PERSONNEL AS PER ICH GCP Definition: Sponsor is an individual, company, institution (or) organization, which takes responsibility for the initiation, management and/or financing of a clinical trial Roles and responsibilities: FDA regulations, an Indian GCP and ICH guideline defines various roles and responsibilities of a sponsor. They are: . Selection of investigator and institution/hospital. . Contracl/Agreements. Duties and functions allocation. . Clinical trial management, data collection, handling and record keeping. . Compensation to subject and investigators. Confirmation of a review by ERP/IRBAEC Aww . Information on investigational products. . Manufacturing, packaging, labeling and coding, investigational products. eon |. Supply and handling investigational products. 10.Safety information 1L.ADR reporting. 12.Contract research organization (CRO) management. 13. Record access. 14.Monitoring, 15.Audit. 16.Premature termination or suspension of a trial. 17.Clinical trial or study reports. 18.Multi-center trials. —_———_—_— kk eee—~—ae__—_S_S_S SS PHARMD GURU Page 1UT a 1) Investigator & institution (or) Hospital selection: « Sponsor should select well qualified, trained and experienced investigators for the conduct of a trial. + Selected institutions or hospitals should have sufficient resources to conduct the trial. « A copy of protocol and an up to date investigator's brochure should be provided to the investigator for the purpose of reviewing the documents. 2) Contracts (or) Agreements: + The sponsor should have an agreement with the investigator for conduct of trial, according to GCP and applicable regulatory requirements. + The agreement should clearly define about: (a) Trial would be conducted according to protocol, provided by sponsor and approved by IEC (b) Sponsor's standard operating procedures (SOP) would be followed. (c) Sponsor has right to monitor, audit and inspect site at any time. (d) Financial aspects, if any. + To confirm the agreement, both sponsor and investigator should sign a copy of protocol. 3) Allocation of duties and functions: + Sponsor should identify, define, allocate and establish all trail related "duties and functions" to qualified persons before trial initiation. 4) Clinical trial management, Data collection, Handling and record keeping: + Sponsor should assess the progress of a clinical trial (safety data, endpoints etc). To check whether to continue, modify (or) to stop a trial + If using electronic data handling systems, in a trial, sponsor should: eT PHARMD GURU Page 2UT a (a) Frame and maintain standard operating procedures (SOP's). (b) Maintain audit trails, appropriate Security System, adequate backup of data, etc. + Sponsors should maintain all sponsor specific essential documents, data confidentiality as per guidelines. + Sponsors should submit required applications to appropriate authority for review, acceptance and permission to begin clinical trial. 5) Compensation to subjects and investigators: + Sponsor should provide insurance (or) legal and financial coverage to the investigator agonist claims arising from trial as per regulations, except claims about malpractice (or) negligence. 6) Confirmation of review by IRB/IEC/ERB: + Sponsor should obtain name and address of investigator's ERB/IRB/IEC. + Sponsor should ensure that IRB/IEC has reviewed the trial protocol. + Sponsor should ensure that ERB/IRB/IEC has approved the protocol to conduct a trial. 7) Information on investigational products: + Sponsor should ensure that sufficient safety and efficacy data from non- clinical studies are available for Investigational drug. + Example: Route of administration, dosage and duration ete. 8) Manufacturing packaging, labeling and according investigational product: + Sponsor should ensure that investigational product is manufactured according to acceptable GMP. + Sponsors should ensure that investigational product is coded and labeled according to regulatory requirements. + Sponsors should provide suitable packaging of investigational product to prevent deterioration during transport and storage. PHARMD GURU Page 3UT a « Sponsors should assess the results of any additional studies of product. 9) Supplying and Handling Investigational product: + Sponsors should supply investigational product to all investigators/institutions involved in trial. + Sponsor should maintain sufficient samples of product from each batch and keep records of analysis to recheck them. + Sponsor should retain the samples, until the analysis of the trial data or complete. 10) Safety information: + Sponsor is responsible for the ongoing safety evaluation of investigational product. + Should take appropriate measures necessary to safeguard studies subjects. 