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

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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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