1. DAIDS Safety Workshop: Part II Expedited Reporting & Assessment
Archita Chatterjee, M.S.
DAIDS RSC Safety Office
Johannesburg, South Africa
29 Aug 2012

2. Objectives Definitions Assessment of Adverse Events
Expedited Reporting Processes
About Manual v2.0

3. Expedited Reporting Materials
Manual for Expedited Reporting to DAIDS v2.0
DAIDS AE Grading Table (Clarification Aug 2009)
Protocol
EAE Reporting Form 2.0
EAE Reporting Form Completion Instructions 2.0

4. Definitions Manual v2.0

5. Expedited Adverse Event Reporting to DAIDS
Two Reporting Categories:
SAE - All Serious Adverse Events
SUSAR - Only Suspected, Unexpected, Serious Adverse Reactions 5

6. Expedited Adverse Event Reporting to DAIDS
The protocol will specify which reporting category will be used
Additional reporting requirements:
The protocol may require other AEs to be reported on an expedited basis; may or may not meet SAE criteria
These other AEs that are required to be reported to DAIDS will be specified in the protocol
Additional reporting requirement as specified in the protocol – Protocol specific reporting
E.g. iPrEx: 1. All Grade 1, 2 & 3 creatinine toxicity, regardless of relationship
2. All Grade 3 hypophosphatemia, regardless of relationship
3. All Grade 4 creatinine or hypophosphatemia (Non-SADR)

7. Expedited Adverse Event Reporting to DAIDS
Study agent(s) – drugs biological agents, combination of drugs and biological agents or devices (approved or investigational) defined in the protocol for which expedited reporting to DAIDS is required
Study agents will be specified in the protocol

8. Reporting Period
Protocol specified reporting period: from enrollment to end of trial follow-up for that participant
After the protocol-defined AE reporting period, unless otherwise noted, only SUSARs will be reported to DAIDS if the study staff becomes aware of the events on a passive basis (from publicly available information)
E.g. of publicly available information - Obituary/Death Notice

9. SAE Definition (ICH E2A)
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose:
Results in death
Is life-threatening
Requires inpatient hospitalization or prolongation of existing hospitalization
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
Is an important medical event that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes listed in the definition above
A persistent or significant incapacity or substantial disruption of the ability to
Conduct normal life functions, or a congenital anomaly/birth defect.
Important medical events that may not result in death, be life-threatening, or require hospitalization
may be considered serious when, based upon appropriate medical judgment, they may jeopardize
the patient or subject and may require medical or surgical interention to prevent one of the outcomes
listed in this definition.

10. Clarification on SAE Definition: Life-threatening
Life-threatening refers to an event in which the patient was 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
e.g., malignancy
If either the investigator or the sponsor believes that an adverse event meets the definition of life-threatening, it must be considered life-threatening for reporting purposes.

11. Clarification on SAE Definition: Hospitalization
Not an AE, but is an outcome of the AE
The following types of hospitalization do not require expedited reporting to DAIDS:
Any admission unrelated to an AE (e.g., for labor/delivery, cosmetic surgery, administrative or social admission for temporary placement for lack of a place to sleep)
Protocol-specified admission (e.g., for a procedure required by protocol)

12. Clarification on SAE Definition: Hospitalization
Admission for diagnosis or therapy of a condition that existed before receipt of study agent(s) and has not increased in severity or frequency as judged by the clinical investigator
A new AIDS-defining event in a subject already known to be HIV-infected would be considered an increase in severity of a pre-existing condition [HIV infection] and would be reportable as an expedited AE

13. Clarification on SAE Definition: Congenital Anomaly/Birth Defect
Do not report clinically insignificant physical findings at birth, including those regarded as normal variants
Report clinically significant anomalies; include all other findings (even if not individually significant)
e.g., an isolated finding of polydactyly or Mongolian spot in an infant with no other findings would not be reported, but polydactyly or Mongolian spot occurring with a major cardiac defect would be included in the SAE report of the major cardiac defect

14. Clarification on SAE Definition: Congenital Anomaly/Birth Defect
Information about congenital anomalies can be found on the Centers for Disease Control and Prevention (CDC) website:
Guidelines for Conducting Birth Defects Surveillance, National Birth Defects Prevention Network (NBDPN), appendix Direct link to document:
This website listing should not restrict the reporting of anomalies that the site investigator deems important for the sponsor to know.

