties to be measured) would separate each treatment. (1)

Fasting and/or Fed Required?we recommend a BE study under fed conditions for all orally administered immediate-release drug products, with the

following exceptions:

• When both test product and RLD are rapidly dissolving, have similar dissolution profiles, and contain a drug substance with high solubility and high permea

(see footnote 3), or

• When the DOSAGE AND ADMINISTRATION section of the RLD label states that the product should be taken only on an empty stomach, or

• When the RLD label does not make any statements about the effect of food on

absorption or administration. (2)

In ANDAs, BE of the test to the RLD is demonstrated in a single dose crossover study. Both treatments should be sprinkled on one of the soft foods mentione

usually applesauce. The BE data should be analyzed using average BE and the 90 percent CI criteria should be used to declare BE. If there are questions abou

design, or the analysis of such BE studies, the sponsors and/or applicants should contact the Office of Generic Drugs.(2)

Critical Dose Drug

Long Half-life Drug

Highly Variable Drug

Rapid Onset Drug

Non-Linear Kinetics

Modified Release

http://www.fda.gov/cder/guidance/bioequivalence/default.htm

http://www.fda.gov/cder/guidance/bioequivalence/default.htm




Parent and/or Metabolite Required?For BE studies, measurement of only the parent drug released from the dosage form, rather than the metabolite, is generally recommended. The rationale

recommendation is that concentration-time profile of the parent drug is more sensitive to changes in formulation performance than a metabolite, which is

metabolite formation, distribution, and elimination. The following are exceptions to this general approach.

• Measurement of a metabolite may be preferred when parent drug levels are too low to allow reliable analytical measurement in blood, plasma, or serum

length of time. We recommend that the metabolite data obtained from these studies be subject to a confidence interval approach for BE demonstration. If

concern related to efficacy or safety for the parent drug, we also recommend that sponsors and/or applicants contact the appropriate review division to det

the parent drug should be measured and analyzed statistically.

• A metabolite may be formed as a result of gut wall or other presystemic metabolism. If the metabolite contributes meaningfully to safety and/or efficacy,

recommend that the metabolite and the parent drug be measured. When the relative activity of the metabolite is low and does not contribute

meaningfully to safety and/or efficacy, it does not have to be measured. We recommend that the parent drug measured in these BE studies be analyzed

using a confidence interval approach. The metabolite data can be used to provide supportive evidence of comparable therapeutic outcome. (1)

Blinding and Data Analysis Subjects with predose plasma concentrations:

• If the predose concentration is ≤ 5 percent of Cmax value in that subject, the subject’s data without any adjustments can be included in all pharmacokinet

and calculations. We recommend that if the predose value is > than 5 percent of Cmax, the subject be dropped from all BE study evaluations.

Data deletion due to vomiting:

• We recommend that data from subjects who experience emesis during the course of a BE study for immediate-release products be deleted from statistica

vomiting occurs at or before 2 times median Tmax. In the case of modified-release products, the data from subjects who experience emesis any time during

dosing interval can be deleted. (1)

Reference ProductFor ANDAs, we also recommend that the BE study be conducted between the test product and reference listed drug using the strength(s) specified in Appro

with Therapeutic Equivalence Evaluations (Orange Book). (1)




Combining Studies

REFERENCES(1) Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations. U.S. Department of H

Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER); March 2003. BP Revision 1.

(2) Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies. U.S. Department of Health and Human Services. Food and Drug Admin

for Drug Evaluation and Research (CDER); December 2002. BP.



Regulatory

BodyFDA TPD

Standards for

BE: Single

Dose Studies

Unless otherwise indicated by a specific guidance, this guidance recommends

that the traditional BE limit of 80 to 125 percent for non-narrow therapeutic

range drugs remain unchanged for the bioavailability measures (AUC and

Cmax) of narrow therapeutic range drugs. (1)

[90%CI of ln-Cmax, ln-AUCt, ln-AUCinf within 80.00-125.00%. Additional PK

Parameters: AUC0-t, AUC0-∞, Cmax, Tmax, λz , and t1/2] (1)

For drugs with uncomplicated characteristics, the follow

in single dose cross-over comparative bioavailability stu

bioequivalence:

a) The 90% confidence interval of the relative mean AU

reference product should be within 80 percent to 125 pe

b) The relative mean measured Cmax of the test to refebetween 80 percent and 125 percent.

