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Development of New Drugs: Lessons from Clinical Trials

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Development of New Drugs: Lessons from Clinical Trials Paul A. Meyers, MD Vice-Chair, Pediatrics Memorial Sloan-Kettering Professor of Pediatrics Weill Cornell ... – PowerPoint PPT presentation

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Title: Development of New Drugs: Lessons from Clinical Trials


1
Development of New Drugs Lessons from Clinical
Trials
  • Paul A. Meyers, MD
  • Vice-Chair, Pediatrics
  • Memorial Sloan-Kettering
  • Professor of Pediatrics
  • Weill Cornell Medical College

2
Combining biological agents with chemotherapy
  • Phase 1
  • Safety profile
  • Pharmacology
  • Active dose/MTD
  • Phase 2
  • Preliminary efficacy
  • Design considerations
  • Phase 3
  • Design considerations
  • Choice of outcome variable
  • Statistical considerations
  • Duration of followup
  • Benefit-risk ratio regulatory considerations

3
Phase 1
  • First-in-man
  • Few anti-cancer agents are tested in healthy
    volunteers
  • Pharmacokinetics, pharmacodynamics, metabolism
  • Toxicity/ active dose/MTD

4
Phase 1 Biologics/BRMs
  • Studies in patients with a variety of cancers,
    usually late stage.
  • Clinical activity may be rare in patients with
    bulky disease
  • Pharmacology
  • Non-linear dose/response (threshold doses,
    tachyphylaxis)
  • Biologic activity passive/active

5
Phase 1 MTP
  • Phase 1 studies in patients with late stage
    cancers
  • Anecdotal responses
  • Optimal biologic activity .5-2mg/m2
  • MTD (ltgrade 3 events) 4-6mg/m2

6
Phase 1 IGF1R Inhibitors
  • Few dose limiting toxicities (antibodies)
    dosing based on biomarkers?
  • Clinical activity

7
Phase 2
  • Larger group of patients (usually 50-200)
  • Obtain evidence of efficacy in target indication
  • Extend safety information
  • Obtain information needed to plan randomized
    efficacy studies

8
Phase 2 Biologics/BRMs
  • Bulk disease vs minimal residual disease
  • Animal models
  • Mechanism of action (passive/active)
  • Activation of host immune system
  • Synergy/antagonism with chemotherapy
  • Preclinical data

9
Phase 2 MTP in osteosarcoma
  • Impact of data from canine OS
  • Expectation of benefit in mrd
  • In vivo evidence of anti-tumor activity

10
Phase 2 MTP and osteosarcoma
  • Planning for Phase 3
  • With/without chemotherapy
  • Proposed mechanism of action
  • a) activation of macrophages
  • b) fas/fas-ligand interaction
  • Administer with chemotherapy
  • Role of adjuvant phase 2 design

11
Phase 2 IGF1R inhibition in sarcoma
  • Single agent vs chemo combination
  • Outcome objective response, PFS, survival
  • Randomized trial or historical control
  • Use of phase 2 data impact design

12
Phase 3
  • Confirmation studies prove that the promising
    effects seen in Phase II are real (usually
    100-1,000 people)
  • Safety

13
Phase 3 Biologics/BRMs
  • Design considerations
  • In combination with other agents
  • Timing of introduction
  • Timing of randomization

14
Phase 3 Design Considerations MTP and
Osteosarcoma
  • Timing of introduction
  • Phase I/II trials suggest use in mrd
  • Introduce after surgical resection of clinically
    detectable disease

15
Phase 3 Design Considerations MTP and
Osteosarcoma
  • Timing of introduction
  • Delayed introduction of new agent will be
    ineffective
  • Failure in osteosarcoma appearance of metastatic
    nodules
  • Reflects events months earlier
  • Timing of randomization

16
Phase 3 Design Considerations Osteosarcoma
Survival DFS
17
Phase 3 Study Design
INDUCTION
MAINTENANCE
D E F I N I T I V E S U R G E R Y
A Cisplatin Doxorubicin HDMTX
Cisplatin, Doxorubicin, HDMTX
A
Cisplatin, Ifosfamide, Doxorubicin, HDMTX
B Ifosfamide Doxorubicin HDMTX
B
20
36
27
Weeks
R
Introduction of MTP
18
Phase 3 Design Considerations IGF R Inhibitors
  • Timing of introduction
  • Phase II trials show objective responses
  • Synergy with chemotherapy

19
Phase 3 Biologics/BRMs
  • Statistical considerations
  • Study design
  • Sample size
  • Interim analyses
  • Choice of outcome variable (endpoints)
  • Duration of follow up
  • Post hoc analyses

20
Phase 3 Statistical Considerations Study Design
  • Factorial Design
  • Address two questions in one clinical trial
  • Marginal analysis
  • Interaction
  • test for interaction
  • proof of no interaction trial sizing

