1

Cosponsored by
FDA's Office of Critical Path Programs (OCPP)
and
The Clinical Trials Transformation Initiative (CTTI)
FDA's CIinicaI Investigator Course
2
Safety in Clinical Trials
Lourdes Villalba, MD
November 9, 2010
Senior Medical Reviewer, Safety Team
Division of Neurology Products
Center for Drug Evaluation and Research
3
utIine
Scope of clinical safety assessment
Clinical safety evaluations
Limitations of premarket database to assess
safety
Postmarketing safety
Example of drug that was withdrawn from
the market for safety reasons (Vioxx)
Summary

utIine
Scope of clinical safety assessment
Clinical safety evaluations
Limitations of premarket database to assess
safety
Postmarketing safety
Example of drug that was withdrawn from
the market for safety reasons (Vioxx)
Summary

Introduction
Evaluation of a drug's safety is an evolving
process
Different from evaluation of efficacy
Does not end at the time of approval

$ources of $afety Information

1
Clinical studies
Non-clinical data
Studies of other indications
Clinical Pharmacology studies
Safety profile of other drugs in the class
Medical literature
Postmarketing experience
1
For products under investigation, the nvestigator Brochure (B)
is equivalent to the Package nsert of an approved drug.

utIine
Scope of clinical safety assessment
Clinical safety evaluations
Limitations of premarket database to assess
safety
Postmarketing safety
Example of drug that was withdrawn from
the market for safety reasons (Vioxx)
Summary

