collaborative safety studies for rare outcomes
Post on 23-Nov-2021
2 Views
Preview:
TRANSCRIPT
Collaborative safety studies for rare
outcomes
1. EULAR Registers and Observational Drug
Studies Meeting
Prag, 14.-15. November 2013
Joachim Listing
Programmbereich Epidemiologie
Deutsches Rheuma-Forschungszentrum Berlin
Outline
Focus on rare life-threatening SAEs
with an incidence rate: ≤1/1000 patient-years
General remarks
Two examples
Invasive malignant melanomas
lymphoma
Power calculation: Aim: Detection of an increase in
the hazard ratio with a power of 80%
25
45
65
85
105
125
145
165
185
1.75 2 2.5 3
RCT
Obs. cohort study
Obst. cohort studyunequal group sizes
Hazard ratio
Number of SAEs which are
required to observe Assumption: SAE rate group A: 0.5 /1000 pyrs
group B: 1.0/ 1000 pyrs
Sample size: 60,000 pyrs per group
DREAM RABBIT
SCQM
MONITOR-NET
RATIO AIR ORA REGATE
HBR GISEA
ARTIS NOR-DMARD
BSRBR
DANBIO
ATTRA
BIOBADASER
Even big registers:
Low power to detect an
increase in the incidence of
rare events
European biologics register
RHEUMA-PT
How should we start with the collaboration?
Discussion of general procedures
Collaborative analysis of one or two important
research questions
How should we start with the collaboration?
Discussion of general procedures
There are recommendations/points to consider
Collaborative analysis of one or two important
research questions
Dixon W et al.
Collaborative safety studies
Comparison of the incidence of invasive malignant
melanoma between biologics naϊve and biologics
exposed RA patients
Investigation of the lymphoma risk in RA patients not
exposed to biologics, exposed to anti-TNFs, or
exposed to non-anti-TNF biologics
Reasons for project 1
Invasive malignant melanoma is a rare life-threatening
malignancy
signals from observational studies of an increased risk
in patients treated with TNF inhibitors
biologically plausible that biologics, and in particular
TNF inhibitors, will increase the risk of melanoma
Possible to restrict the attention to a small number of
confounders
Age
Sex
(sun shine exposure)
Association between biologic treatment and
inicidence of melanona
N
(population)
N of
cases
Odds ratio
Biologics naive 1866 9 Referent
ETA,INF, ADA, or anakinra
exposed
1394 23 2.3 [0.9-5.4]
Total 3260 32
Wolfe F, Michaud K. Biologic treatment of rheumatoid arthritis and the risk of
malignancy. Arthr. Rheum 2007, 2886- 94
Increased inicidence of invasive melanoma
PYRS N of
cases
Incidence
/10,000 pyrs
Hazard ratio
P. Raaschou et al
Biologics naive 203,345 113 5.6 Referent
TNF exposed 57,223 38 6.6 1.5 [1.0-2.2]
L. Dreyer et al.
Biologics naive 9,219 3 3.3 Referent
TNF exposed 15,592 6 3.8 1.5 [0.4-6.3]
P. Raaschou et al. Rheumatoid arthritis, anti-tumour necrosis factor therapy, and
risk of malignant melanoma. BMJ 2013 , 1939
L. Dreyer et al. Incidences of overall and site specific cancers in TNFalpha inhibitor
treated patients with rheumatoid arthritis and other arthritides ARD 2013;79-82
Melanoma risk in biologics naïve RA patients
Studies with n>
5 cases
Country N (popul.) N (cases) SIR [95% CI]
Gridley 1993 Sweden 11683 12 0.9 [0.5-1.6]
Mellemkjaer
1996
Denmark 20699 37 1.1 [0.8 – 1.5]
Thomas 2000 Scotland 7080 26 (f) 1.2 [0.8 – 1.8] (f)
Askling 2005 Sweden 3703 124 1.2 [1.0-1.4]
53056 0.9 [0.2 – 2.2]
Buchbinder 2006 Australia 458 7 3.0 [1.2 – 6.2]
Hellgren 2010 Sweden 6745 11 RR: 1.0 [0.5-2.0]
Mercer 2013 UK 3771 9 2.1 [0.9 – 3.9]
Raaschou 2013 Sweden 42198 113 HR:1.2[0.9-1.5]
Perkins Meta-anal. 1,351,061 pyrs 601 1.0 [0.9 – 1.1]
Melanoma risk in biologics naïve RA patients
Studies with n>
5 cases
Country N (popul.) N (cases) SIR [95% CI]
Gridley 1993 Sweden 11683 12 0.9 [0.5-1.6]
Mellemkjaer
1996
Denmark 20699 37 1.1 [0.8 – 1.5]
Thomas 2000 Scotland 7080 26 (f) 1.2 [0.8 – 1.8] (f)
Askling 2005 Sweden 3703 124 1.2 [1.0-1.4]
53056 0.9 [0.2 – 2.2]
Buchbinder 2006 Australia 458 7 3.0 [1.2 – 6.2]
Hellgren 2010 Sweden 6745 11 RR: 1.0 [0.5-2.0]
Mercer 2013 UK 3771 9 2.1 [0.9 – 3.9]
Raaschou 2013 Sweden 42198 113 HR:1.2[0.9-1.5]
Perkins Meta-anal. 1,351,061 pyrs 601 1.0 [0.9 – 1.1]
Proposal for an EULAR collaborative project
Comparison of the melanoma incidence between
biologics naϊve
anti-TNF exposed
Rituximab (abatacept?) exposed RA patients
Primary outcome: standardized incidence rates (SIRs)
with the general population as reference
Proposal for an EULAR collaborative project
Comparison of the melanoma incidence between
biologics naϊve
anti-TNF exposed
Rituximab (abatacept?) exposed RA patients
Primary outcome: standardized incidence rates (SIRs)
with the general population as reference
Simple project??
