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180218P - KING FAHAD MEDICAL CITY INSTITUTIONAL - REVIEW BOARD SEVERE ADVERSE EVENTS IN RESEARCH SUBJECTS

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Presentation to the Quality Council by Prof OHK MBChB (MUK), MPH (Harvard), DrPH (Harvard) Professor of Epidemiology and Bioethics


DEFINITIONS RELATING TO ADVERSE EVENTS and PROTOCOL VIOLATIONS:

1.1 Adverse Event: Any untoward or unfavourable medical occurrence in a human study participant, including any abnormal sign (e.g. abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participants’ involvement in the research, whether or not considered related to participation in the research. 

1.2 Serious Adverse Events (SAE): Any untoward medical occurrence, whether it is considered related to the study or not, that: (a) Results in death (b) Is life threatening, or places the participant at immediate risk of death from the event as it occurred (c) Requires or prolongs hospitalization (d) Causes persistent or significant disability or incapacity (e) Results in congenital anomalies or birth defects (f) Is another condition which investigators judge to represent significant hazards. 

1.3 Protocol Deviation/Violation: Any intentional or unintentional change from the IRB-approved protocol.


DEFINITIONS RELATING TO ADVERSE EVENTS and PROTOCOL VIOLATIONS:

1.4 Major Protocol Deviation/Violation: A divergence from the approved protocol that adversely affects the risk/benefit ratio of the study; the rights, safety, or welfare of the participants or others; or the integrity of the study. 

1.5 Minor Protocol Deviation/Violation: A divergence from the approved protocol that, in the PI’s judgment, DOES NOT adversely affects the risk/benefit ratio of the study, the rights, safety, or welfare of the participants or others, or the integrity of the study. Examples of possible minor protocol deviations may include but are not limited to (a) Study visit(s) or study procedure(s) conducted out of timeframe (b) Participant failure to initial every page of the consent form (c) Participant failure to return diary (d) Other protocol deviations/violations that only affect logistical or administrative aspects of the study. 

1.6 Related AE: An AE that more than likely was caused by study product or study procedures (e.g., “probably related” or “definitely related”). 


DEFINITIONS RELATING TO ADVERSE EVENTS and PROTOCOL VIOLATIONS, Con’t.:

1.7 Unexpected AE: An AE that is not identified in nature, severity, or frequency in the relevant safety documents(s) for the study product or is not identified as a possible risk in the study protocol or the informed consent form for the study. 

1.8 Not Reportable Events: Typically, a number of events occur during the course of a study that don’t meet reporting requirements. Examples of such events may include: (a) Non-serious adverse events that, in the PI’s judgment, are not related to the study; (b) Non-serious adverse events that are anticipated or expected as part of the study; (c) External serious adverse event reports (e.g., IND Safety Reports) that, in the PI’s judgment, do not adversely affect the conduct of the PI’s study at his/her research facility; (d) Minor protocol deviations (such as study visits performed slightly out of window); € Minor research participant complaints that are adequately resolved by the research staff. 


REPORTS OF ADVERSE EVENTS SUMMARY - 1



REPORTS OF ADVERSE EVENTS SUMMARY - 2



EXAMPLE OF AN E-MAIL REPORTING AN ADVERSE EVENT - 1




EXAMPLE OF AN E-MAIL REPORTING AN ADVERSE EVENT - 2



 

EXAMPLE OF A COMPLETED ADVERSE EVENT FORM



EXAMPLE OF A COMPLETED ADVERSE EVENT FORM 



 

EXAMPLE OF IRB INVESTIGATION OF AN ADVERSE EVENT - 1

  • 15-297E Phase 2, Single-Site, Open-Label, Randomized, 2-Arm Parallel Study to Assess the Efficacy and Safety of Ryanodex (EGL- 4104) as Adjuvant Treatment in Subjects with Exertional Heat Stroke (EHS) (PI Dr. Nawfal Aljerian). 
  • Six adverse events one of them fatal were reported by the PI. IRB reported to CEO and NCBE and started an investigation. 
  • Chair of IRB asked the PI for additional documents (find the info in the email or the minutes listing additional info). 
  • Chair of IRB asked the PI for additional documents (find the info in the email or the minutes listing additional info). 
  • Reviewer’s Comment 1:
    1. The DKs & the DIC reported in the Table may not be a direct effect of Dantroine.
    2. The ARDS and the cardiopulmonary support reported by the investigators are related to the effects of Dantroline.
    3. Dantroline use is associated with dyspnea, respiratory muscle weakness and decreased inspiratory capacity. Therefore, patients who are receiving Dantroline should be monitored for adequate ventilation.
    4. Cardiac arrest may also, be related to the use of Dantroline, since the drug had been reported to cause tachycardia and atrioventricular block.
    5. The investigators need also, to monitor dosing and any drug- drug interactions that may affect Dantroline blood levels and consequently increase the likelihood of adverse effects. 


EXAMPLE OF IRB INVESTIGATION OF AN ADVERSE EVENT - 2 

  • Reviewer’s Comment 2: 
    1. The dosing interval for those recruits who had Dantroline was not precisely shown (whether it was 30, 60, or 90 minutes. 
    2. The potent LYP3A4 liver enzyme inhibitors which were being taken by recruits were not reported. These actually, if were taken concomitantly with Dantroline, will increase its plasma levels and hence lead to its toxicity. 
    3. They did no show whether the recruits had any hypersensitivity to Dantroline or not.
    4. Recruit No: 96013008 is written as assigned to Group "B" which is the standard of care only group. This is absolutely wrong as this patient was assigned to Group "A" as is shown in the Eligibility forms (please also see the Table that depicts the summary of serious adverse events). 


EXAMPLE OF IRB INVESTIGATION OF AN ADVERSE EVENT - 3

  • Reviewer’s Comment 3: 
    1. Recruit No: 96013007 who was assigned to standard of care arm developed DIC. Although the recruit developed DIC, concomitant medications (which were not reported) could have caused this serious side effect. But, the DIC is not relate to Dantroline. 
    2. Drugs such skeletal neuromuscular junction blockers (e.g. Succinylcholine) do produce a serious drug-drug interaction when 
    3. Drugs such skeletal neuromuscular junction blockers (e.g. Succinylcholine) do produce a serious drug-drug interaction when given concurrently with Dantroline. This interaction can lead to Respiratory arrest. 
    4. Recruit No: 96013002 had cardiopulmonary arrest and 96013003 had cardiac arrest which could be ascribed to an interaction with the drugs they are taking for ore-existing diseases. The ECG data (missing) of this recruit were not done which could have warned against a possible toxicity on the heart. 
    5. Recruits No: 96012015 and 96012017 who required intubation which could be ascribed to an interaction with the drugs they are taking for ore-existing diseases. 


EXAMPLE OF REPORTING OF ADVERSE EVENTS TO CEO



 

EXAMPLE OF REPORTING OF ADVERSE EVENTS TO NCBE