Transcript Document

Randomized Clinical Trials in Rheumatology:
Reporting Safety and Outcome Measures
Yusuf Yazıcı, MD
Assistant Professor of Medicine,
NYU School of Medicine
Director, Seligman Center for Advanced Therapeutics
NYU Hospital for Joint Diseases
1
Overview
•
•
•
•
RCT trials are the leading source of data in determining
treatment choices
Good source of efficacy data
Completeness of safety reporting is inadequate
– Methodological concerns
– Reporting selective results
– Errors in reporting
Focus on:
– Time to event
– Standardized incidence ratios (SIR)
– Radiographic data reporting
– Adequate sample size
– False impression of safety
– Disease activity assessment measures
Ioannidis J, Lau J. JAMA 2001;285:437–443.
2
Time to adverse event
3
Time to adverse event
•
•
•
•
Problem in reporting AEs in RCT
Time to event
– Clue to causality
– When to expect AEs in clinical care
Instantaneous risk might be different for drugs, but the
cumulative risk will be similar
‘Average risk’ does not reflect the true risk faced by patients,
especially when decisions are being made at the beginning of
treatment
4
Risk of adverse effects related to drug exposure
Collet JP, Bolvin JF. In: Pharmacoepidemiology, 3rd Edn, Strom BL ed. 2000.
5
TNF inhibitors and lymphomas
•
•
•
•
An increased frequency of lymphomas, tuberculosis and
demyelinating CNS disease has been associated TNF inhibitor
use
SEER database
Based on annual incidence in the population, which is expected
to be evenly distributed
If there is some skewing as to time of malignancies in the
treatment arm, this would make comparisons based on an
annual incidence inaccurate
1. Brown SL, et al. Arthritis Rheum 2002;3151–3158.
2. Yazici Y, Yazici H. Arthritis Rheum 2004; 50: S302
6
TNF inhibitors and lymphomas
•
•
•
TNF inhibitor use and lymphoma development, as reported to
the Federal Drug Administration (FDA)1
Twenty-six lymphomas
– Fourteen occurred within 2 months of use
Non-Hodgkin’s lymphoma (NHL)
– Two-monthly incidence in normal population 3/100,000
– Ten out of 16 occurred in 2 months2
– Two-monthly NHL occurrence in etanercept users
=10/100,000
• Nearly 3-4 times
1. Brown SL, et al. Arthritis Rheum 2002;46:3151–3158; 2. Yazici H. Arthritis Rheum 2003;48:2389.
7
Demyelinating central nervous
system disease
•
•
•
Tumor necrosis factor-α antagonist use and demyelinating
CNS disease
– Nine cases among 77,152 users of etanercept during a
19-month period
– They noted that this frequency was not different from that
found in the general population – 4–6/100,000 per annum
Half of the cases occurred within 4 months of etanercept use
– Four-monthly incidence risk of etanercept use of
5.8/100,000
Four-monthly risk in the general population on the other
hand would be 2.0/100,000, if the upper limit, 6.0/100,000,
quoted for the general population is used
Mohan N, et al. Arthritis Rheum 2001;44:2862–2869.
8
Coccidioidomycosis and TNF inhibitors
•
•
•
Risk of coccidioidomycosis in patients treated with TNF-α
antagonists
Thirteen cases of coccidioidomycosis associated with TNF-α
therapy were reported
Again seven out of 13 cases developed within 2 months of
starting TNF-α therapy
Bergstrom L, et al. Arthritis Rheum 2004;50:1959–1966.
9
Summary of malignancies in randomized
controlled trials
Median: 19 weeks
Bongartz T, et al. JAMA 2006;295:2275–2285.
10
Time to neoplasia
14
Number of neoplasms
12
10
8
6
4
2
0
0–12
13–24
25–36
37–48
49–60
61–72
72+
Weeks
Based on data from Bongartz T, et al. JAMA 2006;295:2275–2285, courtesy of Dr H Yazici
11
Infections
Curtis JR, et al. Arthritis Rheum 2007;56:1125–1133.
