DESIGNING AND PROTOCOL OF BIOEQUIVALNCE STUDIES AS PER CDSCO

EBIN

CDSCO
Central Drugs Standard Control Organization. Directorate General of health services March 2005 Conjugation with schedule Y, D&C act, GCP, GLP, Ethical guidelines.

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

 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

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, its design,condut and evaluation. Situation for using the In-vitro-In-vivo. Steps to taken in different formulation.

DEFINITIONS
BIOAVAILABILITY: It is relative amount of drug from 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 its 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.

SCOPE OF THE GUIDELINES

BE studies for ensure therapeutic equivalence between reference product and test product.

In vivo In-vitro methods

 WHEN BE STUDIES ARE NECESSARY AND TYPES OF STUDIES REQUIRED

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

 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.

 Pharmacokinetic Studies
o Study design
o o o o

 DESIGN AND CONDUCT OF STUDIES

Scientific questions to be answered Nature of the reference drug Availability of analytical method Design in a manner that formulation effect can distinguished

o Study population o Selection of the number of subjects

o Possible withdrawals or drop outs o At least 16 justified for ethical reasons

o Selection criteria for subjects

o o o o o Minimize intra and inter individual variation Healthy adults Risk of women of child bearing potential Elder patient of age 60 years Risk of toxicity studies have to be carried out in patients

o Genetic Phenotyping o Design the protocol to favour of Indian population

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

o Concentration of the drug is too low to accurately measure in the biological matrix o Limitation of analytical method o Unstable drugs o Drugs with short half lives o Prodrug o Racemates

o Bioanalytical methodology
o Bioanalytical methods to determine the drug in plasma, serum, blood or urine etc
o 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 Quality control samples: samples with known concentration is prepared. o Repeat Analysis: due to processing error, equipment failure.

o Statistical Evaluation
o Data analysis o Statistical analysis

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 o o o o Delayed release Sustained release Mixed immediate release and sustained release Mixed delayed and sustained release Mixed immediate and delayed release

o Study parameters
o Different with active ingredient

o Study design
o Dose and Fed state/ fasting state

o Requirements for modified release formulations unlikely to accumulate

o Modified release product is first marketed of that type dosage from the reference product should be immediate release formulation. o If second compare with the same product for BE

o Requirements for modified release formulations likely to accumulate

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

 PHARMACODYNAMIC STUDIES
o Studies in healthy volunteers or patients for parameter to establish equivalence between two products 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 As per IP

DOCUMENTATION
i. ii. iii. iv. v. Clinical Data Details of the analytical method validation Analytical data of volunteer plasma samples Raw data All comments of the chief investigator regarding the data of the study submitted for review vi. A copy of final report

Facilities for conducting BE studies  Legal identity  Impartiality, Confidentiality and integrity  Organisation and management  Documentation and Standard operating procedures  Clinical pharmacological unit

 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 retained by organization carrying out the BE studies for 3 years or after 1 year of expiry of drug.

Special topics
o Food effect bioavailability studies o Long half life drugs o Early exposure o Individual and population bioequivalence

REFERENCE Guidelines for bioavailability and bioequivalence studies by

CDSCO Ministry of health Government of India March 2005