Treatment Effects ARE Heterogeneous What Should We Do About It? - PowerPoint PPT Presentation

Treatment Effects ARE Heterogeneous What Should We Do About It? Scott L. Zeger (sz@jhu.edu) Professor of Biostatistics and Medicine co-Director for Data Science, Hopkins in Health FDA Symposium on Treatment Heterogeneity November 28, 2018 Research reported in this lecture was partially funded by a generous gift from the Greene Foundation and through a Patient-Centered Outcomes Research Institute (PCORI) Award (ME-1408-20318). The views expressed are solely the responsibility of the author and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute (PCORI), its Board of Governors or Methodology Committee.

Talk Outline The Stew • – All treatments have heterogeneous effects Patient’s View • – What is my health state? – What is my health trajectory;? W – What is the expected effect of my trajectory for each of the available interventions? What To Do? • – Statistical science – Clinical science – Health Systems – FDA/Government Review • Nov 28, 2018 FDA 2

The Stew

Axiom: All treatments have heterogeneous effects William Osler said so: “Variability is the law of life, and as no two faces are the • same, so no two bodies are alike, and no two individuals react alike and behave alike under the abnormal conditions which we know as disease.” Assymetry of the null hypothesis: failure to reject null of no heterogeneity is not • evidence in favor of the null. Studies rarely powered to estimate different treatment effects in subgroups, especially less common subgroups. Because they are difficult to estimate does not mean they are not critical to clinical • medicine Nov 28, 2018 FDA 4

Boole -a- Bayes Thomas Bayes 1701-1761 George Boole 1815-1864 Nov 28, 2018 FDA 5

Bouillabaisse This image cannot currently be displayed. Boole – a – Bayes Nov 28, 2018 FDA 6

Patient’s View

Is my tumor indolent or life-threatening? Should I get a biopsy today or wait a year? Should I continue annual check-ups or have my prostate removed or irradiated? Nov 28, 2018 FDA 8

Common Generic Questions 1. What is my health state? 2. What is my trajectory? 3. What other measurements might help clarify my state? 4. Which intervention is best for me today? Nov 28, 2018 FDA 9

Hierarchical Model for Health State/Trajectory ( η it ) with Person-specific Indicator ( δ i ) η i t-1 η i t η it+1 δ i Nov 28, 2018 FDA 10

Effects of Exogenous (X) and Endogenous (Rx) Covariates on Health State/Trajectory with Person-specific Regression Coefficients ( β i ) X it-1 η i t-1 Rx it-1 X it η i t Rx it β i X it+1 η it+1 Rx it+1 δ i Nov 28, 2018 FDA 11

Observations (Y) that Inform about Health State through Coefficients ( ϕ i ) Y it-1 ϕ i X it-1 η i t-1 Rx it-1 Y t X it η i t Rx it Y it+1 β i X it+1 η it+1 Rx it+1 δ i Nov 28, 2018 FDA 12

Treatment Decisions Depend on Pas ast M Meas asured ed Outcomes through Parameters ( ζ i ) Y it-1 ϕ i X it-1 η i t-1 ζ i Rx it-1 Y t X it η i t Rx it Y it+1 β i X it+1 η it+1 Rx it+1 δ i Nov 28, 2018 FDA 13

Y it-1 ϕ i ζ i η i t-1 X it-1 R it-1 Y t X it η i t R it Y it+1 β i X it+1 η it+1 R it+1 δ i Nov 28, 2018 FDA 14

Y it-1 Y it-1 ϕ i ϕ i ζ i ζ i η i t-1 η i t-1 X it-1 X it-1 R it-1 R it-1 Y t Y t X it X it η i t η i t R it R it Y it+1 Y it+1 β i β i X it+1 X it+1 η it+1 η it+1 R it+1 R it+1 δ i δ i β, Σ ϑ RCTs Y it-1 Y it-1 ϕ i ϕ i ζ i ζ i η i t-1 X it-1 η i t-1 X it-1 R it-1 R it-1 Y t Y t X it η i t X it η i t R it R it Y it+1 Y it+1 β i β i X it+1 η it+1 X it+1 η it+1 R it+1 R it+1 δ i δ i Nov 28, 2018 FDA 15

Y it-1 ϕ Y it-1 ϕ ζ X i ζ η i t-1 i X i R it η i t-1 i i t-1 R it i t-1 -1 Y t -1 Y t X it η i t R X it η i t R it Y it+1 it Y it+1 X β i X β i η it+1 it+ R i η it+1 it+ R i 1 1 t+1 t+1 β, Σ ∆ δ i δ i ϑ Ζ Y it-1 Y it-1 ϕ ϕ ζ ζ X i η i t-1 X i i η i t-1 R it i i R it t-1 i t-1 -1 Y t -1 Y t X it η i t R X it η i t R it Y it+1 it X Y it+1 β i X η it+1 β i it+ R i η it+1 1 it+ R i t+1 1 t+1 δ i δ i Nov 28, 2018 FDA 16

