S C Q M

Collaborative effectiveness studies for rares exposures Axel Finckh Div. of Rheumatology & Epidemiology University of Geneva

Outline 1. Rare exposures & cohort studies 2. Practical examples of collaborative registry studies  Pan-EU Abatacept analysis  Impact of obesity

DAG

2

Schematic diagram of concurrent, retrospective, and ambidirectional cohort studies

David A Grimes , Kenneth F Schulz. Cohort studies: marching towards outcomes. The Lancet Volume 359, Issue 9303 2002 341 - 345

Cohort Studies - prospective Advantages:  Exposure is measured before disease onset ((unbiased )  Rare exposures can be examined  Multiple outcomes can be studied for one exposure  Incidence of disease can be measured (calculate RR) Disadvantages: Di d t  Choosing appropriate controls is often difficult  Changes over time in exposure status  Classification of disease may be influenced by exposure  Losses to follow-up (differential) may introduce serious bias Elwood M. 3rd Ed Oxford University Press; Oxford: 2007. pp. 1–570

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David Neto, Axel Finckh, Florenzo Iannone, Estíbaliz Loza, Elisabeth Lie, Piet L.C. Van Riel, Merete L. Hetland, Karel Pavelka, Jacques-Eric Gottenberg Helena Canhão Gottenberg, Canhão, Xavier Mariette and Carl Turesson

Abstract N° 2910

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

Supported by an unrestricted research grant by BristolBristol Myers Squibb I di id l investigators: Individual i ti t           

DN: none AF : Abbvie, Abbvie BMS, BMS Pfizer, Pfizer Roche FI: BMS, Pfizer, Abbvie, UCB, Merck, Roche, Actelion E. Loza: Roche E. Lie: BMS, Pfizer, Abbvie, Roche KP: AbbVie, BMS, MSD, Pfizer, Roche PLC VR: None MLH: Roche, MSD, Pfizer JEG: Abbvie, BMS, MSD, Pfizer, Roche XM Pfi h BMD XM: Pfizer, R Roche, BMD, GSK GSK, LFB CT: Abbvie, BMS, Janssen, MSD, Pfizer, Roche, UCB

? Are there differences among pts initiating Abatacept (ABA) across Europe

? What is the impact of these differences on drug effectiveness

 Analyze A l potential t ti l h heterogeneity t it iin pts t iinitiating iti ti ABA across different European countries and th iimpactt off the th heterogeneity h t it on overallll d the drug retention

NORDMARD DANBIO





 

ARTIS

9 RA european registries: i i ARTIS, ATTRA, BIOBADASER, DANBIO GISEA, DANBIO, GISEA NORDMARD NORDMARD, ORA Reuma.PT ORA, SCQM, Reuma.PT Inclusion l criteria were: - Diagnosis of RA - Initiation I iti ti off ABA treatment t t t

SCQM BIOBADASER

GISEA

Primary endpoint: drug retention of ABA / registry ABA drug retention was analyzed using KaplanMeier curves and multivariate Cox regressions g adjusting for potential confounders

Results: Study population Registers

♦

Combined (3834 PTS)

F‐U 

[pt-yrs [p y ]

F‐U /pt ° Male  [pt-yrs [p y ]

%

Age  [[Yrs]]

RF  %

Anti‐ CCP

Dis  Durat. 

HAQ

%

[Yr]

DAS28 Smoker

BMI

CRP 

ESR

%

[[kg/m2] g ]

[[mg/L] g ]

[[mm/h]]

N° past N° past c‐DMARDs° Biologics°

5421

0.9 [0.4-2.2]

18.9

57.1 ±13.1

74.0

67.7

11.3 ±8.1

1.3 ±0.6

5.0 ±1.3

23.1

25.9 ±5.2

23.5 ±35.6

33.0 ±24.8

2 [1-4]

2 [1-3]

NOR‐DMARD  (52 PTS)

50

0.6 [0.3-1.0]

11.5

51.3 ±12.5

59.6

48.9

14.8 ±9.7

0.9 ±0.5

5.4 ±1.1

23.1

24.0 ±4.1

24.2 ±34.2

36.4 ±28.1

3 [2-4]

2 [2-3]

SCQM (506 PTS)

333

0.3 [[0.1-0.9]]

