Is Survival the Only Thing that Matters?

Drug Development and
Acceptance: Is Survival the Only
Thing that Matters?
Jill M. Kolesar, Pharm.D., BCPS, FCCP
Associate Professor of Pharmacy
University of Wisconsin-Madison
Director- Analytical Instrumentation Laboratory for
Pharmacokinetics, Pharmacodynamics and
Pharmacogenetics (3P)
University of Wisconsin Comprehensive Cancer Center

Outline
• Goal of Drug Development
• Phases of development
– Typical endpoints
– Alternative endpoints

Eschenbach, Plenary Presentation AACR Annual Meeting 2005

Eschenbach, Plenary Presentation AACR Annual Meeting 2005

Eschenbach, Plenary Presentation AACR Annual Meeting 2005

Eschenbach, Plenary Presentation AACR Annual Meeting 2005

Eschenbach, Plenary Presentation AACR Annual Meeting 2005

Oncology Drugs in Development
900
800
700
600
500
837
Average time of clinical development
Phase 1 to FDA approval= 10.8 yrs
Average time at FDA= 1.6 yr
400
300
200
196
219
Clinical trials last 9 years, half of that
is Phase III
100
0
Preclinical Phase 1 Phase 2 Phase 3
67
If we’re going to cure cancer by 2015
we better start doing something new
now!

Oncology: What is changing?
• Combinational chemistry
– More targets to screen
– Typically generate >150,000 per year
– Screened to find 50-100 most active
• Molecular diagnosis
• Targeted therapies
– Faster development
– Bevacizumab
• Less than 5 years
–Imitinib
• Less than 3 (2 months at the FDA)

Targeted Therapies
• Extracellular inhibitors
– Anti-angiogenic/antimetastatic drugs
• Bevacizumab
• Extra- and intracellular inhibitors
– Inhibitory molecules of growth factor receptors
• Erlotinib, gefitinib, cetuximab
• Intracellular inhibitors
– Agents against signal transduction, cell cycle
inhibitors, agents targeting nuclear/extranuclear
• Sorafenib

Who cares about endpoints?
• Industry
– Initial FDA approval>market niche
• USA: FDA
– Typically approves new drugs after phase III comparisons to standard of care
– Patient benefit with favorable risk/benefit profile
– Approvals are commonly based on phase II data and symptom control
• Other countries
– Generally a decision of payer, whether therapy makes clinical and economic
sense
– Same or more rigorous evaluation of efficacy and toxicity
• Prescribers
• Patient

Endpoints
• Efficacy driven endpoints
• Survival
– The real endpoint
• Surrogate endpoints
– response, progression free survival, disease free survival
• Toxicity driven endpoints
– Quality of life
– Symptom control

Endpoints
• Desired endpoints vary with phase of
testing and clinical situation
– Phase I vs III
• Measure of exposure versus improved outcome
– Adjuvant vs Metastatic
• Survival vs quality of life or symptom control

Surrogate Markers
• Replace a distal endpoint (survival) by proxy
endpoint (response, biomarkers)
• Benefits of using surrogate markers
– Reduction in sample size
– Reduction in trial duration
– Reduction in cost
– Reduction in time to evaluate new therapies
• Their use is NOT AS EASY AS IT SOUNDS…
• Use of a marker as surrogate for outcome
requires that you first identify one...

What is a surrogate marker?
• Defining Characteristic:
– a marker must predict clinical outcome, in
addition to predicting the effect of treatment
on clinical outcome
• Operational Definition
– establish an association between marker &
clinical outcome
– establish an association between marker,
treatment & clinical outcome, in which marker
mediates relationship between clinical
outcome and treatment

Surrogate Markers
1) establish an association between marker & clinical outcome.
marker
Clinical
outcome
2) establish an association between marker, treatment &
clinical outcome, in which marker completely mediates
relationship between clinical outcome and treatment.
treatment
marker
Clinical
outcome

Correlative Studies
• It is still valid to look at
markers that you would
expect to be correlated
with the clinical
outcome.
• But, we do not want to be
overconfident by saying
that they are true
‘surrogates.’
• Correlative studies might
include:
– Pharmacokinetics
– Pharmacodynamics
– Other biologic markers that
can be measured in serum,
biopsy samples, etc.
treatment
Clinical
outcome
marker

Characteristics of Oncology Trials
Phase I
Phase II
Phase III
Number of
patients
20-30
30-100
200-5000
Primary Endpoints
Maximum
tolerated dose
Response rate
Time to tumor
progression
Survival
Quality of life
Time to tumor
progression
Cost per patient
100
75
64
Cost per phase
10
22
100

Phase I Endpoints
•The only reason to do a phase I study is to
determine the dose and schedule for
phase II testing
– MTD is a good surrogate for the phase II dose
in cytotoxic agents
– For non cytotoxic agents a measure of
exposure may be more appropriate surrogate

