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.

Acknowledgements

• Patients, physicians and others participating in the studies

• Investigators at Genentech and many other institutions

Today’s Objectives

• Overview of registries– Opportunities and challenges

• Examples of safety evaluations using registries @ Genentech

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

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

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

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)

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)

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.

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 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.

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.

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]

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

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

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

• 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

• 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

• 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

Thank You!

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 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)