Clinical Study Report:

Bioequivalence, General
concepts and overview
Ariya Khunvichai, Ph.D.

20 April 2007
Objective
To assist sponsors in the development of a
report that is complete, free from ambiguity,
well organized, and easy to review
 a clear explanation of how the critical design
features of the study were chosen
 analytical methods
 full description of safety, all individual subject
data (PK ,adverse events or laboratory
abnormalities, demographic information)
 data listings (usually in Appendix)
General Information

 Data should be presented in the report at

different levels
- Most important data (fig, tab) should be placed in
the text to illustrate important points; others should
be provided in section 14 or 16.
 In any table, figure or data listing, detailed
explanations should be provided
 Summary Basis of Clinical Study
Report
1. Title Page
2. Synopsis
3. Table of Contents
4. List of Abbreviation
5. Ethics
6. Investigators and Study Administrative Structure
7. Introduction
8. Study Objectives (from protocol)
9. Investigation Plan (from protocol)
10. Study Patients
11. Pharmacokinetic Evaluation
12. Safety Evaluation
13. Discussion and Overall Conclusions
14. Tables, Figures, referred to but not included in the text
15. References
16. Appendices
1.Title Page: should contain the following information

 Study title
 Protocol identification (code or number)
 Test drug
 Indication
 Development phase
 Study start date (ICH—“first subject enrolled, or other verifiable definition”)
 Study end date (date last subject completed follow-up)
 Principal Investigator (Name and affiliation of principal or coordinating
investigator, or sponsor’s responsible medical officer.)
 Sponsor
 Compliance statement (This study was conducted in full compliance with the
guidelines of Good Clinical Practice and of the World Medical Assembly Declara
tion of Helsinki)
 Date of report
 2. Synopsis: (limited to 3 pages, summarize the study, include numeric data to
illustrate results)

SPONSOR (For Regulatory Authority Use Only)

NAME OF FINISHED PRODUCT

NAME OF ACTIVE INGREDIENT

TITLE OF STUDY

INVESTIGATORS and STUDY CENTERS

PUBLICATION REFERENCE

STUDY PERIOD PHASE OF DEVELOPMENT

date of first enrollment Phase I
date of last completed

http://www.fda.gov/cder/guidance/iche3.pdf
SPONSOR (For Regulatory Authority Use Only)

NAME OF FINISHED PRODUCT

NAME OF ACTIVE INGREDIENT

OBJECTIVES

METHODOLOGY

NUMBER OF SUBJECTS (PLANNED AND ANALYZED)

DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION

TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBERS

DURATION OF TREATMENT

REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBERS

CRITERIA FOR EVALUATION

ANALYSIS METHODS
PHARMACOKINETICS METHODS
SAFETY METHODS

SUMMARY CONCLUSIONS
PHARMACOKINETICS RESULTS
SAFETY RESULTS
 3. Table of contents: should contain the following information

 The page number or other locating information of each

section, including summary tables, figures and graphs
 A list and the locations of appendices, tabulations, and
any case report forms provided

4. List of abbreviations:

 Abbreviated terms should be spelled out and the abbreviation

indicated in parenthesis at first appearance in the text
5. Ethics: should contain the following information
 Ethics committee or Institutional Review Board
The study protocol, informed consent, and other necessary documents were
reviewed and approved by an Ethics Committee (EC) or Institutional Review
Board (IRB) for each study site prior to initiation of the study at that site. A
list of the EC/IRBs that reviewed these documents for the clinical stud sites
is given in Appendix 16

 Ethical Conduct of the Study

This study was conducted in accordance with Good Clinical Practice (GCP) as
described in International Conference on Harmonization (ICH) Guideline E6,
Good Clinical Practice. The ICH GCP guideline is consistent with the
World Medical Assembly Declaration of Helsinki.
5. Ethics: should contain the following information

•Patient information and Consent

Written informed consent was obtained from each patient before the
screening visit. Patients reviewed the subject instructions and
informed consent form, and were given an opportunity to ask questions on
all aspects of the study. Patients were provided with a copy of the signed i
nformed consent form and subject instructions. Originals are on file at the c
linical research facility. A copy of the sample informed consent form is provi
ded in Appendix 16
 6. Investigators and Study Administrative structure
: should contain the following information
A. Investigators.