11) ADR reporting: + Sponsor should report all areas to investigators IEC institutions until regulatory authorities. + Sponsor should provide ADR reporting form to all investigators. 12) Contract Research Organization (CRO) management: + Sponsor should/may transfer any (or) all of the trial related duties and functions to a CRO with an agreement. + CRO should implement quality assurance and quality control. 13) Record access: + Sponsor should provide direct access to source data/document for trial related monitoring, audits and regulatory inspection + Sponsor should check subjects ICD's. eT PHARMD GURU Page 4UT rT 14) Monitoring: + Sponsors should determine the appropriate extent of on the nature of monitoring. « Sponsors should appoint monitors in compliance to GCP. 15) Audi + Sponsors should perform an audit at all trial sites. + Sponsor should appoint qualified and experienced auditors. Also verifies that auditors have documented all observations. + Sponsors should provide an audit Certificate to regulations. 16) Premature termination (or) suspension of a trial: + Sponsor should promptly inform the IRBs/ investigators /regulatory authorities of the termination (or) suspension. Trial and reasons for termination. 17) Clinical trial or study reports: + Sponsor should prepare and provide clinical trial reports to the regulatory agencies after completion (or) premature determination of trial. 18) Multicenter trials: + For multi-center trials, sponsored should ensure that all investigators/institutions are in compliant to protocols while conducting tials. + Sponsored should try hard to start and end studies simultaneous at all sites. py Cer es! Definition: Investigator is defined as a person responsible for the conduct of the clinical trial at a trial site. If the trial is conducted by a team of individuals at the trial site, the investigator is the leader of the team called as principal investigator. eT PHARMD GURU Page 5UT rT Roles and Responsibilities: FDA regulations (21 CFR 312.52), Indian GCP Guidelines (3.3.1) & ICH guidelines mandate that, sponsor only use trained and qualified investigators. The roles and responsibilities of investigator are as follows: 1) Initiating a clinical trial: * contracts and agreements + Obtaining ERB/IRB approval to conduct the trial. + Constituting a study team. + Planning & ensuring resources required for conduct of trial. + Attend the trial training meeting along with study team. 2) Conduct of the trial: = Recruitment of subjects in the study. + Informed consent document administration. «Medical care of trial subjects. + Compliance with protocols schedule of events. + Compliance with ICH-GCP applicable regulatory requirements. + Investigational product storage, handling and accountability. « Randomization procedures and unblinding + Communication with IRB/IEC/ERB. « Communication with sponsor. + Facilitate data collection and monitoring. + Documenting errors, violations, non compliance, etc. + Financial tracking. «Ensuring confidentiality. + Facilitate & corporate insite audit. 3) Site closure: + Final report to IRB/IEC/ERB. + Providing all data/documents required at Site closure to sponsor —_——— ee PHARMD GURU Page 6UT rT + Return of equipment, investigational product (unused) & grants reconciliation. + Archival of trial data for the duration as soon as specified in the contract. + Premature termination (or) suspension of a trial. 1) INITIATING A CLINICAL TRIAL (a) Contracts and agreements: + Investigators should enter into all trial related agreements as per applicable regulatory compliance. (b) Obtaining IEC/IRB/ERB approval to conduct the trial: «Investigator should get approval from JEC/IRB/ERB and ensure that patient enrollment at institution begins after approval. (c) Constituting a study team: + Investigators should constitute a study team - coinvestigators, clinical research coordinators, study nurse (or) Pharmacist. (d) Planning and ensuring resources required for the conduct of trial: + Investigators should ensure adequate number of qualified staff & facilities at site to conduct a trial. (e) Attend trial training meetings along with the study team: + Investigator should ensure that all staff attends the trial meeting organized by sponsor for smooth conduct trial. 