P05_ Dong _TopicsDrugSafety
Transcript of P05_ Dong _TopicsDrugSafety
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Observational Registries:Applications in Safety Evaluation
8th FDA/Industry Statistics WorkshopWashington, D.C. September 14-16, 2005
Wei Dong MD PhD, Katie Miller MSc, Pavel Napalkov MD MPhEpidemiology
Genentech, Inc.
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Acknowledgements
• Patients, physicians and others participating in the studies
• Investigators at Genentech and many other institutions
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Today’s Objectives
• Overview of registries– Opportunities and challenges
• Examples of safety evaluations using registries @ Genentech
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Target Population: All Patients with Disease X
Older, multiplecomorbid diseases
Younger, multiplecomorbid diseases
Older, otherwise healthy
Younger, otherwise healthy
Registry Sampling(few or no exclusion criteria)
Phase III Sampling(multiple exclusion criteria)
Registries vs. RCT: Generalizability
Study Population
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Registries vs. RCT: Scope of Study
RCT
Registries
Less MoreAmount of data collected
# of patients enrolled
1,000s-10,000s
10s-100s
Duration of follow-up
months
years
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Two Types of Registries
Absolute riskAbsolute risk
Relative risk
Risk Estimates
NoYesControl Group
YesYesActive treatment
Patients treated with specific product
Patients with specific disease
Enrollment base
Product-basedDisease-based
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Registries at Genentech
ACUTE CONDITIONS
NRMI (acute MI/ alteplase)
ESIS (acute ischemic stroke/
alteplase)
STARS (acute ischemic stroke/
alteplase)
CHRONIC CONDITIONS NCGS
(growth hormone deficiency/
somatropin)
NCSS (growth hormone deficiency/
somatropin)
RESPONSE (psoriasis/efalizumab)
ESCF (cystic fibrosis/dornase
alfa)
TENOR (asthma)
EXCELS (asthma/omalizumab)
ONCOLOGY
BRiTE (metastatic colorectal cancer/ bevacizumab)
registHER (HER2+ metastatic breast
cancer/ trastuzumab)
LymphoCare (non-Hodgkin’s lymphoma/
rituximab)
PREGNANCY
FOLLOW
(psoriasis/efalizumab) EXPECT
(asthma/omalizumab)
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NRMI: National Register of Myocardial Infarction
• Multi-center, observational cohort study• Eligibility: disease-based
– Patients hospitalized for acute myocardial infarction
– Treated at physician’s discretion
• Initiated in 1990• >2 million patients• >1600 hospitals
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NRMI: Intracranial Hemorrhage (ICH)
Patient Characteristics NRMI-21
(N=71,073) GUSTO-12 (N=10,396)
Baseline
Age, median (IQR) 61 (51-70) 61 (52-70)
Female, % 31 25
Diabetes, % 19 15
Hypertension, % 43 38
ICH, n (%) 625 (0.88) 73 (0.70)
Death, n (%) 331 (53.0) NA
*only includes patients treated with tissue plasminogen activator (tPA), Alteplase
1. Gurwitz J. Risk for intracranial hemorrhage after tissue plasminogen activator treatment for acute myocardial infarction. Ann Intern Med 1998;129:597-604. [Data thru 09/1996]
2. Gore JM. Stroke after thrombolysis. Mortality and functional outcomes in the GUSTO-1 trial. Circulation 1995;92:2811-8.
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Stroke Studies: ICH Risk and tPA• To evaluate the risk of ICH in special populations
• Pooled analysis of 4 prospective cohorts of Alteplase treated patients– Standard Treatment With Alteplase To Reverse Stroke [STARS]1
– Epidemiology Study Of Ischemic Stroke [ESIS]– University Of Texas Houston Stroke Study [UT]– Canadian Activase For Stroke Effectiveness Study [CASES]2
• Systematically collected stroke treatment and outcomes
• Symptomatic ICH was ascertained per head CT scan or MRI and a decline in neurological status – within 72 hours for STARS/ESIS, or 24 hours for UT and CASES
• Albers GW. et al. Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study. JAMA. 283(9):1145-50, 2000.
• Hill MD. Buchan AM. Methodology for the Canadian Activase for Stroke Effectiveness Study (CASES). CASES Investigators. Canadian Journal of Neurological Sciences. 28(3):232-8, 2001
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Incidence Of Symptomatic ICH Among Alteplase-Treated Stroke Patients1
0
5
10
15
No Yes No Yes No Yes No Yes No Yes
Age >70 NIHSS >20 Diabetes CHF Hispanics
% o
f pa
tient
s NINDS
1. Dong W et al.Safety Outcomes of Alteplase in Ischemic Stroke Patients with Special Characteristics. International Stroke Conference 2005.
