2012 AP-ISPOR Luncheon Symposium
Clinical Endpoints: Final versus
Surrogate Endpoint – Implication and
Relevance from a Payer, Physician
and Patient Perspective
Moderator
Bong-min Yang, PhD
Seoul National University
South Korea
Objectives
• To get perspective of the three major stake
h ld
holders
– payer, physician
h i i and
d patient
ti t
• To discuss among panel members and the
audience on its implication and its
relevance in various reimbursement
environments
1
Background
• When conducting cost-effectiveness analysis on drugs, the
ultimately expected clinical value such as survival rate
improvement or decreasing recurrence rate is considered as
an appropriate endpoint
endpoint. Life Years Gained(LYG) or QALYs is
commonly recommended as a final endpoint for cost-effective
ness analysis
• However, the final clinical endpoint is often un-measurable,
except for acute disease which progresses quickly. Also
measuring LYG does not necessarily associated with drug
efficacy or initial intention of development in some cases
• With such limitations, there have been diversified opinions
among researchers and evaluators(payers in most cases),
cases)
and continued discussion to figure out which surrogate
endpoint may well be used for cost-effectiveness analysis
(Ref. Drug Cost-effectiveness Analysis Guideline & Guide to
Document Writing, 2011, HIRA, Korea)
Examples of Recent Issue on Surrogate
vs. Final Endpoint
• Anticancer drugs: takes long for an anticancer drug to
verify its overall survival (OS) from clinical trials
trials. If it had
demonstrated significant improvement in surrogate
endpoint, such as Progression Free Survival(PFS) or
Tumor Response Rate(TRR), it would be regarded to
have proved its efficacy as an effective anticancer drug.
On this, regulatory bodies have shown movement to
approve
pp
oncology
gy drugs
g based on surrogate
g
endpoint
p
re
sults of clinical trials (e.g. Korea-FDA announced the
regulation amendment in 2008). However, the issue still
remains controversial in cases of cost-effectiveness
analyses
2
Examples (2)
• Chronic disease: difficult to continue clinical trial on
chronic diseases such as hypertension and diabetes
untilil d
death,
h which
hi h iis conceptually
ll considered
id d as a fi
finall
endpoint. Hence, had been discussed if blood pressure
or blood sugar (HbA1c) could be an appropriate endpoint
for cost-effectiveness analysis
• Other: osteoporosis - BMD(Bone Marrow Density) vs.
Fracture vs. Mortality rate
Expectation
• Representative experts of payer, physician and patient
invited to express each one’s perspective on the issue of
using proper endpoints in cost-effective analysis
• Discussion and mutual understanding among
researchers and evaluators are crucial since the
endpoint is closely related to the measurement of “effecti
veness,” which is often one of the most important
components in cost-effectiveness analysis
• Moreover,
Moreover very timely topic as multiple Asian countries
are recently considering introduction of HTA system in
their pharmaceutical policy decision making
3
Panelist
• 1. Jasmine Pwu (Taiwan, payer perspective): Director,
INAHTA(International Network of Agencies for Health Te
chnology Assessment) & Director, CDE/HTA (Health Tec
hnology Assessment Division for the Center for Drug
Evaluation) in Taiwan
• 2. Gilberto Lopes (Singapore, physician perspective)
: Senior Consultant in Oncology, Assistant Professor of
Oncology, Assistant Director for Clinical Research – J
ohns Hopkins Singapore International Medical Centre in
Singapore
• 3. John Stubbs (Australia, patient perspective):
E
xecutive officer, Cancer Voices Australia & Member, AN
Z Clinical Trials Advisory Board(Aust. Gov’t)
財團法人醫藥品查驗中心
Center for Drug Evaluation
Final versus Surrogate Final
versus Surrogate
Endpoint – implication and relevance from a payer perspective
Jasmine R. F. Pwu, PhD
Division of HTA, CDE
Taiwan
4
9
Disclaimer
The views presented in this presentation do not Th
i
t d i thi
t ti d
t
necessarily reflect those of the CDE
財團法人醫藥品查驗中心
Center for Drug Evaluation
財團法人醫藥品查驗中心
Center for Drug Evaluation
HTA in Taiwan
5
Key Facts
• Population – 23 million – Aging society
• Parliamentary democracy • 2011 GDP per capita (nominal) ‐ US$21,832 (PPP, IMF) : US$ 39,245
財團法人醫藥品查驗中心
Center for Drug Evaluation
Health Care in Taiwan
• Total health expenditure ‐
p
6.4% of GDP
• National Health Insurance
–
–
–
–
Introduced 1995
Mandatory, single‐payer social health insurance Comprehensive
Low premium & low co‐payment
財團法人醫藥品查驗中心
Center for Drug Evaluation
12
6
New Drug
• “aa newly applied pharmaceutical product that owns newly applied pharmaceutical product that owns
a new chemical entity, new dosage form, new administrated route or new therapeutic effect compound to the listed items in the PBS.”
• Price
Price shall be jointly reviewed and approved by shall be jointly reviewed and approved by
experts in medical and pharmaceutical fields and insurer (BNHI).
財團法人醫藥品查驗中心
Center for Drug Evaluation
Consideration factors for listing
Regulatory body
• Safety
• Efficacy
BNHI
• Comparative effectiveness
C
ti
ff ti
• Budget impact
• Cost‐effectiveness • Ethical/Law/Social/Political Impact
財團法人醫藥品查驗中心
Center for Drug Evaluation
7
Listing Review Process
Application received
Evi‐
dence
Nominate 2+ DBC members as principal reviewers
Principal reviewers made written recommen‐
dations
DBC meeting
DBC: Drug Beneficiary Committee
財團法人醫藥品查驗中心
Center for Drug Evaluation
Decisions made during DBC meetings
• Listing or not
Li ti
t
• Reimbursement price
• Reimbursement criteria/restrictions
b
/
財團法人醫藥品查驗中心
Center for Drug Evaluation
8
Categories for New Drugs
Category 1
Shown substantial improvement in effectiveness, comparing to the best ff i
i
h b
