Download Sequential Parallel Comparison Design for Trials with High Placebo

Sequential Parallel Comparison Design
for Trials with High Placebo Response
Anastasia Ivanova
Department of Biostatistics UNC at Chapel Hill
[email protected]
Placebo response
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Increased placebo response over time
Data from 86 major depressive disorder trials submitted
to FDA during 1986 to 2008 (Khin et al., 2011)
+ US trials
- Non US trials
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Diminished treatment effect over time
.
+ US trials
- Non US trials
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Rising placebo response RCTs and failed trials
Undurraga and Baldessarini 2012
Placebo response
• In many studies in depression and schizophrenia
considered by FDA over 12 year period, 1987 through
1999, in which investigational drug could not be
distinguished from placebo also included an active
standard drug that could not be distinguish from
placebo (Laughren, 2001).
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Placebo response
Yellow pills
make the most effective antidepressants, like little
doses of pharmaceutical sunshine
Red pills
can give you a more stimulating kick
More is better
Placebos taken four times a day deliver greater
relief than those taken twice daily.
More $ is better
Waber, RL, Shiv, B, Carmon, Z, Ariely, D (2008). Commercial
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features of placebo and therapeutic efficacy. JAMA 299: 1016-1017.
Partial List of Illnesses Cited as Having Significant Placebo Responses
Organized by FDA Center for Drug Evaluation and Research Review Divisions
Anesthesia, Analgesic and
Rheumatology
– Arthritis
– Pain
– Psoriatic arthritis
– Rheumatic diseases
Anti-viral
– Herpes simplex
Cardiovascular and Renal
– Heart failure, congestive
– Hypertension
Ear, Nose and Throat
– Tinnitus
Gastroenterology
– Crohn’s disease
– Dyspepsia and gastric
motility
– Gastric and duodenal
ulcers
– GERD
– Irritable bowel syndrome
Gastroenterology (cont.)
– Nausea
– Obesity
– Reflux esophagitis
– Ulcerative colitis
Neurology
– Alzheimer’s Disease
– Autism
– Epilepsy
– Headache
– Migraine
– Multiple Sclerosis
– Parkinson’s disease
– Restless leg syndrome
Psychiatry
– ADHD
– Anxiety disorders
– Binge eating disorder
– Bipolar mania
Psychiatry (cont.)
– Chronic Fatigue syndrome
– Depression
– Insomnia
– Panic disorders
– Schizophrenia
– Social Phobia
Pulmonary and Allergy
– Allergies
– Asthma
– Cough
– Cystic Fibrosis
– Food allergy
Reproductive and Urologic
– Benign prostatic
enlargement
– Erectile dysfunction
– Premenstrual dysphoric
disorder
– Sexual dysfunction, women
– Vulvar vestibulitis
–
Urinary incontinence
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Design options to lower placebo response
Option 1. Parallel single stage design
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PLACEBO
DRUG
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Option 2: The Placebo Lead-in
PLACEBO
No
Response
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PLACEBO
DRUG
Use placebo lead-in (run-in) to eliminate placebo responders
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Advantages of Placebo Lead-In
Advantages
• Possible increase in power from larger effect
size in placebo non-responders
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Placebo response
• Impact of the placebo lead-in duration on the placebo
response in 86 major depressive disorder trials
• 30 trials without placebo lead-in had an average HAMD
total -9.24 and SD 1.87, but 56 MDD trials with placebo
lead-in had an average HAMD total -7.6 and SD 1.83.
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Disadvantages of Placebo Lead-In
Disadvantages
• Longer trial duration
• Might fail to eliminate placebo responders
Analysis has shown that placebo lead-in periods (at least
those that are single blind) rarely deliver their theoretical
benefit. Trivedi and Rush (1994) reported that meta-analyses
of 101 antidepressant studies “reveal that a placebo lead-in
does NOT
(1) lower the placebo response rate,
(2) increase the drug-placebo difference, or
(3) affect the drug response rate post-randomization…”.
• The number of patients recruited is larger than
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the n of the trial
Option 3: The Sequential Parallel
Comparison Design (SPCD)
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PLACEBO
DRUG
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Response
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Option 3: The Sequential Parallel
Comparison Design
•
Sequential Parallel Comparison Design (SPCD) is a
clinical trial methodology developed in 2003 in
Massachusetts General Hospital (Fava et al.,
2003)
–
–
•
after parallel first stage, re-study the patients who
do not respond to placebo
Unlike a placebo lead-in, all patients are utilized
• and, some patients are utilized twice
Massachusetts General Hospital holds a portfolio
of patents related to SPCD, licensed by PPD.