21
Phase 3 Study Design
INDUCTION
MAINTENANCE
D E F I N I T I V E S U R G E R Y
A Cisplatin Doxorubicin HDMTX
Cisplatin, Doxorubicin, HDMTX
A
Cisplatin, Ifosfamide, Doxorubicin, HDMTX
B Ifosfamide Doxorubicin HDMTX
B
20
36
27
Weeks
22
Phase 3 Statistical Considerations Sample size
  • Sample sizepopulation ratio
  • Impact on magnitude of error
  • Regulatory issue need for confirmatory study

23
Phase 3 Statistical Considerations Sample size
  • Jar holding 1,000 marbles, 700 red, 300 blue
  • Sample 50 marbles
  • Mean 35 red, 15 blue (70 red)
  • Standard error of the mean 6.3

24
Phase 3 Statistical Considerations Sample size
  • Jar holding 1,000 marbles, 700 red, 300 blue
  • Sample size 500 marbles
  • Mean 350 red, 150 blue (70 red)
  • Standard error of the mean 1.5

25
Phase 3 Statistical Considerations Sample size
for MTP in Osteosarcoma
  • INT0133 777 patients/48 months
  • Osteosarcoma incidence 350-400/year
  • Sample size 48-55 of population
  • Effect estimate robust, smaller error

26
Phase 3 Statistical Considerations Interim
analyses
  • Timing of interim analyses
  • Pre-defined by events not elapsed time
  • Danger of looking too often

27
Phase 3 Statistical Considerations Interim
analyses and MTP/Osteosarcoma
  • Futility
  • Safety
  • Three interim analyses
  • Modified p-value

28
Phase 3 Statistical Considerations Choice of
outcome variable
  • Progression free survival
  • Event free survival
  • Median survival
  • 80th percentile survival
  • Overall survival
  • Quality of life

29
Pediatric oncology endpoint NCI position (I)
  • Strength of Study Design
  • 1. Randomized controlled clinical trial
  • i. Double-blinded
  • ii. Non-blinded

http//www.cancer.gov/cancertopics/pdq/levels-evid
ence-adult-treatment
30
Pediatric oncology endpoint NCI position (II)
  • Strength of Endpoints
  • A. Total mortality
  • B. Cause-specific mortality
  • C. QOL
  • D. Indirect surrogates
  • i. EFS
  • ii. DFS
  • iii. PFS
  • iv. Response

31
Pediatric oncology endpoint FDA Position
  • Patient Access to New Therapeutic Agents for
    Pediatric Cancer December 2003
  • Report to Congress
  • Surrogate markers could be considered as an
    early means of identifying efficacy, but the use
    of surrogates requires validation of these
    markers and correlation with clinical benefit.

http//www.fda.gov/cder/Pediatric/BPCA-ReportDec20
03.pdf
32
Phase 3 Statistical Considerations Outcome
variable Progression free survival (PFS)
  • Wide applicability in sarcoma
  • Not widely used in pediatric sarcomas
  • Result available relatively quickly
  • Ascertainment bias
  • Predetermined evaluation schedule
  • Central review of imaging
  • Regulatory considerations

33
Phase 3 Statistical Considerations Outcome
variable Event free survival (EFS)
  • Widely employed surrogate for survival
  • Includes secondary malignancy, toxic deaths
  • Ascertainment bias
  • Predetermined evaluation schedule
  • Central review of imaging

34
Phase 3 Statistical Considerations- Outcome
variable Event free survival (EFS) and MTP
  • Interaction between assigned chemotherapy and MTP
    was assessed using the proportional hazards
    regression. A p-value of 0.10 level or less was
    considered evidence of a significant interaction.

35
Phase 3 Statistical Considerations- Outcome
variable Event free survival (EFS) and MTP
  • Event free survival
  • Test of the hypothesis of no interaction (p
    0.102)
  • MTP Hazard ratio
    95 CI
  • Regimen A 0.99 0.69, 1.4
  • Regimen B 0.65 0.45, 0.93
  • All patients 0.80 0.62, 1.0

36
Phase 3 Statistical Considerations- Outcome
variable Event free survival (EFS) and MTP
37
Phase 3 Statistical Considerations- Outcome
variable Event free survival (EFS) and MTP
38
Phase 3 Statistical Considerations- Outcome
variable Survival
  • Not subject to ascertainment bias
  • Many years of followup
  • Lack of QOL data

39
Phase 3 Statistical Considerations- Outcome
variable Survival and MTP in Osteosarcoma
40
Analysis of Interaction
  • Overall survival Test of the hypothesis of no
    interaction (p 0.60)
  • MTP Hazard ratio 95 CI
  • Regimen A 0.76 0.49, 1.2
  • Regimen B 0.66 0.43, 1.0
  • All patients 0.71 0.52, 0.96