currently‐used drug (therapy)
Category 2A
Shown moderate improvement Category 2B
Shown similar clinical values
財團法人醫藥品查驗中心
Center for Drug Evaluation
Price decision
Submission Submission
price
New Drug category International prices
Reimbursement price
Comparators
Restriction in Restriction
in
use
財團法人醫藥品查驗中心
Center for Drug Evaluation
9
Listing Review Process with HTA
Application received
Evi‐
dence
Principal reviewers made written recommen‐
dations
Nominate 2+ DBC members as principal reviewers
DBC meeting
Assessment Report in 42 days
財團法人醫藥品查驗中心
Center for Drug Evaluation
Listing Review Process
Application
Received
d
42 Days
Effectiveness
Economic
+
Assessment
Assessment
=
Evidence
Report
Drug Beneficiary Committee
財團法人醫藥品查驗中心
Center for Drug Evaluation
10
CDE process 1. Effectiveness
Understand the product
• Licensing
• Place in therapy
Find the
Find the comparators
• Same WHO/ATC class
• Head‐to‐head RCTs • Experience from other HTA reports
Effectiveness/
Safety
• Trial results
• Reviews done else‐
l
where
財團法人醫藥品查驗中心
Center for Drug Evaluation
CDE process 2. Economic
Burden of illness
• Prevalence, incidence, etc.
• Resource use
Cost‐
effectiveness
• Experience from other HTA reports
• Industry‐
submitted
• Database search
Budget impact
• Industry‐
submitted
• Estimates of our own
財團法人醫藥品查驗中心
Center for Drug Evaluation
11
財團法人醫藥品查驗中心
Center for Drug Evaluation
What’s value?
More of “Therapeutic Referencing”…
• Clinical effectiveness is the key!
Cli i l ff ti
i th k !
– Treatment effectiveness
– Safety
– Convenience
財團法人醫藥品查驗中心
Center for Drug Evaluation
12
Clinical endpoint considered
• RCT endpoints
RCT d i t
–
–
–
–
Final Surrogate
PRO (QoL)
…
• Clinical relevance (implicit)
• For oncology drugs
– May ask for OS evidence
財團法人醫藥品查驗中心
Center for Drug Evaluation
Challenges
• Still
Still lack of consensus on surrogate outcome l k f
t
t
choices
• OS evidence is not always available
– Wait?
– Modeling PFS to OS?
Modeling PFS to OS?
– Other approaches?
財團法人醫藥品查驗中心
Center for Drug Evaluation
13
財團法人醫藥品查驗中心
Center for Drug Evaluation
Thank you for your attention!
Surrogate vs. Final Endpoint:
Physician Perspective
Gilberto de Lima Lopes, Jr., M.D., M.B.A, F.A.M.S.
Senior Consultant in Medical Oncology
Program Leader for Health Economics and Policy
Assistant Director for Clinical Research
Asst. Professor of Oncology
Johns Hopkins Singapore International Medical Centre
Johns Hopkins University School of Medicine
14
A Physician’s Job:
“T cure sometimes
“To
ti
To relieve often
To comfort always”
Edward Livingstone Trudeau
(1848--1915)
(1848
A Physician’s Role:
Caring for Patients
Designing and Running Clinical Trials
15
Endpoints: Definitions
Primary vs. Secondary
Surrogate vs. Final
Endpoints
The “Ultimate”
Ultimate Final Endpoint:
Overall Survival
Commonly Used “Surrogate” Endpoints:
Response Rate
Progression--Free Survival
Progression
16
Endpoints
Should be Used More Often:
Patient reported Quality of Life
What These Actually Mean:
Response Rate:
RECIST – Response Evaluation Criteria in Solid
Tumors
Complete Response:
Partial Response:
all lesions disappear
there is a 30%
reduction in the sum
of the largest
diameters of
index lesions
17
What These Actually Mean:
What These Actually Mean:
Progression--Free Survival
Progression
Time between randomization or enrollment
in study until there is evidence of
progression
(in
(i RECIST
RECIST, progression
i
means an increase
i
of 20% in the sum of the largest
diameters of index lesions)
18
PFS in NSCLCA:
Pemetrexed vs. Placebo in
Maintenance
What These Actually Mean:
Overall Survival
Time between randomization or
enrollment in study until a patient
dies
19
OS in
NSCLCA: Pemetrexed
What These
Actually
Mean:
vs. Placebo in Maintenance
OS vs. PFS
Overall Survival
Advantages:
Disadvantages:
Definitive
May take longer time
and more patients;
further treatments
may influence results
20
OS vs. PFS
Progression--Free Survival
Progression
Advantages:
Disadvantages:
Shorter Trials, fewer
patients, not
influenced by further
treatments
May not translate
into better Overall
Survival or
Quality of Life
OS vs. PFS
21
OS vs. PFS
Major Problem: PFS benefit does not
always translate into improvement in
OS
Example: Adjuvant
Chemotherapy for Colon
Cancer
SARGENT, ASCO 2004
22
Example:
Bevacizumab in Advanced Breast Cancer
Why Might PFS not Correlate
with OS?
23
Practical Implications
Decision on Primary endpoint of a
clinical trial and adequate yardstick
for new standards of care has to be
done on a case by case basis, taking
in consideration clinical,
methodological and health economics
literature
Practical Implications
For physicians, improving the length
and quality of life of patients is the
yardstick that matters!
24
Thank You!
Everything should be made as simple
as possible…
… but not simpler!
Albert Einstein
Final versus Surrogate Endpoint –
implication and relevance from a
patient perspective
John Stubbs
ISPOR Meeting
Taiwan September 2012
25
Who am I?
 Enrolled in a Clinical Trial
 11 years post BMT for CML
 Ex cancer patient
 Husband/Parent/Businessman
 Board member
 Cancer Consumer Advocate
 Vocal supporter of Research and Clinical
Trials in Australia
What is a clinical trial?
(from the patient)
 Research study conducted on
human volunteers – (note
volunteers)
 Designed to answer specific
scientific questions
 Prevent, diagnose, develop
therapies to treat many
diseases – in my case chronic
myeloid leukaemia
26
Why do people enter a Clinical
Trial?
 Run out of options
 Better treatment longer term (?)
 Altruism
1. control/cure cancer in general
2. not assist me – but children,
grandchildren
3. part of a health improvement
process
4. engage in research
Key Issues
 People affected by cancer/serious illness are





