Guidelines for Preparation of Documents, Clinical Study Report Clinical Trial Monitoring Safety Monitoring in Clinical Trial

Contents
Guidelines for Preparation of Documentation
Clinical Study Reports
Clinical Trial Monitoring
Safety Monitoring in clinical trials
Introduction
Proper documentation is critical to the success of a clinical study.
Every aspect of the study must be documented in order to obtain useful data and demonstrate compliance with Good Clinical Practice (GCP) guidelines and with all applicable regulations.
Investigator’s Brochure (IB)
List of Abbreviations
Contents & Summary
Introduction provides the chemical name (and generic and trade names, if approved) of the investigational product.
Physical, chemical and pharmaceutical properties and formulation of the medicinal product. Non-clinical studies & Clinical Studies and their results.
The Investigator's Brochure should be reviewed at least annually and revised as necessary in compliance with a standard procedures established by drug development company.

1. Seminar on- Guidelines for Preparation of Documents, Clinical Study Report Clinical Trial Monitoring Safety Monitoring in Clinical Trial Guided by: Dr. (Mrs) Nirzarini N. Shah Associate professor (M. Pharm, Ph. D) Head of Department of Pharmacology Presented By: Presented by: Dinesh M. Gangoda M. Pharm (sem-II) Enrollmentno:212010825004 Enrollment no: 212010825004 Subject: Clinical Research and Pharmacovigilance A.R. College of Pharmacy and G.H. Patel Institute of Pharmacy (Affiliated with Gujarat Technological University Ahemdabad) Vallabh Vidya Nagar Anand-388120

2. 2 Contents Guidelines for Preparation of Documentation Clinical Study Reports Clinical Trial Monitoring Safety Monitoring in clinical trials References

3. 1.1 Introduction Proper documentation is critical to the success of a clinical study. Every aspect of the study must be documented in order to obtain useful data and demonstrate compliance with Good Clinical Practice (GCP) guidelines and with all applicable regulations. 3 Guidelines for Preparation of Documentation

4. 1.2 Documentation Requirements in GCP and Federal Regulations GCP guidelines list the essential documents (ICH GCP E6 Section 8) that, at a minimum, must be maintained for every clinical study. These documents are to be maintained by the site and the sponsor, and are classified according to the stage of a study at which they are normally created. These documents may be maintained in multiple locations, depending on whether they are stored with regulatory files or as participant documents. The sponsor and the investigator/institution should maintain a record of the location(s) of their respective essential documents, including source documents. 4

5. 1.3 Examples of Other Sponsor-Required Documents In addition to the essential documents included in the GCP guideline, the sponsor may require other documentation. The following lists examples of other documentation that may apply to clinical trials. 1.4 Certificate of Confidentiality A Certificate of Confidentiality provides an additional level of protection for the privacy of participants in alcohol and drug abuse research studies. 5

6. 1.5 Quality Assurance Documents Quality assurance documents may include the following: Research site Initiation Activation Form, which indicates that a site is ready to start study enrollment. Site visit logs, to record visits to the research site by quality assurance monitors and other personnel. 6

7. 1.6 Training Documents A training plan and verification of compliance with the training plan, including: All training documentation form for each staff. Documentation of required assessments training per the study training plan. Documentation of study–specific training. Pertinent certifications for clinical staff implementing a study intervention. 7

8. 1.7 Behavioral Therapy Documents Many CTN studies involve behavioral interventions. Behavioral studies may require essential documents different from, or in addition to, those required by GCP guidelines. These documents may include therapy manuals and materials, audio and videotapes of treatment sessions, and other documents specific to the behavioral intervention that is being studied. 8

9. 1.8 Source Documents Source documents are original documents, data, and records e.g., hospital records, clinical and office charts, laboratory notes, subjects’ diaries or evaluation checklists, pharmacy dispensing records , and records kept at the pharmacy, at the laboratories and technical departments involved in the clinical trial. [1] 9 Source documents Hospital records Pharmacy dispensing records Evaluation checklists, X-rays, Subject file Automated instruments

10. 1.9 Trial Master File (TMF) Guideline E6 states that trail master file should be established at the beginning of the trial, both at the investigator/institution site and at the sponsors office. A final close-out of a trail only be done when the monitor has reviewed both the investigator/institution and sponsor files and confirm that all necessary documents are in the appropriate files. The file maintained at the site is often called, The Site Master File . The file is generally the responsibility of a designated member of the investigating team at the site of the monitor at the sponsors office. 10

