nouvelles exigences en pharmacovigilance - aprova - rencontres de la recherche clinique
TRANSCRIPT
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NOUVELLES EXIGENCES EN
PHARMACOVIGILANCE EN E.C.
4èmes RENCONTRE DE LA RECHERCHECLINIQUE , DES ARCs & DES TECs,
CNIT PARIS LA DÉFENSE20 MARS 2014
Caroline Pastor, Pharmacovigilance Operations ManagerEvelyne Lacabaratz, Senior Safety Officer
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Strength and Energy
with
Products
LAVOCATirradiated food
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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
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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 !
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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
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Why Pharmacovigilance ?
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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 regulationand Agencies in the 1960s
In 50 countries as sedative and
anti-nausea in pregnancy, in 1rst quarter
Thalidomide: 1958- 1961
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• 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
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• 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 October 2006
2005Birth of
Risk Management
40 years later: Vioxx 1999-2004
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“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
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To be sure we use the samewords !
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What is an adverse event AE? ICH E2A guidelines
Adverse EventAny untoward medical occurrence or clinical investigation in a
subject, who is administered a medicinal product, which doesnot necessarily have a causal relationship with the treatment.
Adverse ReactionEvent 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
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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
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Abnormal Laboratory FindingsLaboratory 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 AEE.g. Shortness of breath due to anaemia
� Lab findings requiring medical intervention / treatment may be an AEE.g. Hypoglycemia requiring treatment
� Clinically significant lab findings can be an AEE.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)
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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 ≠ Severity18
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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 threateningWithin 15 calendar days : all other criteria for se riousnessWithin 7 calendar days: fatal and life threateningWithin 15 calendar days : all other criteria for se riousness
Day zero (D0)Clock starts when the SAE form is received by the sponsor(Staff, PV, CRO)
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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
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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
Providean alternative etiology
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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
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SUSAR Submission
For France as of 17th March 2014:
• Submission to ANSM via email : [email protected]
– CIOMS I Form (pdf) + Accompanying Form
User guidance available on ANSM website
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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
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How to fill in the SAE form?
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Diagnosis missing~ 30% of reported SAE
« Hospitalisation for research of etiology of
neovascularisation » - Not a diagnosis
« Surgical treatment…. »Not a diagnosis
Don’tsDon’tsADVERSE EVENT TERM
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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
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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
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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
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Patient Medical History
Do’sDo’s
Diabetes : since 1997Hypertension : since 2010Myocardial Infarction : March 2010No medical/familial history of…
Stressing upon relevant information which couldexplain the SAE
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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.
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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
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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.
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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 emergencydepartment does not necessarily constitute a SAE
• For chronic or long-term inpatients, inpatientadmission also includes transfer within the hospitalto an intensive care in-patient unit (e.g., from themedical floor to a psychiatric/neurological floor).
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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
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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
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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
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Do not forget !
• Concomitant medications
• Consistency with the CRF
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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”
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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.
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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 ?
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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.
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Reporting of SAEs SAE Collection period:Starts from informed consent signature until the last follow-up visit required by the prot ocol or 30 days after the last administration of study d rug.
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
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Remember !
1. You are one of the key person for the understanding ofthe event !
2. You are one of the key person for the safety of thepatient and the other patients as well !
3. Investigators should tell us the whole story! The patientis in front of them, only!
4. Question: Is it possibly related to the drug or theprocedure ?
5. PV are here to support you and answer your questionsany time !
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Do not hesitate
to contact
Pharmacovigilance Department!
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Thank you for your attention
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