2) CONDUCT OF THE TRIAL (a) Recruitment of subjects in the study: + Investigators should select suitable subjects into the study as per protocol. Sometimes may seek help from other physicians to obtain a required number of subjects. PHARMD GURU Page 7UT a (b) Informed consent document (ICD) administration: « Investigator should comply with regulatory requirements in obtaining and documenting informed consent. + Investigators should ensure that ICD has approved by IRB/IEC/ERB. + ICS should be clear and should be in vernacular language of tial subjects. «Investigator should ensure that the ICD has been signed by subject/his/her legal representative. « Investigate should keep subject's identity confidentially. (c) Medical care of trial subjects: + Investigate should ensure adequate medical care is being provided to a subject for any adverse events during the trial. (d) Compliance with protocol schedule of events: + Investigator should comply with the protocol agreed by the sponsor for the conduct of trial. + Deviations (or) Changes in protocol and reasons for it are to be submitted to TEC/IRB/ERB. (e) Compliance with ICH-GCP regulatory requirements: + Investigators should be in compliance with ICH-GCP regular requirements. (f) Investigational products, storage, handling and accountability: + Investigator should maintain investigational product accountability at trial site. «Investigators should maintain records documenting drug administration to the subjects and storage conditions. (g) Randomization procedures and unblinding: + Investigators should explain sponsor about randomization procedures and unblinding, If the trial requires randomization. PHARMD GURU Page 8UT a «Should follow randomization procedures properly. (h) Communication with the IEC/IRB/ERB: + Investigator should provide ongoing trial reports to IEC/IRB/ERB frequently. (i) Communication with sponsor: + Investigator should provide all the trail related activities, documents etc., to the sponsor. + Should report serious adverse events immediately to the sponsor. (j) Facilitate data collection and monitoring: Investigators should ensure accuracy, legibility and timeliness of data reported to the sponsor. (k) Documenting errors violations and non compliance. (1) Financial tracking: Financial aspects of the trial should be documented in an agreement between sponsor investigator. (m) Ensuring confidentiality: Investigators should ensure confidentiality of trial subjects throughout the trial period. (n) Facilitate and corporate insite audit. 3) SITE CLOSURE (a) Final Report to IRB/IEC/ERB: Investigator should provide the summary of trial's outcome to IRB/IEC/ERB and regulatory authorities. (b) Providing all data/documents required at Site closure to the sponsor. (c) Return of all unused drug products,equipment. (d) Archival of trial data for the duration as specified in contract: PHARMD GURU Page 9UT a + All trial related essential documents should be retained for 5 to 15 years as per agreement or applicable regulatory requirements. (e) Premature termination or suspension of trial: + Investigators should inform trial subject to take care for appropriate therapy in case of any premature termination of trial. + Should provide written explanation for determination of trial to IRB/IEC/ERB. (CLINICAL RESEARCH ASSOCIATE) Definition: Clinical Research Associate is different as a person employed by a sponsor or CRO (clinical research organization) acting on behalf of sponsor, who monitor the progress of a (rial at investigator's site participating in a clinical ial. + A Clinical Research Associate also called a clinical monitor or trial monitor, is a healthcare professional who performs many activities related to medical research, particularly clinical trials employed by a contract research organization (CRO) which works on behalf of pharmaceutical companies. The main tasks of the CRA are defined by good clinical practice guidelines for monitoring Clinical trials, such as those elaborated by the ICH. «Clinical trials may be carried out at various phases, trials on patients with a disease, and studies conducted after the launch of a new drug to monitor safety and side effects. The CRA will be involved in all stages of the clinical trial, including identifying an investigation site and setting up, initiating, monitoring and closing the tial upon completion or termination. The CRA is the first line of communication between the sponsor and investigator throughout the study. Qualification: Depending on the jurisdiction, different education and certification requirements may be necessary to practice as a clinical research associate. A Bachelor’s Degree in a medical, health or science-related area; MS degree preferred. PHARMD GURU Page 10UT rT Minimum of 2 years medical/science background and relevant experience; experience of clinical trial management would be preferable. Knowledge of ICH/GCP guidelines. General knowledge of clinical/ laboratory terminology. Good problem solving and analytical skills. Strong oral and written communication skills in English. yee Ne Must be able to travel if required. Roles and Responsibilities of CRA: There are five major areas of responsibility through which the CRA can impart Knowledge of adverse event reporting to investigators: 1. Providing initial training on adverse event reporting requirements for investigators. 