These standards must be met on log transformed param

• the measured data, and

• data corrected for measured drug content (percent po

Additional PK Parameters to report: AUCT, AUCI, AUC

Tmax, lambda. (1)

Standards for

BE: Steady

State Studies

For steady-state studies, we recommend that the measurement of total

exposure be the area under the plasma, serum, or blood concentration-time

curve from time zero to time tau over a dosing interval at steady state (AUC0-tau), where tau is the length of the dosing interval. (1)

PK Parameters: Cmin (concentration at the end of a dosing interval), Cav

(average concentration during a dosing interval), degree of fluctuation [(Cmax-

Cmin)/Cav], and swing [(Cmax-Cmin)/Cmin] (1)

The 90% confidence interval of the relative mean AUCta

reference formulation should be within 80% to 125%.

The relative mean measured Cmax at steady state of thformulation should be within 80% to 125%.

The relative mean measured Cmin at steady state of th

formulation should not be less than 80%.

[met on both potency uncorrected and corrected data]

PK Parameters: AUCtau, Cmax, Tmax, Cpd, Cmin, fluc

For steady-state studies of drugs with uncomplicated ch

three consecutive pre-dose concentration levels (Cpd) a

evidence of steady state. Generally, observations of Cp

reference products should be recorded at the same time

these measurements could be taken based on the first s

in which a profile over the dosing interval is being estab

usually achieved when repeated doses of a formulation

period that exceeds five disposition half-lives of the mod

Analysis of Tmax, lambda, and fluctuation should b

raw scale, while calculations for AUCX, AUCT, AUC

and

Rapid Onset

Drugs

RAPID ONSET:

An early exposure measure may be informative on the basis of appropriate

clinical efficacy/safety trials and/or pharmacokinetic/pharmacodynamic studies

that call for better control of drug absorption into the systemic circulation (e.g.,

to ensure rapid onset of an analgesic effect or to avoid an excessive

hypotensive action of an antihypertensive). In this setting, the guidance

recommends use of partial AUC as an early exposure measure. We

recommend

that the partial area be truncated at the population median of Tmax values for

the reference formulation. We also recommend that at least two quantifiable

samples be collected before the expected peak time to allow adequateestimation of the partial area. (1)

RAPID ONSET:

To date this standard has only been applied to two drug

ibuprofen and tablet formulations of sumatriptan. This no

that bioequivalence standards for drugs for which an ea

rate of absorption is important because of therapeutic o

example, an analgesic for rapid relief of pain) are as des

guidelines and policy statements. In addition, the relativ

the test to reference formulation should be within 80 to 1

AUCReftmax for a test product is defined as the area u

time of the maximum concentration of the reference pro

each study subject. We reiterate that this notice appliesbioavailability (bioequivalence) studies only. Submission

comparative (superiority) claims, such that time to onse

may need additional pharmacokinetic-pharmacodynamic

BA/BE Guidelines



Specifics for

Modified

Release Drugs

MODIFIED RELEASE:

For modified-release products submitted as ANDAs, the following studies are

recommended: (1) a single-dose, nonreplicate, fasting study comparing the

highest strength of the test and reference listed drug product and (2) a food-

effect, nonreplicate study comparing the highest strength of the test and

reference product (see section VI.A). Because single-dose studies are

considered more sensitive in addressing the primary question of BE (i.e.,

release of the drug substance from the drug product into the systemic

circulation), multiple-dose studies are generally not recommended, even in

instances where nonlinear kinetics are present. (1)

Extra PK parameters:

• Lag-time (tlag) for modified-release products, if present (2)

MODIFIED RELEASE (APPLIES TO SINGLE DOSE)

PK Parameters: AUCX, AUCT, AUCI, AUCX/AUCI, A

lambda. For formulations that are likely to accumulate

(i.e., AUCX/AUCI < 0.8), safety requires that steady-st

in addition to the single-dose studies. Where the AUCX

be reliably determined, accumulation must be assume

Standards for

BE: High

variability

drugs

Non-Linear

Kinetics

(Report C)

NON-LINEAR KINETICS:

These requirements must be met in both the fasting a

where it has been demonstrated that food does not mo

doses within the range of strengths to be marketed. (8

The following pharmacokinetic parameters should be

dose studies: AUCX, AUCI, Cmax and, where possible

parameters should be calculated from steady state stuCpd, and Cmin.

STANDARDS FOR NON-LINEAR KINETICS DRUGS

Single Dose: Standards for bioavailability and bioequiv

described in Report A: "Bioavailability of Oral Dosage

Used for Systemic Effects".

Chronic Dose: For drugs requiring chronic dose studie

bioavailability and bioequivalence standards are requir

1. The 90% confidence interval of the relative mean AU

reference formulation should be within 80 to 125%.