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The Sequential Parallel
Comparison Design
SPCD is sometimes referred to as
• Sequential Parallel Design (SPD)
• Sequential Parallel Design with ReRandomization or SPD - ReR (Chen et al., 2011)
• Doubly Randomized Delayed-Start Design (Liu
et al., 2012)
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SPCD: defining the outcome
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q1
PLACEBO
DRUG
p1
No
Response
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q2
PLACEBO
DRUG
p2
Let q1 and p1 be placebo and drug response rates in Stage 1
Let q2 and p2 be placebo and drug response rates in Stage 2,
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that is, among placebo non-responders
SPCD: Hypothesis testing
• Parallel single stage trial: population = all comers
H0: p1 = q1
• Placebo lead-in:
population = placebo
non-responders
H0: p2 = q2
• SPCD
all comers
H0: p1 = q1
H1: p1 > q1
placebo non-responders
∩
OR
p2 = q2
p2 > q2
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Advantages of the SPCD
Advantages
• Unlike placebo lead-in, no eligible patients are
recruited and then not used
• Increase in power for any given sample size
– From potentially larger effect size in placebo
non-responders
– From reuse of patients
• More responses are observed compared to
parallel design or placebo lead-in
• For any given power, overall trial duration is
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typically shorter because sample size is smaller
Disadvantages of the SPCD
Disadvantages
• Longer trial duration for individual subjects
compared to the parallel design and placebo leadin (because lead-in phase is usually shorter than
full follow-up for response)
• Some controversy regarding hypothesis being
tested. However,
- Use of placebo non-responders (as in placebo
lead-in) is well accepted for Phase 3 by FDA
- 9 completed SPCD MDD trials and 9 ongoing trials,
including completed and ongoing pivotal trials
SPCD data analysis
Linear combination test (Fava et al., 2003)
θˆ1 = pˆ1 − qˆ1
θˆ2 = pˆ 2 − qˆ2
T=
wθˆ1 + (1 − w)θˆ2
w 2Var (θˆ ) + (1 − w) 2Var (θˆ )
1
1
Since cov(θˆ1 , θˆ2 ) asymptotically, T~N(0,1)
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SPCD data analysis
1. Linear combination test (Fava et al., 2003)
test parameter
ˆ
ˆ
T=
wθ1 + (1 − w)θ 2
w 2Var (θˆ ) + (1 − w) 2Var (θˆ )
1
1
2. Score test (Ivanova, Qaqish, Shoenfeld, 2011), binary
outcome
test parameter
r = ( p2 − q2 ) / ( p1 − q1 )
3. Weighted combination of Z-scores (Liu et al., 2012)
test parameter
T =
wZ 1 + 1 − wZ 2
where Z1 is the test statistic for stage 1 and Z2 is for stage 2
Ziprasidone (max 160 mg/day) vs. placebo
for depression
n = 120
Actual Response Rate
Drug
Placebo
Difference
Stage 1
44.8%
31.9%
12.9%
Stage 2
23.8%
28.0%
Conventional Design p-value = 0.19
-4.2% *
(response rates of Stage 1, using
50:50 randomization)
SPCD p-value = 0.42
Note: All p-values are two-sided. SPCD p-values are obtained using the score test with an “r” =
1 (Ivanova et al., 2011). Single stage p-values are obtained using the Fisher’s exact test.
L-methylfolate (7.5 mg/day) vs. placebo
for SSRI-resistant major depression
n = 148
Funded by Pamlab, Inc.
Actual Response Rate
Drug
Placebo
Stage 1
19.4%
28.5%
Stage 2
17.1%
9.1%
Difference
-9.1% *
8.0%
Conventional Design p-value = 0.12 * (response rates of Stage 1, using
50:50 randomization)
SPCD p-value = 0.96
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ADAPT-A: Aripiprazole Augmentation of SSRIs
for major depression with inadequate
antidepressant therapy response
n = 221
Funded by Bristol-Myers Squibb
Actual Response Rate
Placebo
Drug
Difference
Stage 1
18.5%
17.4%
1.1%
Stage 2
18.0%
7.9%
10.1%
Conventional Design p-value = 0.86
͌
9X
(response rates of Stage 1, using
50:50 randomization)
SPCD p-value = 0.19
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L-Methylfolate (15 mg/day) Augmentation of SSRIs vs. placebo
for SSRI-resistant major depression
n = 75
Funded by Pamlab, Inc.
