Observational Registries: Applications in Safety Evaluation 8 th  FDA/Industry Statistics Workshop Washington, D.C. Septem...
Acknowledgements <ul><li>Patients, physicians and others participating in the studies </li></ul><ul><li>Investigators at G...
Today’s Objectives <ul><li>Overview of registries </li></ul><ul><ul><li>Opportunities and challenges  </li></ul></ul><ul><...
Registries vs. RCT: Generalizability Target Population: All Patients with Disease X Registry Sampling (few or no exclusion...
Registries vs. RCT: Scope of Study  Less More Amount of data collected # of patients enrolled 1,000s-10,000s 10s-100s Dura...
Two Types of Registries Absolute risk Absolute risk Relative risk Risk Estimates No Yes Control Group Yes Yes Active treat...
Registries at Genentech
NRMI: National Register of Myocardial Infarction <ul><li>Multi-center, observational cohort study </li></ul><ul><li>Eligib...
NRMI: Intracranial Hemorrhage (ICH) <ul><li>Gurwitz J. Risk for intracranial hemorrhage after tissue plasminogen activator...
Stroke Studies: ICH Risk and tPA <ul><li>To evaluate the risk of ICH in special populations  </li></ul><ul><li>Pooled anal...
Incidence Of Symptomatic ICH Among  Alteplase-Treated Stroke Patients 1   % of patients NINDS <ul><li>Dong W et al.Safety ...
NCGS: National Cooperative Growth Study <ul><li>Multi-center, prospective, observational cohort study </li></ul><ul><li>El...
NCGS: Leukemia <ul><li>Leukemia risk among patients with no risk factors  </li></ul><ul><li>by “person-time at risk” vs. “...
BRiTE: Bevacizumab Regimens Investigation  of Treatment Effects and Safety <ul><li>Multi-center, prospective, observationa...
BRiTE: GI Perforation 1. Kozloff M. et al. Safety of bevacizumab among patients receiving first-line chemotherapy for meta...
EXCELS: Epidemiologic Study of Xolair (omalizumab)  in Patients with Moderate to Severe Asthma <ul><li>Multi-center, prosp...
EXCELS: Approaches to Minimizing Biases <ul><li>Potential for channeling bias </li></ul><ul><ul><li>Collecting data on con...
Discussion <ul><li>Sampling </li></ul><ul><ul><li>True random sample unlikely </li></ul></ul><ul><ul><li>Key is to sample ...
<ul><li>Observational registries are a significant component of safety (and benefit) evaluation </li></ul><ul><li>Given th...
Thank You!
Overview of Registries <ul><li>Large, non-experimental cohort studies </li></ul><ul><li>No randomization of treatment </li...
ICH risk in Activase-treated Stroke Patients 1   1. Dong W et al.Safety Outcomes of Alteplase in Ischemic Stroke Patients ...
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P05_ Dong _TopicsDrugSafety

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  • Two main objectives that I will address simultaneously as we go through the presentation (using GNE registries to demonstrate opportunities and challenges)
  • Table about generalizability Emphasize patients in phase 3 are typically young and otherwise healthy Registry gives sample that is more generalizable
  • Data collected: Refers to amount of data (eg. # of outcomes, # of questions at each follow-up, # of follow-up visits) and level of detail collected for each patient.
  • List GNE’s registries As you (the audience) can see, registries can be used across a wide spectrum of conditions from acute/immediately life-threatening, to chronic/non-life-threatening, and chronic life-threatening.
  • One of the first GNE registries Numerous publications regarding safety, effectiveness, treatment patterns, and change of treatment patterns over time.
  • Focus here could be on getting estimate of rare event for drug with relatively small number in original clinical trial; need to use SIR since we do not have a control group
  • The previous studies described were from older GNE registries, Now I would like to present some early findings from 2 registries that are currently still in the data collect phase. First, is BRiTE.