Phase I Endpoints
• Examples of non MTD exposure end
points
– Pharmacokinetics
• Carboplatin and AUC
– Pharmacodynamics
• Bortezomib and proteosome inhibition
– Genetic polymorphims
• 6-MP and TPMT polymorphisms

Phase II
• The purpose of a phase II is to
demonstrate efficacy, therefore survival or
a surrogate of survival is required
– Survival may be difficult to demonstrate if
• Long natural history of the cancer
• Small sample size or limited activity
• Anti-cancer agents are commonly
approved based on phase II data

Agents Approved on Phase II
Response Data
• Rituximab
• Capecitabine
• Trastuzumab
• Temozolamide
• Gefitinib (failed in subsequent phase IIIs)
• Imitinib
• Topetecan
• Irinotecan
• Docetaxel

Classification of Standard
Cytotoxics
Activity
Large
Small
Toxicity
Significant
Trade-offs
Attempt to manage
toxicity
Castaway
Discontinue Development
Modest
Superstar
May be approved on
phase II data
Incrementalist
Take to phase III if
treatment void

Classification of Targeted Therapies
Toxicity
Strong
Evidence of
Tumor
Regression
Modest
activity, good
pks
Target
inhibition
Target
inhibition
No biological
activity
Significant
Trade-offs
?Castaway
Castaway
Castaway
Manage
toxicity,
consider
phase III
Consider
phase back to
phase I-II
Modest
Superstar
Incrementalist
Incrementalist
Castaway
May approved
on phase II
data
Consider for
phase III
Consider for
phase III if tx
void

Study Endpoints- Response Rates
• Response rates (RR)
– Based on tumor measurements from anatomical
imaging
– RR is the likelihood that the tumor will shrink or
disappear based on observations in a significant
group of patients.
• Response Evaluation Criteria in Solid Tumors
(RECIST)

RECIST Responses
* Complete
Response
(CR):
* Partial
Response
(PR):
* Progressive
Disease (PD):
* Stable
Disease (SD):
Disappearance of all target lesions
At least a 30% decrease in the sum of the
LD of target lesions, taking as reference the
baseline sum LD
At least a 20% increase in the sum of the
LD of target lesions, taking as reference the
smallest sum LD recorded since the
treatment started or the appearance of one
or more new lesions
Neither sufficient shrinkage to qualify for PR
nor sufficient increase to qualify for PD,
taking as reference the smallest sum LD
since the treatment started

Phase III Endpoints
• The purpose of a phase III is to compare
the new treatment to the standard therapy,
therefore the current standard therapy
dictates the endpoints
– If there is no standard therapy
– In the metastatic setting, symptom control and
quality of life are very important
– In the adjuvant setting, survival is important

Study Endpoints- Survival
• Overall survival
• Disease-free survival (DFS): Mathematical curve
estimating the % of subjects that will survive and be
disease free at various periods of time after initial
treatment.
– Patients must be disease free at some time during treatment for
this to be valid
• Progression-free survival (PFS): Mathematical curve
estimating the percentage of patients who will survive
and be without evidence of disease progression at
various time periods after initial treatment

Study Endpoints-Survival
Total Mortality (or overall survival from a defined point in
time) - This outcome is arguably the most important one
to patients and is also the most easily defined and least
subject to investigator bias.
Cause-Specific Mortality (or cause-specific mortality from a
defined point in time) - Although this may be of the most
biologic importance in a disease-specific intervention, it
is a more subjective end point than total mortality and
more subject to investigator bias in its determination. It
may also miss important effects of therapy that may
actually shorten overall survival

Study Endpoints- Others
Carefully Assessed Quality of Life - This is an extremely
important end point to patients. May be used alone or
in conjunction with objective response rates to support
drug approvals
Symptom Control
Biomarkers- Pharmacokinetics, pharmacodynamics,
pharmacogenetics
Clinical Benefit

Case #1
• Gemcitabine for the treatment of
pancreatic cancer
– Pancreas cancer in all stages universally fatal
within 5 years, despite numerous clinical trials
and interventional strategies
– Target symptoms of pancreas cancer are
pain, weight loss and decreased activities

Case #1
– Since no agent had
ever improved survival
or had responses in
pancreas cancer the
FDA decided that
clinical benefit was
reason for approval
– Trial compared
gemcitabine to 5FU
with clinical benefit as
primary endpoint
Clinical
benefit
Time to
progression
Median
survival
5FU
4.8%
1
4.41
Gem
23.8%
3.2
5.65
P value
0.0022
0.0002
0.0025

Conclusions
• Targeted therapies speed drug
development
• Targeted therapies may require alternative
endpoint evaluation
• Want my slides?
jmkolesar@pharmacy.wisc.edu