Safety_Data_Reconciliation_Katalyst HLS

1. Safety Data Reconciliation
1 11/20/2017Katalyst Healthcares & Life Sciences

2. Icons Used
Questions
Demonstration
Hands on
Exercise
Coding
Standards
A Welcome
Break
Tools
2
ReferenceTest Your
Understandin
g
Contacts

3. • Safety data management is the process of capturing, management and
reporting of safety data
• It involves collection, analysis and validation of Safety data collected during
the clinical trails and also after the drug has been released to market
— In investigative clinical research trials, one of the key objectives generally is to
investigate, characterize, establish, or confirm the safety profile of an
investigational product
— Safety reporting should facilitate to identify the trends and salient safety features
of the data pertaining to the product.
— Objective of reporting safety data is to convey information which will facilitate
reliable conclusions to be drawn with respect to safety of a Drug.
Overview
3

4. After this chapter you will be able to understand :
• What is Safety data
• SAE Reconciliation
• Reconciliation Objective
• Reconciliation – Process
• SAE Data Capture in Safety & Project Database
• Listings Generated for Manual Reconciliation
• Data Items to be reconciled – SAE module
• Data Items to be reconciled – Discontinuation module
• Data Items to be reconciled – Concomitant medications module
• Reconciliation Process Flow
• Reconciliation – Roles & Responsibilities
• SAE Reconciler
• Safety Data Manager
• Data Manager
• Reconciliation – Important Documents
• Documents
Objectives
4

5. • As per ICH Guideline :
– It is expected that short-term adverse event rates (cumulative incidence
of about 1%) will be well characterized
– The safety evaluation during clinical drug development is not expected to
characterize rare adverse events, for example, those occurring in less than
1 in 1,000 patients
• Most ADEs occur within the first 3 to 6 months of drug treatment
• The number of patients treated for 6 months at dosage levels intended for
clinical use should be adequate to characterize the pattern of ADEs over time
Do You Know
5

6. • Drugs might have some anticipated risks: e.g Amino-glycosides are known to cause
ototoxicity
• Drugs would have some risks of concern e.g. Almost all drugs are metabolized in
Liver and hence makes it susceptible to drug-induced injury (Hepatic toxicity)
• Serious adverse events of particular concern even if infrequent (1 per 1000)
• Some risks may be missed like those occurring:
– after long-term use
– in special populations
– in association with specific diseases
– in association with concomitant therapy
– in food drug interaction
Do You Know
6

7. • An AE is any untoward medical occurrence in a patient or clinical investigation
subject administered with a pharmaceutical product
• It does not necessarily have a causal relationship with the treatment
• An AE can therefore be any unfavorable and unintended sign (including an
abnormal laboratory finding), symptom, or disease temporally associated with
the use of a medicinal (investigational) product whether or not related to the
medicinal (investigational) product.
- Definition as per ICH GCP
Terminology: Adverse Event (AE )
7

8. A serious adverse event (experience) or reaction is any untoward medical occurrence
that at any dose:
➢ results in death,
➢ is life-threatening,
NOTE: The term "life-threatening" in the definition of "serious" 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.
➢ requires inpatient hospitalization or prolongation of existing hospitalization,
➢ results in persistent or significant disability/incapacity, or
➢ is a congenital anomaly/birth defect
Medical and scientific judgment should be exercised in deciding whether expedited
reporting is appropriate in other situations, such as important medical events that may not
be immediately life-threatening or result in death or hospitalization but may jeopardies the
patient or may require intervention to prevent one of the other outcomes listed in the
definition above. These should also usually be considered serious.
- Definition as per ICH GCP
Terminology: Serious Adverse Event (SAE)
8

9. • SAE data is considered CRITICAL DATA
• SAE data is recorded in both Safety and Clinical databases
• It is essential to understand that this data is submitted to Regulatory Agencies both
at end of study and for subsequent aggregate reporting which occurs well after
database lock
• In addition to this reports, Death Listings and SAE listings are submitted to
regulatory agencies as the appendices to Clinical Study Report (CSR Appendices:
16.2 and 16.3) . These reports and listings are generated from both databases (It
is therefore important that the SAE data in both databases is consistent)
ICH-GCP E2A guidelines dealing with Safety data management
Importance of Safety Data Management
9

10. • Safety reporting is done in case when a trial participant experiences any of the
following:
– Adverse experiences with drugs
– Adverse drug reactions
– Unexpected adverse drug reactions
– Serious adverse drug reactions
• The findings are recorded, investigated, documented and analyzed for
determining the safety profile of the drug
Safety Reporting
10