2. The relative mean measured Cmax of the test to re

should be within 80 to 125%.

3. The relative mean measured Cmin of the test to ref

be within 80 to 125%.

AUCtau* is defined as the area under the plasma conc

after several doses indicating



Long Half-Life

LONG HALF-LIFE DRUGS:

In a BA or pharmacokinetic study involving an oral product with a long half-life

drug, adequate characterization of the half-life calls for blood sampling over a

long period of time. For a BE determination of an oral product with a long half-

life drug, a nonreplicate, single-dose, crossover study can be conducted,

provided an adequate washout period is used. If the crossover study is

problematic, a BE study with a parallel design can be used. For either a

crossover or parallel study, we recommend that sample collection time be

adequate to ensure completion of gastrointestinal transit (approximately 2 to 3

days) of the drug product and absorption of the drug substance. Cmax and a

suitably truncated AUC can be used to characterize peak and total drug

exposure,

respectively. For drugs that demonstrate low intrasubject variability indistribution and clearance, an AUC truncated at 72 hours (AUC0-72 hr) can be

used

in place of AUC0-t or AUC0-∞. For drugs demonstrating high intrasubject

variability in distribution and clearance, AUC truncation warrants caution. In such

cases, we also recommend that sponsors and/or applicants consult the

appropriate review staff. (1)

LONG HALF-LIFE DRUGS:

This notice serves to clarify that for drugs which exhibi

half-life greater than 24 hours, bioequivalence standar

bioavailability studies will be applied to AUC0-72h. For

bioequivalence assessment, it will not be necessary to

hours post-dose, regardless of the half-life. Alternate d

studies could be considered. (3)

Standards for

BE: Critical

Dose Drugs

CRITICAL DOSE DRUGS:

Unless otherwise indicated by a specific guidance, this guidance recommends

that the traditional BE limit of 80 to 125 percent for non-narrow therapeutic

range drugs remain unchanged for the bioavailability measures (AUC and

Cmax) of narrow therapeutic range drugs. (1)

CRITICAL DOSE DRUGS:

1. The 90% confidence interval of the relative mean AU

reference formulation should be within 90.0 to 112.0%

AUCs

as described in Guidelines A and B are to be determin

2. The 90% confidence interval of the relative mean m

to reference formulation should be between 80.0 and 13. These requirements are to be met in both the fasted

4. These standards should be met on log transformed

from the measured data and from data corrected for m

(percent potency of label claim).

5. Steady-state studies are not required for ―critical do

warranted by exceptional circumstances. If a steady-s

90% confidence interval of the relative mean measure

reference formulation should also be between 80.0 an

Data to Analyze

Subjects with predose plasma concentrations:

• If the predose concentration is ≤ 5 percent of Cmax value in that subject, the

subject‘s data without any adjustments can be included in all pharmacokinetic

measurements and calculations. We recommend that if the predose value is >

than 5 percent of Cmax, the subject be dropped from all BE study evaluations.

Data deletion due to vomiting:• We recommend that data from subjects who experience emesis during the

course of a BE study for immediate-release products be deleted from statistical

analysis if vomiting occurs at or before 2 times median Tmax. In the case of

modified-release products, the data from subjects who experience emesis any

time during the labeled dosing interval can be deleted. (1)

The analyses should include all data for all subjects (s

outs and Withdrawal of Subjects from a Study") on me

Supplementary analyses may also be carried out with

subjects initially excluded from the analyses. Such exc

It is rarely acceptable to exclude more than 5 percent

than 10 percent of the data for a single subject-formula



Sampling

Scheme

Criteria

We recommend that blood samples be drawn at appropriate times to describe

the absorption, distribution, and elimination phases of the drug. For most drugs,

we recommend that 12 to 18 samples, including a predose sample, be collected

per subject per dose. This sampling can continue for at least three or more

terminal half lives of the drug. The exact timing for sample collection depends

on the nature of the drug and the input from the administered dosage form. The

sample collection can be spaced in such a way that the maximum concentration

of the drug in the blood (Cmax) and terminal elimination rate constant (λz) can

be estimated accurately. At least three to four samples can be obtained during

the terminal log-linear phase to obtain an accurate estimate of λz from linear

regression. (1)

The duration of blood or urine sampling in a study sho

account for at least 80 percent of the known AUC to in

is usually at least three times the terminal half-life of th

Calculation of the relevant pharmacokinetic parameter

should be collected per subject per dose. There may b

inaccuracies in the estimates of the terminal dispositio

constant is estimated from linear regression using only

these inaccuracies it is preferable that four or more po

the terminal log-linear phase of the curve. (1)

Washout

An adequate washout period (e.g., more than 5 half lives of the moieties to be

measured) would separate each treatment. (1)

The interval should be the same for all subjects and, to

elimination rate between subjects, normally should be mean terminal half-life of the drug. (generally, the inter

should not exceed four weeks). (1,7)

Fasting vs.

