Presented by: Robert Lindblad, M.D. Blake Apple Maria Campanella, B.S.N., R.N., CCRA

1. Identifying, Reporting and Resolving Adverse Events in CTN Trials Presented by: Robert Lindblad, M.D. Blake Apple Maria Campanella, B.S.N., R.N., CCRA

2. Training Outline • Bob Lindblad, MD • Monitoring safety in research studies • Clinical and regulatory importance • New regulations and guidelines • Blake Apple • Safety Reporting – The Site Perspective • Identifying • Naming (Verbatims) • Characterizing • Reporting • Maria Campanella, BSN,RN, CCRA • Responsibility and resources • MedDRA Coding • Resolving • Discussion and guidance • Closing the data base – reconciliation

3. Clinical and Regulatory Importance of Monitoring Safety in Research Studies

4. Why Monitor Safety? HUMAN SUBJECT PROTECTION The Declaration of Helsinki: “Concern for the interests of the subjects must always prevail over the interests of science and society.” “Primum non nocere” Hippocrates, 460-377 BC

5. Why Monitor Safety? GUIDELINES and REGULATIONS • ICH GCP guidelines: “The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.” • The Federal Government: All clinical trials supported or conducted by the Federal Government must monitor and protect the safety of human subjects.

6. Why Monitor Safety • Not an IND study • Funded through NIH • Good Clinical Practice

7. Strategy for Reporting Intervention Population RISK

8. Strategy for Reporting • Identify the Risk in the proposed clinical trial • Tailor the reporting to the identified risk • Maintain standard Adverse Event language • Definitions • Severity grading • Relationship designation

9. New Regulations • FDA issued new regulations regarding safety reporting • Will impact all clinical trial reporting • Increased consistency with ICH and GCP guidelines

10. Summary • Why report Safety? • It is the right thing to do to ensure participant’s well being in a clinical research study • NIDA CTN population meets the definition of a vulnerable population

11. Safety Event Process Recommendations Identifying & Reviewing Resolving AEorSAE Reporting & Verbatims Discussion & Guidance

12. Identifying & Reviewing Identifying Safety Events: What is a “Safety Event”? The term Safety Events includes both Adverse Events and Serious Adverse Events

13. Identifying Safety Events What is an Adverse Event (AE)? Any reaction, side effect, or untoward event that occurs during the course of the clinical trial, whether or not the event is considered clinically significant or related to the intervention.

14. Identifying Safety Events What is a Serious Adverse Event (SAE)? A SAE is an AE that results in: Death or or Is life-threatening or Requires admission to an inpatient medical facility or Prolongs a hospitalization or Persistent or significant disability or incapacity or Is a birth defect or congenital anomaly or Requires medical intervention to prevent one of the above

15. Reporting Safety Events WHEN are AEs and SAEs reported? • Research staff should assess for reportable AEs and SAEs at every study visit. • All reportable AE/SAEs should be entered into the EDC system via the Adverse Events CRF as soon as the site becomes aware of the event. • All information related to a reported AE should be entered into the EDC system within 7 days of the site becoming aware of the event. • All information related to a reported SAEshould be entered into the EDC system within 24 hours of the site becoming aware of the event.

16. So, what Challenges you?

17. Identifying Safety Events Know your Protocol it’s all in the details • The protocol defines the rules for reporting adverse events. • It also defines the notification time frames and reporting responsibilities.

18. Adverse events can be identified through a variety of ways: Direct participant discussions Direct observation of the participant (bruises etc) Family or friends of the participant Newspaper articles, as in death announcements Confidential discussions with other research staff Discussions with outside providers, if the participant has given consent to do so

19. Following up on Unresolved AE/SAE’s It is easy to forget a certain participant has an open AE.

20. Safety events are chronically underreported in clinical trials the participant is not forthcoming with the information the research staff isn’t asking the right questions the information is “hidden” in a progress note and not recorded appropriately as a safety event participants sometimes report AEs in regular conversations Identifying & Reviewing Identifying Safety Events:

21. Reporting Safety Events WHAT information about an AE/SAE needs to be reported: When a Participant Reports an Event, the RA has to figure out: 1- The name of the event 2- The severityof the event 3- The relatedness of the event 4- If the event is a Serious Adverse Event? 5- If the event is a ‘reportable’ one? (To whom, what and when?)

22. Reporting Safety Events The Biggest Challenge?The Name of the Event • Knowing how to take everything that you see and hear during your assessment and boiling it down to one, accurate and succinct term • Avoiding getting caught in the “drama” of the event It sounds a lot easier than it is.

