turacoz - clinical study report

Clinical Study Report

Content

• Introduction

• Clinical Trials (Stages)

• Clinical Study Report (CSR)

• ICHE3 Guidelines for CSR

Introduction

• Report: It is a document that summarizes all the incidences and facts that occurred at a given point of time, places or situation

• Clinical Trial: A research activity that involves administration of a test treatment to some experimental unit in order to evaluate the treatment

• Clinical Study Report: It is a full length detailed document containing the new drug therapeutic efficacy, safety data for an individual study with a therapeutic or diagnostic agent

Clinical Trials

• Clinical trials are research studies involving people and these are the final

• step in a long research process that includes preliminary laboratory research

• and animal testing

• Clinical trials try to answer specific scientific questions to find better ways to

• prevent, detect, or treat diseases, or to improve care for people with diseases

• Clinical trials are necessary in order to generate new drug for its testing its

• efficacy and safety. Clinical Trials are involved in various stages

Phase I

• The drug seems reasonably safe in animal study, but has never been

• tested on humans and Focused on tolerability and safety

• 12-30 (150) healthy people (often males)

• Efficacy on biomarkers if possible

• Single and repeated doses

• Increase dose levels

• Interaction with other drugs

• Pharmacokinetics

• Explorative

• ADME (Absorption, Distribution, Metabolism Excretion)

• Through QT study

• Bridging , PK in other populations

Phase II

• The drug seems to be reasonably safe in humans and there is some sign

• of an effect on something.

• 50-1000 patients

• Extensive monitoring

• Safety and tolerability in patients

• Often complicated design, explorative

• Selection of optimal dose

• Pharmacokinetics in patients

• Effect in special populations

Phase III

• The drug seems reasonable safe to give to patients and we have and idea of which dose to use.

• 500-20000 patients

• Effect is verified in the target population

• Forms the basis of the New Drug Application (NDA)

• Interactions between drugs start to become measurable in the larger

population

• Sub-groups start to be established

• Special features and problems show up

• Confirmative

Phase IV

• Our drug is approved for use on patients .

• Often large 500-30000 patients

• Further investigation of efficacy and safety post approval

• Special populations

• New indications

• Marketing

Observational studies

Data is collected for a set of patients without any randomisation

Prospective: Data is collected after the objectives are set

Retrospective: Data is collected before the objectives are set

timenow

data collection analysis interpretation

The path to a new medicine

Years 1 162 3 4 5 6 7 8 9 10 11 12 13 14 15

No. of compounds Up to 10,000 10-15 1-8 1-3 1

First patentapplication

Clinical trialapplication

Product licenceapplication

Drug Discovery Drug Development Target and leadidentification

Leadoptimisation Concept testing

Developmentfor launch Launch

Clinical DevelopmentPhase I12-150people

Phase II50-1000people

Phase III500-5,000people

Phase IV studies continue

Product lifecycle support

Toxicology and pharmacokinetic studies(absorption, distribution, metabolism, excretion)

Pharmaceutical and analytical development

Process chemistry and manufacturing

Registration and regulatory affairs

Sales and marketing (preparation, promotion, advertising and selling)

The Clinical Study Process

Outline Clinical Study Protocol

Statistical Analysis Plan

Study Conduct

Data CaptureStudy Setup

Statistical Analysis

Clinical Study Report

Publications

Clean File

T i m e

Preparation of statistical analysis

Data base lock

CSR

• A Clinical Study Report (CSR) is one of many types of regulatory documents that comprise a marketing application for a drug, biologic, or device

• A CSR is a descriptive account of a single clinical trial accompanied by tables, listings, and figures (TLFs) displaying all study data and results

• CSR is an extensive and complete document which has to be submitted for obtaining a marketing authorization of IMP to the European Union or the United states.

• The content of a CSR is similar to that of a peer reviewed manuscript.

• The CSR has to follow certain rules made by format of a Clinical Study Report, recommended by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline E3 on Structure and Content of Clinical Study Reports, which was approved in 1996.