Actual Response Rate
Difference
Drug
Placebo
Stage 1
36.8%
19.6%
17.2%
Stage 2
27.7%
9.5%
18.2%
Conventional Design p-value = 0.12
͌
1X
(response rates of Stage 1, using
50:50 randomization)
SPCD p-value = 0.03
n = 19 (25%) : n = 56 (75%)
Drug : Placebo
Stage 1 p-value = 0.21
Stage 2 p-value = 0.22
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Example of a Dose-Finding Study with SPCD:
Alkermes’ Phase 2 Study of ALKS 5461 in Depression
• ALKS 5461, a novel opioid modulator, in patients
with major depressive disorder and inadequate
response to standard therapies
• Primary Endpoint
- Hamilton Depression Rating Scale (HAM-D17)
• Secondary Endpoints
- Montgomery-Åsberg Depression Rating Scale (MADRS)
- Clinical Global Impression (CGI-S)
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Alkermes’ Phase 2 Study of ALKS 5461 in Depression
n = 142
9:2:2
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n = 99
PLACEBO
No
Response
n = 22
LOW DOSE
n = 21
HIGH DOSE
4 wk trt 1 wk
taper
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n = 20
PLACEBO
n = 23
LOW DOSE
n = 22
HIGH DOSE
4 wk trt 1 wk
taper
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Alkermes’ Phase 2 Study of ALKS 5461 in Depression
Response rate
Low+High dose
SPCD Stage 1
SPCD Stage 2
41.9%
37.8%
Placebo
25.3%
5.0%
Stage 1 p-value = 0.122
Stage 2 p-value = 0.006
SPCD
p-value = 0.001
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Difference
16.6%
32.8%
͌
2X
A Two-way Enriched Design (TED)
(Ivanova and Tamura, 2011)
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Response
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Sequential Enriched Design (SED)
(Chen and Tamura, 2014)
PLACEBO
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Response
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Response
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References
Chen Y.F., Yang Y., Hung H., Wang S. Evaluation of performance of some enrichment
designs dealing with high placebo response in psychiatric clinical trials.
Contemporary Clinical Trials 2011; 32: 592-604
Doros G, Pencina M, Rybin D, Meisner A, Fava M. A repeated measures model for
analysis of continuous outcomes in sequential parallel comparison design studies.
Statistics in Medicine in press.
Fava, M, Schoenfeld, D. U.S. provisional Pat. App. No. 60/459,517, filed March 31,
2003; U.S. Pat. App. No. 10/814,852, filed March 31, 2004. Corresponding U.S.
Patents include U.S. Pat. No. 7,647,235, issued January 12, 2010; U.S. Pat. No.
7,840,419, issued November 23, 2010; and U.S. Pat. Nos. 7,983,936; 8,145,504;
8,145,505; and 8,219,419.
Fava M., Evins A, Dorer D., Schoenfeld D. The problem of the placebo response in
clinical trials for psychiatric disorders: culprits, possible remedies and a novel
study design approach. Psychotherapy and Psychosomatics 2003; 72: 115-127.
Fava, M, Mischoulon D, Iosifescu D, Witte J, Pencina M et al. A double-blind, placebocontrolled study of Aripiprazole adjunctive to antidepressant therapy among
depressed outpatients with inadequate response to prior antidepressant therapy
(ADAPT-A Study). Psychotherapy and Psychosomatics 2012; 81, 87-97.
Huang X., Tamura R. Comparison of test statistics for the sequential parallel design.
Statistics in Biopharmaceutical Research 2010; 2: 42-50.
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References
Ivanova, A., Qaqish, B., Schoenfeld D. Sample size and power calculations for the
sequential parallel design. Statistics in Medicine 2011; 30: 2793–2803.
Ivanova A, Tamura RN. A two-way enriched clinical trial design: combining advantages
of placebo lead-in and randomized withdrawal. Statistical Methods in Medical
Research 2011; available in Early View.
Laughren TP. The scientific and ethical basis for placebo-controlled trials in depression
and schizophrenia: an FDA perspective. European Psychiatry 2001; 16:418-423.
Liu Q, Lim P, Singh J, Lewin D, Schwab B, Kent J. Doubly randomized delayed-start
design for enrichment studies with responders or nonresponders. Journal of
Biopharmaceutical Statistics. 2012; 22(4):737-57.
Papakostas GI, Shelton RC, Zajecka JM, Etemad B, Rickels K, Clain A, et al. Lmethylfolate as adjunctive therapy for SSRI-resistant major depression: results
of two randomized, double-blind, parallel-sequential trials. Am J Psychiatry 2012;
169, 1267-74.
Silberman, S Placebos are getting more effective. Drugmakers are desperate to know
why. Wired Magazine 2009, http://www.wired.com/wired/issue/17-09
Tamura RN, Huang X. An examination of the efficiency of the sequential parallel design
in psychiatric clinical trials. Clinical Trials: Journal of the Society of Clinical Trials
2007; 4: 309-317.
Trivedi MH, Rush AJ. Does a placebo run-in or placebo treatment cells affect the
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efficacy of antidepressant medications? Neuropsychopharmacology 1994; 11:33-43.