Good clinical practice Beatrice Vincenzi Head of Clinical Operations, Medical Affairs Region Europe Novartis Oncology

AGENDA GCP: definition and purpose Investigator Profile according to GCP Medical Practice versus Medical Research Investigator responsabilities Summary and Conclusion B.Vincenzi | GCP | Ruxolitinib European Investigator Meeting | Barcelona 12Nov2011 | Confidential EFFECTS-GCP

AGENDA GCP: definition and purpose Investigator Profile according to GCP Medical Practice versus Medical Research Investigator responsabilities Summary and Conclusion B.Vincenzi | GCP | Ruxolitinib European Investigator Meeting | Barcelona 12Nov2011 | Confidential EFFECTS-GCP

GCP: Definition and Purpose International Ethical and Scientific Quality Standard for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of all clinical trials that involve participation of human subjects. PURPOSE The protection of the rights, safety and well-being of trial subjects Clinical trial data are credible and accurate Consistency with the principles of Declaration of Helsinki Unified standard - facilitating mutual acceptance of data B.Vincenzi | GCP | Ruxolitinib European Investigator Meeting | Barcelona 12Nov2011 | Confidential

Investigator Profile according to GCP Qualified by education, training and experience Should know and comply with GCP and local regulatory requirements Must have adequate staff and facilities Have sufficient time B.Vincenzi | GCP | Ruxolitinib European Investigator Meeting | Barcelona 12Nov2011 | Confidential

Medical Practice vs Medical Research Regulatory Authority Ethics Committee Subjects Sponsor CRA Investigator Participating in clinical trial research imposes a greater responsibility than in medical practice for identifying and collecting data, in terms of quantity and quality Neither the Sponsor nor Health Authorities can interact with subjects in a clinical trial in the same way as investigators and their staffs Appropriate, written delegation of study related activities and training B.Vincenzi | GCP | Ruxolitinib European Investigator Meeting | Barcelona 12Nov2011 | Confidential

AGENDA GCP: definition and purpose Investigator Profile according to GCP Medical Practice versus Medical Research Investigator responsabilities Summary and Conclusion B.Vincenzi | GCP | Ruxolitinib European Investigator Meeting | Barcelona 12Nov2011 | Confidential EFFECTS-GCP

Investigator Responsabilities Overview The investigator holds the overall responsibility for conduct of trial as well as the safety, rights and medical care of trial subjects Comply with protocol, GCP and applicable regulatory requirements Document protocol deviation (PD), reason and corrective action Ensure a proper Informed Consent process Keep Investigational Drug accountability and proper storage Maintenance of adequate and accurate records (before/during/after) Maintain regular communication with IRB/IEC (before/during/after) Timely reporting of AEs, familiarity with Investigator Brochure Permit monitoring and auditing by sponsor, and inspection by regulatory authority May delegate responsibilities to associates but must maintain control B.Vincenzi | GCP | Ruxolitinib European Investigator Meeting | Barcelona 12Nov2011 | Confidential EFFECTS-GCP

Investigator Responsabilities: Protocol Compliance (1) Adherence to the protocol is essential to ensure scientific validity of the trial Any protocol modifications must be approved by Novartis and IRB/EC prior to implementation In emergency situations only and to ensure subject safety..... ……implement first and then gain approval ! B.Vincenzi | GCP | Ruxolitinib European Investigator Meeting | Barcelona 12Nov2011 | Confidential

Investigator Responsabilities: Protocol Compliance (2) Any request from an investigator/site to grant exceptions from or ‘waive’ any protocol requirement is not acceptable and will be rejected by Novartis e.g. a request to allow a patient who does not fully meet the protocol inclusion/exclusion criteria to enter the study Novartis policy: NO PROTOCOL WAIVERS Please don’t ask for exceptions or waivers to the protocol B.Vincenzi | GCP | Ruxolitinib European Investigator Meeting | Barcelona 12Nov2011 | Confidential

Investigator Responsabilities: Document Protocol Deviation (1) What is a Protocol Deviation (PD)? Any departure from any protocol requirement, irrespective of the degree of seriousness or potentially resulting consequences. How to handle PD? If any protocol deviation puts the subject’s safety at risk it must be reported to Novartis by the investigator and CRA immediately using the “Notification of PD” form A protocol deviation is…. Continue to read… B.Vincenzi | GCP | Ruxolitinib European Investigator Meeting | Barcelona 12Nov2011 | Confidential

Investigator Responsabilities: Document Protocol Deviation (2) PD may impact: Subject safety The scientific integrity of the trial May have a negative impact on the Health Authorities’ assessments of the study and the site Trial analyses Be aware of IRB/EC and local Health Authority reporting requirements for PD A protocol deviation is…. Continue to read… B.Vincenzi | GCP | Ruxolitinib European Investigator Meeting | Barcelona 12Nov2011 | Confidential