CIinicaI $afety EvaIuations

Exposure
Adverse events
Big ticket items
Definitions
Reporting requirements
Approach to causality assessment
Coding
Ascertainment
Follow up
Other safety evaluations
Adequacy of safety evaluations
9
Exposure
The likelihood of observing an AE depends on
several factors
- Number of patients evaluated
- Duration of treatment
- True risk of a drug-induced reaction (common vs. rare)
- AE risk over time (hazard)
10
HAZARD FUNCTIONS FOR THREE PATTERNS
OF DRUG-INDUCED CLINICAL EVENTS
0'Ne||| RT 1988
H0NTh8 FR0H |N|T| AL 0RUC EXP08URE H0NTh8 FR0H |N|T| AL 0RUC EXP08URE
*
h
A
Z
A
R
0
*
h
A
Z
A
R
0
0 1 2 3 4 5 7 8 9 10 11 12
0E6REA8|NC 0E6REA8|NC
0ELAYE0 (|N6REA8|NC} 0ELAYE0 (|N6REA8|NC}
60N8TANT 60N8TANT
*Hazard: risk per unit time
11
ICH
1
E1A Guidance (1)
Minimum CH recommendation
f chronically administered
100 people total
300-00 people for months
100 people for one year
At clinically relevant doses
1
nternational Conference on Harmonisation (CH-E1A).
CH E1A: Guideline for ndustry. The extent of population exposure to
assess Clinical Safety. For drugs intended for long-term treatment of
non-life-threatening conditions. http://www.fda.gov/downloads/Drugs/Guidance
ComplianceRegulatorynformation/Guidances/ucm0303
12
ICH-E1A Guidance (2)
Safety database in a drug development program
is not expected to detect rare AEs (e.g., those
occurring in < 1 in 1,000 patients)
t is expected to characterize short-term events
(cumulative 3 month about < 1%)
n some circumstances minimum standards for
clinical safety evaluation may not be applicable.
13
!ooIing $afety $tudies
Pooling may improve power and precision for
estimating AE (basis for the ntegrated
Summary of Safety analyses)
- When pooling, need to consider study design, dose,
duration, population (also need to look by individual
study)
Risk number of cases
number of persons exposed
Rate number of cases
person-time exposed
- Using person-time allows adjustment for differential
dropout (assuming that hazard is constant).
Sometimes need to use Kaplan Meier analyses.
=
=
1
#uIe of 3": Capping the risk
-serving no serious AEs in a data-ase
shouId not -e interpreted as no risk"
- "Rule of 3 estimates the upper 9% C for
the risk of an AE= 3/N
E.g. If no case in a 3000 pt data-ase,
the risk of having the AE is < 1/1000.
1
Adverse Event - Big Ticket Items
Deaths*
Serious AE
Discontinuations due to AE*
* Require Case Report Form (CRF) and narrative at the time of NDA
submission. CRF and narratives of Serious AE are usually requested
by Divisions.
1
Adverse Event - Definitions
*
(1)
Adverse Event (or Adverse Experience) (AE):
Any untoward medical occurrence associated
with use of a drug in humans whether or not
considered drug reIated
sign (e.g. abnormal lab finding)
symptom
disease
21 CFR 312.32. Guidance for ndustry and nvestigators: Safety
reporting requirements for NDs and BA/BE studies (Draft Guidance,
September 2010). Definition applies also to biological products.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory
nformation/Guidances/UCM2231.pdf
Effective date for the Final Rule: March 2, 2011.
1
Adverse Event - Definitions (2)
Adverse Reaction
Any AE caused by a drug
Suspected Adverse Reaction
Any adverse event for which there is a reasona-Ie
possi-iIity that the drug caused the AE
Single occurrence of an event that is uncommon and known
to be associated with drug exposure
One or more occurrences of an uncommon event
An aggregate analysis of specific events observed in a
clinical trial indicates those events occur more frequently in
the drug treatment group than in a concurrent or historical
control group
1
Adverse Event - Definitions (3)
Unexpected
Any AE or suspected adverse reaction that is not
Iisted in the investigator brochure or is not listed at
the specificity or severity that has been observed
E.g. Hepatic necrosis if the B only listed elevated hepatic
enzymes
t does include events or reactions that are anticipated
based on class effects or the pharmacological properties of
the drug but are not specifically mentioned with the drug
under investigation
19
Adverse Event - Definitions (4)
Serious: AE that results in
Death or a life-threatening event
npatient hospitalization or prolongation of
existing hospitalization
Persistent or significant disability/incapacity
Congenital anomaly / birth defect
Or it is an "mportant medical event.may
require medical or surgical intervention to prevent
one of the above outcomes, such as allergic
bronchospasm, blood dyscrasias, convulsions, drug
abuse or dependence
20
IND AE #eporting #equirements
*
for Investigators to the $ponsor
mmediate
- All serious AE
whether drug related or not,
even if listed in the protocol
or the B as anticipated to
occur (except study
endpoints)
- Study endpoints that are
