Observational registries applications in safety evaluation
Download
1 / 22

Observational Registries: Applications in Safety Evaluation - PowerPoint PPT Presentation


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. . Acknowledgements.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha

Download Presentationdownload

Observational Registries: Applications in Safety Evaluation

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


Observational registries applications in safety evaluation l.jpg

Observational Registries:Applications 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.


Acknowledgements l.jpg

Acknowledgements

  • Patients, physicians and others participating in the studies

  • Investigators at Genentech and many other institutions


Today s objectives l.jpg

Today’s Objectives

  • Overview of registries

    • Opportunities and challenges

  • Examples of safety evaluations using registries @ Genentech


Registries vs rct generalizability l.jpg

Older, multiple

comorbid diseases

Younger, multiple

comorbid diseases

Older, otherwise

healthy

Younger, otherwise

healthy

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)


Registries vs rct scope of study l.jpg

Registries vs. RCT: Scope of Study

Less

Amount of data collected

More

years

1,000s-10,000s

# of patients enrolled

Duration of follow-up

months

10s-100s


Two types of registries l.jpg

Two Types of Registries


Registries at genentech l.jpg

Registries at Genentech


Nrmi national register of myocardial infarction l.jpg

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


Nrmi intracranial hemorrhage ich l.jpg

NRMI: Intracranial Hemorrhage (ICH)

  • 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]

  • Gore JM. Stroke after thrombolysis. Mortality and functional outcomes in the GUSTO-1 trial. Circulation 1995;92:2811-8.


Stroke studies ich risk and tpa l.jpg

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


Incidence of symptomatic ich among alteplase treated stroke patients 1 l.jpg

Incidence Of Symptomatic ICH Among Alteplase-Treated Stroke Patients1

NINDS

% of patients

  • Dong W et al.Safety Outcomes of Alteplase in Ischemic Stroke Patients with Special Characteristics. International Stroke Conference 2005.


Ncgs national cooperative growth study l.jpg

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

  • Allen D, et al. Risk of leukemia in children treated with human growth hormone: Review and analysis. J Pediatr 1997;131:S32-6.


Ncgs leukemia l.jpg

NCGS: Leukemia

Leukemia risk among patients with no risk factors

by “person-time at risk” vs. “person-time on therapy”

  • 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]


Brite bevacizumab regimens investigation of treatment effects and safety l.jpg

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


Brite gi perforation l.jpg

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


Excels epidemiologic study of xolair omalizumab in patients with moderate to severe asthma l.jpg

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)


Excels approaches to minimizing biases l.jpg

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


Discussion l.jpg

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


Slide19 l.jpg

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.


Slide20 l.jpg

Thank You!


Overview of registries l.jpg

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


Ich risk in activase treated stroke patients 1 l.jpg

ICH risk in Activase-treated Stroke Patients1

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.


ad
  • Login