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Safety Reporting
Paula Nicholson
Research Facilitator
[email protected]
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© Imperial College London
Patricia Henley
Research Facilitator
[email protected]
Review of regulations
Reporting guidelines
Annual safety reports
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The Media
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What is pharmacovigilance?
The science and activities relating to the
detection, assessment, understanding and
prevention of adverse effects or any other
drug-related problems.
WHO, 2002
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me a drug without side effects and I shall
show you a drug that does not work”
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Pharmacovigilance regulations
• 1902: Biologics control act
– Diphtheria antitoxin
• 1964: Committee for drug safety formed
• 1967: WHO resolution laying the basis for
international system of monitoring ADEs
• 1968: Medicines Act UK
• 1988: European rapid alert system
• 1995: European Agency for the evaluation of
medicinal products (EMEA)
• 2004: UK Clinical Trials Regulations
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A Balancing Act – Risk/Benefit
• Define acceptable risk
• Communicate and minimise
the risks
• Monitor effectiveness of
actions taken
• Influence appropriate use
• Characterise the safety profile
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Provision of effective
medicines to patients
who need them
Acronym crazy
• AE
– Adverse Event
• AR
– Adverse Reaction
– Serious Adverse Event
– Serious Adverse Reaction
– Suspected Serious Adverse Reaction
– Suspected Unexpected Serious Adverse Reaction
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Definitions: Adverse event (AE)
• Any untoward medical occurrence in a patient
or clinical trial subject administered a
medicinal product
• Does not need to be related to a drug
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Definitions: Adverse reaction (AR)
• Any untoward and unintended response to
a medicinal product
• Related to any dose administered of
medicinal product
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Definitions: Serious Adverse Event (SAE)
• Any AE or AR that at any dose:
– Results in death
– Is life threatening
– Requires hospitalisation, or prolongation of
existing inpatients’ hospitalisation
– Results in persistent or significant disability or
– Is a congenital anomaly or birth defect
• Severe does not mean serious
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Definition: Suspected Serious Adverse
Reaction (SSAR)
• Any adverse reaction that is classed as
serious AND which is consistent with the
information about the IMP listed in the
SmPC or IB
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Definition: Suspected Unexpected
Serious Adverse Reaction (SUSAR)
• Any adverse reaction that is classed as
serious and is suspected to be caused by the
IMP and is NOT consistent with the
information about the IMP in either the IB or
 Suspected and Unexpected
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Causality Definitions
No evidence of any causal relationship
Little evidence to suggest there is a causal relationship (e.g. the event
did not occur within a reasonable time after administration of the trial
medication). There is another reasonable explanation for the event (e.g.
the patient’s clinical condition, other concomitant treatment).
Some evidence to suggest a causal relationship (e.g. because the event
occurs within a reasonable time after administration of the trial
medication). However, the influence of other factors may have
contributed to the event (e.g. the patient’s clinical condition, other
concomitant treatments).
Is evidence to suggest a causal relationship and the influence of other
factors is unlikely.
There is clear evidence to suggest a causal relationship and other
possible contributing factors can be ruled out.
Not assessable
There is insufficient or incomplete evidence to make a clinical judgement
of the causal relationship.