2. Reviewing data to assure accuracy and completeness of reported events. 3. Providing new information to the investigator. 4. Monitoring the clinical trial to detect potentially unreported adverse events. 5. Assuring follow-up data is reported for adverse events when required. > Assesses site qualification potential: + Reviews study requirements. + Conducts pre-study visits and drafts, pre-study evaluation reports. > Participates in the implementation of clinical studies: + Communicates with investigators and their staff. « Ensures compliance with terms and conditions. + Properly trains site personnel and writes initiation visit reports. > Supervises the conduct of clinical studies: = Acts as liaison between site personnel and the sponsor. * Performs monitoring in the field. « Ensures compliance with protocols, regulatory requirements and GCP. + Writes follow-up visit reports. ee PHARMD GURU Page 11UT a > Ensures the quality of the project: + Verifies materials and data integrity. + Conduct internal audits or regulatory inspections for site personnel. > Closes clinical studies: + Verifies the integrity of investigator files. + Ensures availability of clinical and non-clinical materials. + Jointly reviews with investigators the obligations inherent at the end of the study and writes closure visit reports. > Coordinate Clinical Trials: + Visits trial sites regularly. «Acts as liaison between project managers and research-site personnel. + Maintains the quality of the work and relationships. + Monitors the conduct of clinical trials and compliance with established timelines. > Ensure Quality Assurance of Projects: « Adheres to protocol regulatory requirements, GCP regulations, and SOP. = Ensures compliance with the patient-consent process. + Ensures compliance with the procedures to apply in the event of SAE. * Verifies compliance and quality of collected data. + Verifies the receipt, handling, accounting, storage conditions, and availability of clinical products under investigation. + Verifies investigator records and checks for consistency with the contents of sponsor files. > Some other responsibilities: + Identifying/selecting an investigator who will be responsible for the conduct of the trial at the trial site. + Liaising with doctors/consultants or investigators on conducting the trial. —_——— kk e—————e—_—_—_c_—_s_s_s__ PHARMD GURU Page 12UT a + Setting up the trial sites, which includes ensuring each center has the trial materials, including the trial drug often known as the investigational medicinal product. + Train the study staff in the SOP for the clinical trials as per applicable regulatory requirements. + Verify that the investigator and investigator's team are adequately trained and comply with the protocol. + Source data verification. + ICF review, CRF review, AE review, and Investigational drug accountability + Ensuring all unused trial supplies is accounted for. + Writing visit reports, filing and collecting tial documentation and reports. Definition: Auditor is defined as an independent individual appointed by sponsor or regulatory authorities to conduct a systematic and in depth examination of trial conduct and compliance with protocol GCP standard operating procedures and applicable regulatory requirements. Most auditors visits are prearranged, but some may not, if there is suspected serious branches of GCP or malpractices. Roles and responsibilities: According to ICH-GCP, FDA, auditors perform various roles and responsibilities. There are: 1) Investigational site audits. 2) Clinical department, process audits. 3) Data management audits. 4) Safety Department audits. 5) GCP laboratory audits. 6) Sponsor central file audits. eT PHARMD GURU Page 13,UT rT 1) Investigational sites site audits: « Auditor audits study site to assess a site performance, identifies deficiencies and determines sponsors level of risks. = Auditor conducts audit when sponsor believes that site is non-GCP compliant. 2) Clinical department process audits: + Auditor conducts clinical department process audits. + Need of these audits include: 1. Potential for a regulatory inspection. 2. Desire to improve effectiveness and efficacy. 3. Satisfying concerns of upper level management. 3) Data Management audits: + Auditor conducts data management audits to: Compare data in datasets agonist data in CRFs. Review error programs and query System. Review files structure and merge of data sets. awn Check security and backup procedures. 