Clinical Trial Database Analyses to Inform Regulatory Guidances:

Improving the Efficiency of Schizophrenia Clinical Trials

Islam R. Younis, Ph.D.

Team Leader

Office of Clinical Pharmacology

Office of Translational Sciences

Center for Drug Evaluation and Research

US Food and Drug Administration

2

Disclaimer

• The opinions expressed in this presentation are the presenter’s

and do not necessarily reflect the official views of the United

States Food and Drug Administration (FDA)

• The author has no disclosures related to the content of this

presentation

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Motivation

• Schizophrenia is a devastating illness.

• The antipsychotic development programs have been hindered by

many factors:

– Increase in placebo response

– Decrease in trial success rates (Failure Rate = 38%)

– Large dropouts (40% to 50%) in clinical trials.

• Several large pharmaceutical companies have announced plans to

abandon drug development programs in psychiatric diseases

including schizophrenia.

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Project Goal

• The goal of this project is to evaluate alternative

clinical and regulatory endpoints and design elements

that can improve the success of schizophrenia drug

development programs.

– To provide industry with a more attractive development

program while at the same time providing the high

standard evidence of efficacy and safety that the Agency

requires to approve new drugs.

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Specific Objectives

1. Determine the optimal study duration for establishing efficacy

in schizophrenia trials.

2. Explore the utility of items in the PANSS instrument to

optimize signal to noise ratio.

3. Exploring alternative endpoints to evaluate efficacy in

schizophrenia trials.

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Database Building

Key identifier

variables

Efficacy

dataset

Disposition

AE dataset

All registration

trials for Drug A

All registration

trials for Drug B

All registration

trials for Drug N

Master

schizophrenia

database

contains

subject level

information on

longitudinal

PANSS item

scores,

subscale

scores,

demographics,

dosing, AE

Master database contains efficacy and AE information from

Eight Atypical Antipsychotics approved between 2001 and 2015

The database is QC checked and uses uniform data variables across all

8 NDA’s

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Final Database

Number of NDA’s in the Database (2001-2015) 8

Total Number of Trials 32

Total Number of Treatment Arms 86

Total Number of Subjects 14219

Randomized to Placebo 3533

Randomized to Drug Treatment 10686

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Objective #1. Shortening Trial Duration

• Literature data suggest week 2 response to antipsychotic

treatments can predict response at weeks 4 and 6

• Kinon et al proposed that trial duration from 6 weeks to 2 to 4

weeks may minimize dropouts, leading to a more representative

group of patients completing the study and more robust

conclusions (minimal data imputation)

• Additional benefits for shortening trial duration:

– Reducing exposure to experimental medication (and placebo)

– Allowing exploration of more doses in a trial

– Reducing the cost of drug development program

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Typical Design of Efficacy Trial

Baseline Week 1

End Point

Week 2 Week 3 Week 4 Week 5 Week 6

Drug

Placebo

Active Arm

R

Endpoint: Change from baseline in Positive and Negative Syndrome Scale (PANSS)

Positive Scale (N=7)

Negative Scale (N=7)

General Psychopathology (N=16)

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Longitudinal Mean Change from Baseline in Total PANSS

Treatment discrimination from placebo evident

in change from baseline-total PANSS from Week 1 onwards

www.fda.gov

Placebo

Treatment

Active Control

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Correlation between Early and Late Endpoint

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Effect at Week 4 vs. Week 6

Week 6

No of Positive Treatment Arms: 11 No of Positive Treatment Arms: 10

www.fda.gov

Mixed model repeated measures analysis was used to estimate treatment effects by trials

and assess statistical significance at different time points

Week 4

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Concordance Rate

Week

1,2,3,4 No

No

www.fda.gov

Week Concordance Rate Discordance Rate

Week 1 vs Week 6 68% 32%

Week 2 vs Week 6 74% 26%

Week 3 vs Week 6 83% 17%

Week 4 vs Week 6 93% (80/86) 7% (6/86)

[FN = 6]

Week 6 Results

Positive Negative

Positive Concordance Discordance (False +ve)

Negative Discordance (False –ve) Concordance

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Concordance Rates by Drug

www.fda.gov

15

Adverse Events (Week 4 vs. Week 6)

www.fda.gov

Week 6 Week 4

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Akathisia Somnolence

Agitation TachycardiaHeadache

www.fda.gov

EPS

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Time to Reach Steady State

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Shortening Trial Duration to 4 Weeks is Feasible

• Conclusions based on:

– Analysis of change from baseline in Total PANSS data from

eight NDA’s (N = 14,219; 32 trials, 86 treatment arms)

– Discrimination of treatment effect from placebo consistently

evident from week 2 onwards

– Concordance rate for week 4 trial outcomes to week 6 outcomes

was 93%

– Adequate adverse events captured by 4 weeks

– 32% increase in sample size required in comparison to 6 week

trial

– 30% decrease in dropout rates in a 4 week trial would lead to

better trial interpretation

www.fda.gov

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Objective #2. Optimizing Signal to Noise

Ratio in PANSS

• PANSS is characterized by large variability in

response for both placebo and active drug(s).