15. Clarification on SAE Definition: Important Medical Events
Events considered as important medical events can meet SAE criteria
Examples:
Intensive treatment in an emergency room or at home for allergic bronchospasm
Blood dyscrasias or convulsions that do not result in hospitalization
Development of drug dependency or drug abuse

16. SUSAR Definition
SUSAR is defined as an adverse event that is a Suspected Unexpected Serious Adverse Reaction
For the SUSAR reporting category, an SAE will be reported if it fulfills the following criteria:
Related and
Unexpected

17. SUSAR Reporting Category
Used for some non-IND studies/trials using U.S. FDA-approved agents with approved dosages for approved indications in typical populations
At the discretion of DAIDS

18. Assessment of Adverse Events

19. Assessment AEs are assessed for: Seriousness Severity Relationship
Expectedness
Study physician listed on the 1572/ Investigator of Record (IoR) Agreement is responsible for the assessment of AEs
Sponsor Level: DAIDS MOs provide secondary review

20. Primary Adverse Event Is there an AE?
Example: Primary AE: Myocardial infarction
If there are associated symptoms, what is the primary AE?
Report only one primary AE per report.
Clinically Significant Event Associated with primary AE: Chest pain
Clinically Significant Event Associated with primary AE: Dyspnea
Is there an AE? 20

21. Primary Adverse Event How many primary AEs are there?
Example: Acute renal failure and Gastroesophageal reflux
Events that are not clearly associated with the
primary AE should be reported as separate events.
Primary Adverse Event 1 Acute renal failure
Primary Adverse Event 2 Gastroesophageal reflux
How many primary AEs are there? 21

22. Hospitalization
8 May 2009: 61 year old HIV infected African American male (enrolled 15 Feb 2009), with Grade 4 hospitalization
20 Feb 2009: subject was started on study agents LMN and XYZ
8 May 2009: subject visited study clinic with complaints of abdominal pain and non-bloody diarrhea for the past one week
Vomited three times on the day of clinic visit
Just to illustrate hospitalization is not the AE term; could be gastroenteritis for example
PE: moderately dehydrated aged man with vague generalized abdominal tenderness
No guarding or rebound tenderness. BP: 109/71 mmHg and HR: 69 beats/min
Given IV Ringers lactate and IM diclofenac, 75 mg
Sent to hospital for further work up
Hospital lab results: K+ 2.1 mEq/L (3.5–5.2 mEq/L)
KCL 20 mmol, was added to each liter of Ringers lactate
Results for stool culture pending
May 9, 2009: stable, awaiting discharge

23. Teaching Points
Hospitalization in and of itself is not an AE term; it is an outcome of the AE
Grading should be on the AE, not the outcome of the AE
Primary AE: ?
Abdominal pain, non-bloody diarrhea, vomiting, vague generalized abdominal tenderness
Possible AE term: “Gastroenteritis,” NOT “Hospitalization”
However, if you do not have any information about the actual AE but the event is reportable you can report “Hospitalization.” Submit an update when additional significant information is available

24. Death
14 Jan 2009: 40 year old HIV uninfected Asian female enrolled; started on the study agent XYZ at a dose of 32mg, sublingually, 4 times a week
6 May 2009: Took dose of XYZ; went for clinic visit
10 May 2009: died due to sudden death (AE term reported as “death”)
Hx of illicit drug use [study target pop: drug use]
May 11, 2009: subject’s younger brother called to inform site that subject died on May 10, 2009, at home.
According to the site, there is a hx of illicit drug use. [Note: study population is a drug addicted population]. No recent sickness, hospital admission, self-inflicting injury, violent attack, falls or family history of sudden death.
The site has provided a death certificate which gives the cause of death as “sudden death (cause unknown)”.
The Site Principal Investigator has assessed the event of death as not related to the study agent XYZ

25. Teaching Points
Death in and of itself is not an AE term; it is an outcome of the AE
Primary AE:
Sudden death (per death certificate)
Possible AE Term: Drug overdose (although not enough info provided for this)
However, if you do not have any information about the actual AE but the event is reportable you can report “Death unknown cause.” Submit an update when additional significant information is available
Note: When the term is “Death unknown cause”, relationship CAN NOT be “NR” because can’t assess
Also, death is never an EXPECTED outcome; unless it is a known consequence of the disease and person is at that stage

