Clinical Study Report, Bioequivalence, General Concepts and Overview

Clinical Study Report:Bioequivalence, General concepts and overview

Clinical Study Report:Bioequivalence, General concepts and overview

Ariya Khunvichai, Ph.D.

20 April 2007

Objective

To assist sponsors in the development of areport 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

1. Title Page2. Synopsis3. Table of Contents4. List of Abbreviation5. Ethics6. Investigators and Study Administrative Structure7. Introduction 8. Study Objectives (from protocol)9. Investigation Plan (from protocol)10. Study Patients 11. Pharmacokinetic Evaluation12. Safety Evaluation13. Discussion and Overall Conclusions14. Tables, Figures, referred to but not included in the text15. References 16. Appendices

Summary Basis of Clinical Study Report

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 g

uidelines of Good Clinical Practice and of the World Medical Assembly Declaration of Helsinki)

Date of report

1.Title Page: should contain the following information

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 PERIODdate of first enrollmentdate of last completed

PHASE OF DEVELOPMENTPhase I

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 METHODSPHARMACOKINETICS METHODSSAFETY METHODS

SUMMARY CONCLUSIONSPHARMACOKINETICS RESULTSSAFETY RESULTS

CONCLUSIONS

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

3. Table of contents: should contain the following information

4. List of abbreviations:

Abbreviated terms should be spelled out and the abbreviation indicated in parenthesis at first appearance in the text

Ethics committee or Institutional Review BoardThe study protocol, informed consent, and other necessary documents werereviewed and approved by an Ethics Committee (EC) or Institutional ReviewBoard (IRB) for each study site prior to initiation of the study at that site. Alist of the EC/IRBs that reviewed these documents for the clinical stud sitesis given in Appendix 16

Ethical Conduct of the StudyThis 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

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 andinformed 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 informed consent form and subject instructions. Originals are on file at the clinical research facility. A copy of the sample informed consent form is provided 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)

8. 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 ------

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

Table 7.1: Product Information

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 andpost-treatment periods, therapy withdrawal periods, and single and double-blindtreatment periods. When patients were randomized should be specified. It isusually helpful to display the design graphically with a flow chart that includestiming 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 inthose patients

The precise treatments to be administered in each arm, each period including route administration, dose anddosage schedule

Formulation, strength, batch number, stability, and storage requirements

9. Investigational Plan:9.3 Treatments:9.3.1 Treatments administered

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

A detailed description of the randomization method, including how it wasexecuted, 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:9.3.3 Method of assigning patients to treatment groups

“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

“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:9.3.4 Selection of doses in the study:

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

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 bedescribed, e.g., drug accountability, diary cards, blood, urine or other body fluiddrug level measurements, or medication event monitoring.

Sample collection times and proceduresSample handling and method validation Should refer to Bioanalytical method

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

•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 determiningoccurrence 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:9.4 Assessments:9.4.2 Safety assessment

•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:9.5.1 Pharmacokinetic data:

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%.

•The study should have at least 80% power to conclude BE•Design, variability of the study

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).

9. Investigational Plan:9.6 Determination of Sample Size

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

•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: 10.1 Disposition of Patient:

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 (Test)

Subject #s (Ref.)

11. Bioanalytical, PK and Safety Evaluation : 11.1 Demographic and other Baseline Characteristics:

Age, sex, Weight, Lab values and Concomitant medication should bePresented in by-patient tabular listings (Appendice)

ID Sex Age (year)

Height

(Cm)

BMI

(kg/M2)

Race Weight

(kg)

1 F

2 M

3

4

ID Creatinine

(0.5-1.5 mg/dl)

Albumin

(3.5-5.5 g/dl)

SGOT

(up to 35)

SGPT

(up to 45 U)

Total

Bilirubin

(0.3-1.1 mg/dl)

BUN

(7-17 mg/dl)

1 F

2 M

3

4

Study No.

Treatment Groups

Test ProductN =

Reference ProductN =

Age (years)

Mean ± SD

50 ± 15

Range 21 - 64

Age Groups

< 18 N(%) N(%)

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

Table 11.1 Summary Statistic of Demographic Profile of Subjects Completing the Bioequivalence Study

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

Information Requested Data

Bioanalytical method validation report location

Provide the volume(s) and page(s)

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 (units/mL)

Standard curve range and appropriate 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 11.1 Bioanalytical Method Validation

Study No.Additional information in Volume(s), Page(s)

Reason why assay was repeated

Number of samples reanalyzedNumber of recalculated values used after

reanalysis

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

Table 11.2 Reanalysis of Study Samples

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 concentrationsat each time points•Box plot (AUC, Cmax) by formulations across subjects•ANOVA and 90% CI for AUC and Cmax with geometric mean

DrugDose (# 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. Statistical Summary of the Comparative Bioavailability Data

StudyRef. N

o.

StudyObjective

Study Design

Treatments(Dose, Dosage For

m, Route)[Product ID]

Subjects(No. (M/F)

TypeAge: mean

(Range)

Mean Parameters (+/-SD)

StudyReportLocatio

n

Cmax(units/mL

)

Tmax(hr)

AUC0-t(units)

AUC∞(units)

T½(hr)

Kel(hr-1)

Study #Fasting studytitle

Randomizedsingle-dosecrossover

Test productstrengthTab./Cap./Suspp.o.[Batch #]Ref. productstrengthTab./Cap./Suspp.o.[Batch #]

# completing (#M/#F)Healthy subjectsor patientsmean age(range)

M (%CV)M (%CV)

Median(Range)Median (Range)

M (%CV)M (%CV)

M (%CV)M (%CV)

M (%CV)M (%CV)

M (%CV)M (%CV)

Vol.# p.#

Study #Fed studytitle

Randomizedsingle-dosecrossover

Test productstrengthTab./Cap./Suspp.o.[Batch #]Ref. productstrengthTab./Cap./Suspp.o.[Batch #]

# completing (#M/#F)Healthy subjectsor patientsmean age(range)

M (%CV)M (%CV)

Median (Range)Median (Range)

M (%CV)M (%CV)

M (%CV)M (%CV)

M (%CV)M (%CV).

M (%CV)M (%CV)

Vol.# p.#

Table 11. Individual PK Parameter listing by subject

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

Body System /Adverse Event

Reported Incidence by Treatment Groups

Fasted/Fed Bioequivalence StudyStudy No.

Test Reference

Gastrointestinal disorder•Nausea•Vomiting•Dry mouth•Diarrhea•Vomiting

N (%) N (%)

Psychiatric disordersInsomniaDepressionIrritability

N (%) N (%)

Total N (%) N (%)

11. Bioanalytical, PK and Safety Evaluation : 11.3 Safety Results:11.3.2 Analysis of Adverse Events11.3.3 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 EventsDeaths

• 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 Sign11.6 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 descriptionof 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

(mg)

TREATMENT LAB

COMMENT

ASSAY

NUMBER

Code

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!