Drug Information Association Clinical Forum Presentation
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www.diahome.org Pharmacoepidemiology in clinical drug development Presenter: Dr David E Neasham Company logo here
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Pharmacoepidemiology in clinical drug development
Transcript of Drug Information Association Clinical Forum Presentation
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Pharmacoepidemiology in clinical drug development
Presenter: Dr David E Neasham
Company logo here
www.diahome.org
Contents• Background & contributing areas
• Reasons to perform pharmacoepidemiology studies
• Study design
• Database studies
• Two practical examples:
– YASMIN (ethinylestradiol with drospirenone)
– CRESTOR (rosuvastatin)
• Future directions – Large Simple Trials
• Summary
• Discussion / Q & A
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Background
• Pharmacoepidemiology– Application of epidemiological techniques
to the content area of clinical pharmacology
• Population level• Study of adverse drug effects• Many areas of contribution
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Contributions
• Better quantification of incidence of known adverse and beneficial effects – Higher precision– In patients excluded in pre-marketing
studies – e.g., children, elderly, pregnant women
– Interaction by other drugs or illnesses– Relative to other drugs used for same
indication
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Contributions
• Make available new types of information not obtained through premarketing studies– Discovery of previously undetected
adverse and beneficial effects• Uncommon effects• Delayed effects
– Patterns of drug use
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Contributions
• Contribution to public health – Reassurance about drug safety– Fulfilment of ethical and legal obligations
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Rationale
• Regulatory– e.g., obtain earlier approval for marketing
• Clinical– e.g., hypothesis testing or generating
• Marketing– e.g., assist in repositioning of drug
• Legal– e.g. In anticipation of product liability litigation
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Study design
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Study design: Measuring disease risk
Slide 9 © Imperial College London
Types of error: study bias, chance variation, confounding
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Study design hierarchy+
Brad
ford
Hill cau
sality criteria
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A typical scenario: identifying risks
INCIDENCE OF COMMONLY
OCCURRING EVENT FROM CLINICAL
TRIALS
BackgroundEpidemiology
Risk management strategy Risk management strategy
INCIDENCE OF EVENTIN GENERAL POPULATION
IDENTIFICATION OFRISK FACTORS
POTENTIAL SIGNALS OF RARE EVENTS
SpontaneousReports
ObservationalStudies
Other Activities
1/1,000
1/500
1/100
1/10,000
1/5,000
1/1,000
1/100,000
1/50,000
1/10,000
HYPOTHESIS TESTING1/1,000,000
1/500,000
1/100,000,
Clinical trial Data
Insufficiently powered
Evidence base
Self-report bias
Best study design….
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Safety challenges in pre-approval phase • Challenges of safety signal identification
during pre-approval phase:– pre-approval studies cannot usually be
statistically powered to identify readily low frequency safety events of concern
– samples often narrowly defined – therefore may not be truly representative of final treatment population
– short time frames: mid to long-term effects cannot be thoroughly evaluated
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Post-marketing pharmacovigilance
• Limitations of post-marketing spontaneous reporting systems:– patterns of spontaneous reporting vary by country,
increase during early post-launch period and are affected by publicity → spontaneous reporting rates biased
– limited population level denominator information– for common events (e.g., MI) difficult to separate
actual signals from background noise
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Approval
ClinicalClinical
Product life-cycleProduct life-cycle FIM Ph I Ph II Ph III Ph IV
Toxicology (e.g. genotoxicity assays)
In silico analysis/ structural alerts
Margin of safety & no observed adverse effect level defined