12
Infections
•
•
•
•
Hospital medical records with claims database reviewed
– Median follow up of 17 months
Tumor necrosis factor-based treatment compared with
MTX (or other DMARD-based) treatment
Reviewed 187 out of 217 suspected bacterial infections
– TNF-α antagonist =65 in 2393 exposed persons (2.7%)
– DMARD =58 in 2933 exposed persons (2.0%)
– Number needed to harm =143
– Median time from exposure to medication to infection
was <30 days for both groups
– 93% occurred in 90 days
Multivariable adjustment approximately two times in
TNF-α versus MTX
Curtis JR, et al. Arthritis Rheum 2007; 56:1125–1133.
13
Increased early risk
•
•
•
In the first 6 months
– Thirty-two infections in TNF-α cohort
– Nineteen infections in DMARD cohort
Adjusted hazard ratio of infection in the first 6 months after
start of treatment
– TNF-α compared with MTX controls was 4.2 (95%
confidence intervals [CI] 2.0-88.8)
Similar to JAMA paper
Curtis JR, et al. Arthritis Rheum 2007; 56:1125–1133.
14
Surveillance, epidemiology and end-results
database (SEER)
•
If timing of a malignancy is not evenly distributed, we should not be using a yearly rate to
compare incidence rates
–
–
SEER = 12 expected lymphomas in RA patients over 12 months, 1 per month
TNF-α = 12 seen in RCT
•
•
Conclusion is that there is no difference
TNF-α lymphoma
– Eight in the first 4 months = 2/month
– Four in the last 8 months = 0.5/month
•
In the case of lymphoma development
–
–
•
Using annual incidence risk in the general population as a comparator is inappropriate
Development of such lymphomas was within the few months after drug initiation in more
than 50% of these patients1
The expected random occurrence of lymphomas in the general population would make
the real risk look smaller2
15
Tumor necrosis factor, time to AE
•
•
•
•
•
As more than half of these cases occur during the first months of therapy, quarterly
or monthly (rather than annual) incidence risks in the normal population should be
used for comparison
Increased incidence risks for TNF-α antagonist-related adverse events (AEs)
would necessitate a reexamination of the screening protocols and patient selection
criteria used for these therapies
Does not carry the same message for the practicing physician
Variable period comparison needs to be used
– 2-, 3-, 4-, 6-monthly rates
Excluding events in the first 60–180 days
– Not done with other AEs
– No strong evidence base for doing so
16
Time to adverse event reporting in
randomized controlled trials
•
•
All RCT of cyclo-oxygenase-2 (COX-2) inhibitors and
TNF-α inhibitors
– Industry-sponsored RCTs (91%)
– One-third gave time to AE in the report either as a table, text
or Kaplan-Meier curve
– No better reporting for serious adverse event (SAE)
Eight out of 17 RA–TNF-α trials reporting malignancy used
the Surveillance, Epidemiology and End Results (SEER)
database
Yazici Y, Yazici H. Ann Rheum Dis 2007;66:124–127.
17
Time to adverse event and serious
adverse event
COX-2 (26 studies)
TNF-α (44 studies)
Total (70 studies)
Mean
1541
251
-
Median
602
112
-
Range
67–8076
20–1049
-
Mean number of weeks
12
43
-
Median
6
24
-
Range
4–156
2–52
-
n (%)
n (%)
n (%)
AEs (n and % reported)
19 (73)
36 (82)
55 (79)
Table given for AEs
21 (81)
34 (77)
55 (79)
Time to AEs reported (including SAEs)
6 (23)
17 (39)
23 (33)
Time to SAEs reported
3 (12)
16 (36)
19 (27)
Time reported for 50% of SAEs
3 (12)
9 (20)
12 (17)
Time reported for >50% of SAEs
0
0
0
Time reported for all SAEs
0
7 (16)
7 (10)
SIR based on annual SEER figures
0
8 (18)
8 (11)
2 (8)
4 (9)
6 (9)
Number of patients enrolled
Duration of RCT
Patient-years as time frame
Yazici Y, Yazici H. Ann Rheum Dis 2007;66:124–127. COX-2=cyclo-oxygenase-2; TNF-α=tumor necrosis
factor-α; RCT=randomized controlled trial; AE=adverse event; SAE=serious/severe adverse event;
SIR=standardized incidence ratio; SEER=Surveillance, Epidemiology and End-Results.
