1. Paula Nicholson Research Facilitator P.Nicholson@imperial.ac.uk
Safety Reporting
Thank you
Registration sheets
Questions
Who am i
Paula Nicholson
Research Facilitator
Patricia Henley
Research Facilitator
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2. Outline Review of regulations Definitions Reporting guidelines
Annual safety reports
Exercise
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3. The Media
It’s hardly a week that goes by where we don’t hear of some story in the news about the dangers of taking part in studies, or when something has gone wrong with marketed drugs. Medicine is supposed to make people feel better, not worse..
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4. 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”
All drugs have side effects, this is how you know it’s working!
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5. 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
Diptheria antitoxin: 5 year-old girl given diptheria antitoxin prophylactically, contracted tetanus and died. Investigation showed that the horse (Jim) who had produced toxin had been earlier destroyed due to tetanus. Officials allowed some of the contaminated serum to be distributed – leading to 12 more children dying. Soon after 9 other children died due to contaminated smallpox vaccine
Cmte for drug safety was formed after the thalidomide scandal. Thalidomide was introduced in In animal tests no anti-tumour or sedative effects also was non toxic. Initially used as a sedative, became widely used by pregnant women to combat nausea/morning sickness. Was eventually shown to be linked to the congenital abnormality phocomelia - hands and feet linked to the body – withdrawn from the worldwide market Now being used not only as treatment for leprosy but also for non-small cell lung cancer
Note – if you are running physiological studies, any SAE/SUSARs etc should be reported to REC in normal fashion, but consider the yellow card scheme to report to mhra (more later)
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6. 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
Pharmacovigilance is a balancing act between the risk of harming a patient with the benefit of curing them.
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7. Acronym crazy AE AR SAE SAR SSAR SUSAR Adverse Event Adverse Reaction
Serious Adverse Event
SAR
Serious Adverse Reaction
SSAR
Suspected Serious Adverse Reaction
SUSAR
Suspected Unexpected Serious Adverse Reaction
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8. 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
EG: take aspirin, fall down stairs and break leg
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9. Definitions: Adverse reaction (AR)
Any untoward and unintended response to a medicinal product
Related to any dose administered of medicinal product
AE thought to be reasonably causally related to the IMP.
Eg: Take aspirin, get upset stomach
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10. 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
Life-Threatening: Report if the patient was at substantial risk of dying at the time of the adverse event or it is suspected that the use or continued use of the product would result in the patient's death.
Hospitalization (initial or prolonged): Report if admission to the hospital or prolongation of a hospital stay results because of the adverse event.
Disability: Report if the adverse event resulted in a significant, persistent, or permanent change, impairment, damage or disruption in the patient's body function/structure, physical activities or quality of life.
Congenital Anomaly: Report if there are suspicions that exposure to a medical product prior to conception or during pregnancy resulted in an adverse outcome in the child.
Eg: Take aspirin, get upset stomach, pain gets so bad you end up at A&E where they discover a GI bleed and admit you for an operation to stop the bleeding. Have previous history of ulcers which may have caused the bleeding.
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11. 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
Eg: Take aspirin, get upset stomach, pain gets so bad you end up at A&E where they discover a GI bleed and admit you for an operation to stop the bleeding. No relevant history or concomitant meds
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12. 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
The trial protocol should include a list of known side effects which will be checked against for each sae in terms of expectedness. If the event is not listed as expected, or has occurred in a more serious form than anticipated, this should be considered a susar.
Eg: Take aspirin, have severe stomach pain, go to A&E and turns out your appendix has ruptured and you need emergency operation to fix it.
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13. 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.
How do we know if it is suspected? These are the definitions given to us by the MHRA. The ones marked with a * are the ones that would be reported to the MHRA.
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14. Causality Factors to consider: Nature of the reaction Timing
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
- Positive dechallenge: if the reaction goes away when you stop the medication
Positive rechallenge: if the reaction comes back when you re-introduce the medication (tends not to happen unless for curative reasons, eg giving cytotoxics to an oncology patient). Would obviously give at lower dose.
Should be the local PI’s assessment of causality as they know the patient’s history, their concomitant meds. The CI can not down-grade the PI’s assessment. Both assessments recorded and worst case used for reporting.
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15. Reporting and Handling of AEs and SAEs and SUSARs
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16. 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
On the CTA application, ensure that under what duties are delegated that susar reporting is ticked as yes – sponsor delegated!
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17. Safety Reporting Process Map
In a nutshell – this is the process you would work through if you receive a report of an adverse event!
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18. How to Handle – AEs / ARs Trial Planning Data Collection Reporting
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
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19. All SAEs to be reported to CI within 24 hours on appropriate form
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
Trial planning same as with AEs/ARs
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20. How to report
CIOMS 1
SAE form template
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21. 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
Cover letter for reporting SAEs to MREC on their website and our SOP page
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22. 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
International studies? Non-UK SUSARs should be sent to MHRA as well.
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23. 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
Minimum criteria
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24. 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
Full details of what would be in SUSAR report
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25. 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
f/ups should be sent within 8 days
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26. Where to report SUSARs UK CTIMPs Non-UK CTIMPs Inform all PIs on study
MHRA, PO Box 20, Mitcheldean GL17 0WQ
scanned copy to:
No fax
Non-UK CTIMPs
Clinical Trials Unit, MHRA, Market Towers, London SW8 5NQ
Fax:
Inform all PIs on study
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27. Pregnancy or impregnation Lack of efficacy
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
Pregnancy: need to monitor pregnancy to outcome if someone falls pregnant or makes someone pregnant (boys and girls!!!) if they fall pregnant on clinical trial or where the fetus could have been exposed to the IMP (usually within 30 days after taking the drug depending on half life of drug). It is recommended that the subsequent child be followed up for a few years by GP to determine whether there were any tetragenic effects.
PSUR: usually for medications without marketing authorisation and done by pharmaco. The mhra may request the PSUR, or 6-monthly after authorisation and until placing on market, 6-monthly until 2 years after on market, annually thereafter
Overdose / abuse / misuse not usually reported as SAEs or SUSARs, unless advised to do so by pharmaco. The pharmaco will monitor these situations to see if a pattern emerges.
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28. 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
Yellow Card Scheme: system for early detection of emerging drug safety hazards and routine monitoring for all medicines in clinical use.
SARs reported to either MHRA or Commission on Human Medicines – Jointly responsible for YC scheme. Reported by GPs, Drs, Dentists, Pharmacists, Nurses, Coroners etc. Now
MHRA have opened access to YC data, and now publish anonymised data on the MHRA website as a Drug Analysis Print (DAP): complete list of all Suspected ADRs reported through the YC related to a medicine
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29. 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
1 in
1 in
1 in
1 in
Just demonstrates that to detect something very rare (ie 1 in 10,000), to see just 1 case of the event, you need to recruit 30,000 people!
These figures are increased if the patient population already has a background incidence
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30. 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
Loss of reputation
Loss of employment
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31. Exercise
10 minutes for 10 cases
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32. 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
Rhabdomyolysis: The destruction of skeletal muscle cells. Often the result of electrical injury, alcoholism, injury (or laying in one position for an extended period of time), drug side effects or toxins
Reported to the WHO collaborating centre for international drug monitoring
Between nov 1999 (US), Mar 2000 (Canada), Feb 2001 (Oz), Jun 2001 (EU wide), prescribing info updated
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33. Summary In summary: If in doubt - check with Clinical Research Office
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 Office
Mention CRO audit scheme to help them make sure they’re doing the right thing!
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34. 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
CRO SOP
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