Ph I & II: dose ranging, efficacy & toxicity
Phase III: demonstration of efficacy and safety signal monitoring
Ph IV: spontaneous reporting systems
Exposure in humans
(Potential Denom
inator)Exposure in hum
ans(Potential D
enominator)
Product life-cycle and safety studies
PreclinicalPreclinical Postmarketing pharmacovigilance
Postmarketing pharmacovigilance
Sufficiently powered
Easy study replication
Large database studies
No self-reporting bias
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Example 1
• The YASMIN (ethinylestradiol with drospirenone) study
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Case Study - Yasmin and the Safety of DRSP
• Background– Yasmin is an OC that contains drospirenone (DRSP)
– DRSP has antimineralocorticoid activity and can raise serum potassium
• Phase IV commitment– To obtain safety data related to:
• Complications related to hyperkalemia (elevated serum potassium)
• Physician prescribing and patient monitoring
• Breakthrough pregnancy and birth outcomes
– In 25,000 users of Yasmin and 50,000 users of other OCs
• Wider business implications– Sponsor planned to introduce DRSP into menopausal therapy
– Needed strong basis for later safety claims
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INGENIX Research Database
Women (10-59 yrs)n = 959,482
Propensity score matching of 12 initiator cohorts
(n = 22,429)
New dispensing of Yasmin (n = 31,149)
New dispensing of other OCs (n = 360,505)
≥6 months continuous enrollment (n = 22,887)
≥6 months continuous enrollment (n = 227,596)
Propensity score matching of 12 initiator cohorts
(n = 44,858)1:2 Ratio
Cohort Formation
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• Create matched cohorts of Yasmin and other OC users• Collect comorbidities, demographics, healthcare utilization, exposure to oral contraceptives
• Identify women with hepatic, renal or adrenal insufficiency
• Identify potassium-sparing meds
New OC or New type of OC
OCRx
6 Months Before Dispensing
Prospective Data Collection
• Identify clinical outcomes based on claims data (prescription, diagnoses, procedures and service)
• Hospitalizations for new conditions, clinical events potentially related to hyperkalemia, electrolyte abnormality,inappropriate prescribing, potassium monitoring, pregnancy/fetal malformations
Data Collection
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Yasmin Launch
Q3
Time
Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4
2001 2002 2003 2004
Yasmin
ControlP
Follow-Up
Follow-Up
Yasmin
ControlP
Follow-Up
Follow-Up
Yasmin
ControlP
Follow-Up
Follow-Up
Yasmin
ControlP
Follow-Up
Follow-Up
Yasmin
ControlP
Follow-Up
Follow-Up
Yasmin
ControlP
Follow-Up
Follow-Up
Yasmin
ControlP
Follow-Up
Follow-Up
Yasmin
ControlP
Follow-Up
Follow-Up
Yasmin
ControlP
Follow-Up
Follow-Up
Yasmin
ControlP
Follow-Up
Follow-Up
Yasmin
ControlP
Follow
Follow
Yasmin
ControlP
2005
Q1 Q2 Q3 Q4
Claims-Based Outcomes
Chart-Based Outcomes
Apr. Report
Oct. Report
Apr. Report
Oct. Report
Apr. Report
Oct. Report
Apr. Report
Final Report
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Claims Based Abstraction
Medical Chart Abstraction
Screen Claims Data
Medical
Review
Blinded Chart Reviews to Confirm Outcomes
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Some outcomes may be continuations of pre-existing conditions* No rate ratio calculated as no case in Yasmin Cohort** Composite hyperkalemia outcome comprised of chart-confirmed cases of arrhythmia, syncope, electrolyte disturbance, hyperkalemia, and myocardial infarction.
Syncope
Arrhythmia
Hyperkalemia
Other Electrolyte Disturbance
Dialysis*
Myocardial Infarction*
Hospitalization with Hyper/Hypokalemia*
Death
Composite Hyperkalemia**
0
0
0
0
Incidence Rate Ratio –Yasmin versus Other OC (95% CI)
5.01.0 2.0 4.03.00.50.25 0.330.2
0.1
Rate Ratios
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• Does Yasmin lead to more VTE than other OCs? – NO. We added a new outcome which we could evaluate both
retrospectively and prospectively for the full cohort.• Why do physicians prescribe to women with apparent
contraindications of renal, hepatic, or adrenal disease?– MAY IGNORE NOMINAL CONTRAINDICATION FOR MILD
DISEASE. We directly interviewed physicians with apparently contraindicated prescribing patterns.
