CDSCO GUIDELINES for BA and BE studies

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DEFINITIONS:
BIOAVAILABILITY: refers to the relative amount of drug from an administered dosage form which enters the systemic circulation and the rate at which the appears in the systemic circulation.
BIOEQUIVALENCE: This is the term applied to pharmaceutical equivalents whose rate and extent of absorption are not statistically different when administered to patients or subjects at the same molar dose under similar experimental conditions.

WHAT IS CDSCO?
Means CENTRAL DRUGS STANDARD CONTROL ORGANISATION.
Given by Directorate general of health services,ministry of health and family welfare Government of India, New Delhi

FUNCTIONS OF CDSCO:
Laying down standards of drugs, cosmetics, diagnostics and devices.
Laying down regulatory measures, amendments to Acts and Rules
To regulate market authorization of new drugs and clinical research.
To approve licenses to manufacture certain categories of drugs as Central License Approving Authority i.e. for Blood Banks, Large Volume Parenterals and Vaccines & Sera.
Testing of drugs by Central Drugs Labs.

SCOPE OF GUIDELINES:
WHEN BIOAVAILABILITY STUDIES ARE NECESSARY
INVIVO STUDIES
A) Oral IR formulations with systemic action
.Indicated for serious conditions
.Narrow therapeutic window
.Complicated pharmacokinetics (variable and incomplete absorption)
.Unfavorable physiochemical properties
.Documented evidence for bioavailability problems
.High excipients/active ingredients ratio
B) Non oral and non Parenterals formulations
C) SR or MR acting by systemic absorption
D) Fixed dose combination products with systemic action
E) Non solution for non systemic use

INVITRO STUDIES
A) Drugs which satisfy the following:
.Highest dose strength is soluble in 250 ml
.At least 90% of the administered dose is absorbed.
.80% of dissolution within 15min at 37 c
B) Different strengths manufactured by same manufacturer:
.Same qualitative compositions between the strengths.
.Ratio of active ingredients / excipients is same
.Same method of manufacture
.Equivalence study performed on at least one of the strength
.Where pharmacokinetics is linear over therapeutic dose range

WHEN BIOEQUIVALENCE STUDIES ARE NOT REQUIRED
.Parenterally administered
.When new drug is solution for oral use
.When new drug is a gas
.When it is powder for reconstitution as a solution.
.When it is optic or ophthalmic or topical product prepared as aqueous solution
.When new drug is a inhalation product or a nasal spray.

DESIGN AND CONDUCT OF EXPERIMENTS
PHARMACOKINETIC STUDIES
STUDY DESIGN
The basic design is determined by :
.Scientific questions to be answered.
.Nature of reference and dosage form to be tested.
.Availability of analytical methods.
.Benefit risk ratio considerations in regard to testing in humans.
SS study design is demanded when:
.Dose or time dependent pharmacokinetics.
.MR products.
.Where problems of sensitivity preclude.
.Intra individual variability in the plasma concentration.

STUDY POPULATION
1) SELECTION OF THE NUMBER OF SUBJECTS:
.Error variance from previous studies.
.The significance level desired(0.05)
.Expected deviation from reference product should be compatible with bioequivalence.
.Required discriminatory power (>/= 80%)
2) SELECTION CRITERIA FOR SUBJECTS:
Generally healthy adult male volunteers.
Elderly : 60 yrs or older.
3) GENETIC PHENOTYPING
Parallel group design.
4) STUDY CONDITIONS
Standardization of study environment, diet, fluid intake, post dosing postures, exercise ,sampling schedules etc..
A) selection of blood sampling points
B) Fasting and fed state considerations.

C)STEADY STATE STUDIES:
.Where drug has long t1/2
.Where assay sensitivity is inadequate to follow the elimination phase
.Toxic drugs administered to diseased ,multiple dose is required MR products.
.Drugs which induce their own metabolism
.Enteric coating preparations
.For combination products (plasma conc. Ratio is imp)
.Drugs which exhibit non-linear pharmacokinetics

CHARACTERISTICS TO BE INVESTIGATED DURING "BE" STUDIES-
.Measurements of individual enantiomers is required:
.Where they exhibit different pharmacodynamic characteristics
.Different pharmacokinetic characteristics
.Primary efficacy resides with minor
.Non-linear absorption is present with at least one of the enantiomer.

BIOANALYTICAL METHODOLOGY:
1) prestudy phase
.Stability of the drug/metabolites in the biological matrix
.specificity/selectivity
.Sensitivity
.Precision and accuracy
.Recovery
.Range and linearity
.Analytical system stability
2) study phase
3) quality control samples
4) repeat analysis

STATISTICAL EVALUATION
1) Data analysis:
To limit consumer's risk and also minimizing the manufacturer's risk
2) Statistical analysis:
ANOVA taking sources of variation into account.
90% CI of cmax and AUC should be in the range of 80% -125%.
3) Criteria for bioequivalence:
stringent limits for permissible differences in bioavailability will be required for drugs that have
.Narrow therapeutic index
.Serious ,dose related toxicity
.Steep dose/effect curve
.Non-linear pharmacokinetics within TW.
4) Deviations from study plan

SPECIAL CONSIDERATIONS FOR MODIFIED RELEASE DRUG PRODUCTS:
.Act as MR formulations and meet label claim
.Preclude the possibility of dose dumping
.Performance difference between MR and IR when used as reference
.Similar Therapeutic performance as IR when given in multiple doses
.Produce consistent pharmacokinetic performance
.Plasma levels which lie within the TW

1) Study parameters: depends on API.
2) Study design:
If food has an effect on absorption then 2 separate two way cross over studies (one in fasted & other in fed state)
If food has no effect then,3-way cross over study may be appropriate with
ref product in fasting state
Test product in fasting state
Test product in fed state.

