1. Adverse Events and Serious Adverse Events
Office of Research Education and Regulatory Management

2. Objectives Recognize Adverse Events and serious adverse events
Review FDA inspection findings related to adverse events
Review regulations related to adverse events
Discuss recording and reporting of adverse events
Discuss auditing of adverse events
Demonstrate audit of adverse events

3. FDA Inspection
“Failure to prepare and submit complete and accurate and timely reports of unanticipated adverse device effects”

4. Recognizing
First we will cover recognizing Adverse Events and Serious Adverse Events

5. Adverse Events
Any adverse event associated with the use of a drug in humans, whether or not considered related.
21CFR
Any untoward medical occurrence in a patient administered a pharmaceutical product and which does not necessarily have a causal relationship with the treatment
ICH E6
Although the definitions in the regulations address drugs, we expand the definition for those trials that do not involve drugs.

6. Adverse Event
NCI
An unexpected medical problem that occurs during treatment with a drug or other therapy.
Adverse events do not have to be a caused by the drug or therapy

7. Serious Adverse Event Fred Doesn’t Have Any Money Left Fatal
Disability
Hospitalization
Anomaly
Medically Significant
Life Threatening
This slide lists the event outcomes that are considered serious.
Fun way to remember which events are classified as serious
Fred Doesn’t Have Any Money Left (Wilma went shopping at the Bedrock Mall!)
Serious Adverse Events are those associated with the patient’s participation in research that:
Results in fatality– “Fred”
Results in persistent or significant disability/incapacity – “Doesn’t”
Results in patient hospitalization or prolongation of existing hospitalization – “Have”
Results in a congenital anomaly or birth defect – “Any”
A Medically significant event- “Money”
What is considered medically significant?...
Patient has baseline creatinine of 1.8 due to a renal condition which is Grade 1, not too high but now creatinine jumped to 8. A creatinine of 8 is clinically significant.
Lastly, event is life threatening– “Left” Life threatening events include:
Any adverse pharmaceutical product that places the patient, in the view of the PI, at immediate risk of death from the reaction as it occurred OR if it is suspected that continued use of the product under investigation would result in pt’s death Examples: allergic bronchospasm requiring intensive treatment, gastrointestinal hemorrhage, pacemaker failure

8. Expected Vs. Unexpected
4/5/2017
Expected Vs. Unexpected
Unexpected
Not listed in Investigational Brochure, Informed Consent, or General Investigational Plan
Also not listed in a drug package insert
Expected
Known to Occur and is Listed in the Investigational Brochure, Informed Consent, or General Investigational Plan
To determine if an event is expected or unexpected
Check Investigational Brochure, Informed Consent or General Investigational Plan
To see if the event is listed
If the event is listed, then it is expected
If not, the event is unexpected

9. Recording
Next, talk about recording adverse events.

10. Recording
Know which adverse events the protocol requires to be captured
Sometimes we forget how unique our different protocols are and we go along doing the same thing for every protocol.
Need to be familiar with what adverse events your protocol requires to be captured.
This will vary with your sponsor and with your PI
For example, for a particular protocol, sponsor may only require that you capture Grade 3 or Grade 4 adverse events
Could cut down on your work if that is the case
PI may want to capture every adverse event
This is certainly something you want to discuss with both sponsor and PI before begin protocol

11. Source Documentation
Source Documentation of adverse events include documentation in the medical records of:
Event
Date it occurred
Grade as determined by CTCAE
Expected or Unexpected
Attribution as assigned by PI
Date resolved
Treatment patient received specifically related to event
In order to adequately capture the information to document an adverse event, you need to include:
Event
Date it began
Grade as determined by the appropriate Common Terminology Criteria for Adverse Events
Whether or not it was expected or unexpected
Must have relationship of event to study agent assigned by PI
Date event ended
Document any treatment patient received as a result of the event (took Neurontin for neuropathy, specify dose)

12. Sample Adverse Event Recording Form
See template behind this presentation

13. Here is an example of a template that contains all the required elements and place for physician who is assigning attribution to sign.
You decide what form of documentation works best for your protocol to prompt you to include all of the necessary information including the physician’s signature to confirm the PI is in agreement with the assignment of the attribution of the study product to the event.

14. Attribution (Causality)
The attribution (relationship or causality or drug related assessment) must be determined
A determination made by a clinical investigator that describes the relationship or association of the study product with an adverse experience
This determination must be recorded both in the medical record as well as in the case report form.
Very important part of documentation of adverse events is documentation as to if the event was related to or caused by the pharmaceutical product.
The relationship between the study product and the event must be decided by the clinical investigator and this attribution must be documented indicating the attribution was assigned by the investigator.
BECAUSE, assigning attribution is a medical judgment. And, all AEs are to be communicated to the PI
Plan the best way to document the attribution in the medical record as well as providing a source that the investigator assigned that relationship.
Audits reveal that attribution is found in the CRF but not in source documents.

15. Attribution
What should the investigator consider prior to assigning attribution?
Individual medical history
Known effects of concomitant medications

16. Attribution Definite – Clearly related to study agent
Probable – Likely related to study agent
Possible – May be related to study agent
Unlikely – Doubtfully related to study agent
Unrelated – Clearly not related to study agent
Once again, the determination of attribution is a medical judgment because patients on study trials come with other medical conditions .
The physician must take into consideration the patient’s co-morbidities in order to make an adequate assessment of the relationship between the study agent and the adverse event.