also serious AE if evidence
suggests a causal
relationship (e.g. fatal
anaphylactic reaction)
$AE reports include
causality assessment
Not immediate
(according to the
protocol)
- Nonserious AE
No need for causality
assessment
- Study endpoints that are
serious but not suspected
to be drug related
All AE need to be collected
and recorded in CRF
* 21 CFR 312.. Guidance for ndustry and nvestigators. Safety
reporting requirements for NDs and BA/BE studies (Draft
guidance. September 2010)
21
IND AE Expedited #eporting
#equirement (for the $ponsor)
*
(1)
Potentially serious risks from clinical trials or any
other source must be reported to FDA and all
participating investigators
No later than 1 calendar days after receiving the
safety information and determining it qualifies for
reporting
n an ND safety report (could be electronic)
Unexpected fatal or life-threatening suspected adverse
reactions must be reported to FDA within calendar
days (telephone, fax, email)
* 21 CFR 312.32. Guidance for ndustry and nvestigators. Safety
reporting requirements for NDs and BA/BE studies (Draft guidance.
September 2010).
22
IND AE Expedited #eporting
#equirement (for the $ponsor) (2)
Potentially serious risks requiring ND safety
report include
1
A. Suspected adverse reactions that are both serious
and unexpected (as determined by either nvestigator or
the Sponsor)
B. Findings from other sources that suggest a
significant risk in humans (next slide)
C. ncreased occurrence of serious suspected adverse
reactions (related to rate listed in the protocol or B)
1
Modified from previous 21 CFR 312.32.
23
IND AE Expedited #eporting
#equirement (for the $ponsor) (3)
Findings from other sources, that suggest a
significant risk in humans (result in safety-related
changes in protocol, B, etc)
From other studies
*
Clinical studies, epidemiological studies or pooled
analyses of multiple studies
From animal or in vitro testing
**
Such as carcinogenicity, mutagenicity, teratogenicity,
or significant organ toxicity at or near the expected
human exposure
Bioavailability/Bioequivalence studies
*
* New to CFR. ** Clarified from previous 21 CFR 312.32.
2
Approach to CausaIity Assessment
Uncommon AEs
Require detailed individual assessment
E.g. liver failure, agranulocytosis
Common AEs
ndividual assessment won't help to determine
attribution
E.g. Headache, nausea
Myocardial infarction in elderly population
Require comparisons using a population approach
(risk or rate on drug vs. a control group)
Placebo, active control, other doses in fixed dose study,
historical control
2
Examining IndividuaI Cases of
Uncommon $AEs
Was it "treatment-emergent?
Did it respond to de-challenge?
Was there re-challenge? Result?
Where there concomitant medications?
Were pertinent labs/other tests done?
Was there an obvious alternative cause?
Note to Investigators: provide enough relevant
information in CRF as to allow good quality
narratives
2
*Guidance for ndustry: Premarketing Risk Assessment.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulato
rynformation/Guidances/ucm02002.pdf
Components of a Good Narrative*
2
Designated MedicaI Events
*
Acute pancreatitis Neuroleptic malignant syndrome
Acute respiratory failure Pancytopenia
Agranulocytosis Progressive Multifocal Leukoencephalopathy
Amyotrophic Lateral Sclerosis Product infectious disease transmission
Anaphylaxis and anaphylactoid reactions Pulmonary fibrosis
Aplastic anemia Pulmonary hypertension
Blind Renal failure
Colitis ischaemic Rhabdomyolyisis
Congenital anomalies Seizure
Deaf Serotonin syndrome
Disseminated intravascular coagulation Stevens-Johnson syndrome
Endotoxic shock Sudden death
Haemolysis Suicide
Hemolytic anemia Torsade de Pointes
Liver failure Toxic epidemal necrolysis
Liver necrosis Thrombotic Thrombocytopenic Purpura
Liver transplant Ventricular fibrillation
* List used by Office of Surveillance and Epidemiology. Examples of events that
require extensive evaluation at pre-marketing stage too.
2
Ascertainment of Adverse Events
Clinical AEs
Spontaneously reported symptoms
Open question
Symptoms reported as a result of a probe
E.g. using checklist
Both
Other: Vital Signs, ECGs, laboratory data,
special safety testing
Routine (scheduled by protocol)
By cause
29
Ascertainment of AEs
Suboptimal ascertainment of AE may lead to
missing safety signal
Note to investigators: Please record
relevant AE & abnormal values outside pre-
scheduled protocol assessments too
30
Coding of Adverse Events
Process of converting the investigators'
"verbatim terms to standardized terms,
sometimes called "preferred terms (PT)
Standardization allows sorting of AEs and
grouping of like events
PT are then used to calculate AE incidences
Currently most used: MedDRA (Medical
Dictionary for Regulatory Activities)
31