26. Seriousness Does primary AE meet criteria for an SAE?
Use ICH-SAE definition provided in Manual v2.0
Select appropriate SAE criteria

27. Severity Severity refers to the intensity of a specific event
Events are graded on a severity scale of 1-5:
1 – Mild
2 – Moderate
3 – Severe
4 – Potentially Life-threatening
5 – Death

28. Seriousness is NOT the same as Severity
Based on the intensity of the AE and is not a factor in determining reportability (clinical description)
Based on outcome of the AE and is a factor in determining reportability (regulatory definition)
Seriousness
Severity
Determined using the SAE criteria
Determined using the DAIDS AE grading table ≠ 28

29. Grading Severity of Events
All events reported to DAIDS in an expedited timeframe must be graded for severity
Grading does not determine reportability
Division of DAIDS (DAIDS) Table for Grading the Severity of the Adult and Pediatric Adverse Events Version 1.0 – Dec 2004 (Clarification dated Aug 2009)

30. Severity Grade Grade 1 – Mild Grade 2 – Moderate
Symptoms causing no or minimal interference with usual social & functional activities
e.g., When a subject experiences a chest pain which does not interfere with the subject’s activity of daily living
Grade 2 – Moderate
Symptoms causing greater than minimal interference with usual social and functional activities
e.g., When the chest pain is such that the subject is unable to do some of their activities of daily living

31. Severity Grade Grade 3 – Severe Grade 4 – Potentially Life-Threatening
Symptoms causing inability to perform usual social & functional activities
e.g., When the chest pain is such that the subject is unable to carry out activities of daily living
Grade 4 – Potentially Life-Threatening
Symptoms causing inability to perform basic self-care functions OR medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death
e.g., When the chest pain makes the subject unable to perform basic functions and is at risk of permanent impairment/persistent disability/death if no surgical or medical intervention is done

32. ESTIMATING SEVERITY GRADE
EXAMPLE FROM THE DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTS
CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
ESTIMATING SEVERITY GRADE
Clinical adverse event NOT identified elsewhere in this DAIDS AE grading table
Symptoms causing no or minimal interference with usual social & functional activities
Symptoms causing greater than minimal interference with usual social & functional activities
Symptoms causing inability to perform usual social & functional activities
Symptoms causing inability to perform basic self-care functions OR Medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death
E.g. of grading clinical AE not listed in DAIDS Grading Table/No Exact term listed
This table is used for estimating the severity grade of a clinical AE not specifically listed in DAIDS Grading Table

33. POTENTIALLY LIFE-THREATENING
EXAMPLE FROM THE DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTS
SYSTEMIC
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Chills
Symptoms causing no or minimal interference with usual social & functional activities
Symptoms causing greater than minimal interference with usual social & functional activities
Symptoms causing inability to perform usual social & functional activities
N/A
Fever (nonaxillary)
37.7 – 38.6C
38.7 – 39.3C
39.4 – 40.5C
> 40.5C
This table is used for grading a clinical AE specifically listed in DAIDS AE Grading Table:
e.g., grading by symptomatology
e.g., grading by numerical ranges
An e.g of using DAIDS Grading Table to grade symptoms based on symptomatology and numerical range.

34. Severity Grading Manual Version 2.0
Grade 4 events are referred to as potentially life-threatening events as defined in the DAIDS AE Grading Table
Thus a Grade 4 event per the DAIDS AE Grading Table does not automatically imply that it meets SAE criteria, if it is only potentially life-threatening
[SAE criteria for LT refers to immediate timeframe, not potential at some point in the future, or if more severe]

35. Issues with Grading
Death = Grade 5; clarified in DAIDS AE Grading Table Aug 2009
Potentially life-threatening = Grade 4
Potentially life-threatening means at risk of death should the event occur in a more severe form. This is not the same as immediately life-threatening
Grading abnormal laboratory values associated with a clinical AE:
Does not correspond to grade provided in the DAIDS AE Grading Table
When lab values fall between two grades choose the higher grade
Grading does not appear to reflect the event:
Event led to hospitalization, but graded as “Grade 1” or “Grade 2”
Grade the SAE not the initial AE (initial AE had progressed to level of SAE)

36. Grading: Neonatal Sepsis
Neonatal Sepsis Grade 1
27 day old, male infant, normal delivery, breastfed, nevirapine
2 week visit: crying on urination, amoxicillin for 7 days
3 week visit: refusing feed, brought back to clinic
PE: lethargic, HR: 140 bpm, RR: 58 bpm, T: 37.7°C, WBC: 14,000 with left shift
Sent to hospital for sepsis workup
AE term: Neonatal sepsis, Severity: Grade 1
Neonatal Sepsis is reasonable AE Term
Basis for severity grade?