18
Patient years
19
Patient years
•
•
Commonly used in RCT: ‘patient–years’ to define the time frame
of AE incidence
What is the problem?
– Relatively rare idiosyncratic drug reactions usually occur early in
the treatment course and in only a few individuals
– Apart from the few with AEs, remaining patients who are
prescribed the drug will never get these reactions however long
they use the drug
Paterson KR. BMJ 1995;310:1470.
20
Patient years
•
•
•
•
AE 20% chance in the first month, and not seen after
• 100 patients followed for one year
80% of patients after one year will have no AE
• 20/100 patient years
One more year, no one gets AE
• 20/200 patient years =10/100 patient years
Nothing has changed in the absolute risk when it is started in a
new patient.
21
Patient years (2)
•
•
•
Unduly inflate the denominator of the related incidence ratio;
potential of under-representing AE
– Late-onset AEs are also likely to be missed when we use
patient–years
In short, only “…when an event is (or is believed to be) likely to
occur at any stage during continuous treatment with a drug then
an event rate with a time component (rate per person year, etc)
has a true meaning”
Not clear whether more than one event per patient goes into the
numerator
Paterson KR. BMJ 1995;310:1470.
22
Patient years (3)
•
•
•
If more than one AE/patient is included in a numerator, statistics
done with that incidence ratio will be erroneous
An AE can repeat itself, like skin rashes in TNF-α antagonist use
in any one patient
This leads to over-representation of the said individual in tests of
significance
Paterson KR. BMJ 1995;310:1470.
23
“Statistics are like swimwear – what they reveal is
suggestive but what they conceal is vital.”
–Ashish Mahajan, Lancet 2007
24
Reporting radiographic outcomes
in RA RCTs
25
Conventional wisdom…
Schett et al. Arthritis Rheum 2008
Conventional wisdom…
•
“…studies of anti-TNF therapy plus MTX, compared with the
effect with MTX alone, have shown that although MTX is
relatively effective at relieving clinical symptoms, it has little
or no effect on underlying radiological progression.”
Emery P, McInnes IB, van Vollenhoven R, Kraan MC. Rheumatology (Oxford) 2008
Etanercept versus methotrexate
Klareskog L, et al. Lancet 2004;363:675–681. ACR=American College of Rheumatology;
MTX=methotrexate.
28
Adalimumab versus methotrexate
Breedveld FC, et al. Arthritis Rheum 2006;54:26–37. §p<0.001 vs ADA alone and p=0.022 vs MTX alone;
†p<0.001 vs ADA alone and p=0.002 vs MTX alone; #p=0.043 vs ADA alone; *p<0.001 vs ADA alone and
vs MTX alone; ACR=American College of Rheumatology; ADA=adalimumab; MTX=methotrexate.
29
PREMIER X-ray
Breedveld FC, et al. Arthritis Rheum 2006;54:26–37. MTX=methotrexate.
30
Demographic and study characteristics of four
methotrexate-naïve randomized controlled trials
ERA
TEMPO
IFX early RA
PREMIER
Patients, n
424
682
641
799
TNF arm, n
207
223
NA
274
MTX arm, n
217
228
282
257
Combination arm, n
NA
231
359
268
Double blind duration
12 months
12 months
12 months
12 months
Mean TJC at baseline
31
33
33
31
Mean SJC at baseline
24
23
22
21
Primary efficacy
outcome
ACR-N
(6 months)
ACR-N
(6 months)
ACR-N
(12 months)
ACR 50
(12 months)
Primary radiographic
outcome
Sharp
(12 months)
Sharp
(12 months)
Sharp
(12 months)
Sharp
(12 months)
Yazici Y, Yazici H. Clin Exp Rheumatol 2008;26:449–452.
