697572_634268337552295000

8/3/2019 697572_634268337552295000

http://slidepdf.com/reader/full/697572634268337552295000 1/20

DESIGNING AND PROTOCOL

OF BIOEQUIVALNCESTUDIES AS PER CDSCO

EBIN

8/3/2019 697572_634268337552295000


CDSCO

Central Drugs Standard Control Organization.

Directorate General of health services

March 2005 Conjugation with schedule Y, D&C act, GCP,

GLP, Ethical guidelines.

8/3/2019 697572_634268337552295000


contents

INTRODUCTION

DEFINITIONS

SCOPE OF GUIDELNES ± When bioequivalence studies are necessary and types of studies required

In vivo Studies

In vitro studies

± When bioequivalence studies are not necessary

DESIGN AND CONDUCT OF STUDIES ± Pharmacokinetic Studies

Study design

Study population

Study conditions

Characteristics to be investigated

Bioanalytical methodology

8/3/2019 697572_634268337552295000


Statistical evaluation

Special considerations for modified release drug products

± Study parameters

± Study design ± Requirements for modified release drug products unlikely to accumulate

± Requirements for modified release drug products likely to accumulate

Pharmacodynamic studies

Comparative clinical trials

In- Vitro studies

DOCUMENTATION FACILITIES FOR CONDUCTING BE STUDIES

MAINTENANCE OF RECORDS OF BE STUDIES

RETENSION OF BE SAMPLES

SPECIAL TOPICS

± Food effect bioavailability studies

± Long half life drugs

± Early exposure

± Individual and population bioequivalence

8/3/2019 697572_634268337552295000


INTRODUCTION

Ensuring uniformity in standards of quality,efficacy of pharmaceutical products.

BA/BE focus on the release of the drug from the

dosage form and absorption in to the systemic

circulation.

BE for the comparison of the two drug, several

test method are given to determine the

equivalence. Guidelines describe when BE is required, it¶s

design,condut and evaluation.

Situation for using the In-vitro-In-vivo.

Steps to taken in different formulation.

8/3/2019 697572_634268337552295000


DEFINITIONS

BIOAVAILABILITY: It is relative amount of drugfrom an administered dosage form which enters

the systemic circulation and rate at which the

drug appears in the systemic circulation.

BIOEQUIVALENCE: BE of the drug product is

achieved if it¶s extent and rate of absorption are

not statistically different from those of the

reference product when administered at the

same molar dose.

PHARMACOKINETIC TERMS:

Cmax,Cmin,Cpd,Tmax, AUC0-t, AUC0- etc.

8/3/2019 697572_634268337552295000


SCOPE OF THE GUIDELINES

BE studies for ensure therapeutic equivalence

between reference product and test product.

In vivo In-vitro methods

8/3/2019 697572_634268337552295000


WHEN BE STUDIES ARE NECESSARY AND TYPES OF STUDIES

REQ UIRED

In vivo studies

o Oral immediate release drug formulations

o Non-oral and non-parentral drug formulations designed to act

systemic absorption

o Sustained or modified release drug formulation.

o Fixed dose combination with systemic action.

o Non solution ph. Products which are for non systemic use with

out systemic absorption

8/3/2019 697572_634268337552295000


In Vitro studies

o Drug for which applicant provides the data

Highest dose strength is soluble at 250ml pH 1-7.5

90% is absorbed orally

As per IP

Different strength of the drug manufactured by the same

manufacturer

When bioequivalence studies are not necessary

Parenterally administered drug

New drug in solution for oral, does not contain excipient that produce

GIT irritation.

Drug is gas

New drug is powder and is reconstitution and follow above points New drug is inhalation and no new devices is used for the inhalation.

