serious, it must be recorded as a new AE on the specific AE form of the extension study CRF. The sponsor may contact the investigator to obtain further information.
All AEs that occur from the start of the transition period of the extension study until 15 days after study drug discontinuation must be recorded on specific AE form of the extension study eCRF.
Treatment-emergent AEs are defined as all AEs with onset date from the date of first study drug intake (date of Visit E1 for patients who received placebo in the core study, date of core study Visit 1 for patients who received active treatment in the core study) until 15 days after study drug discontinuation. This definition applies regardless of whether the patient receives commercially available ponesimod after completing study drug treatment.
All AEs occurring during TP1, TP2, and TP3 must be reported on an AE form of the eCRF, regardless of causal relationship. This applies also to AEs occurring during the study drug interruption (e.g., due to planned pregnancy), i.e., all AEs during study drug interruption must be reported on an AE form in the eCRF.
4.2.4.2 Follow-up period
All AEs regardless of causal relationship occurring from 16 days after study drug discontinuation until 30 or 90 days (as applicable) after study drug discontinuation must be recorded on specific AE form of the extension study eCRF.
Follow-up of adverse events
AEs still ongoing after study drug discontinuation for a given patient must be followed up to 30 or 90 days (as applicable) after study drug discontinuation, or until resolution, stabilization or until the event is no longer clinically relevant or until the event is otherwise explained.
4.3 Serious adverse events
Medically significant, or requires intervention to prevent at least one of the outcomes listed above
Life-threatening refers to an event in which the patient was at risk of death at the time of the event. It does not refer to an event that hypothetically might have caused death had it been more severe.
Important medical events that may not immediately result in death, be life-threatening, or require hospitalization may be considered to be SAEs when, based upon appropriate medical judgment, they may jeopardize the patient, and may require medical or surgical intervention to prevent one of the outcomes listed in the definitions above.
The reference safety document to assess whether or not an SAE must be reported by the sponsor to health authorities, ECs/IRBs and investigators in an expedited fashion is the Investigator’s Brochure [Ponesimod IB].
4.3.1.2 Hospitalization - Prolongation of existing hospitalization
Hospitalization is defined as an admission to a hospital or a prolongation of existing hospitalization due to an AE.
If on Days 1, 8, or 15 a patient needs to stay at the hospital more than 12 hours post-dose due to an AE, this constitutes an SAE.
The following reasons for hospitalizations are not considered AEs, and therefore not SAEs:
Hospitalizations for cosmetic elective surgery, social and/or convenience reasons.
Standard monitoring of a pre-existing disease or medical condition that did not worsen, e.g., hospitalization for coronary angiography in a patient with stable angina pectoris.
Elective treatment of a pre-existing disease or medical condition that did not worsen, e.g., elective hip replacement for arthritis. Complications that occur during hospitalization are AEs or SAEs (for example if a complication prolongs hospitalization).
4.3.1.3 Serious adverse events related to study-mandated procedures
Such SAEs are defined as SAEs that appear to have a reasonable possibility of causal relationship (i.e., a relationship cannot be ruled out) to study-mandated procedures (excluding administration of study drug) such as complication of a mandated invasive procedure (e.g., blood sampling, heart catheterization), or car accident on the way to the hospital for a study visit, etc.
Reporting of serious adverse events
4.3.2.1 Treatment period (including transition period and study drug interruption) All SAEs regardless of causal relationship that occur from the start of the transition period until 15 days after study drug discontinuation must be recorded.
Treatment-emergent SAEs are defined as all SAEs with onset date from the date of first study drug intake (date of Visit E1 for patients who received placebo in the core study, date of core study Visit 1 for patients who received active treatment in the core study) until 15 days after study drug discontinuation.
These SAEs are reported on SAE forms and also on the AE form in the extension study eCRF. Therefore, they are entered both in the drug safety and clinical databases, and must be reconciled before study closure.
All SAEs occurring during TP1, TP2, and TP3 must be reported on an AE page of the CRF, regardless of causal relationship. This applies also to SAEs occurring during study drug interruption (e.g., due to planned pregnancy), i.e., all SAEs during study drug interruption must be reported on SAE forms and also on the AE form of the eCRF.
4.3.2.2 Follow-up period
All SAEs regardless of causal relationship occurring from 16 days after study drug discontinuation until 30 or 90 days (as applicable) after study drug discontinuation must be reported.
These SAEs are reported on SAE forms and also on the AE form in the eCRF. Therefore, they are entered both in the drug safety and clinical databases, and must be reconciled before study closure.
4.3.2.3 Reporting procedures
All SAEs, as well as product quality complaints (PQCs), occurring during the study must be reported to the appropriate sponsor contact person by study site personnel within 24 hours of their knowledge of the event.
All SAEs must be recorded on SAE forms, irrespective of the study drug received by the patient, whether or not this event is considered by the investigator to be related to study drug.
These SAE forms must be completed and signed by a physician from the study site and sent to the sponsor within 24 hours using the contact details provided on the form. The investigator must complete the SAE form in English (unless otherwise specified) and assess the relationship to study drug.
Such preliminary reports will be followed by detailed descriptions that should include copies of hospital case reports, autopsy reports, hospital discharge summaries and other documents when requested and applicable. Follow-up information about a previously reported SAE must also be reported within 24 hours of receiving it. The sponsor may contact the investigator to obtain further information.
Suspected (considered related to the study drug) and unexpected (not previously described in the reference safety document) serious adverse reactions (SUSARs) will be expedited by the sponsor to health authorities, ECs/IRBs and investigators, as appropriate.
Unblinding of SUSARs will be performed as appropriate.
MS relapses and associated symptoms are exempt from being reported on an SAE form by the investigator to the sponsor, with the following exceptions:
MS relapses with fatal outcome.
MS relapses that, in the view of the investigator, warrant specific notice due to unusual frequency, severity or remarkable clinical manifestations (these should be reported as an AE on the AE form of the eCRF and, if applicable, on the SAE form).
Follow-up of serious adverse events
SAEs still ongoing at the EOS2 or EOS3 must be followed until resolution or stabilization or until the event is otherwise explained.
New SAEs occurring at any time after the EOS / after the 30-day follow-up period may be reported to the sponsor within 24 hours of the investigator’s knowledge of the event, if felt appropriate by the investigator. Therefore, these SAEs are entered only into the drug safety database and hence will not affect study closure.