37. Grading: Neonatal Sepsis
CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
ESTIMATING SEVERITY GRADE
Clinical adverse event NOT identified elsewhere in this DAIDS AE grading table
Symptoms causing no or minimal interference with usual social & functional activities
Symptoms causing greater than minimal interference with usual social & functional activities
Symptoms causing inability to perform usual social & functional activities
Symptoms causing inability to perform basic self-care functions OR Medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death

38. Grading: Neonatal Sepsis
CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
SYSTEMIC
Fever (nonaxillary)
37.7 – 38.6 Degrees Celsius
38.7 – 39.3
Degrees Celsius
39.4 – 40.5
> 40.5
Grading on basis of fever alone: Grade 1
Grading on clinical basis of possible sepsis:
at least Grade 3
Grade 4 reasonable as well

39. Grading: Respiratory Distress
Respiratory Distress Grade 2
2 day old male, delivered at 39 wks GA by C/S, started on oral zidovudine
PE: pale, flexed, not crying, given CPAP with improvement, APGAR: 6 at 5 minutes and 9 at 10 minutes, weight: 3.35 kg, length: 47.5 cm, HR: 140 bpm, RR: 62 bpm
12 hrs after birth: developed tachypnea and fussiness, RR: 62 bpm, Pulse Ox on room air: 70%
Transferred to NICU, 100% oxyhood, Pulse Ox: 80%, pH: 7.48, pCO2: 27, pO2: 251, HCO3: 20
PE: systolic murmur heard along left sternal border
Echo: Moderate PDA, ASD, patent foramen, mild TR, trivial MR
Respiratory Distress is reasonable AE Term
Basis for severity grade?
Echocardiogram revealed moderate patent ductus arteriosus (PDA) with low velocity left to right flow, elevated right ventricle pressure, and patent foramen atrial septal defect (ASD) with left to right flow. There was also mild tricuspid regurgitation, trivial mitral regurgitation, elevated pressure in the pulmonary artery, and mild aortic hypoplasia with normal volume in the left ventricle cavity. The aortic arch appeared normal in size.
The subject was diagnosed with respiratory distress - hypoxia, presumed infection, gestational diabetes, intrauterine drug exposure, and ABO incompatibility.
(removed HC: 34 cm, )

40. Grading: Respiratory Distress
DYSPNEA OR RESPIRATORY DISTRESS
Pediatric < 14 years
Wheezing OR minimal increase in respiratory rate for age
Nasal flaring OR intercoastal retractions OR Pulse oximetry %
Dyspnea at rest causing inability to perform usual social & functional activities OR pulse oximetry < 90%
Respiratory failure with ventilatory support indicated
Alkalosis
N/A
pH > 7.5 normal, but ≤ 7.5
pH > 7.5 without life-threatening consequences
pH > 7.5 with life-threatening consequences
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
ESTIMATING SEVERITY GRADE
Clinical adverse event NOT identified elsewhere in this DAIDS AE grading table
Symptoms causing no or minimal interference with usual social & functional activities
Symptoms causing greater than minimal interference with usual social & functional activities
Symptoms causing inability to perform usual social & functional activities
Symptoms causing inability to perform basic self-care functions OR Medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death

41. Grading: Respiratory Distress
Grading on basis of respiratory distress: at least Grade 3
Required CPAP at birth
12 hours later: tachypnea and RR: 62 bpm
Room air and 100% O2: 70-80%
Grading on basis of respiratory distress: Grade 4
Need medical intervention beyond O2 therapy
Transferred to NICU
Grading on basis of alkalosis: Grade 2
Not appropriate because it does not reflect clinical picture in totality

42. Relationship Assessment
The terms used to assess the relationship of an event to study agent are:
Related – There is a reasonable possibility* that the AE may be related to the study agent(s)
Not Related – There is not a reasonable possibility that the AE is related to the study agent(s)
*Per 21 CFR , “reasonable possibility” means there is evidence to suggest a causal relationship between the drug and the adverse event.

