Investigator s Responsibility

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2 Investigator s Responsibility Introduction Investigator s Qualifications Clinical Trial Agreement Adequate Resources Medical Care of Trial Subjects Communication with IRB/IEC Study Initiation Patient Recruitment Randomisation & Unblinding Case Report Form Completion and Source documents IP accountability Protocol Compliance Role of Site Coordinator Essential documents Archiving at site

3 Who is the Investigator? A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called principal investigator. (ICH Guideline for GCP 1.34) 3. IRB / IEC ICH GCP 4. Investigator 5. Sponsor

4 CLINICAL TRIAL MILESTONES Investigator Enlistment Protocol Development Informed consent form & patient information sheet IRB /IEC Submission Study initiation investigator s meeting Study initiation site visit Study Monitoring Site Management Clinical Data Management Safety Surveillance Statistical Analysis Final Study Report Study Closeout Archiving Pre Study During Study Post Study

5 Investigator s Qualifications Qualified by Education, Training and Experience Familiar with the use of IP as specified in Protocol, IB & other Information Investigator Comply with GCP & other applicable regulations Permit monitoring & Auditing by sponsor or other Regulatory Authorities Maintain a list of qualified persons responsible for significant trial-related duties

6 So Many Signatures? Confidentiality agreement Protocol Agreement Investigator Signed agreement between investigator and authorities eg Statement of investigator (FDA 1572) Financial Disclosure eg. Form FDA 3455 Clinical Trial Agreement

7 Clinical Trial Agreement It is an agreement between site and sponsor determining the parties rights and responsibilities Indemnification CTA Template approved by PUU in nmrr.gov.my Insurance Publication Confidentiality/Proprietary information

8 Adequate Resources Investigator Must demonstrate potential of recruiting (No. of suitable subjects in agreed time period). By signing the protocol, the investigator agrees to recruit the required number of eligible patients Have sufficient time to conduct & complete trial within agreed time period Have adequate number of qualified Staff & Facilities Ensure all personnel assisting the trial are informed about the protocol, IP, and trial-related duties

9 Medical Care of Trial Subjects A qualified physician (Investigator/Sub- Investigator) should be responsible for all trial related decisions Investigator Provide adequate medical care to subject for any AE & should inform subject when medical care is needed for intercurrent illnesses. Recommended to inform subject s primary physician (with the subject s consent) about his/her participation if he/she has one Should make reasonable effort to ascertain the reason(s) if a subject withdraws prematurely, while fully respecting the subject s rights

10 Communication with IRB/IEC Should have written and dated approval/favorable opinion from IRB/IEC. These includes: Protocol Investigator ICF Consent Form Updates IB and if it is updated during the trial, an updated IB should be given to IRB/IEC Should provide all documents subjected to be reviewed by IRB/IEC

11 STUDY INITIATION Study Initiation Investigator s Meeting Study Initiation Site Visit

12 Study Initiation Investigator s Meeting Objectives 1. To orientate the Investigator/site staff with the requirements of the protocol and to ensure that he/she understands and accepts the obligation incurred in undertaking the study. 2. To ensure that the study is planned, set up, conducted, documented and reported according to the protocol, related SOPs, ICH-GCP and applicable regulatory requirements.

13 Study Initiation Site Visit Main objective To ensure that the site is ready to enrol the first patient. Specific Objectives: 1. To brief investigator and site personnel on study protocol and procedures. 2. To verify the qualifications, resources, staff, and facilities are adequate to properly conduct the study. 3. To verify site has current protocol, standard operating procedures, other essential documents and study supplies to conduct the trial properly.

14 What does the Investigator do prior to Study Initiation Site Visit?

15 Site preparation involves.(1) 1) Site Investigators and SCs must familiarise themselves with the protocol and the study procedures. Each staff should understand his/her responsibilities. 2) Make available all essential documents. The documents are: Investigator File Any additional Investigational Product accountability logs eg. shipping logs. Adequate supply of CRFs, Informed Consent forms, study logs.

16 Site preparation involves.(2) 3)Prepare facilities/equipment for inspection during visit. This will include: i) Storage area for the study documents. ii) Storage area for Investigational products. iii) Patient examination area. iv) Study equipment, if necessary.

17 Site preparation involves.(3) 4)Certain related personnel eg pharmacist, laboratory assistant, pathologist may have to be available during the visit. 5) Prepare list of outstanding problems or queries 6) Locate a room or quiet area with a desk for use by the CRA during visit.

18 After the visit.. Investigator should: Ensure that all deficiencies reported by the CRA, are corrected before enrolling first patient.