31
12-month efficacy and radiographic outcomes
in four methotrexate-naïve randomized
controlled studies
Study
ACR 20
ACR 50 ACR 70
ACR N Sharp
NNT
ERA ETA
72
NR*
NR*
NR*
1.00
15
ERA MTX
65
NR*
NR*
NR*
1.59
-
TEMPO combination
85
69
43
18.3
–0.54
12
TEMPO ETA
75
48
24
14.7
0.52
-
TEMPO MTX
76
43
19
12.2
2.8
-
IFX combination
62.4
45.6
32.5
38.9
0.4
13
IFX MTX
53.6
32.1
21.2
26.4
3.7
-
PREMIER combination
73
62
46
NR
1.3
10
PREMIER ADA
54
41
26
NR
3.0
-
PREMIER MTX
63
46
28
NR
5.7
-
Yazici Y, Yazici H. Clin Exp Rheumatol 2008;26:449–452. ACR=American College of Rheumatology,
NNT=number needed to treat; ERA=Early RA; ETA=etanercept; NR=not reported; NR*=values not given,
only depicted in graphic form; MTX=methotrexate; TNF=tumor necrosis factor inhibitor; TEMPO=Trial of
Etanercept and MTX with radiographic Patient Outcomes; IFX=infliximab; ADA=adalimumab.
32
Radiographic outcomes in four methotrexatenaïve randomized controlled trials
6
5.7
Sharp scale
5
4
3.7
3
2.8
3
2
1.59
1.3
1
1
0.52
0.4
–0.54
0
ERA ETA
ERA MTX
TEMPO
TEMPO
TEMPO
ETA+MTX
ETA
MTX
ASPIRE
IFX+MTX
ASPIRE
MTX
PREMIER
ADA+MTX
PREMIER
ADA
PREMIER
MTX
Sharp score
Yazici Y, Yazici H. Clin Exp Rheumatol 2008;26:449–452.
33
Radiographic outcomes in four methotrexatenaïve randomized controlled trials
450
400
350
Sharp scale
300
250
200
150
100
50
1
1.59
–0.54
0.52
2.8
ERA ETA
ERA MTX
TEMPO
TEMPO
TEMPO
ETA+MTX
ETA
MTX
0.4
3.7
1.3
3
5.7
0
ASPIRE
IFX+MTX
ASPIRE
MTX
PREMIER
ADA+MTX
PREMIER
ADA
PREMIER
MTX
Sharp score
Yazici Y, Yazici H. Clin Exp Rheumatol 2008;26:449–452.
34
•
1.3 (PREMIER combo) vs 5.7 (PREMIER MTX alone)
•
•
•
1.3/448=0.003
5.7/448=0.01
0.01-0.003=0.007
•
Similar to saying pain score of 49.8 (combo) vs 49.1 (alone)
is clinically significant and should lead to treatment
change/preference
Abatacept: limited inhibition of radiographic
progression – mean change in total Sharp
scores (Genant modification)
4
Placebo + MTX (n=195)
Mean change
from baseline
3
Abatacept 10 mg/kg + MTX (n=391)
2.3
50%
inhibition
2
1
*
1.2
0
-1
0
6
Months
12
Mean change from baseline at Month 12
Treatment
Erosion score
JSN score
Total Sharp score
Placebo + MTX
1.14
1.18
2.32
Abatacept + MTX
0.63*
0.58†
1.21*
Kremer J, et al. Ann Intern Med 2006;144:865–876; Genant H, et al. Ann Rheum Dis 2005;64(Suppl III):56.
Abstract OP001. *p<0.05 vs placebo + MTX; †p<0.01 vs placebo + MTX. MTX=methotraxate; JSN=joint
space narrowing.
