Clinical Research Safety Monitoring SAFETY MONITORING IN CLINICAL TRIALS INTRODUCTION: Clinical trials are a cornerstone in search for medical advances. There has been progress in the design and conduct of a clinical trial. This led to an increased awareness of ethical issues and safety monitoring. It is the Policy of National Institutes of Health (NO) that a system should be there to ensure the safety of participants. The establishment of Data safety monitoring boards is required for multi site clinical trials involving potential risks to the patient. GOOD CLINICAL PRACTICE (GCP) A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected. According to the Principles of ICH GCP guidelines The rights, safety, and well-being of the trial subjects are the most important considerations. Safety monitoring is done by v Investigator v IRB/IECs v Sponsor ¥ Monitor Pharma Dost | www.PharmaDost.info Ealinical Research Safety Monitoring IRB — Responsibility: « An IRB/IEC should safeguard the rights, safety, and well- being of all trial subjects. ICH GCP 3.1.1 e¢ The IRB/IEC should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk to human subjects, but at least once per year. INVESTIGATOR — Responsibi * During and following subject participation in a trail, the investigator should ensure that the adequate medical care is provided to the subject for any adverse events, including Clinically significant laboratory values, related to the trail. ICH GCP 4.3.2 SPONSOR — Responsibility: «¢ The sponsor may consider establishing an independent data-monitoring committee (IDMC) to assess the progress of a Clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial ICH GCP 5.5.2 MONITOR - Responsibility: e Determining whether all adverse events (AEs) are appropriately reported within the time periods required by GCP, the protocol, the IRB/IEC, the sponsor, and the applicable regulatory requirements. ICH GCP 5.18.4 Pharma Dost | www.PharmaDost.info [2]re EVO arr aa ty Safety Monitoring SAFETY MONITORING IN DIFFERENT PHASES OF CLINICAL TRIAL: Phase I: Experimental drug given in a small group of people (20- 80) to evaluate its safety , determine a safe dose range, identify side effects. Phase Il: Experimental study drug is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety. Phase Ill: Experimental study drug is given to a larger group of people (1000-3000) to confirm its effectiveness, monitor side effects, collect information for safety. Phase IV: Post marketing studies gives additional information including drug risks, benefits and optimal use. For drugs being studied under investigational new drug applications, the food and drug administration (FDA) published a regulation establishing a new safety reporting paradigm. According to this the clinical investigator and sponsor have to be more responsible in reporting and analysis of serious, unexpected events that might be caused by drug DATA AND SAFETY MONITORING BOARD: (DSMB) This is used mainly for randomized controlled clinical trial. ForThe purpose of the DSMB is to provide oversight and monitoring of the conduct of clinical trials to ensure the safety of participants and the validity and integrity of study data. The National Institutes of Health (NIH) strongly recommends data and safety monitoring in the form of a DSMB for all Phase III clinical trials. For Phase | and Phase II clinical trials, a DSMB may be established if the principal investigator, their institution, or the clinical trial sponsor deems it necessary. For example, a Phase | or II clinical trial that has multiple clinical sites, is blinded (masked), is studying a particularly high- risk intervention(s), is involving a vulnerable population(s), or has a high probability of early termination for safety or efficacy, should consider establishing a DSMB.Responsibilities of the Data and Safety Monitoring Board The DSMB is responsible for reviewing study documentation (e.g., study protocol, the informed consent and other participant handouts, etc.) and ensuring that it has adequate information to assess the safety of the study participants and the efficacy of the intervention during both the treatment and follow-up periods. A comprehensive description of the data and safety monitoring plan, including details about the DSMB composition, safety and operating procedures, frequency of DSMB monitoring (based on anticipated recruitment and/or identified safety concerns), and reporting requirements, should be outlined in the study protocol.The DSMB shall evaluate participant safety data throughout the duration of the trial; evaluate the efficacy of the study intervention(s) at intervals specified in the DSMB charter (described below); andBoard Membership DSMBs are either appointed by NIAAA and act as an independent advisory group to the NIAAA Director, or are appointed locally for investigator-initiated studies[2]. In general, the DSMB voting members are appointed by the clinical trial sponsor or by the Principal Investigator. A DMSB may have as few as