Nouvelles exigences en pharmacovigilance - Aprova - Rencontres de la Recherche Clinique


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Nouvelles exigences en pharmacovigilance - Aprova - Rencontres de la Recherche Clinique

  1. 1. 20/03/2014 1 NOUVELLES EXIGENCES EN PHARMACOVIGILANCE EN E.C. 4èmes RENCONTRE DE LA RECHERCHE CLINIQUE , DES ARCs & DES TECs, CNIT PARIS LA DÉFENSE 20 MARS 2014 Caroline Pastor, Pharmacovigilance Operations Manager Evelyne Lacabaratz, Senior Safety Officer 3 Strength and Energy with Products LAVOCAT irradiated food
  2. 2. 20/03/2014 2 4 Purpose of Safety in Clinical Trials • Understand Investigational Medicinal Product effect • Assess the benefit risk of the product • Meet regulatory requirements to protect: – Study Subject – Study Investigator – The Sponsor • Make decisions quickly for: – patient safety – protocol modification – study termination 5 Investigator = a KEY Role Investigators • Are in front of the patients • Are the key persons responsible for the patients’ safety – have the original safety data • Are the key persons able to understand the event Investigators are the FIRST link in the chain ! 6 CRA = supportive role • Main line of communication between sponsor and investigator (§5.18.4 GCP) • To assist the site team (Investigator, study nurse, site CRA,…) to fulfill the responsibilities of SAE reporting to Sponsor • Ensure respect of reporting timelines
  3. 3. 20/03/2014 3 7 Why Pharmacovigilance ? 9 In 50 countries as sedative and anti-nausea in pregnancy, in 1rst quarter 1961 : teratogenicity in 12 000 neonates with genetic transmission 10 years of law suits Creation of Pharmacovigilance regulation and Agencies in the 1960s In 50 countries as sedative and anti-nausea in pregnancy, in 1rst quarter Thalidomide: 1958- 1961
  4. 4. 20/03/2014 4 10 • 1998 : new approval in USA (FDA) – Leprosy, Lupus, Multiple myeloma, graft • Risk Management Plan : STEPS –“Because of the toxicity …. THALOMID® is approved by FDA … only under a special restricted distribution –Physicians, pharmacists, and patients must be registered in the RMP – Use of 2 types of contraceptive measures RESULTS 80 000 patients monitored within 5 years in US no known cases of fetal exposure Thalidomide : come back 1998 11 • 1999 FDA Approval : anti-inflammatory drug • 2000 Myocardial infarction : risk inferior in comparator • 2001 Re-analysis : cardio-vascular risk : RR: 2,38 • 2002 Change of SPC • 2004 : long term study – risk of cardio-vascular event : x2 vs placebo • Sept 2004 Worldwide withdrawal *from Xavier Kurz, EMA ISOP October2006 2005 Birth of Risk Management 40 years later: Vioxx 1999-2004 12 “Adverse drug reactions remain a major cause of morbidity and mortality (4th cause of death in US) Tsintis P,and coll Drug Safety, 2004;27(8):509-517 5% of all hospital admissions due to an adverse drug reaction (5th cause of hospital death) 197.000 deaths per year in EU ; Total cost :79 billion euros EU Commission evaluation : 2010 A Public Health Issue
  5. 5. 20/03/2014 5 To be sure we use the same words ! 13 14 What is an adverse event AE? ICH E2A guidelines Adverse Event Any untoward medical occurrence or clinical investigation in a subject, who is administered a medicinal product, which does not necessarily have a causal relationship with the treatment. Adverse Reaction Event possibly related to the drug or the procedure Examples of AEs: • Arm fracture due to fall on ice – No relationship to study drug • Tooth abscess – No relationship to study drug • Abnormal Chest X-Ray – Cause unknown • Headache – Related to drug • Skin rash – Related to study drug 15 What is NOT an adverse event? 1) Any continuing medical condition or clinically significant laboratory abnormality with an onset date before the date of enrollment should be considered as pre-existing, and therefore not an AE – If the pre-existing condition worsens, then the worsening is an Adverse Event 2) Medical or surgical procedures (e.g., surgery, endoscopy, transfusion). The condition that leads to the procedure is the AE E.g. Tooth abscess is an AE, Extraction is the treatment 3) Situations where an untoward medical occurrence has not occurred E.g. Hospitalization for elective surgery, E.g. Social and/or convenience admissions
  6. 6. 20/03/2014 6 16 Abnormal Laboratory Findings Laboratory abnormalities are usually not recorded as AEs. BUT this is the Investigators’ judgment to tell us if it is clinically significant. Associated signs and/or symptoms may be an AE E.g. Shortness of breath due to anaemia Lab findings requiring medical intervention / treatment may be an AE E.g. Hypoglycemia requiring treatment Clinically significant lab findings can be an AE E.g. CK > 1,000 with no obvious cause Clinically significant abnormal assessments (E.g. ECG, radiographs, vital signs) must be recorded as AEs (or SAEs) 17 What is a Serious Adverse Event (SAE) ? A SERIOUS ADVERSE EVENT (SAE) is any Adverse Event that, at any dose: is fatal is life-threatening requires initial hospitalisation or prolongation of existing hospitalisation results in persistent or significant disability/incapacity results in a congenital anomaly/birth defect results in an important medical event Seriousness : From AE form to SAE form • On the AE form – Is the event serious? Yes / No If 'YES', complete SAE form immediately (within 24 hours from first awareness at the latest) and transmit immediately to Sponsor’s PV department (§ 4.11 GCP) • On the SAE form – Don’t forget to complete the seriousness criterion Seriousness ≠ Severity 18