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NCGS: National Cooperative Growth Study
• Multi-center, prospective, observational cohort study
• Eligibility: product-based– Treated with growth hormone
• Initiated in 1985
• >24,000 patients
• >400 sites in US and Canada
1. Allen D, et al. Risk of leukemia in children treated with human growth hormone: Review and analysis. J Pediatr 1997;131:S32-6.
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NCGS: Leukemia
Leukemia risk among patients with no risk factors by “person-time at risk” vs. “person-time on therapy”
Time-frame of interest
Observed cases
Expected cases*
Person-years SIR* (95% CI)
At risk 3 3.42 119,846.0 0.88 (0.18-2.57) On GH Therapy
2 2.13 67,773.2 0.94 (0.11-3.40)
*Standardized incidence ratio (SIR) calculated using SEER data
1. Allen D, et al. Risk of leukemia in children treated with human growth hormone: Review and analysis. J Pediatr 1997;131:S32-6. [Data thru 12/1995]
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BRiTE: Bevacizumab Regimens Investigation of Treatment Effects and Safety
• Multi-center, prospective, observational cohort study
• Eligibility: treatment-based – Metastatic colorectal cancer– Treated with bevacizumab (with chemo) as 1st-line therapy
• Select Study Outcomes– Safety: GI perforation– Effectiveness: overall survival
• Data collection– Baseline and every 3 months for up to 3 years– No study-specific visits or evaluations
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BRiTE: GI Perforation
1. Kozloff M. et al. Safety of bevacizumab among patients receiving first-line chemotherapy for metastatic colorectal cancer- preliminary results from a large registry in the US (BRiTE). ASCO 2005.
2. Hurwtz H et al. Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer. NEJM. 2004;350:2335-2342.*Bevacizumab labeling [2004] reports 2% GI perforation
Patient Characteristics (%) BRiTE (N=1367) 1
Study 2107 (N=402)2
Baseline
Age > 65 47 Mean=59.5
Male 54 59
Non-white 18 21
ECOG≥2 7 <1
Surgery 30 days prior to 48 Mostly
Avastin treatment excluded
Incidence of GI Perforation* 1.6 1.5
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EXCELS: Epidemiologic Study of Xolair (omalizumab) in Patients with Moderate to Severe Asthma
• Multi-center, prospective, observational cohort study
• Eligibility: disease-based– Moderate to severe persistent allergic asthma
– 2:1 Xolair-treated vs. Non-Xolair treated
• Selected Safety Outcomes– All malignancies
• Current status– Enrolled 3826 of planned 7500 [as of 09/2005]– 1500 pys accumulated (with <12month f/u for most pts)
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EXCELS: Approaches to Minimizing Biases
• Potential for channeling bias– Collecting data on confounders
• Demographics, asthma severity, history of and risk factors for cancer, etc
– Statistical methods to adjust for confounders• Multivariate regression analysis adjusting for
covariates • Propensity scores to assess prescribing decisions• Sensitivity analysis for residual non-measurable
confounders
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Discussion
• Sampling– True random sample unlikely– Key is to sample a broad range of sites– “Every patient counts” – Don’t cherry pick patients
• CRF– Necessary to revise over time– Try to maintain consistency in key outcome measures
• Comparator cohort– Collection of confounding factors on CRF (i.e., before SAP)– Examine potential bias (extent and direction)– Adjustments for bias
• Potential for nested case-control studies
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• Observational registries are a significant component of safety (and benefit) evaluation
• Given the absence of randomization, these studies need closer attentions to patient enrollment plans, data collection methods and choices of study endpoints in order to minimize potential bias.
Conclusions
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Thank You!
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Overview of Registries• Large, non-experimental cohort studies
• No randomization of treatment
• Minimal or no exclusion criteria in order to capture real-world patients and practices
• Safety endpoints and duration of follow up selected according to disease and product MOA
• Disease-based or product-based registries
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ICH risk in Activase-treated Stroke Patients1
4.6(3.4-6.0)
5.8 (3.2-9.6)
6.8(3.9-10.8)
3.3(1.8-5.6)
30-day Intracranial Hemorrhage
32.5**(29.1-36.1)
Not Recorded
40.0(33.3-47.0)
34.6(29.8-39.6)
30-day complete recovery (i.e., MRS≤1) (%)
23.3**(20.2-26.5)
14.5*(10.3-19.6)
14.8(10.6-20.0)
12.9(9.7-16.6)
30-day mortality (%)
CASESN=1100***
UTN=241
ESISN=236
STARS N=389
1. Dong W et al.Safety Outcomes of Alteplase in Ischemic Stroke Patients with Special Characteristics. International Stroke Conference 2005.*. UT reported in-hospital mortality. **. CASES reported outcomes at 90-day follow up. ***. Sample size and results as August.2001.
Overall ICH: 4.7% (3.8-5.9)