B. The author(s) of the report, including the responsible, such as

Pharmacometrician(s). Where signatures of the principal or coordinating
investigators are required by regulatory authorities, these should be included
in Appendix 16. (see Annex II for a sample form).

The administrative structure of the study should be described

briefly in the body of the report. There should be provided in Appendix 16
a list of the investigators with their affiliations, their role in the study, and
their qualifications (curriculum vitae or equivalent).
 7. Introduction: a brief statement of the development
of test drug/investigational product, rationale and aims
(maximum: one page)

• Study Objectives: describe the overall purpose(s)

of the study

Primary:
To compare the extent and rate of absorption of two formulations of
---- administered at the same dose and dosage form.
Secondary:
To examine the pharmacokinetics of----- and ------
 Table 7.1: Product Information
Product Test Reference
Treatment ID
Product Name
Manufacturer
Batch/Lot No.
Manufacture Date
Expiration Date
Strength
Dosage Form
Bio-batch Size
Production Batch Size
Potency
Content Uniformity (mean,
%CV)
Dose Administered
Route of Administration
 9. Investigational Plan: (From protocol)
Overall Study Design and plan: should include

•Treatments studied (specific drugs, doses, and procedures)

•Patient population and the number of patients
•Level and method of blinding (e.g., open, double-blind, single-blind,
and unblinded patients and/or investigators)
•Study configuration (parallel, cross-over)
•Method of assignment to treatment (randomization)
Sequence and duration of all study periods (prerandomization and
post-treatment periods, therapy withdrawal periods, and single and double-blind
treatment periods. When patients were randomized should be specified. It is
usually helpful to display the design graphically with a flow chart that includes
timing of assessments)
 9. Investigational Plan:
9.1 Discussion if Study design: should include

•Dose selection and Sample time points?

•Single or multiple dose?
•Parallel design ? Indicate
•Selection population (M/F, number of subjects)?
•Randomization was not used ? Indicate
•Washout periods and duration of the treatment period?

9. Investigational Plan:
9.2 Selection of Study Population:

• Inclusion/Exclusion Criteria defined in the protocol

• Removal of patients from Therapy or Assessment
reasons for removing patients from therapy and any planned follow up in
those patients
9. Investigational Plan:
9.3 Treatments:
9.3.1 Treatments administered

The precise treatments to be administered in each arm

, each period including route administration, dose and
dosage schedule

9. Investigational Plan:
9.3 Treatments:
9.3.2 Identity of investigational product

Formulation, strength, batch number, stability,

and storage requirements
9. Investigational Plan:
9.3 Treatments:
9.3.3 Method of assigning patients to treatment groups

A detailed description of the randomization method, including how it was

executed, should be given in Appendix 16.1.7 with references cited if necessary.
A table exhibiting the randomization codes, patient identifier, and treatment
assigned should also be presented in the Appendix.
 9. Investigational Plan:
9.3 Treatments:
9.3.4 Selection of doses in the study:

“The doses used in the study should be given for

all treatments and the basis for choosing them
described (e.g., prior experience in humans, animal data).” –ICH

9. Investigational Plan:
9.3 Treatments:
9.3.5 Selection and timing of doses for each subjects:

“Procedures for selecting each patient’s dose of test drug…and

active control/comparator should be described.
The timing…of dosing and the relation of dosing to meals should be described.
Any specific instructions to patients about when or how to take the dose(s)
should be described. –ICH
9. Investigational Plan:
9.3 Treatments:
9.3.6 Blinding:

9. Investigational Plan:
9.3 Treatments:
9.3.7 Prior and Concomittant Therapy:
 9. Investigational Plan:
9.3 Treatments:
9.3.8 Treatment compliance:

The measures taken to ensure and document treatment compliance should be

described, e.g., drug accountability, diary cards, blood, urine or other body fluid
drug level measurements, or medication event monitoring.
9. Investigational Plan:
9.4 Assessments: (Pharmacokinetics/Safety, Schedule of Assessment)