19 2. Patient Recruitment

20 Patient recruitment strategies Chart reviews & medical records Recommendation by private practitioner / other medical professional, referrals Suitable site eg. A&E for trauma cases suitable for study on emergency treatment Advertisement - IRB/IEC review & approval/favorable opinion prior to use. Internet

21 Important! Not only must patients pass study criteria but they must also be likely to complete the study. Recruitment methods should not in any way coerce or suggest excessive inducement to the subject.

22 Recruitment Process Study Population male/ female with disease X Screening Visit Eligible Subject screening checklist (Inclusion/Exclusion) No Subject Screening Log Screen failure Yes Subject enrolment log Subject identification list Baseline Visit Study Sample (Target 120) DMG Medical history Complete medical exam/ecg Vital sign Lab

23 SUBJECT SCREENING LOG Protocol Number CT6723 Site Name: Site Code: # Date Subject Initial Eligibility If not eligible Reason Investigator / SC Signature & Date

24 The Purpose of the Subject Screening Log: 1. To document that each patient underwent the recruitment process as per protocol. 2. To ensure that no bias was involved in patient recruitment.

25 SUBJECT ENROLLMENT LOG Protocol Number: CT 2374 Site Name : Site Code : # Date Enrolled Subject ID Initial Date of signed Informed Consent Treatment A B Inv/Sc Initial & Date

26 SUBJECT IDENTIFICATION LIST CONFIDENTIAL Protocol Number: Site Name: Site Code : # Date enrolled Subject s Name ID Initial IC No. Address and Tel. No Inv. Sign & Date

27 Randomisation process Definition: Randomisation is the process of assigning study subjects to treatment using an element of chance to determine the treatment assignment in order to reduce bias. In a study, randomisation is conducted: On site Centrally

28 Use of sealed envelopes at site a) Randomisation on-site: A batch of sealed envelopes is sent to the site. The sealed envelopes are numbered and arranged in sequential order. For each patient enrolled, an envelope is picked in order of sequence and opened. Inside the envelope is the patient s treatment number & treatment assignment. Once the envelope is opened, the site must send the randomisation details to the coordinating centre.

29 b) Central Randomisation In CRC - a computerised system is set up. Interactive Voice Response (IVR) Technology is integrated into the system to provide a faster and better service. Automated and no human intervention. Accessible via touch-tone telephone.

30 Unblinding If the trial is blinded The investigator should ensure that the code is broken only in accordance with the protocol Unblinding should be promptly documented Explain to the sponsor any premature unblinding (eg. accidental unblinding or due to seriuos adverse event) of the investigational product

31 Case Report Form (CRF) Completion and Source Documents

32 Definition- CRF ICH GCP 1.11 Glossary A printed, optical or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject.

33 Why CRFs are important? 1. Data on CRFs - the basis for the trial report & also for any publication, as well as making up part of the data for regulatory approval of a new drug. 2. CRFs are designed to facilitate data analysis; all essential data is recorded patient by patient & visit by visit.

34 Investigator s responsibilities (1) 1. The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the CRFs and in all required reports. ICH GCP Data reported on the CRF, that are derived from source documents, should be consistent with the source documents or the discrepancies should be explained. ICH GCP CRF Source document

35 Investigator s responsibilities (2) 3. Any change or correction to a CRF should be dated, initialled and explained (if necessary) and should not obscure the original entry.the investigator should retain records of the changes and corrections. ICH GCP *CRFs must be completed by the investigator or the delegated staff. Signatures & initials of each investigator & delegated staff must be documented in the signature list.

36 The Principal Investigator (PI) is responsible for all data on the CRF,and must sign at least the final page of the CRF book attesting to the accuracy and completeness of the data.

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38 Source Documents and Source Data

39 DEFINITIONS Source Data All information in original records and certified copies of clinical findings, observations, or other activities in a clinical study necessary for the reconstruction and evaluation of the study. Source data are contained in source documents Source Document Original documents, data and records (eg. hospital records, clinical and office charts, lab. notes copies or transcriptions certified after verification as being accurate copies.microfilm or magnetic media ) kept at the pharmacy, the laboratory, and at medico-technical departments involved in the clinical study. (ICH GCP 1.52) (ICH GCP 1.51)

40 Some more facts about source documents Source documents must support the data that is recorded in the CRF. ICH GCP Source documents must be maintained by the investigator at the site. ICH GCP 4.9.4