Investigator Responsabilities: Informed Consent - definition Informed Consent is a process by which a subject voluntarily confirms willingness to participate after having been informed of all aspects of the clinical trial. Informed consent is documented by means of a written, signed, and dated informed consent form. B.Vincenzi | GCP | Ruxolitinib European Investigator Meeting | Barcelona 12Nov2011 | Confidential

Informed Consent Process (1) Investigator Responsabilities: Informed Consent Process (1) Investigator must determine potential trial subjects based on medical history and condition Investigator can delegate the explanation and taking of informed consent to an appropriately qualified site staff member according with local regulations In this case a medically qualified person must be available to address/answer medical questions Relevant details from the patient information must be discussed with potential subjects and time allowed to decide/discuss with family etc B.Vincenzi | GCP | Ruxolitinib European Investigator Meeting | Barcelona 12Nov2011 | Confidential

Informed Consent Process (2) Investigator Responsabilities: Informed Consent Process (2) ICF version to be used is the one prior approved by IEC/IRB Obtain consent prior to subject participation IC form must be signed and dated by the subject or legally authorised representative (if applicable and according to local regulations) IC form must be signed and dated by the person obtaining the consent The subject must receive a copy of the informed consent documentation and Investigator must retain the original at the site It should be documented in source records when consent was obtained B.Vincenzi | GCP | Ruxolitinib European Investigator Meeting | Barcelona 12Nov2011 | Confidential

Investigator Responsabilities: Investigational Drug The investigator must ensure proper drug administration, accountability and storage Limit distribution by authorized individuals Administer only to subjects in the study Administer according to the protocol Store under secure and required conditions Maintain accurate and complete records Return unused drug to Novartis Read… B.Vincenzi | GCP | Ruxolitinib European Investigator Meeting | Barcelona 12Nov2011 | Confidential

Investigator Responsabilities: Maintenance of adequate and accurate records Definition of Source Data/Documents Source data are all original data contained within the source documents and providing information on the subject’s condition before, during, and after the trial Source data must be:  Attributable  Legible  Contemporaneous  Original  Accurate The unwritten golden rule in this business is: “ If it is not documented, it did not happen! “ B.Vincenzi | GCP | Ruxolitinib European Investigator Meeting | Barcelona 12Nov2011 | Confidential

Source Documents: examples Patient Notes containing evidence of patient’s eligibility (inclusion/exclusion criteria) Informed Consent Forms SAE forms Other examples of source documents: Hospital records, Lab notes, Memoranda, Subjects’ diaries or evaluation checklists, Pharmacy logs, Recorded data from automated instruments, X-rays, Pharmacy subject files... Discrepancies between information in Source Documents and the CRF should be explained or resolved B.Vincenzi | GCP | Ruxolitinib European Investigator Meeting | Barcelona 12Nov2011 | Confidential

Investigator Responsabilities few additional key items...... Maintain regular communication with IRB/IEC (before/during/after) Timely reporting of SAEs Familiarity with Investigator Brochure Permit monitoring and auditing by sponsor Permit inspection by regulatory authority (local/international) May delegate responsibilities to associates but must maintain control B.Vincenzi | GCP | Ruxolitinib European Investigator Meeting | Barcelona 12Nov2011 | Confidential EFFECTS-GCP

AGENDA GCP: definition and purpose Investigator Profile according to GCP Medical Practice versus Medical Research Investigator responsabilities Summary and Conclusion B.Vincenzi | GCP | Ruxolitinib European Investigator Meeting | Barcelona 12Nov2011 | Confidential EFFECTS-GCP

Investigator Responsabilities Summary Comply with protocol, GCP and applicable regulatory requirements Document protocol deviation (PD), reason and corrective action Ensure a proper Informed Consent process Keep Investigational Drug accountability and proper storage Maintain adequate and accurate records (before/during/after) Maintain regular communication with IRB/IEC (before/during/after) Timely reporting of AEs, familiarity with Investigator Brochure Permit monitoring and auditing by sponsor, and inspection by regulatory authority May delegate responsibilities to associates but must maintain control B.Vincenzi | GCP | Ruxolitinib European Investigator Meeting | Barcelona 12Nov2011 | Confidential EFFECTS-GCP

if you have any question. Thank you for your cooperation ! Please contact your CRA if you have any question. Thank you for your cooperation ! B.Vincenzi | GCP | Ruxolitinib European Investigator Meeting | Barcelona 12Nov2011 | Confidential