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Sequential Parallel Comparison Design for Trials with High Placebo Response

Anastasia Ivanova

Department of Biostatistics UNC at Chapel Hill

aivanova@bios.unc.edu

Placebo response

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Data from 86 major depressive disorder trials submitted to FDA during 1986 to 2008 (Khin et al., 2011)

Increased placebo response over time

+ US trials- Non US trials

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.

Diminished treatment effect over time

+ US trials- Non US trials

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Undurraga and Baldessarini 2012

Rising placebo response RCTs and failed trials

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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).

Placebo response

Yellow pillsmake the most effective antidepressants, like little doses of pharmaceutical sunshine

Red pillscan give you a more stimulating kick

More is betterPlacebos 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 features of placebo and therapeutic efficacy. JAMA 299: 1016-1017.7

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

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

Partial List of Illnesses Cited as Having Significant Placebo ResponsesOrganized by FDA Center for Drug Evaluation and Research Review Divisions

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

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Design options to lower placebo responseOption 1. Parallel single stage design

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Option 2: The Placebo Lead-in

PLACEBO

PLACEBO

DRUG

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Response

Use placebo lead-in (run-in) to eliminate placebo responders10

Advantages of Placebo Lead-In

Advantages• Possible increase in power from larger effect size in placebo non-responders

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Placebo response

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• 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.

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 the n of the trial 13

Option 3: The Sequential Parallel Comparison Design (SPCD)

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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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SPCD is sometimes referred to as

• Sequential Parallel Design (SPD)

• Sequential Parallel Design with Re-Randomization or SPD - ReR (Chen et al., 2011)

• Doubly Randomized Delayed-Start Design (Liu et al., 2012)

The Sequential Parallel Comparison Design

SPCD: defining the outcome

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Response

q1

p1

q2

p2

Let q1 and p1 be placebo and drug response rates in Stage 1Let q2 and p2 be placebo and drug response rates in Stage 2, that is, among placebo non-responders 17

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 placebo non-responders

H0: p1 = q1 ∩ p2 = q2H1: p1 > q1 OR 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 typically shorter because sample size is smaller 19

Disadvantages of the SPCD

Disadvantages• Longer trial duration for individual subjects compared to the parallel design and placebo lead-in (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)

Since asymptotically, T~N(0,1)

1 1 1

2 2 2

1 2

2 21 1

ˆ ˆ ˆ

ˆ ˆ ˆ

ˆ ˆ(1 )

ˆ ˆ( ) (1 ) ( )

p q

p q

w wT

w Var w Var

θ

θ

θ θ

θ θ

= −

= −

+ −=

+ −

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1 2ˆ ˆcov( , )θ θ

SPCD data analysis

1. Linear combination test (Fava et al., 2003)

2. Score test (Ivanova, Qaqish, Shoenfeld, 2011), binary outcome

3. Weighted combination of Z-scores (Liu et al., 2012)

where Z1 is the test statistic for stage 1 and Z2 is for stage 2

1 2

2 21 1

ˆ ˆ(1 )

ˆ ˆ( ) (1 ) ( )

w wT

w Var w Var

θ θ

θ θ

+ −=

+ −

( ) ( )2 2 1 1/r p q p q= − −

1 21T wZ wZ= + −

test parameter

test parameter

test parameter

Actual Response Rate

Drug Placebo Difference

Stage 1 44.8% 31.9% 12.9%

Stage 2 23.8% 28.0% -4.2%

Conventional Design p-value = 0.19 (response rates of Stage 1, using 50:50 randomization)

Ziprasidone (max 160 mg/day) vs. placebo

for depression

n = 120

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.

*

Actual Response Rate

Drug Placebo Difference

Stage 1 19.4% 28.5% -9.1%

Stage 2 17.1% 9.1% 8.0%

Conventional Design p-value = 0.12 *

L-methylfolate (7.5 mg/day) vs. placebo for SSRI-resistant major depression

n = 148Funded by Pamlab, Inc.

SPCD p-value = 0.96

*

(response rates of Stage 1, using 50:50 randomization)

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Actual Response Rate

Drug Placebo Difference

Stage 1 18.5% 17.4% 1.1%9X

Stage 2 18.0% 7.9% 10.1% ͌

Conventional Design p-value = 0.86 (response rates of Stage 1, using 50:50 randomization)

ADAPT-A: Aripiprazole Augmentation of SSRIsfor major depression with inadequate antidepressant therapy response

n = 221Funded by Bristol-Myers Squibb

SPCD p-value = 0.19

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Actual Response Rate

Drug Placebo Difference

Stage 1 36.8% 19.6% 17.2%1X

Stage 2 27.7% 9.5% 18.2% ͌

L-Methylfolate (15 mg/day) Augmentation of SSRIs vs. placebo for SSRI-resistant major depression

n = 75Funded by Pamlab, Inc.

Conventional Design p-value = 0.12 (response rates of Stage 1, using 50:50 randomization)

SPCD p-value = 0.03

Stage 1 p-value = 0.21

Stage 2 p-value = 0.22n = 19 (25%) : n = 56 (75%)

Drug : Placebo

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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

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LOW DOSE

PLACEBO

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HIGH DOSE

n = 99

HIGH DOSE

LOW DOSE

PLACEBO

4 wk trt

n = 22

n = 21

1 wk

taper

n = 20

n = 23

n = 22

4 wk trt 1 wk

taper

n = 142

9:2:2

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Response rate Low+High dose Placebo Difference

SPCD Stage 1 41.9% 25.3% 16.6%2X

SPCD Stage 2 5.0% 32.8% ͌

Alkermes’ Phase 2 Study of ALKS 5461 in Depression

Stage 1 p-value = 0.122Stage 2 p-value = 0.006

SPCD p-value = 0.001

37.8%

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A Two-way Enriched Design (TED)(Ivanova and Tamura, 2011)

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Response

Sequential Enriched Design (SED)(Chen and Tamura, 2014)

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Response

ReferencesChen 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, placebo-controlled 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. 32

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. L-methylfolate 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 efficacy of antidepressant medications? Neuropsychopharmacology 1994; 11:33-43.

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