41 Exercise!!.on CRF completion

42 INSTRUCTIONS ON COMPLETION OF CRF -(1) 1. The CRF must be completed in BLACK INK BALLPOINT PEN. 2. Ensure that all heading information is completed: Subject ID, Subject Initials and the Study Site Code. 3. All complete dates and times must be provided. If the exact date or time is unknown, give the best estimate based on clinical records and/or patient s recollection. 4. Record any comment and doubt in the comment box at the bottom of each CRF page. 5. Tick the check boxes with ( ). 6. Numerical values must correspond to original documents. 7. Completely fill in the CRF page. 8. If data is not available, indicate NA 9. If test or item was not done, indicate ND 10. If not applicable, please print Not applicable

43 INSTRUCTIONS ON COMPLETION OF CRF (2) 11. The investigator must fill in his/her initial and the date in each CRF page as they are completed. 12. A thorough review of each CRF page should be done by the investigator before the investigator initials and dates the CRF page. Correction Procedure: to rectify errors on a CRF page draw a single line through the error and write in the new value next to the error. The correction must be initialled and dated.

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45 Investigational Product (IP) A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial ( ICH GCP 1.33)

46 Overview of IP Supplies Management Information on IP - safety and efficacy data - update IB Manufacturing of IP - GMP - determine storage temp., condition and time Packaging, Labelling, Coding - mechanism in coding system for blinded trials Supplying and handling of IP - procedures for handling, storage and documentation - system for disposition (ICH )

47 Investigational Product accountability is... The process and documentation by which we account for clinical supplies from the time of packing until use or return and destruction.

48 ICH GCP says Responsibility for investigational product(s) accountability at the trial site(s) rests with the investigator/institution Where allowed/required, the investigator/institution may/should assign some or all of the investigator's /institution s duties for investigational product(s) accountability at the trial site(s) to an appropriate pharmacist or another appropriate individual who is under the supervision of the investigator/institution. (** delegation should be supervised )

49 IP accountability includes records and information on.. product s delivery at trial site inventory at site use by each subject (IP dispensing forms) records of return to sponsor records of disposition of unused products (ICH GCP 4.6.3)

50 Records should include.. dates quantities batch/serial numbers expiration dates (if applicable) the unique code numbers assigned to the investigational product(s) and trial subjects ** Investigators should maintain records that document adequately that the subjects were provided the doses specified by the protocol and reconcile all investigational product(s) received from the sponsor. (ICH GCP 4.6.3)

51 To maintain IP accountability at site Site accountability records should be completed by study site staff. Discrepancies investigated and commented on by investigator (or designated person), signed & dated. Records must have initials/signatures of person who dispensed & who received returns.

52 More of ICH GCP (1) The investigational product(s) should be stored as specified by the sponsor (see and ) and in accordance with applicable regulatory requirement(s) The investigator should ensure that the investigational product(s) are used only in accordance with the approved protocol.

53 More of ICH GCP..(2) The investigator, or a person designated by the investigator/institution, should explain the correct use of the investigational product(s) to each subject and should check, at intervals appropriate for the trial, that each subject is following the instructions properly.

54 Exercise - Drug Accountability! Instructions - You will have to read the description on the Plomox Trial - Then you are required to check the Drug Dispensing Log provided against the 4 bottles (A,B,C,D) given to your group. Look out for any discrepancies. The number of drugs in the bottles and the information on the label of the bottles are correct. - Then the CRF pages should be checked against the Drug Dispensing Log and the bottles given to your group. Please identify the discrepancies and comment on it. - Round up percentage results. - Consider bd dose taken after seeing the doctor.

55 Protocol Compliance

56 Protocol Compliance Investigator should conduct the trial in compliance with the protocol agreed to by the sponsor and, if required,by the regulatory authority(ies) and which was given approval/favourable opinion by the IRB/IEC. ICH GCP Protocol violations Deviations

57 DEFINITIONS Wolf & Makuch 1980 Protocol Violations : were caused by or could have been prevented by the investigator and which materially affect the study results. Major deviation : could not be prevented. Minor deviation : are not likely to affect the evaluation of treatment efficacy. EFCGP Audit working party, 2001 Protocol violation : Serious non compliance may lead to exclusion of patients from eligibility analysis and/or their discontinuation from the study Protocol deviation : less serious non-compliance, may not render a patient ineligible.

58 MAJOR VIOLATIONS Enrolling ineligible patients Informed consent after study procedures Test incorrectly performed or not done Failure to comply with IP dispensing/dosing/storage requirements Patient noncompliance (missed doses/cessation/modification/ prohibited medication/ the ultimate- withdrawal) Incorrect handling of biological samples Failure to report AE/SAE Failure to document deviations as agreed

59 Role of Site Coordinator aka Study coordinator

60 Who is the Site Coordinator? The Site Coordinator (SC) is often a nurse, can also be a pharmacist or allied-health professional with clinical study experience. The success of most trials is highly dependent upon an efficient and effective SC

61 Job description of a Site Coordinator (1) Site related responsibilities: Assist investigator in management of on-time & on-budget completion research. Identify & assist in recruitment of study subjects. Liaise with investigators & CRAs (Clinical Research Associate) & sponsor. Prepare site for CRA s / monitor s visits.