4) Safety Department audits: + Auditors examine a sample of serious adverse event for the criteria as follows: Accuracy of reports and coding. Timeliness of regulatory submission. Match with adverse event data. Pune Appropriate use of technology in processing events. 5) GCP laboratory audits: + Auditor should establish that research was conducted under: 1. Proper authority with sound scientific rationale. PHARMD GURU Page 14UT a 2. Rights/safety/well being of research subjects was protected. + Auditor audits that, the test results are valid and accurately reported. 6) Sponsor central file audits: + Inspection of sponsors, CRO's are conducted trial without prior notification. « Inspections are conducted to determine: 1. Compliance of sponsors to applicable regulations. 2. Sponsor should assure to validity of data submitted to them by investigator. (CONTRACT RESEARCH CORDINATORS (CRC) Definition: CRC ’s are defined as a personnel employed at clinical investigator *s site to record the clinical trial data in compliance with protocol, GCP and applicable regulatory guidelines. Investigator delegates specific duties to CRC. Qualification: Depending on the jurisdiction, different education and certification requirements may be necessary to practice as a clinical research coordinator. A Bachelor's degree programs in clinical research often consist of foundational science courses, managerial skills, and advanced laboratory experiences. Some examples of these include: - Anatomy and physiology + Biology - Biomedical ethics + Chemistry + Psychology of health + Leadership and organizational skills. Roles and Responsibilities of CRA: + The role of a study coordinator in clinical trials is very important. + Every clinical trial site may have one or more study coordinators depending on the workload at the trial site. eee PHARMD GURU Page 15,UT rT + Clinical trials at the site level can be roughly divided into 3 stages. The three stages are: > Before the start of the Clinical Trial: « Feasibility: 1. During this stage, the study coordinator has to collect and complete feasibility questionnaires received from different CRO’s and Sponsors. 2. CRC’s also had to collect the required information from the principal investigator, and send it back to the respective people who contacted the site regarding the study. « Proposal Budget: 1. Collaborates with the Pl and department to prepare a categorized budget and justification. 2. Confirms the accuracy and completeness of budgeted costs. = Institutional Review Board Submissions: 1. Documents to be submitted to the ethics committee normally include the study protocol, investigator brochure and informed consent forms (vernacular languages at the site) with translation certificates. 2. In addition to these documents, investigator's CV, Financial disclosure forms, Insurance statement, and subject diaries if applicable, clinical trial agreement, and different study logs, eCRF, etc also need to be submitted. In all these processes a Clinical study coordinator plays a vital role. After obtaining approval from the ethics committee the clinical trial can be initiated at the site level. > During the conduct of clinical trial: = Informed consent: The study coordinator has to obtain informed consent from the subject. ee PHARMD GURU Page 16UT a * CRC is also responsible for telephonic reminders to the subjects regarding the visits. * If the CRC is involved in data entry then it is the study coordinators responsibility to resolve all queries within 48 hours or as per timeline specified by the sponsor. © Other duties as assigned. > After Close out of the clinical trial: * Before a clinical trial is closed at the site, study coordinators have to check all documents and all the documents have to be updated. + After verification of all documents by the CRA, CRC will assist in archiving the documents at site. © The site has to maintain all study-related records for contracted length of time or 15 to 20 years or whichever is longer. * CRC plays a vital role in managing a clinical trial at the site level and acts as a link between the sponsor, EC, and the Investigator. yg Cot 4 GUL. Definition: Regulatory authorities are the bodies that power to regulate the clinical trials, Regulatory authorities review submitted clinical data and those that conduct inspections. Roles and responsibilities: + Regulatory authorities should: 1. Review clinical trial of both registered and non registered medical substances. 2. Ensure that drug available fulfils the necessary requirements for safety, quality and efficacy. 3. Should terminate any ongoing trial if there are serious breaches or malpractices of GCP. —_——————— Sa kk ———e____cSsSsSS PHARMD GURU Page 18