17. How to Capture Adverse Events?
Split or Lumped
Fever, Diarrhea, and Vomiting (Viral Gastroenteritis)
Cough, Sniffles, Sore throat (Flu)
Some sponsors want the symptoms lumped and others want it separated.
Regardless of how these are captured, we must try to stay consistent.
Reference: When a Cough is Just a Cough: The Trouble with Aes
Herschel R. Lessin, MD

18. How to Capture Adverse Events?
Problems with similar terms
Rash or Dermatitis
Wheezing, reactive airway disease, congestion, cold, , asthma
Sometimes documenting adverse events can be a challenge.
Patients and healthcare workers interchangeably will use terms for symptoms described by subjects.

19. Documenting Resolution Dates
Challenge
Does the patient remember when their adverse event resolved?
Do you call the patient? Or wait till the next visit?

20. Patient Toxicity Diary
Diaries where patients capture toxicities between their follow up appointments

21. Patient Toxicity Diaries
Patient writes down constipation because he did not have a bowel movement one day
Research nurse captures constipation without assessing further
Physician copies the research nurse’s note and also dictates constipation
Did anyone ask about the constipation?
According to CTC V3, constipation is grade 1 only if there is occasional or intermittent symptoms; occasional use of stool softeners, laxatives, dietary modification, or enema

22. Patient Adverse Event Diaries
Advantages
Disadvantages
Allows capturing information on a daily basis while patient is away from clinic
A communication tool for patient returns to clinic
Useful in capturing onset and resolution dates of adverse events
Time consuming
Patient non-compliance
Patient self diagnosis or interpretation
Complicated Instructions

23. Question to ask
When should site staff begin collecting adverse event information?
This is protocol specific. Most of the time, study staff collect information from the time informed consent is obtained.
Generally, reporting of serious events are not required until administration of the investigational product or protocol intervention.
P. 262

24. Question to ask
How long should one collect adverse events after the subject completes study treatment?
There are no requirements or regulations that specify the length of time that Adverse events that should be collected after a subject completes the study treatment period. The protocol should clearly define this. A 30 day follow up period is common. Investigators should consider half lives of investigational products, prior experience with the product, and any delayed adverse event concerns prior to establishing a cut off date or time point.

25. Reporting
We have talked about recognizing and recording adverse events, now let’s talk about reporting adverse events!

26. Reporting Serious Events
An investigator must promptly report to the sponsor any adverse effect that may reasonably be regarded as caused by or probably caused by the drug. If the adverse effect is alarming, the investigator shall report the adverse effect immediately.
21CFR312.64
Investigators assigning attribution is addressed here as well. If the investigator is not aware of adverse events and assign attribution, how can he or she follow this regulation?

27. Reporting Criteria Routine Reporting Expedited Reporting
Know which events can be reported at interim analysis or annual reviews
Expedited Reporting
Know which events require immediate reporting
Need to be familiar with the reporting requirements for your protocol
Once again, be familiar with your protocol
In some protocols, you will be responsible for providing data for the interim analysis (point where evaluate data) or for the annual review
Need to know which events require immediate reporting

28. Reporting Criteria
Know which type of expedited reports each regulatory body requires
FDA
Sponsor
Co-Sponsor
MD Anderson
NCI
Collaborative Groups
Although MD Anderson IRB requires only prompt reporting :
of deaths
and serious, related and unexpected events
Other sponsors might have additional requirements.
Some sponsors require you to report all serious adverse events regardless of the relationship.

29. Issues in reporting Primary events Example
Patient admitted with Congestive Heart Failure
Subsequently develops: Pulmonary Edema and Cardiogenic Shock
Often times, patients are admitted with one diagnosis such as this one. Following admission, secondary events are found.
All of these can be reported using one form listing CHF as the primary event for example here.

30. Consequences of Improper Reporting
Protocol Violations
IRB will close protocol
FDA Hold
Sponsor Hold
Research Privileges Revoked
Patient Safety

31. Auditing
Now we are going to talk about what we are here for today….auditing!

32. Auditing Check Points
How are AEs being recorded in the medical record?
Does documentation include grade, onset, resolution, and attribution?
Be sure that all adverse events are documented appropriately to include the:
Event
Dates for beginning and end
Grade
Was the event resolved
Was it expected or unexpected
Documentation of the attribution assigned by the PI
Documentation of any treatment patient received as a result of the event

33. Auditing Check Points Were all toxicities included?
Was the proper CTCAE version used for the protocol?
Were the toxicities graded appropriately?
Were all toxicities included?
In addition to adverse events described by the patient, are there any abnormal lab values or has
something shown up on any scans or x-rays?
Even though newer protocols require Version 3 of the CTCAE, is that the case for this particular protocol?
Were the toxicities actually graded according to the descriptions provided in the Common Terminology Criteria for Adverse Events?

34. Auditing Check Points Was the event a dose limiting toxicity?
Should the dose have been reduced?
If so, did the research team realize it as such and identify it correctly?
Documentation of a dose limiting toxicity is tremendously important!
That is not only for source documentation purposes, but also for patient safety issues.
Your patient shows up in the ER and there is a good chance the only documentation of a dose reduction would be your notes.

35. Auditing
Are adverse events appropriately reported within the time periods required by regulations, sponsor, and IRB policies?

36. We have reviewed……….
Recognizing adverse events and serious adverse events
Inspections and findings related to adverse events
Regulations related to adverse events
Recording and reporting of adverse events
Auditing of adverse events