Better explain by flow chart

9. Investigational Plan:
9.4 Assessments:
9.4.1 Pharmacokinetics Assessment

Sample collection times and procedures

Sample handling and method validation
Should refer to Bioanalytical method
9. Investigational Plan:
9.4 Assessments:
9.4.2 Safety assessment

•Safety variables, Laboratory tests

•The methods for measuring them
•The persons responsible for the measurements or to review ECG’s
•Any definitions used to characterize outcome (e.g., criteria for
determining
occurrence of acute myocardial infarction, assignment of cause of death)
should be explained in full.
•Any techniques used to standardize or compare results of laboratory
tests or otherclinical measurements (e.g., ECG, chest X-ray)
should also be described.

Data Quality Assurance:

 9. Investigational Plan:
9.5 Planned Methods of Analysis:
9.5.1 Pharmacokinetic data:

•Missing data
•Data below the quantifiable limit
•Data analyzed (Which, When)
-All subjects providing pharmacokinetic assessments will be included in the
analysis. Data analyses will be performed on all PK data after the
databases have been quality assured and has been hardlocked and
the data have been transferred to the Clincial pharmacology Department.
 9. Investigational Plan:
9.5 Planned Methods of Analysis:
9.5.2 Pharmacokinetic analysis:
Noncompartmental analysis will be conducted using the validated
Winnonlin software, version…
The pharmacokinetic parameters will be calculated using actual times.
The elimination rate constant (ke) will be determined using least-squares
regression analysis from the terminal phase of the concentration time profile.
The elimination half-life will be calculated as 0.693/ke.
Area under concentration-time curves will be calculated using
the linear/log trapezoidal method. Extrapolated AUC from the last quantifiable
point (Clast) to infinity (AUC0-∞ ) will be determined as Clast/ke.
Maximum plasma concentration (Cmax) and time to reach Cmax (tmax) will
be obtained directly from observation data.
The central tendency of pharmacokinetic profiles will be graphically
depicted as a mean concentration-time profile constructed using nominal
sampling times. Mean concentrations for any one collection time across
patients reflected at least 2/3 of all patients for whom measurements
had been collected, with missing values ignored.
If a mean was calculated with less than the majority of all patients,
it was not reported in graphs or tables.
9. Investigational Plan:
9.5 Planned Methods of Analysis: (Pharmacokinetics/Safety)
9.5.2 Summary statistic:

Summary statistics (eg mean, median, standard deviation, minimum,

maximum) will be calculated for all pharmacokinetic parameters.
The statistical analysis will be conducted using the validated Winnonlin
software, version…
The 90% confidence interval (CI) for the difference in the means of
the log treansformed (AUC) and (Cmax) will be conducted using
linear mixed-effects model to determine the statistical differences of AUC
and Cmax from an analysis of variance (ANOVA).
According to bioequvalence criteria , the 90% CI of the difference
in Ln(AUC) and Ln(Cmax) or the geometric mean ratio of AUC and Cmax
must lie within 80%-125%.
 9. Investigational Plan:
9.6 Determination of Sample Size

•The study should have at least 80% power to conclude BE

•Design, variability of the study

9. Investigational Plan:
9.7 Changes in conduct of study or planned analysis

Describe any differences from what was planned in the protocol

(e.g., if an analysis was planned in the protocol but was not included in the
CSR, if an analysis that is included in the CSR was not planned in the
protocol,
or if an analysis was done using a different method than stated in the
protocol).
 10. Study Patient:
10.1 Disposition of Patient:

•The number of patients who were randomized, entered,

and completed the study
•The reasons for all discontinuations (e.g.., AE, poor compliance)

10. Study Patient:

10.2 Protocol Deviation:
•Study inclusion/exclusion criteria
(those who entered the study even though they did not satisfy the criteria)
•Conduct of the trial (those who received the wrong treatment)
•Patient assessment
Study No.
Type Subject #s Subject #s
(Test) (Ref.)
11. Bioanalytical, PK and Safety Evaluation :
11.1 Demographic and other Baseline Characteristics:

Age, sex, Weight, Lab values and Concomitant medication should be

Presented in by-patient tabular listings (Appendice)

