Title 16. SAFETY MONITORING IN CLINICAL TRIALS.pdf ✅

PHARMD GURU Page 1 INTRODUCTION: 1) Clinical trials are a cornerstone in medical advances; hence there is a progress in the design and conduct of a clinical trial. 2) This lead to an increased awareness of ethical issues and safety monitoring. 3) Hence a system should be there to ensure the safety of participants. 4) The establishment of a Data safety monitoring boards (DSMB) is required for clinical trials, involving potential risks to the patients. 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: 1) Investigator 2) IRB/IEC`s 3) Sponsor 4) Monitor 1) INVESTIGATOR - RESPONSIBILITY: During and following subject participation in a trial, the investigator should ensure that the adequate medical care is provided to the subjects for any adverse events, related to the trial [ICH-GCP 4.3.2] 2) IRB/IEC - RESPONSIBILITY:  An IRB/IEC should safeguard the rights, safety and well being of all trial subjects.[ICH-GCP 3.1.1]  The IRB IEC should conduct continuing review of each ongoing trial, at definite intervals. At least once per year. 3) SPONSOR - RESPONSIBILITY: Sponsor may consider establishing an independent data monitoring committee (IDMC) (or) DSMB to assess the progress of a clinical trial, which includes the safety SAFETY MONITORING IN CLINICAL TRIALS
PHARMD GURU Page 2 data and to recommend to the sponsor, whether to continue, modify or stop a trial [ICH-GCP 5.5.2] 4) MONITOR - RESPONSIBILITY: Determining whether all adverse events are properly reported within the time period required by:  GCP  Protocol  IRB/IEC  Sponsor and  Applicable regulatory requirements. [ICH-GCP-5.18.4] SAFETY MONITORING IN DIFFERENT PHASES OF CLINICAL TRIALS: PHASE-I: Experimental drug given in a small group of people (20-80) to evaluate its safety, determine a safe dosing range, identify side effects. PHASE-II: Experimental (study) drug is given to a large group of people (100-300) to see its effectiveness and to further evaluate safety. PHASE-III: Experimental drug is given to a large group of people (1000-3000) to confirm its effectiveness, monitor side effects, and collect information for safety. PHASE-IV:  Post marketing studies, gives additional information includes drug risks, benefits, and optimal use.  For drugs being studied under investigational new drug application [INDA], the FDA published a regulation, establishing a new safety reporting paradigm.  According to this clinical investigator and sponsor have to be more responsible in reporting and analysis of serious, unexpected events that might be caused by drug.
PHARMD GURU Page 3 DATA AND SAFETY MONITORING BOARD [DSMB]:  DSMB is a group of individuals with the pertinent experience that reviews on a regular basis is the accumulating data from an ongoing clinical trial.  It is usually appointed by the sponsor.  It is mainly used for Randomized control trials. PURPOSE OF A DSMB:  Protect to the safety of the trial participants.  Identify high rates of ineligibility determined after randomization.  Identify protocol violations under suggest changes to protocol.  Identify unexpected high dropout rates that threaten the trial`s ability to produce credible results.  Ensure the credibility of the study.  Ensure the validity of study results.  Advise the sponsor to regarding the continuing safety of trials subjects. DSMB’S HAVE GENERALLY BEEN ESTABLISHED FOR:  Large randomized multisite studies that evaluate treatments intended to prolong life (or) reduce the risk of a major adverse health outcome.  Any controlled trial of any size that will compare rate of mortality (or) major morbidity. DSMB COMMITTEE COMPOSITION:  The sponsor/trial steering committee, generally appoint members of a DSMB.  Most DSMBs are composed of :  Clinicians, with expertise in relevant clinical specialties.  At least one biostatistician knowledgeable about statistical methods for clinical trials and sequential analysis of trial data  For trials with unusual high risks or with broad public health implications, the DSMB may include a medical ethicist knowledgeable about the design, conduct and interpretation of clinical trials.  Some trials may require participation of:
PHARMD GURU Page 4  Toxicologist’s epidemiologists and clinical pharmacologists in particular cases when such expertise appears important for informed interpretation of interim results.  One or more individuals (often non-scientist) who may help bring to the DSMB, the perspectives of the population under study. Generally, such a DSM remember could be someone with a disease under study or a closed relative of such an individual.  DSMB for international trials will usually include representatives from at least a subset of participating countries (or) regions.  The criteria for selecting all appointees should be:  Their respective expertise and experience.  Their ability to commit to attending DSMB meetings.  Their ability to maintain confidentiality of the interim results they have a reviewed.  Conflict of interest. RESPONSIBILITIES OF DSMB: a) Interim monitoring: 1) Monitoring of effectiveness. 2) Monitoring for safety. 3) Monitoring study conduct. 4) Consideration of external data. 5) Studies of less serious outcomes. b) Early studies c) Other responsibilities: 1) Making recommendations, 2) Maintaining meeting records. a) INTERIM MONITORING: 1) MONITORING FOR EFFECTIVENESS:  A DSMB will recommend early termination on the basis of positive results, only when the data are truly compelling and the risk of false positive conclusion is acceptably low.