11. 1.10 Essential Documents Essential Documents are those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements. These documents are also the ones which are usually audited by the sponsor's independent audit function and inspected by the regulatory authority as part of the process to confirm the validity of the trial conduct and the integrity of data collected. 11

12. 1.10.1 Essential Documents For Clinical Trials The Essential Documents For Clinical Trials are as Follow: 12 1. Investigator's Brochure 2. Clinical Study Protocol 3. Case Report Form (CRF) 4. Informed Consent Form 5. Clinical Study Reports

13. 1.10.2 Investigator’s Brochure (IB) List of Abbreviations Contents & Summary Introduction provides the chemical name (and generic and trade names, if approved) of the investigational product. Physical, chemical and pharmaceutical properties and formulation of the medicinal product. Non-clinical studies & Clinical Studies and their results. The Investigator's Brochure should be reviewed at least annually and revised as necessary in compliance with a standard procedures established by drug development company. 13

14. 1.10. 3 Clinical Study Protocols The Guideline ICH E6 defines the protocol as, A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial. The protocol usually also gives the background and rationale for the trial but these could be provided in other protocol referenced documents also. 14

15. 1.10.2.1 Parts of Protocol Introduction/Abstract Objectives Background/Rationale Eligibility criteria Study design/methods (including drug/device info) Safety/adverse events Regulatory guidance Statistical section (including analysis & monitoring) Human subjects protection/informed consent 15

16. 1.10.3 Case Records/Report Form (CRF) CRF is a paper or electronic document designed to record all the information for an individual study subject required by the Study protocol. All CRF's should include the following data: Study title and number Investigator's name Study subject/patient ID (number and initials) Detailed description of dosage regimens of investigational drug Adverse events (side effects and intercurrent diseases) Conclusion on subject's health Investigator's signature and date. 16

17. 1.10. 5 Informed Consent Informed consent is a process by which a subject voluntary confirms his/her willingness to participate in one or another clinical trial, after having been informed of all aspects of the study. Informed consent should be documented by means of a written, signed and dated Informed Consent Form (ICF). 17

18. 2.1 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. (1) 18 Clinical Study Reports

19. Cont... 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 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 US. 19

20. 2.2 ICH E3 Guidelines for Clinical Study Reports 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. 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 20

21. Cont.. 7. Introduction 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 21

22. 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 22

23. 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 in a list of abbreviations Section 5 . Ethics: Independent Ethics Committee Patient information and consent 23

24. Section 6.0 . Investigator and administrative structure contain The administrative structure of the study, Principal investigator, Coordinating investigator , Administration, Monitoring and evaluation committees , Statistician, Central laboratory facilities, Contract research organization (C.R.O.) 24

25. 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 25

26. 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 26

27. 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) 27

28. Section 10.0 – Study Patients Section 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.). Section 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. 28

29. 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 Section 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 29

30. Section 13 . Discussion And Overall Conclusions The efficacy and safety results of the study and the relationship of risks and benefit. Section 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 Section 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. 30

31. Section 16 . Appendices This section should be prefaced by a full list of all appendices available for the study report. 31

32. 3.1 Introduction Monitoring The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded and reported in accordance with the protocol, SOPs, GCP, and any regulatory requirements”. [1] Monitoring Reports A written report form the monitor to the sponsor after each site visit and other trial related communication according to the sponser SOPs. 32 Clinical Trial Monitoring

33. 3.2 Purpose of Monitoring 1. Protection of rights and wellbeing of human participants. 2. Ensure consent in place for record access. 3. Trial data are accurate, complete and verifiable from source documents . 3.3 Qualities of a good Monitor Appropriately trained, Adequate scientific and/or clinical knowledge. - Documented with training logs and CVs. Thoroughly familiar with: - IMP - Protocol - Consent form - Sponsor & trial SOPs - GCP Knowledge of local laws, regulations, customs & local language. 33

34. 3.4 Types of Monitoring in Clinical Trials Trial Management Group- TMG; This should include individuals responsible for day- to day management of the trial such as principal investigator, statistician, trial coordinator, research nurse, data management personnel etc. Trial Steering Committee- TSC; Which provides overall supervision of the trial and ensures it is being conducted as per regulatory requirements and GCP Good Clinical Practice. The committee monitors the progress of a trial including data completeness and ensures there are no major deviations. 34

35. 3.4 Participant in Monitoring of Clinical Trial Participant in monitoring of clinical trial is the CRA Clinical Research Associate and other members including the project manager, medical monitor, data manager and statistician. Sponsor’s Monitor or Clinical Research Associate CRA Interface with investigative site on behalf of or CRO. May be involved in any or all of the following; Site evaluation and initiation 35