ID Sex Age Height BMI Race Weight

(year) (Cm) (kg/M2) (kg)
1 F
2 M
3
4

ID Creatinine Albumin SGOT SGPT Total BUN

(0.5-1.5 mg/dl) (3.5-5.5 (up to 35) (up to 45 U) Bilirubin (7-17 mg/dl)
g/dl) (0.3-1.1
mg/dl)
1 F
2 M
3
4
Table 11.1 Summary Statistic of Demographic Profile of Subjects Completing the Bioequivalence Study
Study No.
Treatment Groups
Test Product Reference Product
N= N=
Age Mean ± 50 ± 15
(years) SD
Range 21 - 64
Age < 18 N(%) N(%)
Groups
18 – 40 N(%) N(%)
40 – 64 N(%) N(%)
65 – 75 N(%) N(%)
> 75 N(%) N(%)
Sex Male N(%) N(%)
Female N(%) N(%)
Race Asian N(%) N(%)
Black N(%) N(%)
Caucasian N(%) N(%)
Hispanic N(%) N(%)
Other N(%) N(%)
BMI Mean ±
SD
Range
Other Factors
 11. Bioanalytical, PK and Safety Evaluation :
11.2 Bioanalytical Results:

A summary of the bioanalytical evaluation, including the data

for the standard curves and quality control samples analyzed with the study
samples can be found in Section 16.1.13 of this report
 Table 11.1 Bioanalytical Method Validation
Information Requested Data
Bioanalytical method validation Provide the volume(s) and page(s)
report location
Analyte Provide the name(s) of the analyte(s)
Internal standard (IS) Identify the internal standard used
Method description Brief description of extraction method;
analytical method
Limit of quantitation LOQ, units
Average recovery of drug (%) %
Average recovery of IS (%) %
Standard curve concentrations Standard curve range and appropriate
(units/mL) concentration units
QC concentrations (units/mL) List all the concentrations used
QC Intraday precision range (%) Range or per QC
QC Intraday accuracy range (%) Range or per QC
QC Interday precision range (%) Range or per QC
QC Interday accuracy range (%) Range or per QC
Bench-top stability (hrs) hours @ room temperature
Stock stability (days) days @ 4ºC
Processed stability (hrs) hours @ room temperature; hours @ 4ºC
Freeze-thaw stability (cycles) # cycles
Long-term storage stability (days) 17 days @ -20ºC (or other)
Dilution integrity Concentration diluted X-fold
Selectivity No interfering peaks noted in blank plasma
samples
 Table 11.2 Reanalysis of Study Samples

Study No.
Additional information in Volume(s), Page(s)
Number of recalculated values used after
Number of samples reanalyzed
reanalysis
Reason why assay was
repeated Actual number % of total assays Actual number % of total assays
T R T R T R T R
Pharmacokinetic1
Reason A (e.g. below
LOQ)
Reason B
Reason C
Etc.
Total
11. Bioanalytical, PK and Safety Evaluation :
11.3 Pharmacokinetic Results:

11.3.1 Data Sets Analyzed (exactly which patients were included in the analysis)
11.3.2 Results
•Median concentration versus time by Formulation (Test/Reference)
•Summary statistic of PK parameters (min, Max, median, CV) and concentrations
at each time points
•Box plot (AUC, Cmax) by formulations across subjects
•ANOVA and 90% CI for AUC and Cmax with geometric mean
Table 11. Statistical Summary of the Comparative Bioavailability Data

Drug
Dose (# x mg)
Least Squares Geometric Means, Ratio of Means, and 90% Confidence Intervals
Fasted Bioequivalence Study (Study No.)
Parameter Test Reference Ratio 90% C.I.

AUC0-t

AUC∞

Cmax
Fed Bioequivalence Study (Study No.)
Parameter Test Reference Ratio 90% C.I.