three voting members; however, the number of members and the specific composition of the Board will depend on the type and complexity of the clinical trial. The DSMB composition should be multidisciplinary, including but not limited to clinical medicine (appropriate specialty), biostatistics, bioethics, pharmacology (if applicable), clinical trial methodologies, and other disciplines relevant to the study. ForDSMB members shall have no real or perceived conflicts of interest with the clinical trial, including any financial and/or scientific ties to the outcome of the study. Individuals who are invited toThe Chairperson of the DSMB should be selected among the voting members and have previous experience in monitoring clinical trials. The Chairperson should be a good facilitator, communicator, and consensus builder.Data and Safety Monitoring Board Meeting Schedule The frequency and format of DSMB meetings depends on the nature and risk of the studies to be monitored. Meetings may be face-to-face or by teleconference. The Board shall have the option for expedited meetings to review unexpected Serious Adverse Events[3] or other urgent issues that may arise during the course of the trial. Unscheduled meetings may be recommended and initiated by the DSMB Chairperson, the clinical trial sponsor, or the principal investigator.Conduct of the Meetings DSMB meetings are generally divided into three sessions: open, closed and executive. ¢ Open Session The purpose of the open session is to provide relevant information to the Board about general aspects of the trial. The open session may focus on: the background of the study, the protocol, status of the study, problems with accrual and follow-up, baseline demographic data, compliance issues, frequency of adverse events[4], documentation of¢ Closed Session During the closed session, the DSMB reviews and votes on all issues. This session is usually attended by the DSMB members only. The principal investigator or clinical trial sponsor may attend the closed session at the request of the DSMB. During the closed session, the discussions should focus on: treatment safety, efficacy data, whether the primary study question has been answered, the interim results by treatment arm (usually masked), determination of when study data may be released, review of requests for access to the results of the interim analysis, and results of Board actions and recommendations made in the previous meeting.e Executive Session It is recommended that the DSMB have the option of conducting an executive session with DSMB members only. During these sessions, the Board may discuss any unmasked analysis of a blinded clinical trial and other sensitive issues related to the clinical trial. Data and Safety Monitoring Board Recommendations and Meeting Records The DSMB should keep a record or minutes of all meetings. Minutes of open session discussions should be kept separately from the minutes of closed and executive session discussions. TheThe DSMB shall provide a meeting report to the clinical trial sponsor or principal investigator that includes the Board's recommendation(s) and sufficient information to explain the rationale for any recommended changes. The report should also include the minutes of the open session. Meeting minutes of the closed or executive session should not be included, but rather a statement that a closed/executive session was held. The¢ Safety Data Monitoring of safety data should include review of adverse events, serious adverse events, and any data that allows for comparisons of safety among treatment (active and control) groups, e.g. clinical laboratory data, treatment retention, and reasons for subject drop out. Safety information for all studies should be reported to the Board in an un-masked manner. Formal statistical analyses of the safety data may be requested by the RoardPHARMACOVIGILANCE: It is science relating to detection, assessment and prevention of adverse effects and other problems related to the use of medicines. ADVERSE EVENT: An adverse event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a casual relationship with this treatment. SERIOUS ADVERSE EVENT: Any untoward medical occurrence that at any dose: sresults in deathClinical Research Safety Monitoring sis life-threatening ‘requires inpatient hospitalization or prolongation of existing hospitalization results in persistent or significant disability/incapacity sis a congenital anomaly/birth defect METHODS OF COLLECTING ADVERSE EVENTS IN CLINICAL TRIAL: ¥ Volunteer reporting by the patient ¥ Investigator observation v Standard Open question ¥ Checklist v Subject diaries (written or electronic) v Laboratory/Clinical values A randomised controlled trial was conducted in California to determine better method of questioning patients regarding adverse event. Results showed that the percentage of patients reporting adverse event is much higher in case of checklist method when compared to standard open question Pharma Dost | www.PharmaDost.info [es]