11. • Physician/nurse notes in source documentation (progress notes or clinic charts)
• Indications for concomitant medications
• Assessments forms (QOL)
• Abnormal Laboratory Results
• Subject withdrawals and drop-outs
• Reasons for missed visits
• SAE Forms
• Autopsy Reports
• Dosing details forms (Reason for IP interruption as AE)
• Discharge Summary
Where Do You Find AEs?
11

12. AEs can be classified based on following factors :
• Expectedness
• Severity
• Causal Relationship
Classification Of AEs
12

13. Classification Of AEs : Expectedness
13
Expectedness
Expected Unexpected
An expected event is one
where the specificity and
severity of the event are
consistent with the
information in the
investigator brochure or
labeling for the product
An unexpected event is one
where the specificity or
severity is not consistent
with the applicable product
information

14. Classification Of AEs : Severity
14
Severity
Mild Moderate Severe Life Threatening
The AE does not
interfere in a
significant manner
with the patient’s
normal
functioning level
The AE produces
some impairment
of functioning, but
is not hazardous
to health
The AE produces
significant
impairment of
functioning or
incapacitation and
is a definite
hazard to the
patient’s health
(usually
corresponding to a
serious AE)
The patient is in
immediate danger
of death unless
intervention is
done. It does not
mean that the
patient may die at
some time in the
future from the
event or may have
died if the event
had been more
serious or specific

15. Classification Of AEs : Causal Relationship
15
Causal Relationship
Related Non-Related
There is a reasonable
possibility that the event
could have been caused by
the drug
No causal relationship exists
between the study drug and
the event, but an obvious
alternative cause exists, e.g.
the subject’s underlying
medical condition or
concomitant therapy

16. • Medical or surgical procedure (However the indication leading to the
procedure is an AE)
• Pre-existing diseases and condition, which do not change
• The disease being studied (lack of efficacy) might be handled differently for
different indications
• Death (death is an outcome, the underlying cause is an AE)
What is Not an AE?
16

17. • All serious adverse events (SAEs) should be reported immediately to the
sponsor except for those SAEs that the protocol or other document (e.g.
Investigator's Brochure) identifies as not needing immediate reporting
• The immediate reports should be followed promptly by detailed, written
reports
• The immediate and follow-up reports should identify subjects by unique code
numbers assigned to the trial subjects rather than by the subject names,
personal identification numbers and/or addresses
What is Safety Reporting?
17

18. • The investigator should also comply with the applicable regulatory
requirement(s) related to the reporting of unexpected serious adverse drug
reactions to the regulatory authority(ies) and the IRB/IEC
• Adverse events and/or laboratory abnormalities identified in the protocol as
critical to safety evaluations should be reported to the sponsor according to
the reporting requirements and within the time periods specified by the
sponsor in the protocol
• For reported deaths, the investigator should supply the sponsor and the
IRB/IEC with any additional requested information (e.g. autopsy reports and
terminal medical reports)
When is Safety Reporting performed?
18

19. From investigator :
⁻ to sponsor-within 24 hrs everywhere
⁻ to ethics committee-within 7 working days
From sponsor to regulatory :
⁻ for US -15 working days
⁻ for INDIA -14 calendar days
For SUSAR (Suspected Unexpected Serious Adverse Reaction) :
₋ within 7 days & follow up report in next 8 days
₋ in case of death immediately within 24 hrs
Safety Reporting Timelines
19

20. An SAE is followed until :
• Safety: Resolved or judged to be no longer clinically significant
• Clinical: Patient’s last visit according the study protocol
• Post – Study events (serious adverse events that occurred after the patient had
completed a clinical study [including any protocol-required post-treatment
follow-up] will possibly be reported by an investigator to the sponsor. Such
cases should be regarded for expedited reporting purposes as though they were
study reports).
Serious Adverse Event (SAE) : Follow Up
20

21. An SAE report should have to the minimum :
– Identifiable patient
– A suspect drug
– An adverse event
– Identifiable reporter
Recommended Key data elements for inclusion in expedited reports of serious adverse drug reactions as per ICH
GCP is provided on slide 45
Minimum Criteria for a Valid SAE Report
21