MedD#A $tructure - Hierarchy
HLT - High Level Term (1,09)
PT - Preferred Term (1,)
LLT - Lowest Level Term (,2)
Represents a single
medical concept
Used for analyses of AEs
AE as reported on
C#F 'er-atim"
edDRA 13.0
SOC - System Organ Class (2)
HLGT - High Level Group Term (33)
32
Coding !ro-Iems
Coding problems may lead to missing safety
signals
Splitting same AE among similar PT
Hypertension, high blood pressure, etc.
Lumping different terms to same PT
Leg edema, face edema, etc.
Note to Investigators: Please be
consistent and use the most scientific
term when recording AE in CRF
33
Adverse Event FoIIow Up
Follow up AE until resolution
Discontinuations due to AE is an important
component of safety evaluation in a
clinical study
Note to Investigators: please provide
adequate categorization for study
withdrawal; minimize use of "patient
withdrew consent"
3
ther safety evaIuations
Studies in special populations
Hepatic and renal impairment
Pregnancy
Pediatric
Elderly
Evaluations with established recommended
approach, Guidance for ndustry:
Drug induced liver injury. Premarketing clinical evaluation
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory
nformation/Guidances/UCM1090.pdf
Clinical evaluation of QT/QTc interval prolongation
http://www.fda.gov/Regulatorynformation/Guidances/ucm12933.htm
Special considerations
Malignancy, immunogenicity
3
!harmacogenomics and $afety
Pharmacogenomics may help improve the
safety of drugs on an individualized basis.
Many AE are due to individual "overdosing
because of drug metabolism differences.
Examples that made it into labeling
Coumadin: increased risk of bleeding with certain genetic
variants of CYP2C9 and VKORC1 enzymes
Abacavir: hypersensitivity and HLA-B*01
Carbamazepine: Stevens-Johnson syndrome and HLA-
B*102
Tricyclic antidepressants: increased toxicity in poor CYP2D
metabolizers
3
utIine
Scope of clinical safety assessment
Clinical safety evaluations
Limitations of premarket database to assess
safety
Postmarketing safety
Example of drug that was withdrawn from
the market for safety reasons (Vioxx)
Summary
3
imitations of !remarket Data-ase
to Assess $afety (1)
nherent to the database
Limited exposure (size, duration)
Narrow population
Lack of pre-defined safety endpoint(s)
Multiple comparisons
mprecision of estimates due to small numbers
owever, no need to get a p<0.05 to suspect a
safety signal]
3
imitations of !remarket Data-ase
to Assess safety (2)
Related to adequacy/quality/integrity of trials*
e.g.
ncomplete ascertainment of AE
nadequate follow up
Suboptimal recording in CRF
Suboptimal narratives
Suboptimal source data availability
Coding problems
* Also applies to postmarketing trials
39
utIine
Scope of clinical safety assessment
Clinical safety evaluations
Limitations of premarket database to assess
safety
Postmarketing safety
Example of drug that was withdrawn from
the market for safety reasons (Vioxx)
Summary
0
!ostmarketing $afety
Major source: Spontaneous reporting from FDA
AERS (Adverse Event Reporting System)
Big issues: Under reporting/ ncomplete reporting/
No denominator. No control. Note to Investigators:
Please continue AE reporting after drug is approved.
Spontaneous reporting from other regulatory
agencies and World Health Organization
Postmarketing studies by sponsors, academia, FDA
Clinical trials, observational studies, registries, meta-
analyses
Sentinel nitiative
Active surveillance system that will enable FDA to
actively query diverse automated healthcare data
holders
1
utIine
Scope of clinical safety assessment
Clinical safety evaluations
Limitations of premarket database to assess
safety
Postmarketing safety
Example of drug that was withdrawn from
the market for safety reasons (Vioxx)
Summary
2
ExampIe of Drug that was
Withdrawn from the Market: 'I*
Rofecoxib: Cyclooxygenase-2 (COX-2) selective
non steroidal anti-inflammatory drug (NSAD)
- Does not block COX-1 mediated PG synthesis in
G mucosa (G sparing) at clinically relevant doses
- COX-2 mediates PG
2
synthesis in endothelium
and it is not expressed in platelets
Could unopposed platelet thromboxane A2 be pro-
thrombotic?
1
* NDA submitted December 1998
1
cAdam et al. PNAS, January 1999
3
'ioxx NDA- $erious and Non-serious,
C' !otentiaIIy Throm-otic" Events
*
-week to -month controlled OA studies
Vioxx 12., 2
& 0 mg/d
buprofen
00mg TD
Nabumet.
mg BD
Diclofenac
mg BD
Placebo
1
N= 330
n (%)
N=
n (%)
N= 11
n (%)
N= 9
n (%)
N= 3
n (%)
All 32 (1.0)
I 7 (0.2)
(0.)
-
-
-
10 (2.0)
2 (0.4)
(0.)
2 (0.3)
* Investigator reported events (Includes terms such as I,
coronary artery disease, ischemic heart disease, cerebrovascular
accident and TIA). N = patients randomized. n= patients with
event.
1
Placebo exposure: 6-18 weeks only.
CV safety: Vioxx between ibuprofen and diclofenac

