understanding+objec0ves+and+endpoints+in+ … · 2017. 4. 6. ·...
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Understanding objec0ves and endpoints in Clinical Cancer Trials (Incl. Role of PRO
Pa0ent Reported Outcomes and Quality of Life aspects)
Professor Franck Bonnetain Methodology and quality of life unit in oncology (EA 3181)
University hospital of Besançon, France & EORTC QOL Group
2nd EORTC Cancer Clinical Research Methodology Course for Patient Advocates , Brussels
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COI
• NOVARTIS • MERCK SERONO • CELGENE • AMGEN • ROCHE • NESTLE • INTEGRAGEN • IPSEN • BAYER • CHUGAI • ERYTECH
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Introduc0on
• Design of clinical trials requires : – Primary outcome with corresponding primary endpoint – Endpoint ≠ objec0ve (but related) – Conclusion based on the Primary objec0ve = why do this trial ? – Hypotheses:
• To improve the primary endpoint • Difference / equivalence/ superiority/non inferiority
• Should be Clinically meaningful for the pa:ents in Phase III: – Therapeu0c strategy should demonstrated a clinical benefit
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Introduc0on
• Endpoint refers to an outcome measure in clinical trial for primary and secondary objec:ves of the study. – Outcomes measured during the course of the trial – Endpoints served to define and to answer the ques0on (Friedman, Furberg, and DeMets)
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Introduc0on • Appropriate choice of endpoint as primary Depend on . . .
– Phase of the trial (II, III, IV etc..) – Disease, cancer localiza0on – Treatment se\ng (progressive, adjuvant, pallia0ve etc ..) – Therapy – Feasibility
• Key Requirements for Drugs Approval (FDA) or to change prac0ce : – Demonstra0on of efficacy = Clinical benefit with acceptable
safety in adequate and well-‐controlled studies • Longer Life • Be_er Life (Health related Quality of life) • With Safety • And acceptable Cost
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• In order for an endpoint to achieve its poten0al to improve cancer care delivery, 3 prerequisites apply
– Technically sound (reproducibility, validity etc..)
– Persuasive evidence about the effect of interven:ons on those outcomes, with due a_en0on to the causal linkages among intermediate, Clinical, and final Outcome
– The willingness and ability to translate findings into informa:on that decision makers find understandable and compelling.
(Lipscomb J, et al. Cancer outcomes research. J Natl Cancer Inst 2004)
Should be used at the Meso (trials), Micro (clinician-patient decision making) and Macro (Population
surveillance of trends) levels
Introduction
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Introduc0on
Different type of endpoints :
– Clinical vs. surrogate
– Landmark vs. time-to-event
– Binary vs. continuous
– Single event vs. Composite
– Objective vs subjective
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Endpoints • Overall survival:
– To improve length of survival 0me is a major goal of cancer = gold standard for phase III trials.
– Time from clinical trial randomiza0on un0l death from any cause.
– Direct measure of clinical benefit for the pa0ents – Calculated with precision. – Could take 0me to be evaluated, requiring rela0vely large and/or lengthy clinical trials.
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Endpoints • Disease-‐free survival (DFS):
– “the 0me from randomiza0on un0l recurrence of tumor, second cancer or death from any cause whichever occur first (FDA 2007).
– “Although overall survival is a conven0onal endpoint for most adjuvant se\ngs, DFS can be an important endpoint in situa0ons where survival may be prolonged, making a survival endpoint imprac0cal.” (FDA 2007).
– To be used DFS should be surrogate of OS as in some cancer localiza0on : Colon, gastric, head & neck.
– DFS needs to be evaluated carefully — a pa0ent’s quality of life (QOL) in the period of extended DFS is an important considera0on for payers, provides, and pa0ents alike
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• Tumor Response
– Measuring tumor shrinkage to assess if treatment is having an effect on the tumor.
– Primary endpoint in Phase II trials but is olen measured in Phase I and III trials as well as secondary objec0ves.
– Response is not an endpoint for adjuvant clinical trials where the primary tumor has been « removed » surgically since in that case there are no detectable tumors to measure.