22. • Extracting listings from Safety Database and Clinical Database
• Reconciling mandatory/agreed upon SAE data points
• Communicating internally with coders to resolve coding issues in Study Database
• Checking internally with Data Entry to resolve data issues
• Raising SDARF (Safety Database Amendment Request Form) for missing/inconsistent
SAE data in Safety Database
• Raising query to site in Database (DQF) when a field/s of SAE data is/are
missing/inconsistent on both Databases (Once resolution received from site
confirms data in eCRF is correct, prepare and send an SDARF to safety team asking
to update safety database.)
• Sending mail to Monitor when data in between clinical and safety is
missing/discrepant
• Preparing SRS log to capture discrepancies and actions taken Between clinical and
safety
• Filling the monthly on-going Reconciliation form & Final SAE Reconciliation Form
• Tracking all request forms sent and filling the corresponding tracker on a regular
basis
Roles & Responsibilities of Safety Data Manager
22

23. • Answering to missing/inconsistent data queries from SAE reconcilers
• Updating the Safety Database on the basis of DCRFs and related mails
Roles & Responsibilities : Safety Data Manager
23

24. Process of comparing SAE data that appears in both the safety and clinical
databases and must be cleaned 100%, with all acceptable discrepancies
documented
SAE Reconciliation
24
Clinical
Database
Safety
Database

25. • SAEs from clinical trials and marketed products are supposed to be reported
directly to a safety group or safety coordinator
• Because of the detailed information related to the case of a serious event, and
because of the reporting requirements, these safety groups frequently use a
specialized database for the processing and management of SAE data
• The SAE report (called a case) is entered in this database initially and updated
as follow-up information becomes available
Safety Database
25

26. • A collection of clinical data or information as per the protocol for all subject
during the life of clinical trial, typically organized for ease and speed of search
and retrieval
• SAEs occurring during clinical trials are also reported to the Data Management
Center along with the rest of the patient’s trial data
• This version of the information is then entered separately into the clinical data
management system.
• In EDC Studies, AE page have been entered directly in clinical database
• Entire information relating to SAE like event name, relationship, action taken
etc., are entered in clinical Database after SDV
Clinical Database
26

27. Examples of Clinical/Project Database:
– RAVE
– InForm
– Oracle Clinical
Examples of Safety Database:
– ARGUS
– ARISG
– AERS
– SAFIRE
Examples of Clinical & Safety Databases
27
Clinical
Database
Safety
Database

28. Data Flow Into Reporting Databases
28
Source Document Database
Adverse Event
Monitoring Form
Case Report Form
SAE Reporting
SAE & Efficacy Reporting
Clinical Database
Safety Database
Data Type

29. • It involves the comparison of key safety variables between Clinical Database
and Safety database
• It is performed to ensure consistency between events residing in Safety
database and those residing in the clinical database
• It is an iterative process that occurs several times during the study
• When to reconcile is determined by the frequency of data receipt, scheduling
of safety updates, and timing of interim and final reports
SAE Reconciliation :
The Process
29

30. Data Management staff, when reconciling, look for:
• Analyze data from the Safety and Clinical Databases to determine if there are
any discrepancies
– Cases found in the Safety Database but not in the Clinical Database
– Cases found in the Clinical Database but not in the Safety Database
– Deaths reported in one but not the other, perhaps because of updates to the SAE
report
– Cases where the basic data matched up but where there are differences, such as in
onset date
• Determine whether a discrepancy between data points is acceptable or not
• Issue queries or document on a spreadsheet all discrepancies
Reconciliation Process
30

31. • Populate Case IDs in the Clinical database when edit checks identify it as
missing
• Document the status of events/cases in the reconciliation spreadsheet
• Coordinate with the study team on outstanding issues
• Close queries when issues are resolved
Reconciliation Process
31

32. SAE Reconciliation Process Flow
32
Obtain the SAE
information to be
reconciled from
the safety and the
clinical databases
Two databases are
compared
programmatically
Manually reconcile
safety database &
Clinical database
through listings
Clinical data management
Identifies the discrepancies
& generates queries to the
site
Review the query
resolution
Determine
if clinical
Database
needs
updating
Update clinical
database as
per DCF
resolution
Monitor safety
database as
per DCF
resolution
Confirm safety
database
updates
Final unresolved
inconsistencies
should be
documented in a
CDM Data
Handling Report
or the equivalent
Close the
DCF
End
Process
Yes
No

33. • There are roughly 18 fields on the Adverse Event Line Listings which are
reconciled
• Understanding the data capture conventions between the two Databases is
critical
What is Reconciled?
33

34. Fields Reconciled by Safety Data Manager
34
TACO Fields
• T : Adverse event term
• A : Action taken
• C : Causality
• O : Outcome
Non TACO Fields
• Demography
• Total Daily Dose
• Therapy dates
Additional Fields
Reconciled
• Case ID
• Patient ID
• Date of Death

