Clinical Study Report: Bioequivalence, General concepts and overview

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Clinical Study ReportBioequivalence, General
concepts and overview

• Ariya Khunvichai, Ph.D.
• 20 April 2007

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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)

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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

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Summary Basis of Clinical Study Report

• Title Page
• Synopsis
• Table of Contents
• List of Abbreviation
• Ethics
• Investigators and Study Administrative Structure
• Introduction
• Study Objectives (from protocol)
• Investigation Plan (from protocol)
• Study Patients
• Pharmacokinetic Evaluation
• Safety Evaluation
• Discussion and Overall Conclusions
• Tables, Figures, referred to but not included in
  the text
• References
• Appendices

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1.Title Page should contain the following
information

• Study title
• Protocol identification (code or number)
• Test drug
• Indication
• Development phase
• Study start date (ICHfirst 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
  sponsors 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 Declaration of Helsinki)
• Date of report

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2. Synopsis (limited to 3 pages, summarize the
study, include numeric data to illustrate
results)
http//www.fda.gov/cder/guidance/iche3.pdf
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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

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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.

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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 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

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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).
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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 ------
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Table 7.1 Product Information
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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)

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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

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9. Investigational Plan 9.3 Treatments 9.3.1 T
reatments 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 I
dentity of investigational product
Formulation, strength, batch number, stability,
and storage requirements
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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.
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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 patients dose of
test drugand active control/comparator should
be described. The timingof 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
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9. Investigational Plan 9.3 Treatments 9.3.6
Blinding
9. Investigational Plan 9.3 Treatments 9.3.7
Prior and Concomittant Therapy
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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.
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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
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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 ECGs
• 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
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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.

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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.
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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.
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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).
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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

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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)
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Table 11.1 Summary Statistic of Demographic
Profile of Subjects Completing the Bioequivalence
Study
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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
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Table 11.1 Bioanalytical Method Validation
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Table 11.2 Reanalysis of Study Samples
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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

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Table 11. Statistical Summary of the Comparative
Bioavailability Data
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Table 11. Individual PK Parameter listing by
subject
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11. Bioanalytical, PK and Safety Evaluation
11.3 Safety Results 11.3.1 Brief summary of
Adverse Events
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11. Bioanalytical, PK and Safety Evaluation
11.3 Safety Results 11.3.1 Display of Adverse
Events
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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

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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
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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)
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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

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Thank you and Discussions!