• Several guidelines are applicable to the clinical development of IMPs for human use (eg, ICH M4E, ICH E3, E3 CTD , Canadian, USFDA Requirement, TGA).

• Each guide line has own sections of rules which CSR has to be followed.

• Even country has its own set of fundamental rules in order to prepare CSR.

• However, the ICH E3 guideline only provides information on the structure and content of full Clinical Study Reports.

Various Guidelines and their links

• ICH (international Conference on Harmonisation) http://www.ich.org/products/guidelines.html

• FDA (Food and Drug Agency) (http://www.fda.gov/)

• EMEA (European Medicines Agency) http://www.emea.europa.eu/

• Canadian (http://www.hc-sc.gc.ca/dhp-mps/ prodpharma/ applic- demande/guide-ld/ich/ efficac / e3-eng.php)

• Australian TGA (http://www.tga.gov.au /sites /default /files/clinical-trials- handbook.pdf).

http://www.ich.org/products/guidelines.html

http://www.fda.gov/

http://www.emea.europa.eu/

ICH E3 GUIDELINES FOR CLINICAL STUDY REPORT

Structure of full CSR

Structure of a full Clinical Study Report according to the International Conference on Harmonization of Technical Requirements

For Registration of Pharmaceuticals for Human Use (ICH E3) guideline (5,6)

• 1. Title Page

• 2. Synopsis

• 3. Table of Contents

• 4. List of Abbreviations and Definitions of Terms

• 5. Ethics

• 6. Investigators and Study Administrative Structure

• 7. Introduction

Structure of full CSR (cont.)

• 8. Study Objectives

• 9. Investigational Plan

• 10. Study Patients

• 11. Efficacy Evaluation

• 12. Safety Evaluation

• 13. Discussion and Overall Conclusions

• 14. Tables, Figure and Graphs Referred to But Not Included in the Text

• 15. Reference List

• 16. Appendices


Section 1. Title Page

• Study Title

• Name of test drug/investigational product

• Studied indication, study design

• Sponsor name and address

• Protocol identifier

• Dates of initiation, early termination, termination, completion of the study

• Completion name and address of Principal Investigator

• GCP statement to state whether the study was conducted in compliance with GCP guideline and date of the report


Section 2. Synopsis: Synopsis summarizes the study in brief.

Section 3. Table of contents for the individual clinical study report

This section contains the table include summary tables, figures and graphs.

Section 4. List of Abbreviations: This section include a list of abbreviations

Section 5. Ethics:

• Independent Ethics Committee,

• Patient information and consent


Section 6.0. Investigator and administrative structure contains

• The administrative structure of the study,

• Principal investigator,

• Coordinating investigator,

• Steering committee,

• Administration,

• Monitoring and evaluation committees,

• Institutions,

• Statistician,


• Central laboratory facilities,

• Contract research organization (C.R.O.),

• Clinical trial supply management) should be described briefly in the body of the report.

Section 7.0. Introduction contains

• Context of the development of the test drug/investigational product.

• Relating the critical features of the study to that development.

Section 8.0-Study Objectives

A statement describing the overall purposes of the study should be provided.


Section 9.0-Investigational plan

Section 9.1-Overall study design and plan – Description

• Treatments studied (specific drugs, doses and procedures)

• Patient population studied and the number of patients to be included

• Level and method of blinding/masking

• Kind of control method of assignment to treatment (randomization, stratification)

• Sequence and duration of all study periods

• Blind treatment periods. (see Annexes IIIa and IIIb for an example)

• Any safety, data monitoring or special steering or evaluation committees

• Any interim analyses


Section 9.2 –Discussion on study design and choice of control groups.

The specific control chosen and the study design used

Section 9.3 – Selection of Study Population

9.3.1 Inclusion Criteria

9.3.2 Exclusion Criteria

9.3.3 Removal of patients from therapy or assessment

Section 9.4- Treatments

9.4.1 Treatment administered –

The precise treatments or diagnostic agents to be administered in each arm of the study, for each period of the study, route and mode of administration, dose and dosage schedule.