'I NDA- Approved 4/99

~000 subjects; exposure > minimum CH
Safe and effective for intended indications at
intended dose (12. & 2mg for OA; 0mg for pain)
Safety profile similar to other NSADs
Caveats
% women with OA
few used low dose aspirin for CV prophylaxis
NSAD comparators: ibuprofen & diclofenac*
Vioxx G Outcomes Research study ("VGOR)
already ongoing. Postmarketing trial to support
removal of G WARNNG from NSAD template
* Cox-2 selectivity of diclofenac similar to that of celecoxib

'I- 'IG# $tudy

Design
~,000 subjects with RA, 1:1 randomization
Vioxx 0mg/d vs. naproxen 1000 mg/d
Excluded subjects taking low dose ASA
Primary endpoint
Perforation, Symptomatic ulcer, Bleeding (PUBs)
Primary analysis: Superiority to comparator
Results
Succeeded on primary endpoint but found excess of
M with Vioxx (0.%) vs. naproxen (0.1%)
id Vioxx increase risk of I (FA) or did naproxen decrease
risk of I (Sponsor)?
id it apply to the 25 mg dose?

'IG# Confirmed C' Throm-otic

Events, Time to Event !Iot
Hazard #atio 'ioxx vs. Naproxen
Overall 2.4
> 8 months 4.0

'I after 'IG# (1)

VGOR presented to FDA Arthritis AC
meeting to discuss G claim (02/2001)
Panel (including two cardiologists)
concerned but inclined to believe sponsor's
interpretation
Recommended inclusion of CV information
in labeling and evaluation of additional data
Submissions for completed studies were pending:
ADVANTAGE (00-pt study in osteoarthritis) and
Rheumatoid Arthritis efficacy database*
Additionally, studies in prevention of Alzheimer's (3000
patients) were ongoing (placebo-controlled, 2 mg
dose, elderly, allowed use of low dose ASA)**
* ADVANTAGE: supported increased CV risk of Vioxx vs. naproxen
**Alzheimer's studies: no increased risk of M compared to placebo

'I after 'IG# (2)

Sponsor's meta-analysis of CV events in Vioxx
controlled studies
No excess CV risk as compared to placebo
April 2002: RA supplement approved; VGOR
G and CV data included in labeling
Epidemiologic data
ncreased CV risk for 0 mg dose but conflicting
results for 2 mg dose
October 2002, sponsor submitted protocol
Pooled analysis of CV/Thrombotic events in 3
randomized, DB, PC, chemo-prevention studies
(2,000 patients for up to years)
- Adenomatous polyp prevention (APPROVe) ongoing
- Prostate cancer (PCC) just started
- Recurrent colon cancer (VCTOR) planned
9
'ioxx - $eptem-er 2004
Merck withdrew Vioxx from the market upon 1-
year interim results of the APPROVe study
Vioxx 2 mg/day vs. placebo
3 year duration planned
~1300 patients per arm
2% male
19% low dose aspirin
0
'ioxx - A!!#'e
1
1-year nterim Analysis of APTC
2
events
1
APPROVe: Adenomatous Polyp Prevention trial.
2
Anti-Platelet Trialist
Collaboration composite endpoint (CV & unknown cause of death + non-fatal
M + non-fatal stroke).
3
Rate per 100 patient-years at risk. PYR= patient
years at risk: Vioxx= 300 and placebo= 333.

RR= Overall relative rate
Vioxx to placebo. *p< 0.0.
Vioxx 2 mg
N=12
n Rate
3
Placebo
N=1299
n Rate
RR

APTC(patients) 3 1.11 1 0. 2.0

*
CV Deaths
0.20 0.1 1.30
M (all)
21 0. 9 0.2 2.3
*
NF sch Stroke
10 0.33 0.1 1.1
NF Hem. Stroke
1 0.03 1 0.03 1.09
1
'ioxx FoIIow up
CV data (clinical trial and epidemiological) from all
selective and non-selective NSADs discussed at
FDA Arthritis/DSaRM AC meeting (2/0)
Conclusion on NSADs and CV risk*
All COX-2 selective agents increased CV risk (no
ranking)
Available data do not clearly demonstrate that COX-2
selective agents confer a greater CV risk than non-
selective agents.
New Class labeling for potential increase in CV risk
added to all NSADs.
* John Jenkins & Paul Seligman. FDA Memorandum.
NSADS and CV risk (April 200)
2
What to do with a safety signaI?
Once a signal is identified or suspected
s there other supportive evidence?
s it biologically plausible?
Could it be explained by chance?
How can it be studied further?
Observational study (ies)
Clinical trial Feasible? Ethical?
s a regulatory action needed?
Risk/benefit
Additional tools since FDAAA
1
1
FDA Amendment Act of 200
3
utIine
Scope of clinical safety assessment
Clinical safety evaluations
Limitations of premarket database to assess
safety
Postmarketing safety
Example of drug that was withdrawn from
the market for safety reasons (Vioxx)
Summary

$ummary
Evaluation of safety is an evolving process
Premarketing database is not expected to identify
rare events
Once a safety signal is identified ask how to best
evaluate further (in the pre- or postmarketing setting)
nvestigators may improve quality of safety
assessments by
Providing relevant/complete AE information
Using the most scientific term when reporting
Recording AEs from non-scheduled tests too
Continuing to report AE once drug approved

"uestions?

AcknowIedgements
Judy Racoosin, M.D., M.P.H.
Robert Temple, M.D.
Sally Yasuda, Pharm. D.