21.7

57.1 ±13.1

71.6

63.2

9.9 ±8.7

1.1 ±0.5

4.2 ±1.0

24

25.9 ±5.1

13.9 ±16.3

25.9 ±20.3

1 [[0-2]]

1 [[0-2]]

ATTRA (215 PTS)

341

1.2 [0.5-2.6]

20.9

50.1 ±12.5

70.1

74.7

11.2 ±7.7

1.5 ±0.5

5.7 ±1.1

22.9

25.5 ±4.9

25.7 ±29.3

38.3 ±24.3

4 [2-5]

_

GISEA ((375 PTS))

4760

1.0 [0.4-2.0]

13.3

56.5 ±12.5

73.6

81.7

10.6 ±8.4

1.4 ±0.8

5.0 ±1.2

22.3

25.8 ±5.0

39.0 ±66.0

34.4 ±23.4

1 [1-2]

ORA (1032 PTS)

1750

1.3 [0.5-2.8]

20.9

58.1 ±13.6

71.3

69.8

13.6 ±9.4

1.2 ±0.7

5.3 ±1.2

_

_

25.0 ±33.0

35.6 ±27.7

2 [2-3] 3 [2-4]

ARTIS (1019 PTS)

1531

1.0 [0.5-2.1]

20.7

58.6 ±12.4

_

_

9.6 ±3.9

1.3 ±0.7

5.1 ±1.3

57.5

24.8 ±1.5

19.6 ±26.5

30.4 ±23.0

1 [1-2]

2 [1-3]

DANBIO (315 PTS)

411

0.7 [[0.3-2.0]]

19

56.0 ±12.5

84.3

59.3

11.4 ±9.6

1.4 ±0.7

4.9 ±1.2

63.5

26.3 ±5.6

18.3 ±26.2

_

4 [[3-6]]

1 [[1-2]]

BIOBADASER (283 PTS) *

484

1.4 [0.6-2.5]

18.4

56.6 ±13.1

83.7

60

12.1 ±8.4

1.7 ±0.7

5.1 ±1.6

13.6

_

18.1 ±26.0

33.6 ±27.7

_

2 [1-3]

Reuma.PT ((37PTS))

45

1.1 [1.4-1.5]

13.5

59.0 ±14.1

57.1

51.6

12.3 ±8.3

1.6 ±0.7

5.5 ±1.6

23.5

27.2 ±5.7

15.4 ±15.4

40.6 ±24.8

1 [1-3]

2 [1-3]

2 [1-3]

Legend Table: ♦ Variables are expressed in means and Standard Deviation, if not indicated otherwise. # Modified HAQ (MHAQ) instead of HAQ. ° Medians [Interquartile Ranges] *The 40 patients from LOCALREG (Spain) registry were aggregated within BIOBADASER

Results: Crude drug retention per country Survival Estimate / register 1.0

ARTIS ATTRA BIOBADASER DANBIO GISEA NORDMARDS ORA REUMAPT SCQM

Fre eedom from Event

0.8

logRank test: P5 [3.7 – . ]

0.57 0.56 [0.44 ‐ 0.70] [0.46 ‐ 0.72]

33

0.9 [0.5 – 2.0]

1.68 1.89 [1.30 – 2.75] [1.16 – 2.44]

628

1.7 [1.5 – 1.9]

1.07 1.13 [1.0 1– 1.28] [0.93 – 1.23]

19

1.3 [1.0 – .]

09 0.97 1.22 [0.77 – 1.93] [0.56 – 1.67]

234

0.9 [0 8 – 1.1] [0.8 1 1]

2.12 2.01 [1.79 79 – 2.51] 2 51] [1 73 – 2.35] [1.73 2 35] [1

* HR > 1 means higher discontinuation °Multivariate adjustments for demographic variables (age, gender), disease characteristics (RF, DAS28 at baseline, Disease duration) and treatment characteristics (N° of prior biologic failures, calendar year of treatment initiation, ABA approval in BIO naïve patients)

