Pot otentia ial l trial d des esigns s and suitable e study - - PowerPoint PPT Presentation

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Pot otentia ial l trial d des esigns s and suitable e study populati tions EMA MA stakeho eholde der i interaction o n on the d dev evelopm pmen ent o of medicinal p produc ducts f for ch chronic n c non-infectious l liver

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SLIDE 1

Pot

  • tentia

ial l trial d des esigns s and suitable e study populati tions

EMA MA stakeho eholde der i interaction o n on the d dev evelopm pmen ent o

  • f medicinal p

produc ducts f for ch chronic n c non-infectious l liver er di dise sease ses ( s (PBC, P , PSC, N NAS ASH)

3 3 De December 2018 2018 Bettina E Hansen IHPME, University of Toronto Toronto Center for Liver Disease, UHN Gastro & Hepatology, Erasmus MC, The Netherlands

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SLIDE 2

Selecti ection

  • n o
  • f study population

PBC UDCA

Non-Responders

Progressive disease Cirrhosis, portal hypertension and/or HCC Premature death or OLT

Responders

Reduced liver related deaths or OLT

Symptomatic/Asymptomatic

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SLIDE 3

New Treatment (Rx) if insufficient response to UDCA

PBC UDCA

Non-Responders

Progressive disease Cirrhosis, portal hypertension and/or HCC Premature death or OLT

Responders

Reduced liver related deaths or OLT

Symptomatic/Asymptomatic

New Rx

slide-4
SLIDE 4

Inclu clusio ion cr criteria ia of

  • ften r

rela elated t to

  • res

esponse cr criteria ia

Duration: 1 year POISE1 – trial Inclusion: ALP>1.67 OR abnormal bilirubin, but bilirubin < 3xULN Response: ALP<=1.67 AND min. 15 % reduction compared to baseline AND normal bilirubin BEZURSO2 - trial Inclusion: Non-responder according to Paris I Response: normal bilirubin, normal ALP, AST, ALT, albumin and PT

1Nevens et al ; NEJM 2016; 2Corpechot at al; NEJM 2018

slide-5
SLIDE 5

Study y population: h high r risk

EMA advocates a study population:

  • at highest risk for progression

 in urgent need of new treatment

  • risk population after min 1 year of

UDCA:

  • ALP >2 xULN ? AND ?
  • abnormal bilirubin
  • additional selection may depend on
  • AST, albumin, GGT, Mayo risk

Reflection paper on regulatory requirements for the development of medicinal products for chronic non-infectious liver diseases (PBC, PSC, NASH); 2018; Prentice, Stat in Med; 1989

8.9% 7.9%

17.5% 65.8%

Hansen, Global PBC dec 2018

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SLIDE 6

Su Suitable s study dy popul ulatin

Selection of an appropriate study population is critical to:

  • Ethical acceptability
  • Minimize bias confounders
  • Numbers of subjects
  • Speed of enrollment
  • Interpretation and extrapolation of data
  • Acceptance by physicians and regulatory authorities
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SLIDE 7

St Study p population: at r risk

ALP ≥ 1.67

Normal bilirubin Abnormal bilirubin

ALP < 1.67 ALP < 1.67 ALP ≥ 1.67

Lammers et al, Gastroenterology 2014

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SLIDE 8

Zoomin ing i in on A ALP LP belo elow 2 2 and n nor

  • rmal b

l bilir lirubin in

Murillo et al., AASLD 2017; Murillo et al., AASLD 2018

A lk a lin e p h o s p h a ta s e (× U L N ) H a z a rd ra tio fo r tra n s p la n ta tio n o r d e a th (9 5 % C I)

2 3 2 3 4 1 1 1.67

B iliru b in (× U L N ) H a z a rd ra tio fo r tra n s p la n ta tio n o r d e a th (9 5 % C I)

0 .0 0 .5 1 .0 1 .5 1 2 3 4 5 6 0 .7 1

T im e 0 c o h o rt

Abnormal

Alkaline phosphatase (ALP) Bilirubin ALP: lower is better Bilirubin: > 0.6 - 0.7 at higher risk

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SLIDE 9

Rotterdam am Di Disease se S Stage: B Biliru rubin & & albumin

1Kuiper et al; Gastroenterology 2009; Hansen 2017 APASL

CLINICAL EVENT N=296 Early

Both normal

N=2039 MODERATE

One Abnormal

N=1084 Advanced

Both abnormal

N=238 N=57 N=133 N=106

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SLIDE 10

Use e of Globe s scor

  • re or
  • r oth
  • ther r

risk s scores t to s

  • sel

elect ct study po population

Lammers et al., Gastroenterology 2015 http://globalpbc.com/globe HR globe score > threshold = 4.5 C-stat = 0.82

50th percentile 100

These patients could potentially benefit of additional therapies

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SLIDE 11

Discu cussio ion: s : sel elect ctio ion of

  • f h

high r risk p pop

  • pula

latio ion

PROS

  • In urgent need
  • Balance of cost benefit?
  • ….

