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Clinical Endpoints: Final versus Surrogate Endpoint Implication and

2012 AP-ISPOR Luncheon Symposium

Surrogate Endpoint – Implication and Relevance from a Payer, Physician

and Patient Perspective

ModeratorBong-min Yang, PhD

Seoul National UniversitySouth Korea

Objectives

• To get perspective of the three major stakeh ld h i i d ti tholders – payer, physician and patient

• To discuss among panel members and the audience on its implication and its relevance in various reimbursement environmentsenvironments

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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 Life Years Gained(LYG) or QALYs isan appropriate endpoint. Life Years Gained(LYG) or QALYs is commonly recommended as a final endpoint for cost-effectiveness 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)among researchers and evaluators(payers in most 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 If it hadverify its overall survival (OS) from clinical 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 oncology drugs based on surrogate endpoint repp gy g g psults 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

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Examples (2)

• Chronic disease: difficult to continue clinical trial on chronic diseases such as hypertension and diabetes

il d h hi h i ll id d fi luntil death, which is conceptually considered as a final 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 analysisusing 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 “effectiveness,” which is often one of the most important components in cost-effectiveness analysis

• Moreover very timely topic as multiple Asian countries• Moreover, very timely topic as multiple Asian countries are recently considering introduction of HTA system in their pharmaceutical policy decision making

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Panelist• 1. Jasmine Pwu (Taiwan, payer perspective): Director,

INAHTA(International Network of Agencies for Health Technology Assessment) & Director, CDE/HTA (Health Technology Assessment Division for the Center for Drughnology 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 – Johns Hopkins Singapore International Medical Centre in SingaporeSingapore

• 3. John Stubbs (Australia, patient perspective): Executive officer, Cancer Voices Australia & Member, ANZ Clinical Trials Advisory Board(Aust. Gov’t)

財團法人醫藥品查驗中心Center for Drug Evaluation

Final versus SurrogateFinal versus Surrogate Endpoint – implication and

relevance from a payer perspectiveJasmine R. F. Pwu, PhD

Division of HTA, CDE

Taiwan

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Disclaimer

Th i t d i thi t ti d t

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The views presented in this presentation do not necessarily reflect those of the CDE



HTA in Taiwan

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Key Facts

• Population

– 23 million

– Aging society

• Parliamentary democracy


• 2011 GDP per capita (nominal) ‐ US$21,832

(PPP, IMF) : US$ 39,245

Health Care in Taiwan

• Total health expenditure ‐ 6.4% of GDPp

• National Health Insurance

– Introduced 1995

– Mandatory, single‐payer social health insurance

– Comprehensive


– Comprehensive

– Low premium & low co‐payment

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New Drug

• “a newly applied pharmaceutical product that ownsa 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 shall be jointly reviewed and approved by


Price shall be jointly reviewed and approved by experts in medical and pharmaceutical fields and insurer (BNHI).

Consideration factors for listing

Regulatory body

• Safety

• Efficacy

C ti ff ti

BNHI


• Comparative effectiveness

• Budget impact

• Cost‐effectiveness

• Ethical/Law/Social/Political Impact

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Listing Review Process

Application received

Evi‐dence

Nominate 2+ DBC

members as principal reviewers

Principal reviewers made written

recommen‐dations

DBC

meeting


dations

DBC: Drug Beneficiary Committee

Decisions made during DBC meetings

Li ti t• Listing or not

• Reimbursement price

b /


• Reimbursement criteria/restrictions

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Categories for New Drugs

Category 1 Shown substantial improvement in ff i i h beffectiveness, comparing to the best currently‐used drug (therapy)

Category 2A Shownmoderate improvement


Category 2B Shown similar clinical values

Price decision

Submission

New Drug category

Submission price

Comparators

Restriction in


Reimbursement price

International prices

Restriction in use

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Listing Review Process with HTA



Evi‐denceEvi‐

dence

Nominate 2+ DBC


Nominate 2+ DBC



recommen‐dations


recommen‐dations

DBC

meeting

DBC

meeting


dationsdations

Assessment Report in 42 days

Listing Review Process

ApplicationdReceived

EffectivenessAssessment

EvidenceReport

EconomicAssessment

+ =

42 Days


Drug Beneficiary Committee

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CDE process 1. Effectiveness

Understand Find the Effectiveness/the product

• Licensing

• Place in therapy

Find the comparators

• Same WHO/ATC class

• Head‐to‐head RCTs

Effectiveness/Safety

• Trial results

• Reviews done l


• Experience from other HTA reports

else‐where

CDE process 2. EconomicBurden of illness

Cost‐effectiveness

Budget impact

• Prevalence, incidence, etc.