  • To start, I’d like to give just a brief overview of what registries are. Lack of randomization: need to think about risk factors for outcomes and collect data on these factors so one can describe and control for potential confounders Two type of registries, which I will now go into more detail about in a minute Talk about how minimal exclusion criteria increases generalizability by including people that are often excluded from phase 1-3 trials (e.g. elderly, patients with comorbid diseases, patients with multiple concomitant medications.) (go to next slide while describing)
  • P05_ Dong _TopicsDrugSafety

    1. 1. Observational Registries: Applications in Safety Evaluation 8 th 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.
    2. 2. Acknowledgements <ul><li>Patients, physicians and others participating in the studies </li></ul><ul><li>Investigators at Genentech and many other institutions </li></ul>
    3. 3. Today’s Objectives <ul><li>Overview of registries </li></ul><ul><ul><li>Opportunities and challenges </li></ul></ul><ul><li>Examples of safety evaluations using registries @ Genentech </li></ul>
    4. 4. Registries vs. RCT: Generalizability Target Population: All Patients with Disease X Registry Sampling (few or no exclusion criteria) Phase III Sampling (multiple exclusion criteria) Study Population Older, multiple comorbid diseases Younger, multiple comorbid diseases Older, otherwise healthy Younger, otherwise healthy
    5. 5. Registries vs. RCT: Scope of Study Less More Amount of data collected # of patients enrolled 1,000s-10,000s 10s-100s Duration of follow-up months years RCT Registries
    6. 6. Two Types of Registries Absolute risk Absolute risk Relative risk Risk Estimates No Yes Control Group Yes Yes Active treatment Patients treated with specific product Patients with specific disease Enrollment base Product-based Disease-based
    7. 7. Registries at Genentech
    8. 8. NRMI: National Register of Myocardial Infarction <ul><li>Multi-center, observational cohort study </li></ul><ul><li>Eligibility: disease-based </li></ul><ul><ul><li>Patients hospitalized for acute myocardial infarction </li></ul></ul><ul><ul><li>Treated at physician’s discretion </li></ul></ul><ul><li>Initiated in 1990 </li></ul><ul><li>>2 million patients </li></ul><ul><li>>1600 hospitals </li></ul>
    9. 9. NRMI: Intracranial Hemorrhage (ICH) <ul><li>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] </li></ul><ul><li>Gore JM. Stroke after thrombolysis. Mortality and functional outcomes in the GUSTO-1 trial. Circulation 1995;92:2811-8. </li></ul>
    10. 10. Stroke Studies: ICH Risk and tPA <ul><li>To evaluate the risk of ICH in special populations </li></ul><ul><li>Pooled analysis of 4 prospective cohorts of Alteplase treated patients </li></ul><ul><ul><li>Standard Treatment With Alteplase To Reverse Stroke [STARS] 1 </li></ul></ul><ul><ul><li>Epidemiology Study Of Ischemic Stroke [ESIS] </li></ul></ul><ul><ul><li>University Of Texas Houston Stroke Study [UT] </li></ul></ul><ul><ul><li>Canadian Activase For Stroke Effectiveness Study [CASES] 2 </li></ul></ul><ul><li>Systematically collected stroke treatment and outcomes </li></ul><ul><li>Symptomatic ICH was ascertained per head CT scan or MRI and a decline in neurological status </li></ul><ul><ul><li>within 72 hours for STARS/ESIS, or 24 hours for UT and CASES </li></ul></ul><ul><li>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. </li></ul><ul><li>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 </li></ul>
    11. 11. Incidence Of Symptomatic ICH Among Alteplase-Treated Stroke Patients 1 % of patients NINDS <ul><li>Dong W et al.Safety Outcomes of Alteplase in Ischemic Stroke Patients with Special Characteristics. International Stroke Conference 2005. </li></ul>
    12. 12. NCGS: National Cooperative Growth Study <ul><li>Multi-center, prospective, observational cohort study </li></ul><ul><li>Eligibility: product-based </li></ul><ul><ul><li>Treated with growth hormone </li></ul></ul><ul><li>Initiated in 1985 </li></ul><ul><li>>24,000 patients </li></ul><ul><li>>400 sites in US and Canada </li></ul><ul><li>Allen D, et al. Risk of leukemia in children treated with human growth hormone: Review and analysis. J Pediatr 1997;131:S32-6. </li></ul>