Results: Adjusted drug retention per country Adjusted Survival estimates 1.0

ARTIS ATTRA BIOBADASER DANBIO GISEA NORDMARDS ORA REUMAPT SCQM

Frreedom from E Event

0.8

0.6

50% 0.4

0.2

0.0 0

1

2

3

Years since the 1st ABA administration

4

5

Results: Adjusted drug retention per country Adjusted Survival estimates 1.0

ARTIS ATTRA BIOBADASER DANBIO GISEA NORDMARDS ORA REUMAPT SCQM

GDP per capita (€) 2011 rank : Norway (~44000Euros) Switzerland ((~35000Euros)) 0.8 Danmark (~32000Euros) Sweden (~32000Euros) France (~25000Euros) Italy(~25000Euros) 0.6 Spain (~24000Euros) Czech Rep (~20000Euros) Portugal (~19000Euros) Frreedom from E Event

1. 2. 3. 4. 5. 6. 7 7. 8. 9.

50%

0.4

GDP (> 30’000): 1.43 (1.29 - 1.58)

0.2

0.0 0

1

2

3

Years since the 1st ABA administration

4

5

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



Patient characteristics at ABA initiation varied across European countries, probably reflecting differences in eligibility g y criteria and prescription patterns Large differences in ABA drug retention retention, with a trend to shorter ABA maintenance in countries with relatively liberal access to biologics National differences need to be accounted for h analyzing l l dd when pooled data ffrom severall national registries

• •

Objective: To analyze the impact of obesity on RA disease activity in patients initiating their 1st biologic agent Exposure Variable: WHO BMI categories:

 BMI ≥ 18.5, 8 5, < 25: 5  BMI ≥ 25, < 30:  BMI ≥ 30, 30 < 35:  BMI ≥ 35:

“normal o a weight” eg “overweight” “obese obese class I” I “obese class II”

European Congress of Rheumatology EULAR 2013 in Madrid, Abstract FRI0099

Swiss cohort BMI 35 (N=818) (N=318) (N=106)

55 (43 – 63)

58 (49 – 66)

58 (49 – 65)

55 (49 – 60)

% Female

83

67

70

84

% RF+

77

75

64

76

% Anti-CCP

66

65

55

60

% Steroids

53

55

58

56

% DMARDs

81

81

84

81

age

US cohort US cohort BMI 18.5-25 18 5-25 (CORRONA) (N=1113) age % Female % RF+ RF % anti-CCP+ % Steroid % DMARDs

57 83 75 71 35 79

BMI 25-30 (N=1334)

BMI 30-35 (N=799)

BMI≥35 (N=797)

58 71 77 71 35 80

57 73 75 65 33 80

55 85 71 65 31 81

Association of BMI with DAS28 remission at 12 Mo follow-up 1

OR

0.8

0.6

0.4

Response rates were adjusted for potential confounders using logistic regression. CORRONA and SCQM were analyzed independently with similar models and results compared.

Conclusions •

Data from ttwo o different pop populations lations indicate that obesity is a risk factor for inferior response to biologic agents t and d shorter h t drug d retention t ti in i patients ti t with ith longstanding RA

•

It is uncertain whether this is explained by suboptimal dosing of these therapies in obese patients or by a true biologic effect of adipose tissue 20

Collaborative (effectiveness) studies for rares exposures p •

Large g collaborative studies are well suited to studyy rare exposures p

•

Large collaborative studies may allow examining multiple potential effects of a single exposure and testing of multiple hypotheses

•

BUT, the possibility of bias relating to multiple comparisons means that analyses and results should be hypothesis driven and biologically plausible

21

Thank you !!!

http://upload.wikimedia.org/wikipedia/commons/e/e6/Views_of_Geneva.jpg

Results: Crude drug retention by stop reasons Kaplan Meier Analysis 1.0

Overall Ineffectiveness Adverse Events Other Reason or Remission

Freedom from Event F

0.8

0.6

50% 0.4

MST = 1.75yrs [1.61-1.91]

0.2

Total Patients at Risk

0.0

3819

0

1827

1057

562

236

66

1

2

3

4

5

Years After first Admin

14

6

Assumption: Countries with high income => easy access to Bio (+ refunded by health insurance) => frequent switch?

HR

robust se

lower .95

upper .95

P.VALUE 

AgeBaseline g

0.996

0.002

0.993

1.000

0.051

Gender (F)

1.006

0.061

0.892

1.134

0.922

GDP_group (2)*

1.428

0.051

1.291

1.579