35. Adverse Events
– Nausea, Headache
Laboratory data
– Hematology, Blood chemistry, Urine analysis, etc
Vital signs
– Blood pressure, Pulse rate, Respiration rate, body temperature
Physical examinations
– Weight, Cyanosis (bluishness) , Dolor (pain), Calor (heat), Rubor
(redness) ; Tumor (swelling)
Diagnostic procedures
– USG, MRI, CT Scan, ECG, etc
Safety Reconciliation Related Modules
35

36. Adverse Event Term - refers to a singular and specific medical term for an AE
listed on the AEM Form. When you reconcile the Event Term field, you should
examine the Term, Onset and Cessation Date
Action Taken - refers to any change in study drug dose in response to an SAE
reported on the AEM Form.
Causality - refers to the most likely cause, in the Investigator’s opinion, of an AE
reported on the AEM Form.
Clinical Outcome - refers to the Outcome of an AE reported on the AEM Form.
TACO Field Definitions
36

37. Demography Module, but not be limited to the following:
– Subject Identification
– Weight
– Date of Birth
– Gender
– Race
Discontinuation Module, but not be limited to the following:
– Subject Identification
– Primary reason for discontinuation being an event
– Cause of hospitalization
– Cause of death listed on the death certificate
– Autopsy Result
NON-TACO Field Definitions
37

38. Concomitant medications Module, but not be limited to the following:
– Subject Identification
– Medication name
– Start Date
– Stop date or Ongoing
– Indication
NON-TACO Field Definitions
38

39. • Clinical Database Listings:
• Safety Database Listings:
• Both the listings are manually compared to identify any discrepancies, and to
ensure that the coding of SAEs is consistent.
Listings Generated for Manual
Reconciliation
39

40. The person responsible for SAE Reconciliation along with other clinical study team,
together determine how frequent the SAE data will need to be reconciled
The interval between rounds is based on the :
– complexity of the protocol
– data loads or subject visits
– subject enrollment
– frequency of reported SAEs in both Databases
– Milestones
– and timelines including database lock
It is important to remember that frequency of reconciliation are only of value when
the data is being updated in both databases on a frequent basis
Ongoing SAE Reconciliation
40

41. • If the Safety database is not updated on timely basis, then frequent
reconciliation will be counter productive and the individual reconciling the
protocol will be looking at the same set of discrepancies with each round
• If the DCFs are not responded to quickly by the site, and there are a high
number of outstanding queries from the previous round of reconciliation, again
frequent rounds of reconciliation will not be productive
SAE Reconciliation : Points to consider
41

42. • The Reconciliation Spreadsheet is created by generating an excel Adverse
Events Listing
• It is used to document all findings, acceptable or not, utilized for tracking
• It is then posted to on study specific folders/SharePoint /secure server
• The person responsible for the reconciliation maintains and updates this
spreadsheet for their particular protocol
• Can be called differently based on project/client terminologies (E.g. SAE
Tracker, Safety Tracker/sheet)
SAE Reconciliation Spreadsheets
42

43. Reviewing the Output
43
After generating a report from the Safety Database and associated listings
of AEs/SAEs, dosing, final status, and demography from the Clinical
Database a review is performed
• During this review discrepancies are identified
— A discrepancy is defined as a data point that does not match exactly. Any
discrepancy should be analyzed to determine if a query for additional or updated
information is necessary, or a documented reason as to why a discrepancy is
acceptable which is entered on the Reconciliation Spreadsheet
• Need for a Query :
— A query is an official communication to the investigative site to question on a
discrepant data on the case report form. It’s essential to raise a query for the
audit trail purpose.
➢ DCFs are created for discrepancies between the Safety and clinical Databases
using a standard query text
➢ Manual Queries are posted in case of EDC studies.

44. Documents
44
Recommended Key data elements for inclusion in expedited
reports of serious adverse drug reactions as per ICH GCP

45. Questions
45

46. • Name safety relevant data?
• What can be a AEs?
• Name 3 places where You can Find AE?
• What is the Classification of AE?
• What is an SAE?
• What does TACO stand for?
• Name 2 examples of Safety Databases?
Test Your Understanding
46

47. In this session the following topics were covered:
• The safety data involved in clinical trials
• Importance of Safety data in clinical trail
• The processes involved in management of Safety Data
• The SAE reconciliation activities
Summary
47

48. You have successfully completed - Safety Data Reconciliation
Thank You
&
Questions
11/20/2017
Contact:
Katalyst Healthcare’s & Life Sciences
South Plainfield, NJ, USA 07080.
E-Mail: info@KatalystHLS.com