36
Change in total Sharp score
A new way of assessing radiographic
outcomes: cumulative probability plots
40
30
Increasing score
20
10
Unchanged
0
Decreasing score
–10
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Cumulative probability
Landewe R, van der Heijde D. Arthritis Rheum 2004;50:699–706.
37
Probability curves
38
BeSt study: design
Group 2
Step-up
Combo
Group 1
Sequential
Mono
n=126
n=121
Group 3
Initial
Combo
n=133
Group 4
IFX
+ MTX
n=128
MTX 15 mg
MTX 15 mg
MTX 7.5 mg/wk + SSA +
pred 607.5 mg/day
MTX 25 mg +
IFX 3 mg/kg
n=120
MTX 25 mg
MTX 25 mg
MTX 25 mg + SSA + pred
SSA
MTX + SSA
MTX + CsA + pred
MTX + IFX 10 mg/kg
Leflunomide
MTX + SSA + HCQ
MTX + IFX
n=25
SSA
MTX + IFX
n=49
MTX + SSA + HCQ + pred
Leflunomide
Leflunomide
Gold
MTX + IFX
n=12
MTX + CSA + pred
MTX + CsA + pred
AZA + pred
Leflunomide
MTX + CSA + pred
Gold
Gold
AZA + pred
AZA + pred
Gold
Goekoop-Ruiterman YP, et al. Arthritis Rheum 2005;52:3381–90.
39
BeSt study
Goekoop-Ruiterman YP, et al. Ann Intern Med 2007;146:406–15.
40
TICORA: intensive versus routine control
of disease activity in rheumatoid arthritis
•
•
•
Objective:
– 18-month study to determine whether closely monitored
step-up therapy with non-biologic DMARDs would result in
significantly better outcomes than routine care
Study population:
– 110 patients aged 18–75 years with RA of <5 years’ duration
and active disease (Disease activity score [DAS] >2.4)
Outcomes:
– Primary:
• % of patients achieving a DAS score of <2.4
– Secondary:
• % of patients achieving remission (DAS score <1.6)
• % of patients achieving American College of Rheumatology–
20, 50 and 70 responses
Grigor C, et al. Lancet 2004;364:263–269. TICORA=Tight Control of Rheumatoid Arthritis.
41
TICORA: intensive versus routine control of
disease activity in rheumatoid arthritis (2)
•
•
Intensive care group:
– Monthly review of disease activity and measurement of DAS
– Intra-articular corticosteroid injection of swollen joints as required
– Intramuscular corticosteroid injection given as ‘bridge therapy’
during first 3 months of a new DMARD
– Structured escalation of therapy if DAS >2.4 after 3 months of a
new DMARD:
SSZ  MTX + SSZ + HCQ  MTX (up to 25 mg/wk); SSZ (up to 5 g/d)
 prednisolone 7.5 mg/d  switch to MTX + CSA  switch to leflunomide
Routine care group:
– Review every 3 months (with no measure of DAS)
– Management at the discretion of attending rheumatologist
(i.e. DMARD therapy; intra-articular, intramuscular and/or oral
corticosteroids)
Grigor C, et al. Lancet 2004;364:263–269. TICORA=Tight Control of Rheumatoid Arthritis.
42
Tight control for rheumatoid arthritis:
TICORA study
43
Tight control for rheumatoid arthritis:
TICORA study (2)
Number of patients responding at 18-month assessment
Intensive group Routine group
(n=55)
(n=55)
Odds ratio
(95% CI)
p*
EULAR good
response
45 (82%)
24 (44%)
5.8 (2.4–13.9)
<0.0001
EULAR
remission
36 (65%)
9 (16%)
9.7 (3.9–23.9)
<0.0001
ACR 20
response
50 (91%)
35 (64%)
5.7 (1.9–16.7)
<0.0001
ACR 50
response
46 (84%)
22 (40%)
6.1 (2.5–14.9)
<0.0001
ACR 70
response
39 (71%)
10 (18%)
11 (4.5–27)
<0.0001
Grigor, et al. Lancet 2004;364:263–269. *Mantel-Haenszel procedure used. EULAR=European Union
League Against Rheumatism; ACR=American College of Rheumatology.