AUC0-t

AUC∞

Cmax
 Table 11. Individual PK Parameter listing by subject

Subjects Mean Parameters (+/-SD)

Treatments Study
Study (No. (M/F)
Study Study (Dose, Dosage Report
Ref. Type Cmax
Objective Design Form, Route) Tmax AUC0-t AUC∞ T½ Kel Locatio
No. Age: mean (units/
[Product ID] (hr) (units) (units) (hr) (hr-1) n
(Range) mL)
Test product
strength Media
Tab./Cap./Susp # completing n M
p.o. (#M/#F) (Rang M M (%C M
Fasting Randomized
[Batch #] Healthy subjects M (%CV) e) (%CV) (%CV) V) (%CV) Vol.#
Study # study single-dose
Ref. product or patients M (%CV) Media M M M M p.#
title crossover
strength mean age n (%CV) (%CV) (%C (%CV)
Tab./Cap./Susp (range) (Rang V)
p.o. e)
[Batch #]
Test product
strength Media
Tab./Cap./Susp # completing n M
p.o. (#M/#F) (Rang M M (%C M
Randomized
Fed study [Batch #] Healthy subjects M (%CV) e) (%CV) (%CV) V) (%CV) Vol.#
Study # single-dose
title Ref. product or patients M (%CV) Media M M M M p.#
crossover
strength mean age n (%CV) (%CV) (%C (%CV)
Tab./Cap./Susp (range) (Rang V).
p.o. e)
[Batch #]
11. Bioanalytical, PK and Safety Evaluation :
11.3 Safety Results:
11.3.1 Brief summary of Adverse Events

Table Number of Subjects Who Reported Adverse Events in

Each Study Period
Study Period/Variable Test Reference
Study Period N= N=
nSubjects with at least 1 adverse event (n [%])
nSubjects with at least 1 adverse event related to study
drug (n [%])
nSubjects with at least 1 SAE (n [%])
nSubjects with at least 1 SAE related to study druga (n
[%])
nNumber of adverse events leading to discontinuation
nNumber of adverse events leading to dose
interruption
 11. Bioanalytical, PK and Safety Evaluation :
11.3 Safety Results:
11.3.1 Display of Adverse Events

Reported Incidence by Treatment Groups

Body System / Fasted/Fed Bioequivalence Study
Adverse Event Study No.
Test Reference
Gastrointestinal disorder
•Nausea
•Vomiting
•Dry mouth
N (%) N (%)
•Diarrhea
•Vomiting

Psychiatric disorders
Insomnia
N (%) N (%)
Depression

Irritability

Total N (%) N (%)

11. Bioanalytical, PK and Safety Evaluation :
11.3 Safety Results:
11.3.2 Analysis of Adverse Events
11.3.3 Listing of Adverse Events by Subjects

11. Bioanalytical, PK and Safety Evaluation :

11.3 Safety Results:
11.3.4 Deaths, Other Serious Adverse Events, And
Other Significant Adverse Events

• Listing of Deaths, Other Adverse Events, and Other Significant

Adverse Events
Deaths
• Narratives of Deaths, Serious Adverse Events, and Significant
Adverse Events
11. Bioanalytical, PK and Safety Evaluation :
11.4 Clinical Laboratory Evaluation:
11.4.1 Listing of individual laboratory measurements by subject

11. Bioanalytical, PK and Safety Evaluation :

11.5 Vital Sign
11.6 Safety Conclusions
13. Discussion and Overall Conclusions :
14. Table, Figure and Graph

15. References

16. Appendices
16.1 Study information (Protocol and Protocol Amendment, list and
description
of investigator, Signature of investigators, randomization scheme and codes)

16.2 Subject data listings (Discontinued patient, Protocol deviations,

Demographic data, Adverse event listings (each patient,
Listing of individual laboratory measurements by patient)

16.3 Case report forms

16.5 Bioanalytical, pharmacokinetic, and pharmacodynamic appenices

(Listing of individual concentrations, Listing of PK parameters,
BA validation report including chromatogram of standard, unknown sample
and drug-free Biological matrix and all previous mentions,
all PK noncompartmental analysis and statistical output)
SUBJID NRT ART DOSE TREATMENT LAB ASSAY Code
(mg) COMMENT NUMBER

1 0 Test BQL

1 0.25 Test BQL

1 0/5 Test
The Last Step!!!

 All Clinical study reports must be approved

by the PI , and sponsors (PK, BA,)
 The report should be approved (signed and
dated) by the responsible persons
Thank you and
Discussions!