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Adverse Event reporting in clinical trials

Adverse Event reporting in clinical trials. Overview. Covering. Definitions Terminology Reporting requirements Legislation Researchers responsibilities Practicalities Examples Question and answers. What are Adverse Events? (AE). Definition -

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Adverse Event reporting in clinical trials

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  1. Adverse Event reporting in clinical trials Overview

  2. Covering • Definitions • Terminology • Reporting requirements • Legislation • Researchers responsibilities • Practicalities • Examples • Question and answers

  3. What are Adverse Events? (AE) Definition- Any untoward medical occurrence in a subject to whom a medicinal product has been administered, including occurrences which are not necessarily caused by or related to that product. Elective hospitalisations for pre-treatment conditions (e.g. elective cosmetic procedures) are not adverse events. Abnormal laboratory values should not be reported as adverse events; although any clinical consequences of the abnormality should be reported as adverse events.

  4. Serious Adverse Events (SAE) Definition. Any adverse event, adverse reaction or unexpected adverse reaction, respectively, that: • results in death • is life-threatening • requires hospitalisation or prolongation of existing hospitalisation • is a persistent or significant disability or incapacity OR • consists of a congenital anomaly or birth defect, • Regardless of the Investigator’s or Sponsor’s opinion on the relationship to test treatment”.

  5. SUSAR- Serious Unexpected Serious Adverse Reaction Definition. Any event (excluding any event that is clearly due to disease progression as defined in the protocol) which is: • Associated with a study patient’s death, • Associated with in patient hospitalisation or prolonged hospitalisation • Life threatening to a study patient • associated with a severe or permanent disability of a study patient • a congenital abnormality/birth defect • or significant other reason including cases of newly diagnosed cancer AND which is considered to have a reasonable causal relationship with the study drug (suspected) and the nature of severity of which are inconsistent with the available product information (unexpected).

  6. Adverse Reaction (AR) • Definition : any untoward and unintended response in a participant to an investigational medicinal product, which is related to any dose administered to that subject.

  7. Other terms • ADR (Adverse Drug Reaction) • SUSAR (Suspected Unexpected Serious Adverse Reaction) • CIOMS

  8. How are they assessed? On 5 dimensions • Classification • Severity • Seriousness • Causality • Expectedness

  9. Assessment of Severity • 1 = MILD - aware of sign or symptom, but easily tolerated • 2 = MODERATE - discomfort enough to cause interference with usual activity • 3 = SEVERE – incapacitating, with inability to work or do usual activity • 4 = LIFE-THREATENING - Refers to an event in which the patient was, in the view of the Investigator, at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe. • 5 = FATAL

  10. Assessment of Seriousness • Usually defined in the protocol • Mild, moderate or severe • This is an intensity rating whilst severity is a regulatory definition. • You can have moderately serious events that are not classed as severe.

  11. Assessment of Causality (relatedness) • The Directive gives a classification for the relationship of the product being studied to the adverse event. It is not mandatory to use these categories. • Not related – temporal relationship of the onset of the event, relative to the administration of the product, is not reasonable or another cause can by itself explain the occurrence of the event. • Unlikely • Possibly related – temporal relationship of the onset of the event, relative to administration of the product, is reasonable but the event could have been due to another, equally likely cause.

  12. Assessment of Causality • Probably related – temporal relationship of the onset of the event, relative to the administration of the product, is reasonable and the event is more likely explained by the product than by another cause. • Definitely related – temporal relationship of the onset of the event, relative to the administration of the product, is reasonable and there is no other cause to explain the event or a re challenge (if feasible) is positive. • Of the above definitions, • “possibly”, “probably” and “definitely” related to an investigational medical product are considered adverse reactions • “unlikely” and “not related” do not qualify as a causal relationship.

  13. What to report and to whom?

  14. Why report everything? • You do not know what might be important • You do not know all effects of an intervention • Remember-for most drugs the full adverse event profile is not known until after the drug has been marketed and is widely used. It is vital that all possible serious effects are known before is reaches this stage. • Patient safety should always be the first concern

  15. MHRA • A Sponsor shall ensure that all relevant information about a suspected unexpected serious adverse reaction (SUSAR) which occurs during the course of a clinical trial in the United Kingdom and is fatal or life-threatening is reported as soon as possible to the MHRA, the competent authorities of any EEA State, other than the United Kingdom, in which the trial is being conducted, and the relevant Ethics Committee. • This needs to be done not later than seven days after the Sponsor was first aware of the reaction. • Any additional relevant information should be sent within eight days of the report

  16. Investigator Responsibilities • The investigator shall report any serious adverse event (SAE) which occurs in a subject immediately to the Sponsor. • The immediate report may be made orally or in writing and shall be followed by a detailed written report on the event.