    13. 13. NCGS: Leukemia <ul><li>Leukemia risk among patients with no risk factors </li></ul><ul><li>by “person-time at risk” vs. “person-time on therapy” </li></ul><ul><li>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] </li></ul>
    14. 14. BRiTE: Bevacizumab Regimens Investigation of Treatment Effects and Safety <ul><li>Multi-center, prospective, observational cohort study </li></ul><ul><li>Eligibility: treatment-based </li></ul><ul><ul><li>Metastatic colorectal cancer </li></ul></ul><ul><ul><li>Treated with bevacizumab (with chemo) as 1 st -line therapy </li></ul></ul><ul><li>Select Study Outcomes </li></ul><ul><ul><li>Safety: GI perforation </li></ul></ul><ul><ul><li>Effectiveness: overall survival </li></ul></ul><ul><li>Data collection </li></ul><ul><ul><li>Baseline and every 3 months for up to 3 years </li></ul></ul><ul><ul><li>No study-specific visits or evaluations </li></ul></ul>
    15. 15. 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
    16. 16. EXCELS: Epidemiologic Study of Xolair (omalizumab) in Patients with Moderate to Severe Asthma <ul><li>Multi-center, prospective, observational cohort study </li></ul><ul><li>Eligibility: disease-based </li></ul><ul><ul><li>Moderate to severe persistent allergic asthma </li></ul></ul><ul><ul><li>2:1 Xolair-treated vs. Non-Xolair treated </li></ul></ul><ul><li>Selected Safety Outcomes </li></ul><ul><ul><li>All malignancies </li></ul></ul><ul><li>Current status </li></ul><ul><ul><li>Enrolled 3826 of planned 7500 [as of 09/2005] </li></ul></ul><ul><ul><li>1500 pys accumulated (with <12month f/u for most pts) </li></ul></ul>
    17. 17. EXCELS: Approaches to Minimizing Biases <ul><li>Potential for channeling bias </li></ul><ul><ul><li>Collecting data on confounders </li></ul></ul><ul><ul><ul><li>Demographics, asthma severity, history of and risk factors for cancer, etc </li></ul></ul></ul><ul><ul><li>Statistical methods to adjust for confounders </li></ul></ul><ul><ul><ul><li>Multivariate regression analysis adjusting for covariates </li></ul></ul></ul><ul><ul><ul><li>Propensity scores to assess prescribing decisions </li></ul></ul></ul><ul><ul><ul><li>Sensitivity analysis for residual non-measurable confounders </li></ul></ul></ul>
    18. 18. Discussion <ul><li>Sampling </li></ul><ul><ul><li>True random sample unlikely </li></ul></ul><ul><ul><li>Key is to sample a broad range of sites </li></ul></ul><ul><ul><li>“ Every patient counts” – Don’t cherry pick patients </li></ul></ul><ul><li>CRF </li></ul><ul><ul><li>Necessary to revise over time </li></ul></ul><ul><ul><li>Try to maintain consistency in key outcome measures </li></ul></ul><ul><li>Comparator cohort </li></ul><ul><ul><li>Collection of confounding factors on CRF (i.e., before SAP) </li></ul></ul><ul><ul><li>Examine potential bias (extent and direction) </li></ul></ul><ul><ul><li>Adjustments for bias </li></ul></ul><ul><li>Potential for nested case-control studies </li></ul>
    19. 19. <ul><li>Observational registries are a significant component of safety (and benefit) evaluation </li></ul><ul><li>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. </li></ul>Conclusions
    20. 20. Thank You!
    21. 21. Overview of Registries <ul><li>Large, non-experimental cohort studies </li></ul><ul><li>No randomization of treatment </li></ul><ul><li>Minimal or no exclusion criteria in order to capture real-world patients and practices </li></ul><ul><li>Safety endpoints and duration of follow up selected according to disease and product MOA </li></ul><ul><li>Disease-based or product-based registries </li></ul>
    22. 22. ICH risk in Activase-treated Stroke Patients 1 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) 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 (%) CASES N=1100 *** UT N=241 ESIS N=236 STARS N=389

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