  7. 7. 20/03/2014 7 19 What is a SUSAR ? Suspected Unexpected Serious Adverse Reaction • It is possibly related to the study drug or to study procedure • It is not listed in the Investigator’s brochure Must be reported to Authorities! Within 7 calendar days: fatal and life threatening Within 15 calendar days : all other criteria for seriousness Within 7 calendar days: fatal and life threatening Within 15 calendar days : all other criteria for seriousness Day zero (D0) Clock starts when the SAE form is received by the sponsor (Staff, PV, CRO) 20 Minimum information required for initial SAE report Must be filled in on the initial SAE form to make a valid case:  Patient Identification Information  Investigator  Adverse event term  Criteria of seriousness  Investigator Causality Assessment Is there a reasonable possibility of a causal relationship? Binary (CT3-2011) YES NO A DIAGNOSIS OR A SYNDROME 21 Causality assessment • Is there a reasonable possibility of causal relationship? – To the study drug ? – To the comparator? – Related to procedure ? • IF NOT RELATED : what is the cause of the event ? – Underlying disease – Disease progression – Other illness – Concomitant drug or therapy Provide an alternative etiology
  8. 8. 20/03/2014 8 22 SUSAR Submission Sponsor’s responsibility (§5.17 GCP): • To National Competent Authorities – Indirect electronic submission via Eudravigilance (EVCTM Prod) – Direct Submission (CIOMS I Form/Medwatch) • To Ethics Committees • To Investigators Regulatory requirements • Clinical trials: SUSARS : 7 days (death/life-threatening ) / 15 days (other SUSAR) • D0 : clock start: date of awareness 23 SUSAR Submission For France as of 17th March 2014: • Submission to ANSM via email : – CIOMS I Form (pdf) + Accompanying Form User guidance available on ANSM website 24 Periodic reports • Developement Safety Update Report - DSUR (ICH Guideline E2F -Sept 2010) • Annual review and evaluation of pertinent safety information collected during the reporting period related to a drug under investigation, whether or not it is marketed. • Covered period : – From Development International Birth Date (DIBD) = date of 1st authorization to conduct a clinical trial in any country worldwide. – To Data Lock Point (DLP) = last day of the one year reporting period. • Submitted to all concerned regulatory authorities no later than 60 calendar days after the DLP and to Ethics Committees. • Periodic Summary Safety Report - PSSR • 6-month SUSAR line listing
  9. 9. 20/03/2014 9 25 How to fill in the SAE form? 26 Diagnosis missing ~ 30% of reported SAE « Hospitalisation for research of etiology of neovascularisation » - Not a diagnosis « Surgical treatment…. » Not a diagnosis Don’tsDon’ts ADVERSE EVENT TERM 27 ADVERSE EVENT TERM PROVIDE a single unifying diagnosis or syndrome that encompasses all signs and symptoms. Where more than one diagnosis exists, multiple SAE forms could be submitted, if no link between diagnoses ; medical discussion Do’sDo’s Angioedema Use common English medical term
  10. 10. 20/03/2014 10 28 This is not a SAE Diagnosis…. • The seriousness criterion : e.g. death, hospitalisation, • An investigation (e.g. angiogram), • or a procedure (e.g. knee replacement). Are not SAEs DIAGNOSIS 29 Patient Medical History 1. Incomplete medical history; Sometimes the section is empty! 2. No dates : is it ongoing? 3. Is there a link with the reported SAE ? 4. Must be consistent with the CRF page of medical history Don’tsDon’ts 30 Patient Medical History Do’sDo’s Diabetes : since 1997 Hypertension : since 2010 Myocardial Infarction : March 2010 No medical/familial history of… Stressing upon relevant information which could explain the SAE
  11. 11. 20/03/2014 11 31 SAE Form : Dates of Onset and End date • Onset Date : – Date of the first sign/symptom of the adverse event – Could start as non serious and become serious – Hospitalization date could be the onset date, but not necessarily. – Date when AE becomes serious must be mentioned in narrative • End Date : – SAE resolved / or returns to baseline. – If the SAE has not yet resolved, leave blank. – If hospitalized, the discharge date may not always be the end date. 32 SAE Form : Seriousness criteria / Death Death is an outcome and a seriousness criterion and not a diagnosis All deaths, regardless of cause, must be reported for subjects on trial. Exception Sudden death without known etiology or if the subject is found dead without a known cause 33 SAE Form : Seriousness criteria /Life-threatening The subject was at immediate risk of death from the event. It does not include an event that might have led to death, if it had occurred with greater severity; It does not include an event that may eventually lead to death.