9.4.2 Identity Of Investigational Product

• A brief description of the test drug(s) /investigational product(s) (formulation, strength, batch number(s)

• If more than one batch of test drug/investigational product were used, patients receiving each batch should be identified in appendix 16.1.6.

Section 9.4.3- Method of Assigning Patients to Treatment Groups

• Centralized allocation,

• Allocation within sites,

• Adaptive allocation should be described in the text of the report, including any stratification or blocking procedures.

Section 9.4.4 – Selection of doses in the study

The doses or dose ranges used

Structure of full CSR (cont.)Section 9.4.5 – Selection and timing of dosing for each patient• Procedures for selecting each patient's dose of test

drug/investigational product and active control/comparator• The timing (time of day, interval) of dosing and the relation of

dosing to mealsSection 9.4.6 – Blinding• Specific blinding, How bottles were labeled, Labels that reveal

blind-breakage, Sealed code list/envelopes, Double dummy techniques etc.

Section 9.4.7 – Prior and concomitant therapy• The medication allowed during the course of the trial along with

IMP.• Concomitant therapy effect drug-drug interaction or to direct effects

on the study endpoints

Structure of full CSR (cont.)Section 9.4.8 – Treatment Compliance• The measures taken to ensure treatment compliance, drug

accountability• Diary cards.• Blood, urine or other body fluid drug level measurements.• Medication event monitoring. Section 9.5- Efficacy and Safety VariablesSection 9.5.1 - Efficacy and safety variables assessed and flow chart• The specific efficacy and safety variables to be assessed and

laboratory tests to be conducted, their schedule (days of study, time of day, relation to meals, and the timing of critical measures in relation to test drug administration, e.g., just prior to next dose, two hours after dose),

• The methods for measuring them, and the persons responsible for the measurements should be described.

Structure of full CSR (cont.)• The frequency and timings of safety and efficacy visits

• Any definitions used to characterize outcome (e.g., criteria for determining occurrence of acute myocardial infarction) of adverse events

• Any techniques used to standardize or compare results of laboratory tests or other clinical measurements (e.g., ECG, chest X-ray)

• The means of obtaining adverse events, causality assessment and severity of adverse event assessed

Section 9.5.2 – Appropriateness of measurement

• If any of the efficacy or safety assessments was not standard,

• Widely used and generally recognized as reliable, accurate, and relevant, its reliability, accuracy and relevance should be documented.


Section 9.5.3- Primary efficacy variable(s)

• The primary measurements and endpoints used to determine efficacy

Section 9.5.4 – Drug concentration measurement

• Any drug concentrations

• The sample collection times and periods in relation to the timing of drug administration

Section 9.6 – Data Quality Assurance

• Description of the Quality control,

• Training, monitoring

• Quality assurance aspects

Section 9.7 - Statistical Methods Planned In The Protocol And Determination Of Sample Size


9.7.1 – Statistical Analysis Plan

• which analyses, comparisons and statistical tests were planned

• Excluded Patients data and specific sub groups data

Section 9.7.2 – Determination Of Sample Size

• The planned sample size and the basis for it, such as statistical considerations or practical limitations.

• Methods for sample size calculation

Section 9.8 – Changes in the conduct of the study or planned analysis

• Any change in the conduct of the study or planned analyses (e.g., dropping a treatment group, changing the entry criteria or drug dosages, adjusting the sample size etc.) instituted after the start of the study


Section 10.0 – Study Patients

10.1 – Disposition of Patients

• Clear accounting of all patients who entered the study

• The numbers of patients who were randomized, who entered and completed each phase of the study, (or each week/month of the study)

• Reasons for all post-randomization discontinuations, grouped by treatment and by major reason (lost to follow-up, adverse event, poor compliance etc.).