Trends in the melanoma incidence per 100,000
(age standardized, world age population)
Erdmann, Friederike, et al. "International trends in the incidence of malignant
melanoma 1953–2008—are recent generations at higher or lower risk?."
International Journal of Cancer 132.2 (2013): 385-400.
Incidence of malignant melanoma in the general
population
Clear dependence on age and sex
Increasing incidence
Stronger trends in older subjects
Differences between the countries not explained by
sunshine exposure
Incidence of malignant melanoma in the general
population
Clear dependence on age and sex
Increasing incidence
Stronger trends in older subjects
Differences between the countries not explained by
sunshine exposure
Pooling of the data is not possible
Country-specific analyses need to be performed
Further steps
Working group meeting Friday 4 pm
Chairs: Louise Mercer, Joachim Listing
Determination of study procedures
Case definition
Exposure definition
Statistical analysis
Timelines, co-authorship
Lymphomas in Swedish RA patients
Comparison of 6,604 RA pts. exposed to biologics (ARTIS)
67,743 RA pts. from RA register
471,024 persons from the general population
Cross-linkage with cancer and cause-of-death register.
26 incident lymphomas in ARTIS = 96/100.000 person-years
0 1 2 3 4
vs. General
population
vs. biologics
naive RA
population
2.72 (1.82 – 4.08)
1.35 (0.82 – 2.11)
Relative risk for lymphoma
in anti-TNF treated RA
patients Askling et al., Ann Rheum
Dis 2009;68(5):648-53
Anti- TNF
Lymphomas in Swedish RA patients
Relative Risk for lymphoma in Swedish patients with RA,
by year of anti-TNF treatment start
0
0,5
1
1,5
2
2,5
3
3,5
1999-2001 2002-2003 2004-2006
Askling et al., Ann Rheum Dis 2009;68(5):648-53
Association between disease activity and incidence
of lymphoma
E. Baecklund et al. Arthr. Rheum. 2006, p. 692-701
Lymphoma risk in RA
Major concern: TNF inhibitors increase the lymphoma
risk
J. Askling et al., F. Wolfe et al: No clear signal
Meta-analysis of RCTs:
odds ratio (TNF vs. controls): 2.1 [0.6 – 8.4]
(only 10 RCTs contribute to this result!)
Still a need to re-evaluate this risk
Wolfe F, Michaud K. Arthr Rheum (2007) 2886-95.
Askling J et al. AnnRheumDis (2009) 648-53
Lopez-Olivo et al. JAMA (2012) 898-908
Open questions
Do we still have cases with persistently highly active
disease?
How should we deal with changing treatments in
these cases?
How should we deal with confounding by indication in
general?
Which risk factors need to be considered?
Which type of analysis should we perform?
Risk factors to be considered
Age, sex
activity of RA
Immunosuppressive treatment?
(specific infections e.g.hepatitis viruses (HBV, HCV))
(herbicides, pesticides, dioxin,…)
(x-ray, radiation)
Which type of analysis should be applied?
Calculation of SIRs?
Provides additional information
Cave: confounding by indication
Cox or Poisson regression
Nested case control studies
Pooling data and performing a Cox regression?
Only confounders assessed equally can be used
DAS28(ESR), DAS28(CRP), CDAI are not exchangable
Exclusion of patients with missing data
Impact of factors on treatment decisions likely
different in different countries
E.g. the impact of the number of nbDMARD failures
Adjustment for confounding by indication by PS
methods not possible
Contrast between high precision (narrow confidence
limits) of the results and a large portion of
uncontrolled confounding
Which type of analysis should be applied?
Calculation of SIRs?
Provides additional information
Cave: channeling bias
Cox or Poisson regression
No pooling of data
Disadvantage: Exclusion of registers with low
numbers of lymphoma in the case of register
specific analyses
Nested case control studies
Proposal to investige the risk of developing
malignant lymphomas in RA exposed to biologics
Performing nested case control studies
Agreement on factors which will be used to match
cases who developed a lymphoma with controls who
did not
Register specific matching factors are allowed
„Fuzzy overlap“ of these matching factors accross
registers is needed
Further steps
Working group meeting Friday 4 pm
Determination of study procedures
Case definition
Exposure definition
Statistical analysis
Timelines, co-authorship
top related