  17. Sponsor responsibilities • The Sponsor shall keep detailed records of all adverse events relating to a clinical trial which are reported to him by the investigators for that trial. • The Licensing Authority may require the Sponsor to send those records, or copies of such records, to the authority.

  18. Reporting to the Ethics Committee • The ethics committee should routinely receive the following: • Expedited reports of all suspected unexpected serious adverse reactions (SUSARs) occurring in the UK in the trial for which the ethics committee gave a favorable opinion. This includes SUSARs associated with active comparator drugs. See also timelines for expedited reporting. • 6-monthly safety reports on the safety of subjects in all clinical trials of the investigational medicinal product (IMP) for which the sponsor is responsible worldwide, with a global line listing of SUSARs occurring in these trials in the reporting period. • Annual safety reports on the safety of subjects in all clinical trials of the IMP for which the sponsor is responsible worldwide, with an aggregated global line listing of all suspected serious adverse reactions (SSARs) occurring in these trials in the reporting period. • Any significant finding by and recommendations of an independent data monitoring committee or equivalent body established for the trial.

  19. Reporting Severity and causality must be assessed and assigned by a medically qualified practitioner for All AEs, SAEs and SUSARs.

  20. How do you describe an AE? • Wherever possible describe in terms of change in status or diagnosis rather than symptoms • E.g. influenza, rather than stomach upset, fever and shivering.

  21. When do you follow AE’s up to? • Conclusion • Resolution • Stabilisation

  22. Follow up • Until fully investigated to the Sponsor/ Investigators requirements. • You may chose to report significant events beyond the defined treatment and assessment period. • New events occurring during this period may also have to reported(at sponsors/investigators discretion).

  23. What happens to adverse events? • Tabulation at the end of study • Need to think about this as you report • Events need to be classified according to MEDRA for final report (and publication)

  24. How to report? • Via EMAIL • Followed up by paper • If needed direct report Timeframes • AE as soon as possible and within 7 days • SAE/SUSAR Immediately and always within 24 hours

  25. Why time limits? • So that Sponsor can review event • If needed can request further information • Allows unblinding if needed • And can follow expedited reporting procedures as legally required • This includes alerting other IMP users worldwide if needed

  26. What does R and D do with reports? • Reviews then • Assesses expectedness • If necessary can change the severity (can only increase severity) • Enters event into study log • If more than one study of that IMP in progress will cross reference

  27. References and sources of information • http://www.wctn.org.uk/downloads/EU_Directive/Directive.pdf • http://www.opsi.gov.uk/si/si2004/20041031.htm • Amendment 2006 • http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-10/11_ca_14-2005.pdf (Detailed guidance).

  28. Examples • Patient has been enrolled into a study of RA. On return for their randomisation visit they report that they have had an exacerbation of their joint pain. • What would you do?

  29. Examples • A patient in a clinical trial of a acute treatment (intravenous infusion) has an adverse event during the follow-up period. The event has not resolved by the end of the assessment period of the study according to the study schedule. • What would you do?

  30. Examples • During participation in a long terms follow up study for a new drug for diabetes a patient is admitted to hospital for planned dental surgery. • What would you do?

  31. Examples • During participation in a study of a new dementia treatment a patient is admitted for respite care in a NHS care facility as his main carer has been hospitalised. • What would you do?

  32. Examples • A participant in a trial contacts you on the phone reporting new episodes of chest pain that are not resolved with medication. They are in a trial of a new drug targeting the coronary system. • What would you do?

  33. Examples • You are reviewing a patient at a routine assessment for a clinical trial. At the assessment the patient tells you that they attended A and E whilst on holiday recently and were admitted to the unit fro 24 hours for observation. • What would you do?

  34. Examples • You are assessing a participant in a study and notice that they seem to have a severe rash that appears to be new. The patient says that this is distressing and has been getting more severe. There is no previous history in the notes and this is not a noted effect in the investigators brochure. • What would you do?

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