• It is proposed that shorter and more clinically

relevant scales can be derived from the PANSS

since not all items of the PANSS are sufficiently

sensitive to detect true treatment effect.

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Derivation of Modified PANSS

Delusions

Conceptual Dis-

organiza-tion

GrandiosityExcitement

Hallucinatory behavior

Suspicious-ness

30 item PANSS

Hostility

Blunted Affect

Emotional Withdrawal

Difficulty abstract thinking

Social withdrawal

Poor rapport

Lack of Spontaneity

Stereotyped thinking

Somatic Concern

Anxiety

DepressionMannerisms

Guilt Feelings

Motor RetardationTension

Unusual Thought

Dis-orientation

Disturbance of Volition

Lack of Judgement

Poor Attention

Poor Impulse Control

Un-cooperative

Pre-occupation

Social Avoidance

www.fda.gov

Positive subscaleNegative subscale

General Psychopathology

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Ideal Item Characteristic Curve (ICC)

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1. The distribution of the response (option)probability curve is in increasing order across the symptom severity ( 1 to 7)

2. Each option has a region in which has the highest probability of being chosen

3. The ICC rapidly increases with small increase in severity

4. The item options span the entire continuum of the symptom severity

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Positive PANSS Items-ICC

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Derivation of Modified PANSS

Delusions

Conceptual Dis-

organiza-tion

GrandiosityExcitement

Hallucinatory behavior

Suspicious-ness

30 item PANSS

Hostility

Blunted Affect

Emotional Withdrawal

Difficulty abstract thinking

Social withdrawal

Poor rapport

Lack of Spontaneity

Stereotyped thinking

Somatic Concern

Anxiety

DepressionMannerisms

Guilt Feelings

Motor RetardationTension

Unusual Thought

Dis-orientation

Disturbance of Volition

Lack of Judgement

Poor Attention

Poor Impulse Control

Un-cooperative

Pre-occupation

Social Avoidance

Item Response Theory Methodology

19 item PANSS

www.fda.gov

Positive subscaleNegative subscale

General Psychopathology

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Comparison of Modified PANSS with

Literature Reports

FDA Database

(N = 14219)

Santor et al, 2007

(N = 9205)

Khan et al, 2011

(N = 7348)

Only RCTs

(8 Different Anti-

Psychotics)

RCTs (Olanzapine)

+ Observational

Only RCTs

(RIS, RIS- depot,

PALI)

Positive Subscale P1, P3, P4,

P6, P7

P1, P2, P3,

P4, P5, P6

P1, P2, P3,

P4, P5, P6

Negative Subscale N1,N2,N3,

N4,N5,N6

N1,N2,N3,

N4,N6

N1, N2, N3,

N4, N6, N7

General

Psychopathology

Subscale

G4, G8, G9, G11,

G12, G13, G15,G16

G2, G3,G4,

G7,G8,G14, G16

G4, G6, G7, G8, G9,

G13, G14

No of Sensitive

Items identified 19 18 19

Total PANSS Score 133 126 133

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Longitudinal Mean Change from Baseline in

Modified PANSS vs Total PANSS

Modified PANSS Total PANSS

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Effect at Week 6 (Total PANSS vs Modified PANSS)

No of Positive Treatment Arms =11 No of Positive Treatment Arms =11

Modified PANSS Total PANSS

28www.fda.gov

Week 6 Week 4

Overall 97.6% (84/86)

[FN = 1, FP = 1]

93.2% (80/86)

[FN = 5, FP = 1]

1 100% 100%

2 100% 80% [FN = 2]

3 100% 100%

4 100% 100%

5 100% 90.9% [FN = 1]

6 100% 88.2% [FN = 1, FP =1]

7 90% [FP = 1] 100%

8 92.3% [FN = 1] 92.3% [FN = 1]

Concordance Rate

Modified PANSS vs. Total PANSS Outcome

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Sample size

(Modified PANSS vs. Total PANSS at 4 and 6 Weeks)

www.fda.gov

Week

DD

Total PANSS

(SD=20)

Sample

Size

(1:1)

DD

Modified PANSS

(SD=13)

Sample

Size

(1:1)

4 5.4 502 4.22 402

6 6.7 380 4.92 296

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Modified PANSS + Shortened Duration

is a Feasible Option

• Conclusions based on:

– Derivation of a 19-item PANSS (consisting of sensitive items)

using Item Response Theory methodology.

– Change from baseline in Modified PANSS at 4 weeks and 6 weeks

compared with total PANSS at 6 weeks

– Concordance rates for week 4 trial (modified PANSS) outcomes

to week 6 outcomes (Total PANSS) was 93%

– Sample size estimates using modified PANSS at 4 weeks similar

to that of 6 week trial using Total PANSS

www.fda.gov

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Acknowledgment

Project Team

Mathangi Gopalakrishnan, PhD

Mehul Mehta, PhD; Ramana Uppoor, PhD; Hao Zhu, PhD OCP

Peiling Yang, PhD; Hsien Ming J Hung, PhD OB

Mitchell Mathis, MD; Tiffany Farchione, MD, Lucas Kempf, MD DPP

Thomas Laughren, MD

Issam Zineh, Pharm D

Critical Path