1. 1 Nuts and Bolts of Safety Reporting The Role of the CRO Dr. Noa Lowenton Spier Pharma-Clinical S.A.G

2. 2 Accurate safety reporting Ensure subjects safety Avoid unpredictable events Positive data Supporting drug development The importance of safety reporting from clinical trials

3. 3 The essence of safety reporting from clinical trials is to reflect accurately the course of events occurring in subjects who administered a pharmaceutical product Day to day practice of the medical doctor treating a patient is different from the required practice for conducting a clinical trial All adverse events must be classified as serious or not serious Clinical trials ‘language’ may differ from the common and acceptable practice The challenge – how to communicate the information in a way that reflects reality best?

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5. 5 How to determine the intensity/severity of AE/SAE Mild: awareness of sign(s) or symptom(s) which is/are easily tolerated Moderate: Enough discomfort to cause interference with usual activity Severe: incapacitating or causing inability to work or to perform usual activities Determination of intensity is case specific.

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7. 7 How to determine the reason for seriousness of an adverse event? The Investigator must document and report at least one reason why an event is considered Serious A Serious Adverse Event is an untoward medical occurrence that: 1)results in death 2)is life-threatening 3)requires hospitalization or prolongs hospitalization 4)results in persistent or significant disability or incapacity 5)is a congenital anomaly or birth defect 6)is an important medical event

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9. 9 Causal relationship A ‘trial drug’ (investigational medicinal product in EU CT directive terminology) comprises all pharmaceutical formulations to be used in a clinical trial according to protocol (i.e. test drug, comparative drug, including placebo, basic medication) The investigator is requested to assess the causal relationship for a trial drug administered by the subject Medical judgement should be used to determine the relationship, considering all relevant factors, including pattern of reaction, temporal relationship, positive de- challenge or re-challenge, confounding factors such as co-medication, co-diseases and relevant history

10. 10 Causal relationship cont. 1)Unrelated 2)Unlikely 3)Possible 4)Probable 5)Definite 1) No 2) Yes Expedited reporting (SUSARs)

11. 11 Overall case assessment Is the investigator provided with sufficient tools to support clinical judgment and case assessment? The first assessment may balance the tip for an expedited reporting One single case in a single site might support a trend or a signal The sponsors’ global view vs. the investigators’ familiarity with the specific case & subject

12. 12 Safety reporting - the CRO CRA (Clinical Research Associate) - the field monitor Knowledge in ICH GCP, sponsors’ SOPs, trial protocol, trial drug profile, MOH regulations and guidelines, local IRBs regulations The CRA integrates his/her knowledge to ensure proper conduct of a clinical trial while taking into account the subjects’ safety, ethics and adherence to trial protocol The CRO - assisting the investigator communicating data to the sponsor and verifying that the data reported are accurate and reliable

13. 13 Accurate safety reporting Ensure subjects safety Avoid unpredictable events Positive data Supporting drug development Safety reporting - the CRO Remember the first slide? An independent CRO and its’ staff are free from potential conflicts of interests