Y Y Y X η Y X η R i η ϕ R i ϕ X X η ζ ζ R i t ϕ R i i i i t ζ ϕ i i ζ Y i Y i i t t t t η - i - i i i t X i Y t X t η i Y Y i R t i t t - η i Y - - X 1 η R X i Y t t η - i - - X 1 η t R t X i Y - R t - - 1 η R 1 i i i R t - X - - 1 η β i 1 1 i 1 i i - R t X 1 β i 1 i i - R t t i t i t 1 β i 1 i 1 i i t i t i t i t 1 β i 1 i t i t i t 1 t t + t i t i i t i β t t + t i t t t δ i t i + 1 t δ i t + β t + + + 1 t δ i t + + + t δ 1 , ∆ + + 1 + 1 1 + + 1 1 i 1 1 , ∆ + 1 i 1 1 1 i 1 Σ 1 i Y Y Σ η Y Y η X X ϑ Ζ R η R i i ϕ η X ϕ ζ X ζ R ϑ Ζ R i i t i ϕ ζ ϕ i i t i ζ i i Y i t Y t - η Y i t i t t - η i X t i i i Y X i Y t R i i Y η t R X η t - t X t - i Y - 1 η - - 1 X t η i i Y t R i - X - R t t R X η - t i β i 1 - - 1 i R i 1 i 1 i - - X η - R 1 β i 1 i 1 i - i t i 1 t i t i R t i 1 β i 1 i t i t t i t 1 β 1 i 1 t i 1 i t i i t t i t t + i i t t i t δ t t i t t t + t i t t + i t δ + + 1 t i t δ + + t + + 1 i t + + 1 δ + 1 i 1 + + 1 + 1 1 1 + 1 1 1 i 1 1 i 1 1 i Y Y η X η i X R ϕ i ζ R ϕ ζ i t i i t i i - Y i t t i t - Y t X η i Y t η i i R 1 t X Y - - R 1 - η - - X t - X η 1 i 1 R t i i 1 i 1 R 1 β i 1 i i t β i Y i t t t Y t i i t t i t i η t + i X X η i t t + R i t β i t ϕ R i + δ 1 t ζ ϕ + + δ 1 ζ + + i i t t 1 + i i i 1 , ∆ 1 Y i 1 1 t t - η i Y i 1 X i Y t t - η i i t R t X i Y - 1 η R Σ - X - - X 1 η - R t 1 i i - R t Y β i 1 i 1 i i i Y 1 β i 1 t i t 1 η t i t i t i t η X t i t i X ϑ Ζ t + R i R i ϕ i t β t + ϕ ζ t δ i t ζ + t δ t i t + 1 + 1 i i + + i i Y 1 , ∆ + i Y t - 1 1 t - i X t η i i Y 1 i 1 t η i t 1 i t X Y R 1 R 1 - - X η Σ - - - - X η R t Y Y t 1 i 1 i i 1 i 1 R i 1 β i η 1 i i η X β t i t i t X t t i R ϑ Ζ R i ϕ i t i t i ϕ ζ t t t + ζ i i i t t t + t δ i t i i + 1 i i Y t + i Y η + δ 1 + t - t X t - i Y + 1 X t η i i Y t R i + 1 t R X η 1 1 i 1 - - 1 1 - - X η - R 1 - i t i i i R t i 1 β i 1 i 1 β 1 i 1 i 1 i t i t i i t t t i t t t i t t + t i t δ t + i t + + 1 δ + + 1 + + 1 1 1 1 1 i 1 i Y Y η X η R i X ϕ R i ζ ϕ ζ i i t i i i t Y i t t - η i Y X i Y t t - η i t R t X i Y - 1 η R - X - - 1 η - R t X 1 i i - R t β i 1 i 1 i i 1 β i 1 i t i t 1 t i t i i t t i t t t i i t + β t + t δ i t + t δ + 1 + + + 1 , ∆ + 1 1 1 1 1 i 1 i Σ Y Y η X η X R ϑ Ζ R i i ϕ ζ ϕ ζ i t i t i i i Y i Y η t - t X t - i Y X t η i Y t R i t i X η R 1 - - 1 - - X η - R - i t i i R t i 1 β i 1 i 1 β 1 i 1 1 i t i i t i i t t t i t t t i t t + i t δ t t + i t + δ + 1 + + 1 + 1 + 1 1 1 i 1 1 i Nov 28, 2018 FDA 17