36. Project Manager - responsible for overall implementation of trial; oversee progress of trial; global trial communications; reporting to regulators, budget and cost control. Medical Monitor- individual with expertise in trial related therapeutic area; involved in protocol devlopments, safety reporting, interpretation of data and clinical findings. Data Manager - generate data queries to ensure quality of data; maintain ongoing data entry; monitor data analysis and provide reports. Statistician- analysis of data – provide reports for data safety monitoring board DSMB 36

37. 37 3.5.1 Before Monitoring visit Review the status of data entry Review action item from last visit Review regulatory binder. 3.5.2 During Monitoring visit Site, Staffing, research labs or other facilities. Regulatory files and study records Any problems and issues 3.5 Monitoring Process

38. 38 3.5.3 After Monitoring visit Complete site visit report Submit the report to the sponsor

39. 4.1 Introduction Monitoring patient safety during clinical trials is a critical component throughout the drug development life cycle. Pharmaceutical sponsers must work proactively and collaboratively with all stakeholders to ensure a systemic approach to the safety Monitoring. 39 Safety Monitoring in clinical trials

40. 40 1. Sponsor 2. Subjects 3. Investigators 4.2 Stakeholders in Safety Monitoring

41. Sponsors Clinical trials sponsor, usually pharmaceutical companies, are responsible for developing the clinical trial protocol describes every aspect of the research, including the rationale for the experiment, objectives, trial populations with detailed inclusion and administration of the investigational therapies, trial procedures, data collection standard, endpoint and sample size. 41

42. Subjects Subject are patients or healthy volunteers who agree to participate in a Clinical trial and have signed. Other information provides important safety information so the subjects can make an informed decision on whether to participate in a trial. 42

43. Investigators Investigators are qualified individuals who are trained and experienced to provide medical care to subjects enrolled in the clinical trials. Investigators identify potential subjects and educate them about the trial participation to ensure that can make an informed decision. They are responsible for notifying their institutional review boards and the sponsor of any issues during that Safety and subjects. 43

44. Institutional review board/ Ethics Committee The institutional review board (IRB), also known as the ethics committee, is changed with protecting the rights and welfare of human subjects recruited to participate in research protocols. The IRB review all clinical trial protocols involving human subjects that the particular institution is involved with and has the authority to approve, disapprove or require modifications to the protocols. 44

45. Data& Safety Monitoring Board The data and safety Monitoring Board(DSMB) also called data monitoring committee (DMC). The DSMB may review efficacy data at pre- defined in term oints to and evidence of efficacy. Not all clinical trials require a formal DSMB. DSMB are most common in double blind randomized phase-3 trials, members of DSMB typically including clinical trial Physians with the biostatician and possibly persons. 45

46. Regulatory Authorities In the US, prior to initiation of a first in human clinical trial, pharmaceutical sponsers must submit an Investigational New Drug (IND) application to the FDA as required by law. The FDA review the IND (typically within 30 days) for safety to ensure that research subjects will not be subjected to unreasonable risk. The European Medicines Agency (EMA) is European union’s FDA equivalent. The agency has several scientific committee that carry out pharmaceutical companies. 46

47. Medical community and patients Clinical trials generate data that contribute to the body of the knowledge about the treatment and the disease that benefit the border medical community and ultimately the patients. Communicating Sefety Information among Stakeholders Timely communication among the various stakeholders is critical to ensure subject Sefety in clinical trials, sponsors of clinical trials are accountable for monitoring the subjects. 47

48. Cont… However, Sefety Information may come from sources outside the immediate clinical trial. The sponsor is required to promptly review all information relevant to the safety of the drug and to update subjects, investigators, IRBs and regulatory authorities of any new risks associated with the use of the investigational drug from Clinical trial or other sources. The goal of safety Monitoring in clinical trials is to identify evaluate, minimize and appropriately manage risks. 48

49. References M’U.R. Naidu, P.Usha Rani. ‘‘A practical Guide to human Research and Clinical Trials.’’ PharmaMed press, sultan Bazar, Hedrabad; ( 2011 ): pp no- 203to 214. Dr. Ravindra B. Ghooi, Sachin C. Itkar. ‘‘Essential of clinical Research’’. Nirali Prakashan, Sivaji Nagar, Pune. 5 th edition April ( 2019 ), PP- 1.5 to 1.14. Images- From Google website 49

50. 50 Thank You…