Turacoz - Clinical Study Report

“CSR is a detailed regulatory document which gives the information about the methods and results (related to efficacy and safety) of a clinical trial. CSRs are created as a part of the process of submitting applications to the Regulatory Authorities for new medical treatments and for its approval. CSRs can be full, abbreviated, synopsis, supplementary, observational etc as per the results and requirements”.

1. Clinical Study Report

2. Content Introduction Clinical Trials (Stages) Clinical Study Report (CSR) ICHE3 Guidelines for CSR

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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 time now data collection analysis interpretation

10. The path to a new medicine Years 1 16 2 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 patent application Clinical trial application Product licence application Drug Discovery Drug Development Target and lead identification Lead optimisation Concept testing Development for launch Launch Clinical Development Phase I 12-150 people Phase II 50-1000 people Phase III 500-5,000 people Phase IV studies continue Product life cycle 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)

11. The Clinical Study Process Outline Clinical Study Protocol Statistical Analysis Plan Study Conduct Data Capture Study Setup Statistical Analysis Clinical Study Report Publications Clean File T i m e Preparation of statistical analysis Data base lock

12. 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.

13. 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.

14. 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).

15. ICH E3 GUIDELINES FOR CLINICAL STUDY REPORT

16. 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

17. 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

18. Structure of full CSR (cont.) 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

19. Structure of full CSR (cont.) 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

20. Structure of full CSR (cont.) 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,

21. Structure of full CSR (cont.) 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.

22. Structure of full CSR (cont.) 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

23. Structure of full CSR (cont.) 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.

24. Structure of full CSR (cont.) 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

25. 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 meals Section 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

26. 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 Variables Section 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.

27. 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.

28. Structure of full CSR (cont.) 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

29. Structure of full CSR (cont.) 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

30. Structure of full CSR (cont.) 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

31. Structure of full CSR (cont.) 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

32. Structure of full CSR (cont.) 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

33. Structure of full CSR (cont.) 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 .

34. 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 )

35. Structure of full CSR (cont.) 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.

36. Structure of full CSR (cont.) 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

37. Structure of full CSR (cont.) 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

38. Structure of full CSR (cont.) 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 .

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