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Factors to consider:
• Nature of the reaction
– ARs commonly caused by medicines, eg skin rxns
• Timing
– e.g. anaphylaxis usually occurs within minutes
• Relationship to dose
– Positive dechallenge
– Positive rechallenge
• Local PI decision
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Reporting and Handling of
AEs and SAEs and SUSARs
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Sponsor delegated responsibilities
– Ongoing safety evaluation of IMPs
– Notifying all PIs, RECs and MHRA of any AEs/ ARs/
SAEs/ SUSARs that may affect subject safety
– Retain detailed records of all AEs
– Reporting SUSARs to MHRA / MREC / Sponsor
– Annual safety reports to MHRA and MREC
– Unblinding
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Safety Reporting Process Map
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How to Handle – AEs / ARs
• Trial Planning
– Include list of expected side effects
• Data Collection
– Keep list of all AEs and ARs that occur during the
• Reporting
– Depends on terms of contract with company
– If Phase 4, list under marketing authorisation
– MREC / MHRA don’t require reporting
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How to Handle - SAEs
• Assess AE for
– seriousness
– causality
– expectedness
• All SAEs to be reported to CI within 24
hours on appropriate form
• Reported via annual safety report
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How to report
• SAE form
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Annual Safety Reports – by IMP
– To MREC and MHRA and Sponsor
– Due anniversary CTA
– Pre-2004, due anniversary DDX
• Non-CTIMPs:
– To MREC and Sponsor
– Due anniversary of ethics approval
• To include:
– Report on subject’s safety
– Line listing of all SAEs
– Aggregate summary table of SAEs
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How to Handle - SUSARs
• Assess AE for
– seriousness
– causality
– expectedness
• If serious, suspected causally related and NOT
expected SUSAR
• Expedited reporting to MHRA / MREC / Sponsor
– fatal or life threatening = 7 days, follow-up in 8 days
– other = 15 days
– Report even if occurred outside UK
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SUSARs - What to report
Initial expedited reports must contain:
• A suspected investigational medicinal product
• An identifiable subject
– initials, sex, age, date of birth, trial number
• An adverse event assessed as serious and unexpected
and a reasonable suspected causal relationship
• An identifiable reporting source
– Health care professional to report to regulatory authority
• Clinical trial identification
– EudraCT number
– Unique Sponsor’s ID number
• Treatment assignment after unblinding and validation (or
not) of the suspected causes
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Data Elements for SUSAR Report
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Medical History
Daily dose of suspected medicinal product and regimen
Start date
End date
Indications for which suspect medicinal product was
Starting date of onset of reactions (or time to onset)
Causal relationship assessment
Concomitant Drugs listed
Concomitant Start date
Concomitant End date
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SUSAR Additional Information (Follow-up)
• If serious, criterion or criteria for regarding the case as
• Full description of reactions
• Patient outcome (at case level and when possible at
event level)
• For a fatal outcome, cause of death and a comment on
its possible relationship to the suspected reactions
– Any autopsy or post mortem findings
• Other relevant aetiological factors
• Stopping date and time or duration of treatment
• Specific tests and/or treatment required and their
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Where to report SUSARs
– MHRA, PO Box 20, Mitcheldean GL17 0WQ
– Email scanned copy to:
[email protected]
– No fax
– Clinical Trials Unit, MHRA, Market Towers, London
– Fax: 020 7084 2443
• Inform all PIs on study
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Special situations
• Pregnancy or impregnation
– Follow up to birth
• Lack of efficacy
– Not normally reported but can be discussed in
periodic safety update report
• Overdose / abuse / Misuse
– Pharma companies should provide guidance
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Why do we need to monitor safety post
• Clinical trials only encompass a very small
selected section of the population
• No pregnancy
• Concomitant medications are controlled
• Long term use
• Yellow card scheme
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Number of patients required to detect
adverse reactions
Incidence of adverse
Number of patients required
Number of adverse reactions detected
One case
Two cases
Three Cases
1 in 100
1 in 200
1 in 1000
1 in 2000
1 in 10000
These figures are increased if the patient population already has a
background incidence
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What can the regulators do to you?
• Criminal Sanctions
– Personal Fines
– Imprisonment
• Civil Liability
– Claims for negligence (failure to act with reasonable
• Regulatory
– Revocation of marketing authorisation
– Regulatory inspection/enforcement action
– Loss of credibility with regulatory agencies
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• 10 minutes for 10 cases
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Pharmacovigilance in practice Cerivastatin
• Cerivastatin (Baycol) approved as a lipid regulating agent in
• By 2000, 549 cases of rhabdomyolysis associated with
cerivastatin use had been reported
• Consequently a signal was issued regarding cerivastatin
and rhabdomyolysis
• Between 1999 and 2001 prescribing information was
updated to include contraindication for cerivastatin and
• Aug 2001, Bayer voluntarily withdrew cerivastatin from the
market on the grounds of increased risk of rhabdomyolysis,
particularly when used in combination with gemfibrozil
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• In summary:
– Pharmacovigilance is an integral part of any
clinical trial
– Failure to comply with regulations can send you to
– Safety of participants is paramount
If in doubt - check with Clinical Research Office
[email protected]
[email protected]
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Useful Websites
• Detailed guidance on the collection, verification and
presentation of adverse reaction reports arising from
clinical trials on medicinal products for human use
• MHRA guide on safety reporting
• COREC guide on safety reporting
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