interested in clinical trials
Clinical trials are not available to all
Long time for answers
Processes to be streamlined/transparent
Ethics and governance
g
Lack of knowledge of PBS process
27
Terminology - Definitions

Surrogate endpoint
For new drugs
 Intervention
 15 years for a trial
to get enough
survival events
(prostate cancer))
(p
 correlation is weak
in prostate cancer
– but better in other
diseases.

Indicative Markers
For radiation
oncology
 Intervention
 Measure overall
survival
 Strong correlation
3 months to 5 years
 Better?
What does this mean?
 Patients have difficulty understanding the






system
Cost of development
Long time for patients to wait for results –
and so the impact
Sponsors use endpoints to reduce time
and size
So the benefit – short term gain
Quality of life??
The validation
28
Trials in Australia
 Good (nay, enviable) record for trials
in Australia
 Small patient pool, links to
international trials
 Cost of development
 Lot of ‘red
red tape’
tape re ethics and
governance
 Public Hospitals
What can the system do?
 A surrogate endpoint is one that you hope
reflects what you really want to measure
– explain??
 Provide better evidence
 Explain Clinical efficacy
 Point out safety issues
 Explain the cost
 Explain bias
But will this assist the patient?
29
For the Patient
 Minimise bias
 Blinding trials Endpoints that minimise bias
 Internal consistency of subgroups,
endpoints
 Magnitude of change of endpoint
 Clinical significance
g
 Underpowered trials--guessing treatment
effect
 Isolating effect of drug/treatment
For the Patient Continued….
 Life-threatening nature of diseases--
patient access vs necessary data for
approval
 Where the drug appears to provide
benefit over available therapy
 Approval based on a surrogate that is
reasonably likely to predict clinical
benefit – cost to Govt and community
30
Our System?






Medicare
Public and private
Linkages
National regulators –
TGA
PBAC
PBS
Most trials in public sector
But most patients are unaware
of processes
And so…..
 Patients rely on the skill and
professionalism
f
off their doctors
 Rely on their belief in the clinical
effectiveness of the process
 But as there is still lack of agreement
amongst professionals
 What’s next?
31
What Aussie patients are
doing!
 Cancer Clinical Trials portal
 Clinical trials information sheet
 Writing Articles
 MJA Meeting
 Lobbying Governments
 Speaking at conferences on the matter
 Members of clinical trials groups
 Breaking down the barriers!
Thank you!
32