• Resource use

• Experience from other HTA reports

• Industry‐submitted

• Database search

• Industry‐submitted

• Estimates of our own


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What’s value?

More of “Therapeutic Referencing”…

Cli i l ff ti i th k !• Clinical effectiveness is the key!

– Treatment effectiveness

– Safety

– Convenience


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Clinical endpoint considered

RCT d i t• RCT endpoints

– Final

– Surrogate

– PRO (QoL)

– …


• Clinical relevance (implicit)

• For oncology drugs

– May ask for OS evidence

Challenges

Still l k f t t• Still lack of consensus on surrogate outcome choices

• OS evidence is not always available

– Wait?

– Modeling PFS to OS?


Modeling PFS to OS?

– Other approaches?

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Thank you for your attention!

Surrogate vs. Final Endpoint: Surrogate vs. Final Endpoint: Physician PerspectivePhysician Perspective

Gilberto de Lima Lopes, Jr., Gilberto de Lima Lopes, Jr., M.D., M.B.A, F.A.M.SM.D., M.B.A, F.A.M.S..

Senior Consultant in Medical OncologySenior Consultant in Medical OncologyProgram Leader for Health Economics and PolicyProgram Leader for Health Economics and Policy

Assistant Director for Clinical ResearchAssistant Director for Clinical ResearchAsst. Professor of OncologyAsst. Professor of Oncology

Johns Hopkins Singapore International Medical CentreJohns Hopkins Singapore International Medical CentreJohns Hopkins University School of MedicineJohns Hopkins University School of Medicine

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A Physician’s Job:A Physician’s Job:

“T ti“T ti“To cure sometimes“To cure sometimesTo relieve oftenTo relieve often

To comfort always”To comfort always”

Edward Livingstone TrudeauEdward Livingstone Trudeau(1848(1848--1915)1915)

A Physician’s Role:A Physician’s Role:

Caring for PatientsCaring for PatientsCaring for PatientsCaring for PatientsDesigning and Running Clinical TrialsDesigning and Running Clinical Trials

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Endpoints: DefinitionsEndpoints: Definitions

Primary vs. SecondaryPrimary vs. SecondaryPrimary vs. SecondaryPrimary vs. SecondarySurrogate vs. FinalSurrogate vs. Final

EndpointsEndpoints

The “Ultimate” Final Endpoint:The “Ultimate” Final Endpoint:The Ultimate Final Endpoint:The Ultimate Final Endpoint:Overall SurvivalOverall Survival

Commonly Used “Surrogate” Endpoints:Commonly Used “Surrogate” Endpoints:Response RateResponse RateResponse RateResponse RateProgressionProgression--Free SurvivalFree Survival

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EndpointsEndpoints

Should be Used More Often:Should be Used More Often:Should be Used More Often:Should be Used More Often:Patient reported Quality of LifePatient reported Quality of Life

What These Actually Mean:What These Actually Mean:

Response Rate: Response Rate: RECIST RECIST Response Evaluation Criteria in Solid Response Evaluation Criteria in Solid RECIST RECIST –– Response Evaluation Criteria in Solid Response Evaluation Criteria in Solid

TumorsTumors

Complete Response:Complete Response: all lesions disappearall lesions disappearPartial Response:Partial Response: there is a 30% there is a 30%

reduction in the sum reduction in the sum of the largest of the largest diameters of diameters of index lesionsindex lesions

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ProgressionProgression--Free SurvivalFree Survival

Time between randomization or enrollment Time between randomization or enrollment in study until there is evidence of in study until there is evidence of progressionprogression

(i RECIST i i (i RECIST i i (in RECIST, progression means an increase (in RECIST, progression means an increase of 20% in the sum of the largest of 20% in the sum of the largest diameters of index lesions)diameters of index lesions)

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PFS in NSCLCA: PFS in NSCLCA: PemetrexedPemetrexed vs. Placebo in vs. Placebo in

MaintenanceMaintenance


Overall SurvivalOverall Survival

Time between randomization or Time between randomization or enrollment in study until a patient enrollment in study until a patient diesdies