CONS

  • May be to late
  • Treatment not efficient in high risk group
  • Other population need to wait
  • Extrapolation of results questionable
  • Ethical aspects
  • ….
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SLIDE 12

Recycle an and R Reuse se d data an and knowled edge

Hu Huge d databanks a are e part t of t the soluti tion - Especially these are powerful:

  • For rare diseases and events are distant in time
  • To gain knowledge of the natural history / standard of care
  • To understand differences in disease stage, patient characteristics, geographical

differences

  • To study outcomes
  • To study biomarkers
  • To support the search for potential surrogate endpoints
  • To use for design of new studies (power analysis, selection of patients)
  • To use as potential historical controls
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SLIDE 13

Des esign of

  • f phase 3

3 and 4 4 stu tudie ies

  • Phase 3
  • Two/3 arm study (active arm (add on ) versus control arm (UDCA))
  • intermediate endpoint
  • Phase 4 confirmatory study
  • two arm study: active versus control
  • true endpoint = liver transplantation or death, decompensation, MELD>14
  • Power calculation – min 8-15 years follow-up n>500 patients – event driven
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SLIDE 14

Des esign p phase 4 4 confir firmatory s stu tudy u using a a (historical) m matched con

  • ntrol a

l arm

phase 2 phase 3 phase 2 long-term follow-up phase 3 long-term follow-up long-term follow-up study of Standard of Care (SOC)

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SLIDE 15

SOC

New

Des esign P Phase 4 4 con

  • nfir

firmatory s stu tudy u using a a match ched con

  • ntrol a

l arm

Pros

  • reuse of gained knowledge
  • reuse of data

= recycling data and knowledge

  • reduction of study-time
  • to clinical endpoint
  • to assess benefit or harm
  • to approval for the patients

Cons

  • selection bias
  • heterogeneity
  • quality bias
slide-16
SLIDE 16

SOC New

Des esign p phase 4 4 confir firmatory s stu tudy u using a a match ched con

  • ntrol a

l arm

How to solve Cons

  • selection bias

 Use incl/excl criteria

  • heterogeneity

 use weights (IPTW) to stabilize differences

  • quality bias

 minimize bias, install quality control Consider if disease is rare and/or chronic = clinical endpoint is far away

slide-17
SLIDE 17

An e example

SOC

Phase 3

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SLIDE 18

Selecti ection

  • n

In the control cohort apply Selection criteria phase 3

  • ALP>1.67xULN or bilirubin>1xULN
  • Bilirubin<threshold xULN
  • UDCA min 12 months or untreated
  • Of all visits fulfilling above first visit selected
  • diagnosed after 1990 to control for
  • population differences
  • UDCA dosage differences
  • Changes in treatment of decompensation
  • Listing for liver transplantation

SOC

Phase 3

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SLIDE 19

Comparison

  • n P

Phase e 3 an and Sele elect ctio ion

Phase 3 Selection p n=137 n=361 Sex %Female 83.9% 92.5% 0.007 Age, yr (mean,SD) 58.8 (11.9) 54.9 (12.2) 0.002 UDCA % 97.8% 94.2% 0.10 Duration UDCA(yr) 3.6 (3.4) 3.9 (3.7) 0.001

(mean, SD)

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SLIDE 20

Comparis ison P Phase 3 3 and S Sele elect ctio ion

Control Phase 3 10 9 8 7 6 5 4 3 2 1

  • 1

GLOBE SCORE GGT plat/100 ALT AST albumin ALP bilirubin

p=0.18 p=0.44 p=0.001 p=0.001 p=0.02 p=0.39 p=0.001

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SLIDE 21

Comparis ison P Phase 3 3 and G Global S l Sele elect ctio ion IPTW weig eighted a analy lysis is

Phase 2 Global p n=135 n=361 sum of weights sum of weights Sex %Female 90.4% 88.7% 0.75 Age, yr (mean,SD) 55.8 (11.8) 56.4 (12.7) 0.63 UDCA 94.1% 95.2% 0.65 Duration UDCA(yr) 3.8 (3.7) 3.8 (3.6) 0.98

(mean, SD)

SOC New

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SLIDE 22

Comparis ison P Phase 2 2 and G Global S l Sele elect ctio ion

IPTW w weighte ted a analys ysis

control with IPTW phase 3 with IPTW 10 9 8 7 6 5 4 3 2 1

  • 1

GLOBE SCORE GGT plat/100 ALT AST albumin ALP bilirubin

p=0.63 p=0.31 p=0.70 p=0.25 p=0.75 p=0.73 p=0.51 p=0.66

slide-23
SLIDE 23

SOC New

Des esign p phase 4 4 confir firmatory s stu tudy u using a a match ched con

  • ntrol a

l arm

How to solve Cons  selection bias  use incl/excl criteria  heterogeneity  use weights to stabilize differences

  • quality bias

 minimize bias, install quality control Consider if disease is rare and/or chronic = clinical endpoint is far away

slide-24
SLIDE 24

Qu Quality ity c contr trol

  • SOP which includes:
  • Site visits: at site data inspection/capture
  • REDCAP data collection – safe tracking and storing
  • Queries automatically generated
  • Lab-test provided with units and Upper/Lower Limit of Normal
  • All clinical endpoints (decompensation, HCC, liver transplantation,

death and cause of death) reassessed by board of experts Inclusion of other SOC-databases:

  • Prospective data collection in parallel with phase 3
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SLIDE 25

Comments a and d discu cussio ion

  • In case of rare/chronic disease reuse/recycle of historical database is

feasible

  • Selection bias can be avoided
  • Heterogeneity can be avoided with use of IPTW weights to mimic a

RCT

  • Quality control rules must be applied and standardized
  • Consider prospective SOC/registry cohort to run in parallel