Observational Registries: Applications in Safety Evaluation

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Observational RegistriesApplications in Safety
Evaluation

• 8th FDA/Industry Statistics Workshop
• Washington, D.C. September 14-16, 2005
• Wei Dong MD PhD, Katie Miller MSc, Pavel Napalkov
  MD MPh
• Epidemiology
• 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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Todays Objectives

• Overview of registries
• Opportunities and challenges
• Examples of safety evaluations using registries _at_
  Genentech

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Registries vs. RCT Generalizability
Target Population All Patients with Disease X
Study Population
Registry Sampling (few or no exclusion criteria)
Phase III Sampling (multiple exclusion criteria)
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Registries vs. RCT Scope of Study
Less
More
Amount of data collected
Registries
RCT
years
1,000s-10,000s
of patients enrolled
Duration of follow-up
months
10s-100s
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Two Types of Registries
Disease-based Product-based
Enrollment base Patients with specific disease Patients treated with specific product
Active treatment Yes Yes
Control Group Yes No
Risk Estimates Absolute risk Relative risk Absolute risk
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Registries at Genentech
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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 physicians discretion
• Initiated in 1990
• gt2 million patients
• gt1600 hospitals

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NRMI Intracranial Hemorrhage (ICH)

1. Gurwitz J. Risk for intracranial hemorrhage after
   tissue plasminogen activator treatment for acute
   myocardial infarction. Ann Intern Med
   1998129597-604. Data thru 09/1996
2. Gore JM. Stroke after thrombolysis. Mortality
   and functional outcomes in the GUSTO-1 trial.
   Circulation 1995922811-8.

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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 STARS1
• Epidemiology Study Of Ischemic Stroke ESIS
• University Of Texas Houston Stroke Study UT
• Canadian Activase For Stroke Effectiveness Study
  CASES2
• 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

1. 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.
2. 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
NINDS
of patients

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
• gt24,000 patients
• gt400 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 1997131S32-6.

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NCGS Leukemia

• Leukemia risk among patients with no risk
  factors
• by person-time at risk vs. person-time on
  therapy

1. Allen D, et al. Risk of leukemia in children
   treated with human growth hormone Review and
   analysis. J Pediatr 1997131S32-6. 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.
20043502335-2342. Bevacizumab labeling 2004
reports 2 GI perforation
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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
• 21 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 lt12month 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 Dont 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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Conclusions

• 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.

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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
STARS N389 ESIS N236 UT N241 CASES N1100
30-day Intracranial Hemorrhage 3.3 (1.8-5.6) 6.8 (3.9-10.8) 5.8 (3.2-9.6) 4.6 (3.4-6.0)
30-day complete recovery (i.e., MRS1) () 34.6 (29.8-39.6) 40.0 (33.3-47.0) Not Recorded 32.5 (29.1-36.1)
30-day mortality () 12.9 (9.7-16.6) 14.8 (10.6-20.0) 14.5 (10.3-19.6) 23.3 (20.2-26.5)
Overall ICH 4.7 (3.8-5.9)
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.