Fed: SingleDose

we recommend a BE study under fed conditions for all orally administered

immediate-release drug products, with the

following exceptions:

• When both test product and RLD are rapidly dissolving, have similar

dissolution profiles, and contain a drug substance with high solubility and high

permeability (BCS Class I) (see footnote 3), or

• When the DOSAGE AND ADMINISTRATION section of the RLD label states

that the product should be taken only on an empty stomach, or

• When the RLD label does not make any statements about the effect of food on

absorption or administration. (2)

In ANDAs, BE of the test to the RLD is demonstrated in a single dose crossover

study. Both treatments should be sprinkled on one of the soft foods mentioned

in the labeling, usually applesauce. The BE data should be analyzed using

average BE and the 90 percent CI criteria should be used to declare BE. If

there are questions about other foods, the design, or the analysis of such BE

studies, the sponsors and/or applicants should contact the Office of Generic

Drugs.(2)

For uncomplicated drugs in immediate-release dosage

documented serious safety risk to subjects from single

the drug or drug product in the absence of food, then a

study conducted in the presence of only a sufficient qu

the toxicity may be acceptable for purposes of BE ass

Fasting vs.Fed: Modified

Release

We recommend that food-effect BA and fed BE studies be performed for all

modified release dosage forms.

A second or subsequent market entry MR formulation

the Group I or II MR product with which bioequivalence

formulations should be administered as single doses.

studies is to evaluate the bioequivalence of the test an

products under both fasting and fed conditions. Howevmay require that an investigation be conducted after th

appropriate meal at a specified time before taking the

manufacturers should consult with Health Canada befo

(7)

Fasting vs.

Fed: Critical

Dose

CRITICAL DOSE:

In general BE should be demonstrated under both fast

For complicated drugs in immediate-release dosage fo

modified-release dosage forms [#5.3], if there is a doc

risk to subjects from single-dose administration of the

either the absence or presence of food, then an appro

conducted in the indicated condition of use (fed or fast

acceptable for purposes of BE assessment. (5)

Blinding

If possible, the study should be conducted in such a w

aware of which product is administered. Furthermore,

adverse reactions and the person conducting the anal

know which product was administered. Other individua

administration of the drugs, the surveillance of the pat

plasma (or blood, or serum) data should not know whic

administered. (1)

Reference

Product

For ANDAs, we also recommend that the BE study be conducted between the

test product and reference listed drug using the strength(s) specified in

Approved Drug Products with Therapeutic Equivalence Evaluations (Orange

Book). (1)

• a drug product that has been issued a notice of comp

section C.08.004 of the Food and Drug Regulations, a

in Canada by the innovator, or

• a drug product acceptable to the Director. (1)



Metabolites

For BE studies, measurement of only the parent drug released from the dosage

form, rather than the metabolite, is generally recommended. The rationale for

this recommendation is that concentration-time profile of the parent drug is

more sensitive to changes in formulation performance than a metabolite, which

is more reflective of metabolite formation, distribution, and elimination. The

following are exceptions to this general approach.

• Measurement of a metabolite may be preferred when parent drug levels are

too low to allow reliable analytical measurement in blood, plasma, or serum for

an adequate length of time. We recommend that the metabolite data obtained

from these studies be subject to a confidence interval approach for BE

demonstration. If there is a clinical concern related to efficacy or safety for the

parent drug, we also recommend that sponsors and/or applicants contact the

appropriate review division to determine whether the parent drug should be

measured and analyzed statistically.• A metabolite may be formed as a result of gut wall or other presystemic

metabolism. If the metabolite contributes meaningfully to safety and/or efficacy,

we also recommend that the metabolite and the parent drug be measured.