23. The Name of the Event The Verbatim = the AE description Simple Accurate 2-3 words Prefer a diagnosis to symptoms HINT! It doesn’t mean to write down verbatim what the participant says. Naming the Events

24. Naming the Events Examples of AE’s that were incorrectly reported during other clinical trials Oops!

25. Naming Safety Events HINT! Enter Verbatims that make sense. Normally normal after drinking coffee

26. Naming Safety Events Avoid Vague or Ambiguous Medical Terms

27. Naming Safety Events HEARS NEW AGE MUSIC WHEN THE FURNACE TURNS ON Could this be a hallucination?

28. Naming Safety Events HINT! No acronyms or abbreviations “LK RTCTL UNSP XTRNDL ORG”

29. Naming Safety Events Watch out for Abbreviations and Acronyms

30. Naming Safety Events HINT! Stick to the facts. Do not need qualifiers. How about Abdominal discomfort. “ABDOMINAL DISCOMFORT SECONDARY TO AIRPLANE FOOD INGESTION”

31. Naming Safety Events Avoid Extraneous Data Keep it simple

32. Naming Safety Events HINT! Watch for typos! They can change the meaning. How about Back pain. “MUSCLE PAIN IN THE BAG”

33. Naming Safety Events Where is it?Body Site is Needed for Certain Conditions

34. Naming Safety Events How aboutExcessive Urination. PEES LIKE A CAMEL

35. Naming Safety Events We Need Complete Medical Terminology

36. Naming Safety Events “PATIENT RECENTLY BEGAN NEW JOB WHERE HE WORKS AROUND CHICKEN WINGS AND BARBECUE SAUCE” Nice Information! But what is The adverse event?

37. Naming Safety Events HINT! Enter only one event per CRF. “HEADACHES andSEEING PEOPLE IN ROOM, SEEING CHICKENS AT WINDOW”

38. Naming Safety Events Don’t Place Multiple Diagnoses in One Entry

39. Reporting Safety Events Reporting Safety Events Why is the getting the verbatim right so important? MedDRA Coding (Medical Dictionary for Regulatory Activities)

40. MedDRA Coding • MedDRA - the Medical Dictionary for Regulatory Activities • medical terminology used to classify adverse event • coding allows health authorities and the biopharmaceutical industry to more readily exchange and analyze data related to the safe use of medical products. • MedDRA was developed by the International Conference on Harmonisation (ICH)

41. MedDRA Coding

42. MedDRA Coding • The structural elements of the MedDRA terminology are as follows: • SOC – Highest level of the terminology, and distinguished by anatomical or physiological system, etiology, or purpose • HLGT – Subordinate to SOC, superordinate descriptor for one or more HLTs • HLT – Subordinate to HLGT, superordinate descriptor for one or more PTs • PT – Represents a single medical concept • LLT – Lowest level of the terminology, related to a single PT as a synonym, lexical variant, or quasi-synonym (Note: All PTs have an identical LLT).

43. MedDRA Coding

44. Reporting Safety Events Once you’ve named the event, then you have to characterize it. Events are characterized by determining the relatedness and severity.

45. Reporting Safety Events Relatedness requires an assessment of temporal relationships The relatednessof the event refers to whether the event is thought to have been caused by or made worse by the study intervention

46. Event Relatedness • Is the event related to the study intervention that the participant has been randomized to? • NO Unrelated No reasonable temporal sequence and if the event can most likely be explained by the study participant’s clinical disease state or by other therapies • YES Possibly A reasonable temporal sequence, follows a known response pattern, but could have been produced by the study participant’s clinical state or by other therapies • YES Probably A reasonable temporal sequence, follows a known response pattern, cannot be reasonably explained by the known characteristics of the study participants clinical state or other therapies • YES Definitely A temporal sequence follows a known response pattern.

47. Reporting Safety Event - Severity • Grade 1 – Mild • Transient or mild discomfort (less than 48 hours) no or minimal medical Intervention/therapy required, hospitalization not necessary. • Grade 2 - Moderate • Mild to moderate limitation in activity, some assistance may be needed; no or minimal intervention/ therapy required, hospitalization possible. • Grade 3 - Severe • Marked limitation in activity, some assistance usually required; medical intervention/ therapy required, hospitalization possible. • Grade 4 - Life-threatening • Extreme limitation in activity, significant medical/ therapyintervention required, hospitalization or hospice care probable. • Grade 5 - Death • Remember that death is not the SAE…the cause of the death is the SAE…death is the outcome.

48. Reporting Safety Events Remember that Severe and Serious are not the same thing • Serious events may be Grade 2 (Moderate) • Grade 3 (Severe) events are NOT always serious Know your protocol! Death or or Is life-threatening or Requires admission to an inpatient medical facility or Prolongs a hospitalization or Persistent or significant disability or incapacity or Is a birth defect or congenital anomaly or Requires medical intervention to prevent one of the above

49. Your Protocol Your IRB HINT! Your site specific IRB requirements may differ from protocol reporting requirements Reporting Safety Events The reportability of an event in CTN trials based on TWO things: Protocol

50. Reporting Safety Events WHO “reports” AEs and SAEs? • The participant Study staff • The study staff EDC Site IRB • EDC NIDA CTN Safety Office • NIDA CTN Safety Office Sponsor