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What These Actually Mean:What These Actually Mean:OS in NSCLCA: OS in NSCLCA: PemetrexedPemetrexedvs. Placebo in Maintenancevs. Placebo in Maintenance

OS vs. PFSOS vs. PFS

Overall SurvivalOverall Survival

Advantages: Advantages: DefinitiveDefinitiveDisadvantages:Disadvantages: May take longer time May take longer time

and more patients; and more patients; further treatments further treatments further treatments further treatments may influence resultsmay influence results

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ProgressionProgression--Free SurvivalFree Survival

Advantages: Advantages: Shorter Trials, fewer Shorter Trials, fewer patients, not patients, not influenced by further influenced by further treatmentstreatments

Disadvantages:Disadvantages: May not translate May not translate Disadvantages:Disadvantages: May not translate May not translate into better Overall into better Overall Survival or Survival or Quality of LifeQuality of Life


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Major Problem: PFS benefit does not Major Problem: PFS benefit does not always translate into improvement in always translate into improvement in OSOS

Example: Adjuvant Example: Adjuvant Chemotherapy for Colon Chemotherapy for Colon

CancerCancer

SARGENT, ASCO 2004

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Example: Example: Bevacizumab in Advanced Breast CancerBevacizumab in Advanced Breast Cancer

Why Might PFS not Correlate Why Might PFS not Correlate with OS?with OS?

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Practical ImplicationsPractical Implications

Decision on Primary endpoint of a Decision on Primary endpoint of a Decision on Primary endpoint of a Decision on Primary endpoint of a clinical trial and adequate yardstick clinical trial and adequate yardstick for new standards of care has to be for new standards of care has to be done on a case by case basis, taking done on a case by case basis, taking in consideration clinical, in consideration clinical, methodological and health economics methodological and health economics methodological and health economics methodological and health economics literatureliterature

Practical ImplicationsPractical Implications

For physicians, improving the length For physicians, improving the length and quality of life of patients is the and quality of life of patients is the yardstick that matters!yardstick that matters!

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Thank You!Thank You!

Everything should be made as simple Everything should be made as simple Everything should be made as simple Everything should be made as simple as possible…as possible…

… but not simpler!… but not simpler!

Albert EinsteinAlbert Einstein

Final versus Surrogate Endpoint –implication and relevance from a

John Stubbs

ISPOR Meeting

implication and relevance from a patient perspective

ISPOR Meeting Taiwan September 2012

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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

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Why do people enter a Clinical Trial?

Run out of options Better treatment longer term (?) Altruism

1. control/cure cancer in general2. not assist me – but children,

grandchildren3. part of a health improvement

process4. engage in research

Key Issues

People affected by cancer/serious illness are 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 governanceg Lack of knowledge of PBS process

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Terminology - Definitions Surrogate endpointFor new drugs

Indicative MarkersFor radiation For new drugs

Intervention 15 years for a trial

to get enough survival events (prostate cancer)

For radiation oncology Intervention Measure overall

survival Strong correlation (p )

correlation is weak in prostate cancer – but better in other diseases.

Strong correlation 3 months to 5 years

Better?

What does this mean?

Patients have difficulty understanding the 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 Sponsors use endpoints to reduce time

and size So the benefit – short term gain Quality of life?? The validation

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Trials in Australia

Good (nay, enviable) record for trials Good (nay, enviable) record for trials in Australia

Small patient pool, links to international trials

Cost of development Lot of ‘red tape’ re ethics and Lot of red 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 biasBut will this assist the patient?

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For the Patient

Minimise bias Minimise bias Blinding trials Endpoints that minimise bias Internal consistency of subgroups,

endpoints Magnitude of change of endpoint Clinical significanceg 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 Approval based on a surrogate that is reasonably likely to predict clinical benefit – cost to Govt and community

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Our System?

MedicarePublic and private Public and private

Linkages National regulators –

TGAPBACPBS

Most trials in public sector

But most patients are unaware of processes

And so…..

Patients rely on the skill and f fprofessionalism of 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?

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What Aussie patients are doing!

Cancer Clinical Trials portalCancer Clinical Trials portal Clinical trials information sheet Writing Articles MJA Meeting Lobbying Governments Speaking at conferences on the matter Speaking at conferences on the matter Members of clinical trials groups

Breaking down the barriers!

Thank you!

Documents

Eli Lilly All Slides - ISPOR · Comparators Restrictionin ... Magnitude of change of endpoint ... Microsoft PowerPoint - Eli Lilly All Slides.pptx