New FDA Safety Reporting
Requirements 2010
John McLane, Ph.D.
COO & Vice President Clinical and Regulatory Affairs
Clinquest, Inc.
jmclane@clinquest.com
Fulfilling the Promise of Medicine Together
Safety Reporting Requirements

Different requirements for

Different requirements depending on type of
study and funding
• Sponsors
• Investigators
• IRBs
•
FDA

Drug


•
•
2

IND vs Postmarketing
Device
Food Supplements
Federal
ICH
Fulfilling the Promise of Medicine Together
FDA: Sept 2010

Guidance for Industry And Investigators:
• Safety Reporting Requirements for INDs
and BA/BE Studies

New Regulations
• 21 CFR 312 IND Safety Reporting
• 21 CFR 320 BA/BE Studies
Refers to Drugs and Biologicals
 Closer alignment to ICH/EMA
requirements

3
Fulfilling the Promise of Medicine Together
Why New Regs and Guidances?


Too many reports unfiltered
SAE reports associated with
•
Manifestations of the disease

•
Common in study population

•


4
morbidity for stroke
Strokes in elderly population
Study Endpoints
Confusion with phrase: “associated with the
use of the drug” and “reasonable possibility”
Refine definitions
Fulfilling the Promise of Medicine Together
Define: Adverse Event (AE)
Same as adverse experience
 Untoward medical occurrence
associated with the use of a drug

• Whether or not considered drug related

Note separation from causality
Unfavorable or unintended sign or
symptom
 Temporally associated with any use of
the drug

5
Fulfilling the Promise of Medicine Together
Define: Suspected Adverse Reaction (SAR)
Any AE reasonably possibility that drug
caused AE
 Decreased level of certainty then an
adverse reaction
 1st use of “reasonable possibility”
 The SAR & use of “reasonable
possibility” is consistent with concepts
about causality defined in ICH E2A

6
Fulfilling the Promise of Medicine Together
Define “reasonable possibility”

Single occurrence of an uncommon
event
• AE know to be associated with drug
•

exposure
Ex. Stevens-John syndrome
1 or more events not commonly
associated with drug exposure
• Not common in the study population

7
Aggregate analysis of events that occur
more frequently in tx arm
Fulfilling the Promise of Medicine Together
Define: Unexpected AE or SAR

Safety event:
• Not described in IB or protocol
• Event is of greater severity/specificity than
previously described

Hepato-necrosis is a Unexpected AE if IB has
only hepatitus
• Event is described as seen in similar drugs
(class effect) but not yet observed with this
drug

8
First occurrence of this type of event is a UAE
Fulfilling the Promise of Medicine Together
Define: Serious (SAE)

Similar to prior use:
• Death
• Life-threatening

Excludes AE or SAR that had it occurred in
more serious form might have caused death
• In-patient hospitalization
• Prolongation of hospitalization
• Congenital anomaly/birth defect

9
Refines the use of medical judgments
by either investigator or sponsor
Fulfilling the Promise of Medicine Together
Safety Monitoring
Sponsor Evaluate
Safety of Drug for
subjects
Serious, Expectedness, Reasonable
Possibility
Analysis with other events related to
drug use
10
Fulfilling the Promise of Medicine Together
Review of Safety Information

Get safety information from all sources
• Domestic/foreign trials

Foreign data to US: Safe Harbor Requirements
• Clinical epidemiology studies
• Annual literature review for safety
• Animal or in vitro expts.

Report in safety reports
•
•
11
ID all IND safety reports similar in nature
previously reported
Notify FDA and all “participating investigators” 15
day reports
Fulfilling the Promise of Medicine Together
SUSARS
For the first time FDA recognizes
SUSARs
 Three criteria

• Suspected adverse reaction
• Serious
• Unexpected

12
Expedited IND safety report
Fulfilling the Promise of Medicine Together
Conclusion

Move towards harmonization
• FDA will accept CIOMS I forms
• Use of SUSAR

Clear definition
• Replace “associated with the use of the
drug” with “reasonable possibility”
13
Fulfilling the Promise of Medicine Together
14
Fulfilling the Promise of Medicine Together
Relationship between AEs and UAPs

The diagram illustrates three key points:
• The vast majority of adverse events occurring in human
•
•
15
subjects are not unanticipated problems (area A) and do not
need to be reported to the IRB.
A small proportion of adverse events are unanticipated
problems (area B) and need to be reported to the IRB.
Unanticipated problems include other incidents, experiences,
and outcomes that are not adverse events (area C) and need
to be reported to the IRB.Fulfilling the Promise of Medicine Together