e-Pharmacovigilance
Jennifer Haas MD, Aarthi Iyer MPH,
E. John Orav PhD, Gordon D. Schiff MD,
D id W.
David
W Bates,
B t MD
Academyhealth 2010
Concerns About Drug Safety
• Ongoing public health concern
– 51% have serious ADE recognized post-approval
– 10% black
bl k box
b warning/
i / withdrawn
ithd
• Need for more “pro-active”
p
post-marketing
p
g
surveillance
• “Missing
Missing voice
voice” of patients
IVR
• Interactive Voice Response
p
–
–
–
–
–
Systematic
Cost effective way to contact populations
Cost-effective
Standard interview
Opportunity for immediate notification
Interoperate
p
with EHR
Protocol
• Eligible adult patients:
– PCP visit
– Target drug
– English
• “Opt-out”
• Called 2 – 6 weeks post-visit
– 3 months later if drug still on med list
• If multiple
lti l drugs:
d
mostt recently
tl prescribed
ib d or randomly
d l
select
• Note in EHR
• Email PCP for “severe” side effects
Target
g Drugs
g
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Ibandronate (Boniva)
Raloxifene ((Evista))
Rosuvastatin (Crestor)
y
)
Ezetimibe/ Simva ((Vytorin)
Sitagliptin (Januvia)
Exenatide (Byetta)
Pioglitazone (Actos)
Rosiglitazne (Avandia)
Valsartan (Diovan)
Irbesartan (Avapro)
Losartan (Cozaar)
Aliskiren (Tekturna)
Etanercept (Enbrel)
Infliximab (Remicade)
Montelukast (Singulair)
Fluticasone propionate/salmeterol (Advair)
•
Trospium chloride (Sanctura)
•
Varenicline (Chantix)
•
•
Gabapentin (Neurontin)
Pregabailin
b ili (Lyrica)
( i )
•
•
Eszopiclone (Lunesta)
Zolpidem (Ambien)
•
Modafinil (Provigil)
•
•
•
Sildenafil
Sild
fil (Vi
(Viagra))
Vardenafil (Levitra)
Tadalafil (Cialis)
•
•
•
•
•
Duloxetine (Cymbalta)
Aripiprazole (Abilify)
Olanzapine (Zyprexa)
Q i i (Seroquel)
Quetiapine
(S
l)
Risperidone (Risperdal)
Survey
• Adherence
– If not
not, why?
• Problems with:
– Sleep
Sleep, mood,
mood GI,
GI HA,
HA fatigue,
fatigue memory,
memory confusion,
confusion
hallucinations, muscle aches, incontinence, rash, sexual
function, cough, SOB, swollen legs, bleeding, change
off weight
i h
•
•
•
•
Severity: mild, moderate, severe
Timing
Think related to drug?
Does PCP know?
– If “no”, want PCP notified by e-mail?
Documentation
• EHR: All
• Email
– Non-adherence: chronic drugs,
g , only
y if ppatient
says has not discussed with PCP and patient
wants us to notifyy
– Symptoms
•
•
•
•
Any reports of falling down,
down rash over most of body
Most others: “severe”
Some targeted to drug
Patient requests notification
Analysis Plan
• Look for “signal” associated with drug-side
effect
ff t combinations
bi ti
– Potential for subgroups related to age, gender,
creatinine clearance
• See if documentation associated with
subsequent change in management:
– Medication
M di ti stops
t
or changes
h
Preliminary Recruitment
• Calls 11/20/08 – 3/2/10: 6,161 potentially eligible
– Opt-out after receiving letter:
8%
• Among those who did not opt-out:
– 10% disconnected phone
– 34% no one ever answered
d
• Among those contacted:
– 38% opted out during call
– 17% hung up
• Respondents n = 1543
– Final 28% of those with a working phone
– 45% of those contacted
• Average
A
answered
d call
ll duration:
d
i
~44 min.
i
• E-mails sent to doctors:
13%
Factors Associated with Participation
18-45 yrs (vs. 56 - 65)
>=66 (vs. 56 - 65)
Black (vs. white)
Hispanic (vs. white)
<$50,000 (vs. more)
Seizure (vs. insomnia)
Asthma
s
a (vs.
( s insomnia)
so
a)
0.1
1
10
Odds Ratio (95% C.I.)
Follow-up Survey
• 80% of patients still on target drug 3
months
th later
l t
• Overall pparticipation
p
rate 70% of those
contacted (53% of eligible with working
phone).
phone)
• Similar patterns by patient and drug
characteristics
h
i i although
lh
h fewer
f
significant
i ifi
differences
Observed – Expected
p
RED
99% CI
ORANGE
95% CI
YELLOW
90% CI or step-based algorithm
W
WeightGain
Tremors
SwollLegs
SleepMuch
SleepLittle
SOB
SexFunc
OffBalance
Nausea
Memory
Lighthead
Incont
HA
Halluc
Fatigue
Diarrhea
Depress
Cough
Constip
n
374
185
133
132
111
87
61
56
36
31
28
MuscleAch
M di ti
Medication
Alert
Al t
Zolpidem
Valsartan
Sildenafil
Gabapentin
Varenicline
Rosuvastatin Calcium
Losartan
Montelukast
Irbesartan
Tadalafil
Pregabalin
Confusion
Abd Pain
Sample Alert Output
Additional Symptom Detail
Hallucination
2
1.5
1
0.5
0
Varenicline
Gabipentin
Sexual Function
5
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
Observed
Expected
Varenicline
Nausea
Gabipentin
Fatigue
2
5.5
5
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
15
1.5
1
05
0.5
0
Varenicline
Gabipentin
Varenicline
Gabipentin
Patient Reported Outcomes
18
16
17.2
15.2
14
Worry/ discomfort
12
Seek
S
k med
d
attention
Clinic visit
10
8
9.2
7.7
Lab Test
6
ED/ hospital
4
2
0
2.7
Next Steps
• Patient level
– Look to see if alerts resulted in change of
management
– Unintended management issues
• Population
P
l ti level
l l
– Enrollment/ monitoring continues
– When to stop monitoring a drug?
• Subpopulations
– When to report to FDA?
• Side effects > 2x of product label?
Limitations/ Considerations
• Reach
– No Spanish
– No inbound calling
• Best control group?
Conclusions
• Detecting drug-symptom signal
• Complicated how to integrate with patient's
care/ providers
• Attribution of a symptom to a particular
d
drug
is
i complicated
li
d for
f patients/
i
/ providers
id
– Underscore the need for statistics