© imperial college londonpage 1 paula nicholson research facilitator [email protected]...

© Imperial College London

Paula NicholsonResearch Facilitator

[email protected]

Patricia HenleyResearch Facilitator

[email protected]

Safety Reporting


Outline

• Review of regulations• Definitions• Reporting guidelines• Annual safety reports• Exercise


The Media


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

“Show me a drug without side effects and I shall show you a drug that does not work”


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


A Balancing Act – Risk/Benefit

Provision of effective medicines to patients who need them

• Define acceptable risk

• Communicate and minimise the risks

• Monitor effectiveness of actions taken

• Influence appropriate use

• Characterise the safety profile


Acronym crazy

• AE– Adverse Event

• AR– Adverse Reaction

• SAE– Serious Adverse Event

• SAR– Serious Adverse Reaction

• SSAR– Suspected Serious Adverse Reaction

• SUSAR– Suspected Unexpected Serious Adverse Reaction


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


Definitions: Adverse reaction (AR)

• Any untoward and unintended response to a medicinal product

• Related to any dose administered of medicinal product


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

incapacity– Is a congenital anomaly or birth defect

• Severe does not mean serious


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

• http://emc.medicines.org.uk

http://emc.medicines.org.uk/


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 SmPC

Suspected and Unexpected


Causality Definitions

Relationship Description

Unrelated No evidence of any causal relationship

Unlikely 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).

Possible* 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).

Probable* Is evidence to suggest a causal relationship and the influence of other factors is unlikely.

Definitely* 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.


Causality

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


Reporting and Handling of AEs and SAEs and SUSARs


Sponsor delegated responsibilities

• EVERYTHING!!– 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


Safety Reporting Process Map


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

study

• Reporting– Depends on terms of contract with company– If Phase 4, list under marketing authorisation– MREC / MHRA don’t require reporting


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


How to report

• CIOMS 1• SAE form

template


Annual Safety Reports – by IMP

• CTIMPs:– 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


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


SUSARs - What to reportInitial 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


Data Elements for SUSAR Report• Age • Sex• Medical History• Daily dose of suspected medicinal product and regimen• Start date• End date• Duration• Indications for which suspect medicinal product was

prescribed• Starting date of onset of reactions (or time to onset)• Dechallenge• Rechallenge• Causal relationship assessment• Concomitant Drugs listed• Concomitant Start date• Concomitant End date


SUSAR Additional Information (Follow-up)

• If serious, criterion or criteria for regarding the case as serious

• 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

results


Where to report SUSARs

• UK CTIMPs– MHRA, PO Box 20, Mitcheldean GL17 0WQ– Email scanned copy to:

[email protected]– No fax

• Non-UK CTIMPs– Clinical Trials Unit, MHRA, Market Towers,

London SW8 5NQ– Fax: 020 7084 2443

• Inform all PIs on study

mailto:[email protected]


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


Why do we need to monitor safety post marketing?

REAL LIFE IS NOT LIKE A CLINICAL TRIAL• Clinical trials only encompass a very small

selected section of the population• No pregnancy• Concomitant medications are controlled• Long term use• Yellow card scheme


Number of patients required to detect adverse reactions

Incidence of adverse Number of patients required

reactions Number of adverse reactions detected

One case Two cases Three Cases

1 in 100 300 480 650

1 in 200 600 960 1300

1 in 1000 3000 4800 6500

1 in 2000 6000 9600 13000

1 in 10000 30000 48000 65000

These figures are increased if the patient population already has a background incidence


What can the regulators do to you?

• Criminal Sanctions– Personal Fines

– Imprisonment

• Civil Liability– Claims for negligence (failure to act with reasonable care)

• Regulatory – Revocation of marketing authorisation

– Regulatory inspection/enforcement action

– Loss of credibility with regulatory agencies


Exercise

• 10 minutes for 10 cases


Pharmacovigilance in practice - Cerivastatin• Cerivastatin (Baycol) approved as a lipid regulating agent in

1998• 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 gemfibrozil• Aug 2001, Bayer voluntarily withdrew cerivastatin from the

market on the grounds of increased risk of rhabdomyolysis, particularly when used in combination with gemfibrozil


Summary

• In summary:– Pharmacovigilance is an integral part of any

clinical trial– Failure to comply with regulations can send you to

jail– Safety of participants is paramount

If in doubt - check with Clinical Research [email protected] [email protected]/clinicalresearchoffice



http://www.imperial.ac.uk/clinicalresearchoffice


Useful Websites

• Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use– http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-

10/21_susar_rev2_2006_04_11.pdf• MHRA guide on safety reporting

– http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&nodeId=993

• COREC guide on safety reporting– http://www.corec.org.uk/applicants/apply/safety.htm

• CRO SOP– http://www3.imperial.ac.uk/clinicalresearchoffice/

standardoperatingprocedures

© imperial college londonpage 1 paula nicholson research facilitator [email protected]...

Documents

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