Clinical Trial Database Analyses to Inform Regulatory Guidances: Improving the Efficiency of Schizophrenia Clinical Trials

Transcription

1 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 2 2

3 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. 3

4 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. 4

5 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. 5

6 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 6

7 Final Database Number of NDA s in the Database ( ) 8 Total Number of Trials 32 Total Number of Treatment Arms 86 Total Number of Subjects Randomized to Placebo 3533 Randomized to Drug Treatment

8 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 8

9 Typical Design of Efficacy Trial R Drug Placebo End Point Active Arm Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Endpoint: Change from baseline in Positive and Negative Syndrome Scale (PANSS) Positive Scale (N=7) Negative Scale (N=7) General Psychopathology (N=16) 9

10 Longitudinal Mean Change from Baseline in Total PANSS Treatment discrimination from placebo evident in change from baseline-total PANSS from Week 1 onwards Placebo Treatment Active Control 10

11 Correlation between Early and Late Endpoint 11

12 Effect at Week 4 vs. Week 6 Week 6 Week 4 No of Positive Treatment Arms: 11 No of Positive Treatment Arms: 10 Mixed model repeated measures analysis was used to estimate treatment effects by trials and assess statistical significance at different time points 12

13 No Week 1,2,3,4 No Concordance Rate Positive Week 6 Results Negative Positive Concordance Discordance (False +ve) Negative Discordance (False ve) Concordance 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] 13

14 Concordance Rates by Drug 14

15 Adverse Events (Week 4 vs. Week 6) Week 6 Week

16 Akathisia EPS Somnolence Headache Agitation Tachycardia 16

17 Time to Reach Steady State 17

18 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 18

19 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. 19

20 Derivation of Modified PANSS Blunted Affect Emotional Withdrawal Poor rapport Excitement Grandiosity Suspiciousness Stereotyped thinking Social withdrawal Difficulty abstract thinking Lack of Spontaneity Delusions Conceptual Disorganization Hallucinatory behavior Hostility Negative subscale 30 item PANSS Positive subscale Social Avoidance Somatic Concern Anxiety Guilt Feelings Preoccupation Unusual Thought Disorientation Poor Attention Tension Mannerisms Depression Motor Retardation Uncooperative Lack of Judgement Disturbance of Volition Poor Impulse Control General Psychopathology 20

21 Ideal Item Characteristic Curve (ICC) 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 21 21

22 Positive PANSS Items-ICC 22 22

23 Derivation of Modified PANSS Blunted Affect Emotional Withdrawal Poor rapport Excitement Grandiosity Suspiciousness Stereotyped thinking Social withdrawal Difficulty abstract thinking Lack of Spontaneity Delusions Conceptual Disorganization Hallucinatory behavior Hostility Negative subscale item PANSS Positive subscale General Psychopathology Social Avoidance Somatic Concern Anxiety Guilt Feelings Preoccupation Unusual Thought Disorientation Poor Attention Tension Mannerisms Depression Motor Retardation Uncooperative Lack of Judgement Disturbance of Volition Poor Impulse Control Item Response Theory Methodology 23

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25 Comparison of Modified PANSS with Literature Reports FDA Database (N = 14219) Only RCTs (8 Different Anti- Psychotics) Positive Subscale P1, P3, P4, P6, P7 Negative Subscale General Psychopathology Subscale N1,N2,N3, N4,N5,N6 G4, G8, G9, G11, G12, G13, G15,G16 Santor et al, 2007 (N = 9205) RCTs (Olanzapine) + Observational P1, P2, P3, P4, P5, P6 N1,N2,N3, N4,N6 G2, G3,G4, G7,G8,G14, G16 Khan et al, 2011 (N = 7348) Only RCTs (RIS, RIS- depot, PALI) P1, P2, P3, P4, P5, P6 N1, N2, N3, N4, N6, N7 G4, G6, G7, G8, G9, G13, G14 No of Sensitive Items identified Total PANSS Score

26 Longitudinal Mean Change from Baseline in Modified PANSS vs Total PANSS Modified PANSS Total PANSS 26

27 Effect at Week 6 (Total PANSS vs Modified PANSS) Modified PANSS Total PANSS No of Positive Treatment Arms =11 No of Positive Treatment Arms =11 27

28 Concordance Rate Modified PANSS vs. Total PANSS Outcome 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% % [FN = 1] 92.3% [FN = 1] 28

29 Sample size (Modified PANSS vs. Total PANSS at 4 and 6 Weeks) Week DD Total PANSS (SD=20) Sample Size (1:1) DD Modified PANSS (SD=13) Sample Size (1:1)

30 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 30

31 Acknowledgment Project Team Mathangi Gopalakrishnan, PhD Mehul Mehta, PhD; Ramana Uppoor, PhD; Hao Zhu, PhD Peiling Yang, PhD; Hsien Ming J Hung, PhD Mitchell Mathis, MD; Tiffany Farchione, MD, Lucas Kempf, MD OCP OB DPP Thomas Laughren, MD Issam Zineh, Pharm D Critical Path 31

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