3) Req for MR formulations unlikely to accumulate:
AUC0-t/AUC0-a >/= 0.8
4)Req for MR formulations likely to accumulate:
AUC0-t/AUC0-a

PHARMACODYNAMIC STUDIES
.Following requirements should be considered while assessing the results
.Response measured should be pharmacological
.Methodology should be validated
.Neither the test nor the reference should produce maximal response
.Response should be measured under double blind conditions quantitatively
.Non responders should be excluded
.Placebo effects should be studied priorly
.Cross over or parallel study design should be used
.Underlying pathology and natural history should be considered
.Statistical considerations are similar to pharmacokinetic study

COMPARATIVE CLINICAL STUDY:
.Terms that have to be defined in the protocol
.Target parameters representing clinical end points.
.Size of acceptance range has to be defined
.The statistical method employed.
.Where, appropriate placebo effects should be included.
.Safety end points in final comparative assessments

IN VITRO STUDIES
.The design should include:
.Individually testing of at least 12 dosage units of each batch.
.Percentage of drug released versus time profile for each batch.
.Determining the dissolution profile in at least 3 aqueous media( pH 1-6.8)
.Conducting tests on each batch using same apparatus.

DOCUMENTATION:
CLINICAL DATA
A) all relevant documents as required to be maintained for compliance with GCP guidelines
DETAILS OF THE ANALYTICAL METHOD VALIDATION
A) system suitability test
B) linearity range
C) lowest limit of quantitation
D)QC sample analysis
E) stability sample analysis
F) recovery experiment result

ANALYTICAL DATA OF VOLUNTEER PLASMA SAMPLES WHICH SHOULD INCLUDE THE FOLLOWING
A) validation data of analytical methods used
B) chromatograms of all volunteers, including any aberrant chromatograms
C) Inter and intra-day variation
D) Details of any repeated chromatograms
E) Calibration status of the instruments
RAW DATA
ALL COMMENTS OF INVESTIGATOR (data submitted for review)
A COPY OF FINAL REPORT

STUDY REPORT:
Table of contents
Title of study
Names and credentials of investigators and their signatures
Site of study and facilities used
Period of dates over which clinical and analytical steps were conducted
Names and batch numbers of the products compared
A signed declaration that this was identical to that intended for marketing
Results of assays
Full protocol for the study
Report of protocol deviations
Documentary evidence
Demographic data of subjects
Details & justifications of protocol deviations
Details of drop outs
Details of analytical methods used
Respective chromatograms covering the whole concentration range
Sampling schedules and deviations
Details of how pharmacokinetic parameters were calculated
Documentation related to statistical analysis:
Randomization schedule
Volunteer wise Plasma conc. and time points
AUC, Cmax ,tmax,ke,and t 1/2
Log transformed measures used for BE demonstration
ANOVA for AUC, Cmax
Inter, intra subject variability
Confidence intervals for AUC
Geometric, arithmetic, ratio of means
Partial AUC ,if used

FACILITIES FOR CONDUCTING BA/BE STUDIES:
Legal identity
Impartially, confidentially, independence and integrity
Organization and management
Documented SOP
Clinical pharmacological unit

MAINTAINENCE OF RECORDS OF BA/BE STUDIES
RETENTION OF BA/BE SAMPLES
SPECIAL TOPICS:
Food effects bioavailability studies
Long half life drugs
Early exposure
Individual and population bioequivalence.

References:
www.cdsco.nic.in accessed on 10 aug 2010.
Pharmaceutical bioequivalence by peter G.welling, Francis L.S. Tse, Shrikant V.Dighe, Marcel Dekker series, 1991.
Handbook of bioequivalence testing by sarfaraz K.Niazi, Informa Health care, USA, 2007.

About the Author

D Shravani's picture
Author: D Shravani

Comments

Prof. J. Vijaya Ratna's picture

Dear Shravani You have produced a good abstract of the guidelines. It is very useful for quick reference. Thank You. Vijaya Ratna
D Shravani's picture

Hello mam, Its my pleasure consolidating such useful information.. even i learned a lot during this consolidation process (its mutual actually!!..."symbiosis")

Regards,
Shravani
Team:"CHAR"MINAR
http://www.pharmainfo.net/dshravani

kranthi kumar's picture

Dear Shravani, This is good even though lenghy, I am glad to know about CDSCO, is the only organization that controls standards of drugs or is there any other organizations with it ?
D Shravani's picture

Helo Kranthi, Its lengthy...i know..but i helpless there is so much of matter which cannot be shrinked into a small paragraph. The essence would be lost in that case.. CDSCO is the main governing body..though there are small other subsidiary bodies existing...

Regards,
Shravani
Team:"CHAR"MINAR
http://www.pharmainfo.net/dshravani

Santosh kumar. JH's picture

Good source of information provided.... Can you clarify me what was this Parallel group design and cross over studies? What was the population size for pharmacodynamic studies ?
P.V.ABHIGNA's picture

Dear Shravani, Good source of information fo quick reference. Can u pls tell me how does CDSCO lay the standards and is it that we use these standards as reference? Can u also tell me about parallel group design?

ABHIGNA.P.V.

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