8/3/2019 697572_634268337552295000


DESIGN AND CONDUCT OF STUDIES Pharmacokinetic Studies

o Study designo Scientific questions to be answered

o Nature of the reference drug

o Availability of analytical method

o Design in a manner that formulation effect can distinguished

o Study population

o

Selection of the number of subjectso Possible withdrawals or drop outs

o At least 16 justified for ethical reasons

o Selection criteria for subjectso Minimize intra and inter individual variation

o Healthy adults

o Risk of women of child bearing potential

o Elder patient of age 60 years

o Risk of toxicity studies have to be carried out in patients

o Genetic Phenotyping

o Design the protocol to favour of Indian population

8/3/2019 697572_634268337552295000


o Study conditions

o Standardisation of environment usually diet, fluid intake, post

dosing postures, exercise, sampling schedule.

o Selection of blood sampling points

o Fasting and fed state considerations

o Steady state studies

o Characteristic to be investigated during BE studies

oConcentration of the drug is too low to accuratelymeasure in the biological matrix

o Limitation of analytical method

oUnstable drugs

oDrugs with short half lives

oProdrug

oRacemates

8/3/2019 697572_634268337552295000


o Bioanalytical methodology

o Bioanalytical methods to determine the drug in plasma,

serum, blood or urine etco Pre study Phase: actual start of studies & validation of method on

biological matrix

o Study Phase: Validated bioanalytical method is applied to the

actual analysis of samples from BE

o Q uality control samples: samples with known concentration isprepared.

o Repeat Analysis: due to processing error, equipment failure.

o Statistical Evaluation

o Data analysiso Statistical analysis

8/3/2019 697572_634268337552295000


o Criteria for BE studies

o 90% confidence Interval for AUC and C max

o Tighter limits for permissible differences for drugs

o Narrow therapeutic index

o Serious dose related toxicity

o Step dose curve

o Non linear pharmacokinectics.

o Wider limits for sound clinical justification

o Deviation from the study plan

o Drop outs

o Special considerations for modified release drug products

o Delayed release

o Sustained release

o Mixed immediate release and sustained release

o Mixed delayed and sustained release

o Mixed immediate and delayed release

8/3/2019 697572_634268337552295000


o Study parameters

oDifferent with active ingredient

o Study designoDose and Fed state/ fasting state

o Requirements for modified release formulationsunlikely to accumulate

oModified release product is first marketed of that typedosage from the reference product should be immediaterelease formulation.

o If second compare with the same product for BE

o Requirements for modified release formulationslikely to accumulate

o Single dose and steady dose of modified releaseformulation should compare with immediate release

8/3/2019 697572_634268337552295000


PHARMACODYNAMIC STUDIES

o Studies in healthy volunteers or patients for

parameter to establish equivalence between twoproducts

o Studies necessary if analysis of the drug in plasma

or urine is not sufficient accuracy and sensitive

COMPARATIVE CLINICAL STUDIES

o If plasma concentration is not suitable to asses

equivalence

o Comparative clinical studies for orally administered

drug concentration

o Outline what other methods were tried and why

unsuitable in the final report of BE

In Vitro studies

8/3/2019 697572_634268337552295000


DOCUMENTATION

i. Clinical Data

ii. Details of the analytical method validation

iii. Analytical data of volunteer plasma samples

iv. Raw datav. All comments of the chief investigator

regarding the data of the study submitted for

review

vi. A copy of final report

8/3/2019 697572_634268337552295000


Facilities for conducting BE studies

Legal identity

Impartiality, Confidentiality and integrity

Organisation and management

Documentation and Standard operating procedures

Clinical pharmacological unit

8/3/2019 697572_634268337552295000


Maintenance of records for BE studies

o At least 2 years after the expiration date of the

drug

Retention of BE samples

o All samples used in BE studies should be retainedby organization carrying out the BE studies for 3years or after 1 year of expiry of drug.

Special topics

o Food effect bioavailability studies

o Long half life drugso Early exposure

o Individual and population bioequivalence

8/3/2019 697572_634268337552295000


REFERENCE

Guidelines for bioavailability and

bioequivalence studies

by

CDSCO

Ministry of

health

Government

of India

March

8/3/2019 697572_634268337552295000


697572_634268337552295000

Documents

Transcript of 697572_634268337552295000