The Time Course of Placebo Response in Clinical Trials
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1 The Time Course of Placebo Response in Clinical Trials Do Antidepressants Really Take 2 s To Work? Nick Holford Department of Pharmacology and Clinical Pharmacology, University of Auckland, New Zealand
2 Clinical Pharmacology = Disease Progress + Drug Action NHG Holford, 05, all rights reserved.
3 Old Model - New Meaning E max Conc E = E0 + EC50 + Conc Disease Progress Drug Action NHG Holford, 05, all rights reserved.
4 Components of a Disease Progression Model Baseline Disease State Natural History Placebo Response Active Treatment Response S(t) = S0 +Nat. Hx. + Plac + Active NHG Holford, 05, all rights reserved.
5 Linear + Offset (Symptomatic) S( t) 0 ( S + E t ) + t = ( ) α status Temporary Improvement Natural History time NHG Holford, 05, all rights reserved.
6 Eptastigmine Imbimbo et al. Two-year treatment of Alzheimer's disease with eptastigmine. The Eptastigmine Study Group. Dementia and Geriatric Cognitive Disorders 1999;(2): NHG Holford, 05, all rights reserved.
7 Disease Progress Placebo Response Q: How can disease progress and placebo response be separated? A: Model based assumptions e.g. disease progress is linear placebo increases, reaches peak, decreases NHG Holford, 05, all rights reserved.
8 Placebo Response Alzheimer s Disease Disease Progress Placebo Response ADASC score ADASC score time(days) time(days) Holford & Peace, Methodologic aspects of a population pharmacodynamic model for cognitive effects in Alzheimer patients treated with tacrine. Proc Natl Acad Sci 89 (1992): NHG Holford, 05, all rights reserved.
9 Linear + Offset + Placebo Griggs RC, Moxley RT, Mendell JR, Fenichel GM, Brooke MH, Pestronk A, et al. Prednisone in Duchenne Dystrophy: A randomized, controlled trial defining the time course and dose response. Archives of Neurology 1991;48: NHG Holford, 05, all rights reserved.
10 The Placebo Effect True or False? NHG Holford, 05, all rights reserved.
11 Anti-Depressant Response Everybody knows anti-depressants take 2 to 4 weeks to work Almost all anti-depressant drugs block amine transporter re-uptake 5-HT, dopamine, noradrenaline Know to have a rapid effect crack cocaine Serotonergic syndrome Why is the anti-depressant response delayed? NHG Holford, 05, all rights reserved.
12 Response Placebo Treatment starts NHG Holford, 05, all rights reserved.
13 Simple Placebo Response S0 Baseline Tlag Lag time Drem Remission Dose Trem Remission Half-Life Placebo Treatment starts NHG Holford, 05, all rights reserved.
14 Full Placebo Response first order absorption and elimination 25 Tlag=Lag time S0=Baseline Drem=Remission Dose 15 Trel=Relapse Half-Life Trem=Remission Half-Life s NHG Holford, 05, all rights reserved.
15 Investigation 1 Placebo treated profiles from 4 clinical studies NHG Holford, 05, all rights reserved.
16 What Determines the Time Course of Placebo Response? Placebo Arm of Double Blind Randomized Phase II Study of Four New Potential Anti- Depressants Total 582 patients, 3864 observations Developer 1, Study A (154 patients) Developer 1, Study B (141 patients) Developer 2, Study C (149 patients) Developer 2, Study D (138 patients) NHG Holford, 05, all rights reserved.
17 Study A Placebo ID NHG Holford, 05, all rights reserved.
18 Study B Placebo ID NHG Holford, 05, all rights reserved.
19 Study Placebo Model 4 Placebo Data Sets Parameter Description Estimate Units S0 Baseline 24 Tlag Lag time 4.7 days Drem Remission dose.6 Trem Remission half-life 60 days Trel Relapse half-life 280 days NHG Holford, 05, all rights reserved. iba_plaro_sdymixfix_s0sexwtsdyfix_tlwt_teme
20 Relapse Mixture Model Assume some patients have relapse Patients who do not relapse have infinite relapse half-life Probability of patient having a relapse is estimated NHG Holford, 05, all rights reserved.
21 Relapse Probability Study A Study B Study C Study D 98% 45% 29% 18% There are clearly study specific influences on the probability of relapse during the clinical trial NHG Holford, 05, all rights reserved. iba_plaro_sdymixfix_s0sexwtsdyfix_tlwt_teme
22 Is It a Design Issue? Observation Times Study A Study B OBS Day Study C OBS Day Study D OBS Day OBS Day NHG Holford, 05, all rights reserved.