62 Job description of a Site Coordinator (2) Manage investigational product supply processliaise with sponsor. Schedule & manage subject visits. Complete, review & store CRFs. Collect & maintain Essential documents.

63 To summarise The SC administers clinical trial tasks for Investigator The SC helps the investigator complete the clinical study correctly by assuring compliance with the protocol, study procedures and details. Investigators often delegate many administrative & some subject-related activities to the SC. Investigators may delegate study responsibilities to a SC or other person, but retain full responsibility for all the study activities.

64 Essential Documents (ED)

65 Essential Documents ICH definition: documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced ICH GCP 1.23

66 Importance of Documentation 1. Demonstrate compliance of investigator, sponsor and monitor with GCP and applicable regulatory requirements 2. Basis for Audit and Inspection 3. Assist in successful management of trial

67 Critical Documents Documents which show the site s suitability to conduct the study Documents should be available prior to study initiation CVs of site staff, protocol agreement page, ethics approval letter, informed consent document

68 GCP REQUIREMENTS FOR ED (1) The Investigator should maintain the documents and should take measures to prevent accidental or premature destruction of these documents The Sponsor should retain all of the sponsor specific essential documents pertaining to the trial in conformance with the applicable regulatory requirements

69 GCP REQUIREMENTS FOR ED (2) Archived at site and at the sponsor Monitor s responsibilities: Determining whether the investigator is maintaining the essential documents

70 Essential Documents Grouped in 3 sections according to the stage of the trial: (during which they will normally be generated) 1) Before the Clinical Phase of the Trial Commences 2) During the Clinical Conduct of the Trial 3) After Completion or Termination of the Trial ICH GCP 8.1 Refer (ICH GCP 8.2) for list of essential documents.

71 Before the Clinical Phase of the Trial Commences- (1) Signed and dated Protocol/ amendments Sample Patient Information Sheet and Informed Consent Form Investigator s Brochure Sample CRF Advertisement for subject recruitment (if used) Financial agreement (where required) Insurance/letter of indemnity (where required) Research agreement (where required) Communication with sponsor/irb

72 Before the Clinical Phase of the Trial Commences- (2) IRB Approval approval of protocol,site,icf IRB composition (if not specified in IRB letter of approval) Investigators CVs-signed personally and dated Signature Sheet & Authorisation Sheet Reference Range of Local Labs and updates when applicable Certification/ Accreditation of Local lab must be current Study Procedures (Site SOPs) Shipping records for Investigational Product (IP)

73 Before the Clinical Phase of the Trial Commences- (3) Sample of IP label Sealed envelope of Treatment Code Emergency unblinding procedures (if not already described in protocol) Treatment decoding log (emergency unblinding) Study Initiation Report

74 In addition to all documents listed above, the following documents are also required during the Clinical Conduct of the Trial-(1) All previously-mentioned document updates Monitoring Visit Report Signed & dated informed Consent forms Source Documents - historical document Signed, dated and Completed CRF (copy) Documentation of CRF Correction AE & SAE Report Sponsor s Safety Update

75 In addition to all documents listed above, the following documents are also required during the Clinical Conduct of the Trial-(2) Interim/Progress Report to IRB/IEC Subject Screening Log/Screen Failure Log Patient Identification List Subject Enrolment Log IP Accountability Log Record of Retained Body Fluids/Tissue Sample

76 In addition to all documents required before & during the trial, the following are required After Completion or Termination of the Trial Audit certificate (if available) Documentation of IP destruction Study Close-out Report Final Report by Investigators to IRB Clinical Study Report

77 7. Archiving of trial related documents at site

78 What is archiving Definition:The storing of files, records, and other data for reference and alternative backup.

79 Investigator s Responsibility: Archiving The investigator must document & archive everything concerning the study BECAUSE.. information is required should there be re-examination of study data at a future date.

80 Important 1. If the documents are moved or the investigator moves elsewhere, the sponsor must be informed formally where the documents are located. 2. Documents and other study materials can be accessed by staff restricted to the investigators, study personnel and regulatory authorities. 3. All data and documents or study materials should be made available whenever it is requested by relevant authorities, in the presence of the investigator.

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