  12. 12. 20/03/2014 12 34 SAE Form : Seriousness criteria / Hospitalization • Initial hospitalization is defined as any formal in- patient admission (even if less than 24 hours). • Presentation and care within an emergency department does not necessarily constitute a SAE • For chronic or long-term inpatients, inpatient admission also includes transfer within the hospital to an intensive care in-patient unit (e.g., from the medical floor to a psychiatric/neurological floor). 35 SAE Form : Seriousness criteria / Medically significant • Important medical event that may jeopardise the patient or may require intervention to prevent one of the other serious criteria. Medical judgment • Ex: Allergic bronchospasm requiring intensive treatment in an emergency room 36 SAE Form : Narrative Most of the time very poor narrative. • No description, • No sequence of events, • No relevant tests and lab results, • No actions taken to treat event • No sufficient detail to allow a complete medical assessment Don’tsDon’ts
  13. 13. 20/03/2014 13 37 SAE Form : Narrative Tell us a story ! Clear, concise description of • Sequence of events in chronological order • Summary of all relevant clinical information – Medical status prior to the event, – Signs and/or symptoms, – Relevant lab data and tests results, – Clinical course, – Actions to treat event : drug, surgery, tests…. , – Outcome, – Possible etiology Do’sDo’s 38 Do not forget ! • Concomitant medications • Consistency with the CRF 39 Data Accuracy • Unreadable data • Incomplete data : – start date, end date missing • Inaccurate data : – confusion : concomitant treatment and those administered to treat the event • Inconsistent data – Outcome : “not recovered” and end date provided • Blank field – add ”None ” or ”Not applicable”
  14. 14. 20/03/2014 14 40 Source documentation The following documents could be submitted in addition to the SAE form, when relevant • Hospital Discharge Summary • Any relevant tests or procedures reports (X-ray, ECG, …) • Death Certificate, Autopsy report - if applicable Supporting documents do not replace the narrative writing by the investigator. 41 Follow-up • Patients should be followed up – Until the event is resolved or stabilized – Until follow-up is necessary according to Sponsor and/or the Investigator • If case not complete, PV will ask you to answer precise questions on SAE query form – When was the patient discharged ? – As the patient experienced anemia, could you provide all Hb results ? – How did you treat the event ? Drugs? Surgical procedure? – What examination did you perform ? 42 SAE and CRF Reconciliation • Information on AE page of the CRF must be in accordance with the SAE forms! • Check that information is the same especially: – Event verbatim, – Seriousness – Onset and stop dates, – Outcome, – Investigator causality assessment, – Action taken with study drug.
  15. 15. 20/03/2014 15 43 Reporting of SAEs SAE Collection period: Starts from informed consent signature until the last follow-up visit required by the protocol or 30 days after the last administration of study drug. REGARDLESS OF RELATIONSHIP 1- Investigators complete the “Serious Adverse Event Form” IMMEDIATELY 2- Investigators SEND the SAE form to PV DEPARTMENT WITHIN 24 HOURS BY FAX OR BY E-MAIL 44 Remember ! 1. You are one of the key person for the understanding of the event ! 2. You are one of the key person for the safety of the patient and the other patients as well ! 3. Investigators should tell us the whole story! The patient is in front of them, only! 4. Question: Is it possibly related to the drug or the procedure ? 5. PV are here to support you and answer your questions any time ! 45 Do not hesitate to contact Pharmacovigilance Department!
  16. 16. 20/03/2014 16 46 Thank you for your attention Please visit us at