When the relative activity of the metabolite is low and does not contribute

meaningfully to safety and/or efficacy, it does not have to be measured. We

recommend that the parent drug measured in these BE studies be analyzed

using a confidence interval approach. The metabolite data can be used to

provide supportive evidence of comparable therapeutic outcome. (1)

Determination of bioequivalence should be based on d

Waiver of the measurement of the parent drug will not

concentrations of the parent drug cannot be reliably m

parent drug is not detectable due to rapid biotransform

available assay methodology. In such instances, the u

be acceptable. The measured metabolite should be a

major one, and appropriate scientific justification for a

measurement of the parent drug and the use of metab

provided. The choice of using the metabolite instead o

clearly stated, a priori, in the objective of the study in t

For the purpose of this guidance, a pro-drug is to be tr

That is, if the substance released from the dosage formis reliably measurable in the systemic circulation, it sho

assessment of bioequivalence. It is not generally cons

measure both

parent drug and metabolite levels for the purpose of b

assessment. However, quantitation of metabolite level

helpful, e.g., to explain extreme values caused by meta

subject. In those rare situations where use of drug con

justifiable for the assessment of relative bioavailability

concentrations may be used. That is, use of metabolite

Combining

Studies

If two or more studies have been completed, they may

requirements are met.

a) The same protocol must be used for all studies.

Specifically, this means that the same analytical metho

samples drawn at the same time, and the same lots o

used.b) Two consistency tests must be done on the studies

meaningful.

The first test is the test of equality of the residual mean

of the residual from the first study to the residual for ea

(For each ratio, the smaller of the two residuals must b

denominator.) This ratio is compared to an F statistic,

freedom associated with the residuals. If the ratio is gr

value, the studies may not be combined. The second t

study interaction and is carried out as shown in Table 7

Sources:

(1) Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally

Administered Drug Products — General Considerations. U.S. Department of

Health and Human Services, Food and Drug Administration, Center for DrugEvaluation and Research (CDER); March 2003. BP Revision 1.

(1) Guidance for Industry: Conduct and Analysis of Bio

Bioequivalence Studies - Part A: Oral Dosage Formula

Effects. Health Products and Food Branch Guidance D

(2) Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence

Studies. U.S. Department of Health and Human Services. Food and Drug

Administration. Center for Drug Evaluation and Research (CDER); December

2002. BP.

(2) DRAFT GUIDANCE FOR INDUSTRY: Use of Meta

Comparative Bioavailability Studies. Health Products a

2004/05/05.

(3) NOTICE TO INDUSTRY: Bioequivalence Requirem

Drugs. file 05-113899-750. June 22, 2005.

(4) NOTICE TO INDUSTRY: Bioequivalence Requirem

an Early Time of Onset or Rapid Rate of Absorption Is

drugs). 05-113913-859. June 22, 2005.

(5) GUIDANCE FOR INDUSTRY: Bioequivalence Req

Bioavailability Studies Conducted in the Fed State. He

Branch. 05-114865-164. July 21, 2005.

(6) GUIDANCE FOR INDUSTRY: Bioequivalence Req

Drugs. Health Products and Food Branch. 06-112871-

(7) GUIDANCE FOR INDUSTRY: Conduct and Analys

Bioequivalence Studies - Part B: Oral Modified Releas

Products and Food Branch Guidance Document. 1996



Canadian BA/BE Drug Classification System

Critical Dose Drugs

Cyclosporine C - Critical Dose Drug

Digoxin C - Critical Dose Drug

Flecainide C - Critical Dose Drug

Lithium C - Critical Dose Drug

Phenytoin C - Critical Dose Drug

Sirolimus C - Critical Dose Drug

Tacrolimus C - Critical Dose Drug

Theophylline C - Critical Dose Drug

Warfarin C - Critical Dose Drug

Drugs with Non-Linear Kinetics

Acetylsalicylic acid C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)

Acyclovir C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)

Carbamazepine C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)

Cephalosporins C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)Disopyramide C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)

Fluorouracil C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)

Glucocorticosteroids C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)

Griseofulvin C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)

Levodopa C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)

Phenytoin C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)

Propranolol C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)

Rifampin C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)

Valproic acid C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)

Verpamil C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)



FDA Special Guidances/Exceptions: Bioequivalence

FDA Special Guidances:

Clozapine Steady-state study in patients required at 100 mg. See http://www.fda.gov/CDE

Potassium Chloride Steady-state study required. See http://www.fda.gov/CDER/GUIDANCE/old195f

FDA Exceptions:

Source: http://www.fda.gov/cder/orange/obannual.pdf

The following drugs are defined by the 2008 FDA Orange Book as, "DRUG PRODUCTS WHICH

MUST DEMONSTRATE IN VIVO BIOAVAILABILITY

ONLY IF PRODUCT FAILS TO ACHIEVE ADEQUATE DISSOLUTION"

http://www.fda.gov/cder/orange/obannual.pdf

http://www.fda.gov/cder/orange/obannual.pdf



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