23 A Second Kind of Placebo Effect The Observation Placebo Each observation acts as a dose of observation placebo Observation placebo conc rises and falls like oral drug absorption model Observation placebo conc can shorten remission and relapse half-lives of the study placebo model NHG Holford, 05, all rights reserved.
24 Observation Placebo Effect Obs Placebo onset half-life Obs Placebo disappearance half-life Obs Placebo effect on remission Obs Placebo effect on relapse 0.12 days 31 days -40% -64% NHG Holford, 05, all rights reserved. iba_plaro_sdymixfix_s0sexwtsdyfix_tlwt_teme
25 Investigation 2 A traditional placebo controlled study of a potential new antidepressant NHG Holford, 05, all rights reserved.
26 Model Models Equations Disease Progression S ( t) = S0 Placebo Response ( ln(2)/ Trem ( t Tlag) Placebo( t) = Drem 1 e ) Effect Compartment Concentration Ce( t) = DoseRate Clearance ln(2)/ Teq t ( 1 e ) Drug Action PD( Ce) = Beta Ce Time Course ( t) = S( t) + Placebo( t) + PD( Ce( t)) NHG Holford, 05, all rights reserved.
27 Typical Profiles ID NHG Holford, 05, all rights reserved.
28 DOSE 0 Placebo ID NHG Holford, 05, all rights reserved.
29 DOSE 1 New AntiDepressant ID NHG Holford, 05, all rights reserved.
30 Parameter Estimates Parameter S0 Tlag Drem Trem Beta Teq RUV Description Baseline Lag time Remission decrease Remission half-life Effect potency Equilibration half-life Residual Error Units units days units days units days units Estimate FIX* 2.69 PPV PPV=Population Parameter Variability (coefficient of variation of a log normal distribution) RUV=Residual Unidentified Variability (standard deviation of a normal distribution) FIX FIX *=Longer Teq worsened objective function. Design of trial did not allow estimation of shorter Teq. 0.5 days is PK half-life. NHG Holford, 05, all rights reserved.
31 Bootstrap Statistics Table 3 Bootstrap Statistics (00 replicates) of Parameter Estimates for the Model Parameter Population Estimate Population Parameter Variability Median Lower 2.5% ile Upper 97.5%ile Median Lower 2.5% ile Upper 97.5%ile S Tlag Drem FIX - - Trem Beta -1.45* RUV * = Significantly different from zero based on 95% bootstrap confidence interval NHG Holford, 05, all rights reserved.
32 Investigation 2 Conclusion Big placebo response Small antidepressant effect Rapid onset of active drug? NHG Holford, 05, all rights reserved.
33 Investigation 3 Retrospective analysis of large clinical database Positive and Negative trials NHG Holford, 05, all rights reserved.
34 Patients with Major Depressive Disorder enrolled in Placebo Controlled Clinical Trials of Anti-Depressants Data Set 4 Marketed Antidepressants + 2 IND (Active) Drugs + Placebo Patients 2,794 15,968 NHG Holford, 05, all rights reserved.
35 Placebo NHG Holford, 05, all rights reserved.
36 Marketed Active Drug NHG Holford, 05, all rights reserved.
37 Placebo ' s Hi Median Lo Placebo NHG Holford, 05, all rights reserved.
38 Marketed Active Drug ' s Hi Median Lo Obs NHG Holford, 05, all rights reserved.
39 Placebo Response Parameters Parameter Units Population Variability Estimate (PPV x 0) S Tlag Day Remission Dose Thalf Remission Day Thalf Relapse Day RUV PPV=Population Parameter Variability (coefficient of variation of a log normal distribution) RUV=Residual Unidentified Variability (standard deviation of a normal distribution) NHG Holford, 05, all rights reserved.
40 Active Treatment Effects Parameter Units Population Variability Estimate (PPV x 0) Emax ED50 dose/day * Teq days Teq=Effect compartment equilibration half-life *=Dose rate for each drug normalized to the median dose NHG Holford, 05, all rights reserved.
41 Placebo and Active Drug Response s Active Treatment start NHG Holford, 05, all rights reserved.
42 Investigation 3 Conclusion Big placebo response Small antidepressant effect Rapid onset of (marketed) active drugs NHG Holford, 05, all rights reserved.
43 Application of Placebo Models to Depression Clearer description of depression Separation of Magnitude and Time Course of Drug Action Dispel unsubstantiated mythology! NHG Holford, 05, all rights reserved.
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