10.2 – Protocol Deviations

• All important deviations related to study inclusion or exclusion criteria, conduct of the trial, patient management or patient assessment and their impact on analysis


SECTION 11.0 – Efficacy Evaluation

11.1 – Data Sets Analyzed

11.2 – Demographic and other baseline characteristics

11.3 Measurements of treatment compliance

11.4 Efficacy results and tabulations of individual patient data

11.4.1 Analysis Of Efficacy

11.4.2 Statistical/Analytical Issues

11.4.2.1 Adjustments for Covariates

11.4.2.2 Handling of Dropouts or Missing Data

11.4.2.3 Interim Analyses and Data Monitoring

11.4.2.4 Multicenter Studies

11.4.2.5 Multiple Comparison/Multiplicity


11.4.2.6 Use of an "Efficacy Subset" of Patients

11.4.2.7 Active-Control Studies Intended to Show Equivalence

11.4.2.8 Examination of Subgroups

11.4.3 Tabulation of individual response data

11.4.4 Drug dose, drug concentration, and relationships to response

11.4.5 Drug-drug And Drug-disease Interactions

11.4.6 By-patient Displays

11.4.7 Efficacy Conclusions


12. Safety Evaluation

• Extent of exposure (dose, duration, number of patients)

• Most common adverse events, laboratory test changes etc.

• Serious adverse events and other significant adverse events

12.1 Extent Of Exposure

• The extent of exposure to test drugs/investigational products and to active control

• Patients exposed.

• Duration of exposure.

• Dose to which they were exposed.

Structure of full CSR (cont.)12.2 Adverse Events (AEs)

12.2.1 Brief summary of adverse events

• The overall adverse event experience in the study

12.2.2 Display Of Adverse Events

All adverse events occurring after initiation of study treatments (including events likely to be related to the underlying disease or likely to represent concomitant illness, unless there is a prior agreement with the regulatory authority to consider specified events as disease related)


12.2.3 Analysis of adverse events

12.2.4 Listing of adverse events by patient

All adverse events for each patient, including the same event on several occasions giving both preferred term and the original term used by the investigator

12.3 This section contains information of

• Deaths,

• Other SAEs,

• Significant adverse events

• Serious adverse events,

• Significant adverse events deserve special attention.


12.4 Clinical Laboratory Evaluation

12.4.1 Listing Of Individual Laboratory Measurements By Patient

12.4.2 Evaluation Of Each Laboratory Parameter

12.4.2.1 Laboratory Values Over Time

12.4.2.2 Individual Patient Changes

An analysis of individual patient changes by treatment group. A variety of approaches may be used, including:

• Shift Tables: These tables show the number of patients who are low, normal, or high at baseline and then at selected time intervals.

• Tables showing the number or fraction of patients who had a change in parameter of a predetermined size at selected time intervals.

• A graph comparing the initial value and the on-treatment values of a laboratory measurement


12.4.2.3 Individual Clinically Significant Abnormalities

Clinically significant changes (defined by the applicant)

A narrative of each patient whose laboratory abnormality was considered a serious adverse event and, in certain cases, considered an other significant adverse event

12.5 Vital signs, physical findings and other observations related to safety

12.6 Safety conclusions

The overall safety evaluation of the test drug(s)/investigational product(s) with particular attention to events resulting in changes of dose or need for concomitant medication, serious adverse events, events resulting in withdrawal, and deaths.

13. Discussion And Overall Conclusions

The efficacy and safety results of the study and the relationship of risks and benefit


14. Tables, figures and graphs referred to but not included in the text

14.1 Demographic Data :Summary figures and tables

14.2 Efficacy Data :Summary figures and tables

14.3 Safety Data :Summary figures and tables

15. Reference List

A list of articles from the literature pertinent to the evaluation of the study

Copies of important publications should be attached in an appendix (16.1.11 and 16.1.12).

16. Appendices

This section should be prefaced by a full list of all appendices available for the study report.

Thank You

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