43. Relationship Assessment
When an SAE is assessed as “not related” to study agent(s), an alternate etiology, diagnosis, or explanation for the SAE should be provided
If new information becomes available, the relationship assessment of any AE should be reviewed again and updated, as required
When the study agent is a fixed dose combination agent, an assessment of attribution will be made for each component and the combination agent as a whole

44. Expectedness
Expected AEs are events that have been previously observed with use of the study agent(s). It is not based on what might be anticipated from the pharmacological properties of the study agent
Listed in the Investigator’s Brochure or Package Insert
SAE Reporting Category:
Sponsor to determine expectedness
SUSAR Reporting Category:
Site physician and Sponsor to determine expectedness

45. Expedited Reporting Processes

46. Overview of Reporting Timelines

47. SAE Reporting Category Flowchart

49. Adverse Events Not Requiring Expedited Reporting to DAIDS
An SAE occurring before exposure to a study agent
Immune reconstitution inflammatory syndrome (IRIS), even if the event otherwise meets the reporting criteria. IRIS is an intense immune reaction that may result from a response to HIV treatment and is an anticipated event for antiretroviral therapies
Note : Pharma partners have requested IRIS events as expedited if meet SAE criteria. Under Discussion

50. New/Initial Reports AEs that are reportable on New/Initial Reports:
New AE
Recurrent AE: only if the initial AE has resolved, is now reoccurring, and meets expedited reporting criteria to DAIDS
Pre-existing condition with increase in severity

51. Updated Information
Sites must follow each AE until the AE is resolved or stable
For each AE reported to DAIDS, sites are required to submit an updated report to DAIDS as soon as significant additional information becomes available. The following are examples that must be submitted:
An updated report documenting the stable or resolved outcome of the AE, unless the initial report included a final outcome
Any change in the assessment of the severity grade of the AE or the relationship between the AE and the study agent
Additional significant information on a previously reported AE (e.g., cause of death, results of re-challenge with the study agent(s))

52. Reporting Timeframe
Within 3 reporting days of site awareness that an event has occurred at a reportable level
“Reporting days” are those that count toward the 3-day timeline provided for the reporting of SAEs to DAIDS

53. Reporting Days
The criteria used to determine reporting days are as follows:
A reporting day starts at 12:00 AM (midnight) and ends at 11:59 PM local time
A day is counted as a reporting day regardless of the time of day that awareness occurred. The day a site indicates that site personnel became aware of an SAE that meets reporting criteria shall count as day 1 if that day occurs on a reporting day (i.e., Monday through Friday). If that day occurs on a non-reporting day (i.e., Saturday or Sunday), then the next reporting day shall count as day 1
Monday through Friday count as reporting days
Saturday and Sunday are not considered reporting days
Any holiday (U.S. or in-country/local) that occurs on a Monday through Friday counts as a reporting day

54. Site Investigator Signature
A site physician investigator or sub-investigator listed on the 1572 or the IoR Agreement must:
Review and verify the completed report for accuracy and completeness
Sign the report
This physician makes the site’s final assessment of the relationship to study agent(s)

55. Site Investigator Signature
In the rare event that such physician(s) are not available for signature, sites may submit without signature to meet the reporting timeframe
However, the signature and any necessary corrections or additions must be submitted within the next three reporting days
The IoR or designee is responsible for designating at least one other physician who can perform the assessment and signature so as to provide uninterrupted coverage of monitoring AEs that will require expedited reporting

56. DAERS DAERS: DAIDS Adverse Experience Reporting System:
An integrated module that is part of the DAIDS Enterprise System (DAIDS-ES)
A secure, confidential, web-based system through which sites are required to submit expedited reports to DAIDS
For sites where DAERS has been implemented, all EAEs and supporting information will be submitted to DAIDS using the DAERS, unless the system is unavailable for technical reasons
Use DAIDS EAE reporting form if DAERS not implemented

57. How to Report SAEs Reports must be submitted via DAERS
DAERS, via web:
For emergency use only:
FAX:
or (USA only)
If ing, scan or FAX signature page

58. Where to Get Help RSC Safety Office:
Telephone:
or (USA only)
FAX:
or (USA only)
RSC Website:
DAIDS-ES Support:
Telephone:
or (USA only)
FAX:
For reporting and timeline issues – RSC Safety Office
For DAERS system/technical issues – DAIDS-ES Support

59. Questions?