44
TICORA 2
• 96 RA patients, with <1 yr of disease
• No previous DMARDs (except HCQ)
• DAS28 every month, treatment adjusted
•
•
•
– IA as needed
Primary outcome was DAS28
– Blinded assessment
85% had erosions at baseline
DAS28 6.9
Saunders SA et al. Arthritis Rheum 2008;58:1310-17
45
TICORA 2
46
TICORA 2
47
TICORA 2
48
‘Efficacy versus safety
versus efficacy and safety trials’
49
‘Efficacy and safety’ randomized
controlled trials
•
•
•
•
Trend of increasing number of RCT called ‘efficacy and
safety’ trials
All RCT of TNF-α inhibitors in RA, psoriatic arthritis (PsA)
and ankylosing spondylitis (AS)
Only original reports
– ‘Efficacy’, ‘safety’ or ‘efficacy and safety’
– Power for safety and efficacy
– Type II error
Power
– Alpha
– Beta
– Expected treatment effects in both arms
Yazici Y, et al. Rheumatology 2008;47:1054–1057.
50
Powering for safety analysis
•
Twenty-four out of 34 (71%) so-called ‘efficacy and safety’
trials
– Five called such in the title
•
Of these 24 so-called ‘efficacy and safety’ trials, only 1 gave
safety as a primary or secondary end point
•
•
Only one study, labeled safety gave it as an endpoint
No power calculations in 22/24 to look at AE in “efficacy and
safety” studies
– Only 3/22 had “type II error” discussion
51
‘Efficacy’, ‘safety’ and ‘efficacy and safety’
TNF-α RCT
15%
26%
Efficacy - 9
Safety - 1
3%
Efficacy and Safety - 19
Efficacy and Safety in title - 5
56%
TNF-α=tumor necrosis factor inhibitor-α; RCT=randomized controlled trial.
52
Powering for safety analysis (2)
•
11 gave statistics for SAE
– 2/11 had power calculations
– 2/11 showed statistically significant differences
– Of the remaining 9, only 2 discussed type II error
•
24 articles gave partial statistics for AE
•
18/24 (75%) no type II discussion
•
•
6 out of 34 (18%) did not give any power or sample size
calculation for efficacy
19/28 (68%) with power information gave all 3 components
53
Before and after 2004
Safety/safety and efficacy
Efficacy
25
20
4
15
10
5
16
5
8
0
Before 2004
After 2004
54
‘Efficacy and safety’
•
•
•
•
Designating RCT as ‘safety’ as well as ‘efficacy’ has the potential
to give false impressions that lack of AE increase is evidence of
overall safety of the medication tested
Only one of these trials was powered to look at safety
In addition, RCT are highly selective for lack of major
comorbidities
– So even if they were powered to look at safety, results need to
be interpreted with caution
– Phase IV trials
Randomized controlled trials report on AEs, but these efficacy
trials cannot provide any conclusive evidence about safety;
these shortcomings should be reported and required by journals
and reviewers
55
Disease activity measurement in RA
56
Pincus et al. Arthritis Rheum 2003
Patient–reported outcomes
Strand et al, Rheumatology 2004
Conclusions
•
•
Time to adverse effect
• Causation
• What to expect for the clinician
Patient years
• Falsely give sense of experience
• Rare adverse effects hard to analyze
•
SEER
•
Radiographic data not as important as clinical response
•
Randomized controlled trials provide information about efficacy and not
safety. They report on AEs that happen during a defined time in a small,
selected population
59
“We become confident in our educated guesswork to
the point where it is easy to confuse personal opinion
with evidence, or personal ignorance with scientific
uncertainty”
–David Naylor, MD, PhD (1954–)
60
Esra & Leyla