Paula Nicholson Research Facilitator P.Nicholson@imperial.ac.uk Safety Reporting Thank you Registration sheets Questions Who am i Paula Nicholson Research Facilitator P.Nicholson@imperial.ac.uk Patricia Henley Research Facilitator P.Henley@imperial.ac.uk © Imperial College London

Outline Review of regulations Definitions Reporting guidelines Annual safety reports Exercise © Imperial College London

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.. © Imperial College London

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! © Imperial College London

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 1957 . 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 Was eventually shown to be linked to the congenital abnormality phocomelia - hands and feet linked to the body – withdrawn from the worldwide market 1961. 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) © Imperial College London

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. © Imperial College London

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 © Imperial College London

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 © Imperial College London

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 © Imperial College London

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. © Imperial College London

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 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 © Imperial College London

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. © Imperial College London

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. © Imperial College London

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. © Imperial College London

Reporting and Handling of AEs and SAEs and SUSARs © Imperial College London

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! © Imperial College London

Safety Reporting Process Map In a nutshell – this is the process you would work through if you receive a report of an adverse event! © Imperial College London

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 © Imperial College London

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 © Imperial College London

How to report CIOMS 1 SAE form template © Imperial College London

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 © Imperial College London

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. © Imperial College London

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 © Imperial College London

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 © Imperial College London

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 © Imperial College London

Where to report SUSARs UK CTIMPs Non-UK CTIMPs Inform all PIs on study MHRA, PO Box 20, Mitcheldean GL17 0WQ Email scanned copy to: pharmacovigilance@mhra.gsi.gov.uk No fax Non-UK CTIMPs Clinical Trials Unit, MHRA, Market Towers, London SW8 5NQ Fax: 020 7084 2443 Inform all PIs on study © Imperial College London

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. © Imperial College London

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 © Imperial College London

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 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 © Imperial College London

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 © Imperial College London

Exercise 10 minutes for 10 cases © Imperial College London

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 © Imperial College London

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 Paula.Nicholson@imperial.ac.uk Patricia.Henley@imperial.ac.uk www.imperial.ac.uk/clinicalresearchoffice Mention CRO audit scheme to help them make sure they’re doing the right thing! © Imperial College London

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 London

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