• Why do physicians not perform potassium monitoring as recommended in the label?– DISAGREE WITH LABEL. We surveyed physicians with
patients who by label should have been monitored, but were not.
Flexible Data Collection Facilitates Risk Management
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Example 2
• The CRESTOR (rosuvastatin) studies
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Brief background
Rosuvastatin
• Hepato-selective and relatively hydrophilic hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin)
• Approved by FDA on 12 August, 2003
• Management of dyslipidemia
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Potential safety issues
• Results from controlled clinical studies and use in clinical practice → statins generally well tolerated with low frequency of significant side effects
• Known important but rare adverse events within class are rhabdomyolysis, myopathy, and increase in hepatic transaminases
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Potential safety issues
• Added concerns from withdrawal of cerivastatin in 2001 due to excess cases of fatal rhabdomyolysis
• Comorbidities and concomitant medications may increase risk of myotoxicity, depending on properties of given statin
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Evolution of Lipid Management ATP Guidelines*
ATP I (1988) ATP II (1993) ATP III (2001)
Diet; low-dose,non-statin monotherapy
High-dose statin, combination therapy
Low- to moderate-dose statin monotherapy
Increasing aggressiveness of cholesterol-lowering therapy
* The National Cholesterol Education Program Adult Treatment Panel (ATP)
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The CRESTOR study program
An international collaborative pharmacoepidemiology safety program involving many groups…• AstraZeneca R&D• Centro Español de Investigación
Farmacoepidemiológica (CEIFE), Spain• PHARMO Institute, Netherlands• i3 Drug Safety, US• Drug Safety Research Unit (DSRU), UK
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Pharmacoepidemiology program design
• Program consisted of nine studies grouped into three components:– Patient characteristics studies (x 4
databases)– Safety evaluation studies (x 4 databases)– Prescription-event monitoring study (DSRU)
• All studies performed according to GPP guidelines and reviewed and approved by ethics committees
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Pharmacoepidemiology program overview
Table: Study parameters
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Pharmacoepidemiology program
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Numbers and incidence rates of study outcomes
Results from McAfee et al. (2006) (Ingenix)
Safety evaluation studies
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Pooled person-time and outcomes
Outcome Person-years N Person-years N
Myopathy 260,844 9 196,911 9
Rhabdomyolysis 260,889 9 196,929 7
Renal dysfunction 260,772 95 196,870 57
Hepatic dysfunction 260,852 22 196,914 14
Intent-to-treat Current use
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Future directions• Large Simple Trials
• Conditions appropriate for conduct of LST– Important research question– Uncertainty re: RISKS– Confounding by indication– Relative risk small (potential residual confounding)
• Feasibility– Simple testable hypothesis– Treatment to be tested relatively uncomplicated– Hard end-points– Follow-up needed– Good recruitment levels
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Future directions• Large Simple Trials• Large Simple Trial (LST) Of Cardiovascular Safety Of
Ziprasidone And Olanzapine- (Zodiac) - Pfizer • Condition(s) targeted: Schizophrenia • Intervention: Ziprasidone (Drug); Olanzapine (Drug) • Phase: Phase 4 • Primary objective of study to estimate relative incidence
among users of ziprasidone and olanzapine of non-suicide mortality.
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Future directions• Large Simple Trials
• Efficiency of LSTs could be enhanced using health delivery systems databases
• Relevant outcomes (e.g., hospitalizations for gastrointestinal bleeding) could be captured electronically which would eliminate need to contact patients for follow-up
• Still necessary to identify eligible subjects, obtain consent and randomize treatment
• Could be a very effective hybrid method
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Contents
• Background & contributing areas
• Reasons to perform pharmacoepidemiology studies
• Study design
• Database studies
• Two practical examples:
– YASMIN (ethinylestradiol with drospirenone)
– CRESTOR (rosuvastatin)
• Future directions
• Summary
• Discussion / Q & A
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Pharmacoepidemiology in clinical drug development
Dr David E [email protected]+44 (0)1628 408442
Questions & answers
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