– RECIST criteria were commonly used with classifica0on as Complete Response, Par0al response, Stability, Progressive
– With immunotherapy and some biotherapy RECIST criteria reflec0ng tumor shrinkage may not be the most appropriate metric :IRECIST, CHOI criteria etc
Endpoints
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Endpoints • Progression Free survival & :me to progression:
– Measures the length of 0me that a pa0ent is both alive and without worsening of their cancer. These are typical endpoints for phase II and III.
– This is not a direct measure of clinical benefit
– Time to Tumor Progression (TTP) is defined as the 0me from randomiza0on to 0me of progressive disease.
– The progression-‐ free survival (PFS) dura0on is defined as the 0me from randomiza0on to objec0ve tumor progression or death (all causes)
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Endpoints
• Pa:ent-‐Reported Outcomes (PRO)
– Any report of the status of a pa:ent’s health condi:on assess directly from the pa:ent, without interpreta:on of the pa:ent’s response by a clinician or anyone else.
• Fa0gue (MFI20), Pain (BPISF) • Then PRO include Health related Quality of life / Quality of life
– Improvement of PRO is considered a direct clinical benefit and may be an appropriate endpoint for regular approval (FDA).
• FDA drug approvals have used pa0ent symptom assessments and/or physical signs represen0ng symptoma0c improvement as primary efficacy endpoints.
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Endpoints
• WHO defini0on of Health (1948) : «Health is a state of complete physical, mental and social well-‐being and not merely the absence of disease or infirmity »
How to assess this definiAon of Health ?
• Health related Quality of life : mul0dimensional concept including at least physical, mental and social dimensions and symptoms related to the treatment
HRQoL to assess perceived health in all dimensions by the patients
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Physical
Social Psychological
Key components of HRQoL instruments
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Endpoints • Health related Quality of Life:
– MulAdimensional concept to assess indirectly health perceived by paAents according the health defined by WHO in 1948
– Based on subjec0ve measures of how well the pa0ent is func0oning and enjoying life. This takes into account both benefits of treatment and loss of quality of life due to the side effects of treatment, progression etc.
– HRQOL is assessed with validated ques0onnaire like EORTC QLC30 for cancer pa0ents with added modules specific of cancer localiza0on & treatments ( BR23, ELD14, OV28….etc)
– HRQOL is typically an endpoint of phase III and now of phase II
– Improvement in signs or symptoms must clearly dis0nguish between tumor symptoms and drug toxicity.
– Pa0ent-‐reported outcomes are op0mally evaluated in randomized, blinded trials by the pa0ents.
HRQOL is prognostic of OS duration in numerous cancer localizations
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Figure 1 : A causal pathway model of health-related quality of life. The horizontal arrows indicate the main, but not exclusive, direction of causality. Wilson IB, Cleary PD. JAMA 1995;273:59–65
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Endpoint classifica0on according to the clinical benefit for the pa0ents
• Clinical benefit meaning should be reaffirmed
• What is a composite endpoint ?
• What is a surrogate endpoint ?
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• Clinical endpoints = Pa:ent centered endpoints – Characteris0c or variable that reflects how a pa0ent feels (QoL), func0ons (QoL, PRO), or
survives (OS): OS, Health related Quality of Life (QoL), fa:gue, pain
• Biomarkers = tumor centered endpoints – A characteris0c that is objec0vely measured and evaluated as an indicator of normal biological
processes, pathogenic processes, or pharmacologic responses to a therapeu0c interven0on: PFS, DFS, RECIST
• « Surrogate Endpoints » : – A biomarker that is intended to subs0tute for a clinical endpoint = for a « pa0ent center
endpoints » – A surrogate endpoint is expected to predict clinical benefit : surrogate validaAon using meta
analysis approaches and should be done by cancer localizaAon & treatment modaliAes
Ref : Temple, JAMA 1999;282:790. Ref : Biomarkers Definitions Working Group, Clin Pharmacol Ther 2001;69:89.