41
Phase 3 Statistical Considerations- Outcome
variable Survival and MTP in Osteosarcoma
42
Phase 3 Statistical Considerations- Outcome
variable Survival and MTP in Osteosarcoma
Survival by MTP Assignment
43
Phase 3 Statistical Considerations- Outcome
variable Survival and MTP in Osteosarcoma
44
Phase 3 Statistical Considerations Outcome
variable Quality of life
  • Incorporates survival
  • Adds dimension related to non-lethal toxicity
  • Increasingly considered optimal endpoint

45
Phase 3 Statistical Considerations Duration of
follow-up
  • Dependent on variable and population
  • PFS in late stage patients shorter followup
  • DFS, EFS in mrd patients multi year
  • Survival need to monitor late effects, need for
    life time followup

46
Phase 3 Statistical Considerations Duration of
follow-up and MTP/Osteosarcoma
  • Cooperative group fiscal decision to close study
    to followup
  • Difficulty obtaining followup after official
    study closure
  • Older study, no social security numbers

47
Phase 3 Statistical Considerations Duration of
follow-up and IGF1R inhibition/sarcoma
  • Phase II study PFS, not designed to capture
    survival
  • Phase III study EFS, must be designed to capture
    survival

48
Phase 3 Statistical Considerations Post hoc
analyses
  • Analyses of important subgroups should be a
    regular part of the evaluation of a clinical
    study (when relevant), but should usually be
    considered exploratory, unless there is a priori
    suspicion that one or more of these factors may
    influence the size of effect (CPMP/EWP/908/99).

49
Phase 3 Statistical Considerations Post hoc
analyses and MTP/Osteosarcoma
50
Subgroup Analysis Caveat
  • Clearly significant overall results may
    therefore provide strong indirect evidence of
    benefit in subgroups where the results,
    considered in isolation, are not conventionally
    significant (or even, perhaps, slightly
    adverse).
  • ISIS-2 (Second International Study of Infarct
    Survival) Collaboration Group, The Lancet 1988, 2
    (8607)349-360.

51
Neoadjuvant Histologic Response Patients gt 16
Years
p0.0626 Includes patients who progressed
before surgery or for whom data not available
52
Neoadjuvant Histologic Response Patients lt 16
Years
p0.9421 Includes patients who progressed
before surgery or for whom data not available
53
Phase 3 Statistical Considerations Post hoc
analyses and MTP/Osteosarcoma
54
Phase 3 Statistical Considerations post hoc
analyses - Post relapse survival
  • Post relapse treatment
  • alloBMT in hematologic malignancy
  • Retrieval therapies for solid tumors
  • Surgery, radiation, chemo

55
Phase 3 Statistical Considerations post hoc
analyses Post relapse survival and MTP in
osteosarcoma
  • Surgical resection of metastatic sites necessary
    for survival
  • No impact of chemotherapy on post relapse
    survival
  • INT 0133, no difference in surgery for recurrence
  • Survival is the ultimate endpoint

56
BenefitRisk Ratio
  • Introduction of new agents
  • Robust indication of benefit
  • Ascertainment of risk in appropriate setting
  • Favorable benefitrisk ratio argues for early
    introduction

57
MTP in osteosarcoma Benefitrisk ratio
  • Statistically significant 30 reduction in the
    risk of death
  • No grade III or IV toxicity attributed to MTP
  • Very favorable benefitrisk ratio

58
IGF1R inhibition in sarcoma Benefitrisk ratio
  • Phase I, Phase II studies of IGF1R MoAb
    favorable toxicity profile
  • Phase III studies in non-sarcoma indications in
    combination with chemothearpy low toxicity
  • Probable favorable benefitrisk ratio in phase
    III trials in sarcoma

59
Regulatory Issues
  • Requirement for placebo
  • Need for large sample size
  • Requirement for confirmatory studies

60
Regulatory issues Requirement for placebo
  • Placebos considered unacceptable for minors
  • MTP associated with fever, chills
  • What to use for placebo?
  • IGF1R formulation hard to blind pharmacist

61
Regulatory issues Sample size
  • Orphan diseases
  • Track record in pediatric oncology
  • One phase III randomized study/decade
  • International collaboration
  • EURO-Ewing, EURAMOS

62
MTP in osteosarcoma Requirement for confirmatory
studies
  • MTP in OS largest prospective randomized trial
    ever completed
  • Sample size 45-50 population
  • Robust survival advantage
  • Favorable benefitrisk ratio
  • Difficulty mounting successor study

63
IGF1R inhibition in sarcomas Requirement for
confirmatory studies
  • European, US regulators
  • Will require confirmatory studies which
    demonstrate survival advantage
  • Plan to acquire survival data from all studies
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