Endpoint classification in oncology
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- 1st : OS
- 2nd : PRO & HRQOL
Endpoint classifica0on for FDA
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Composite endpoint
• One Endpoint based on at least 2 events, components
• Combina0on of various clinical events that might happen
• Ex with PFS : including local progression, metastases or death (all causes), where any one of those events would count as part of the composite endpoint
Mainer CL. Clinical Trials Dictionary, 1996.
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Discomfort : yes vs no
Could move to composite endpoint ?
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Composite endpoint
• Advantages – To improve rate of event – To improve sta0s0cal power – To reduce trial dura0on and or number of pa0ent
• But each of component should be clinically meaningful • Important to look at effects on each of the components • Similar effects (certainly, direc0on of effects) should be seen on all components
• No one component should dominate the endpoint • If it does, this might limit the licensed indica:on
Definition is a key component
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CONS composite endpoints:
- To reach statistical significance
- Smallest effect for the most important component
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Definition of composite endpoint is then crucial
To allow comparison of the results between trials
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DATECAN PROJECT 28
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DFS at 10 years from 55.5 to 59.3% !
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• Clinical benefit required surrogacy : – Impact of treatment on the surrogate (PFS, DFS etc..) should predict effect
of treatment on the clinical endpoints (OS, HRQOL etc) – A simple correla:on is not sufficient : if tumor shrinkage was correlated
with OS ≠ surrogacy
– Surrogate evalua:on should be done by cancer localiza:on, se[ng, type of treatment etc and then always done a posteriori
– Gold standard for valida0on : Meta-‐analy0c approach
Surrogacy/surrogate endpoints
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PFS « surrogate » of OS for chemotherapies
But since ASCO 2013 PFS could not be considered as a good
« surrogate » for biotherapies
- Interest for the patients to improve PFS without OS improvement ?
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PFS Trial-level association
R2 = 0.88 (95% CI 0.77 – 1)
Surrogacy of PFS for OS in T3-‐T4 Rectal Cancer
3 year PFS Rates : - CRT = 64.3% (95% CI: 61.0-67.5%) - RT = 60.6% (95% CI: 57.2-63.9%)
P=0.49
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DFS is s0ll surrogate in adjuvant colon cancer
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PFS as surrogate in breast cancer
! At the individual level PFS et OS:
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! At the trial level
PFS in breast cancer
PFS is not surrogate of OS in mBC
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The real objective of the treatment is to improve Survival duration and/or Quality of life
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So where are we going = co-primary endpoints - Patient centered endpoints : SG & QdV - Tumor Centered endpoint: PFS, DFS etc
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• HrQoL should be a co-‐primary endpoint with tumor centered endpoint to be in line with :
– Trials dura0on and sample size
– Demonstra0on of clinical benefit for the pa0ent
New challenge to implement such design in oncology
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Two phase III RCT in glioblastoma for regular approval of Bevacizumab
• Two me too trials: – STUPP + /-‐ Bevacizumab in Glioblastoma
– No effect on OS – Posi0ve effect on PFS – While OS and PFS were co-‐primary (« single sufficient ») no impact was observed on OS : pa0ent clinical benefit is ques0onnable for regulatory approval
– Then HrQOL was regarded as primary endpoint but Different results for HrQOL
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Co-‐primary endpoints
• Which methodology
• Key point: decision rules
• «alternaAve primary endpoint or single sufficient » – Treatment will be declared as efficient if at least one endpoint is clinically and
sta0s0cally significant – Alpha type (false +) should be controlled
• « mulAples co-‐primary endpoints » – Treatment will be declared as efficient if the two endpoint are clinically and
sta0s0cally significant – To control sta0s0cal power (false -‐)
Co-primary could be composite endpoints
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In Ederly cancer patients
HrQOL should be co-primary / composite endpoint
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-‐ Primary or co-‐primary endpoints in oncology
-‐ To demonstrate that new therapeu0c strategies reach a clinical benefit for the pa0ent
-‐ To individualize treatment based on HrQOL
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Thank you for your a_en0on