1 biomarkers as surrogates tipping the balance toward persuasiveness everylife foundation rare...
TRANSCRIPT
1
Biomarkers as Surrogates
Tipping the Balance Toward Persuasiveness
EveryLife Foundation Rare Disease WorkshopMay 2013 Washington, DC
Marc K Walton MD, PhDAssociate Director for Translational Medicine
Office of Translational SciencesCDER-FDA
The views expressed are those of the author, and do not necessarily represent an official FDA position
2
Biomarkers in A&WC Studies (Phase 3)
• Secondary endpointSupportive of primary EP findingsObjective, preciseHelps decrease uncertainties regarding primary efficacy
endpoint results interpretation• Primary Endpoint
Surrogate endpoint for a specific Context of UseWell established relationship to clinical outcome
Conventional marketing approval“reasonably likely to predict…” relationship
Accelerated approval provisions of regulations
3
Surrogate Endpoint
• Stands in place of an efficacy endpointFeels FunctionsSurvives
• Usually intended as a prediction of a future clinically meaningful outcomeRequires assumptions about future clinical
course after biomarker measurement with continued drug treatment
4
Questions for Evaluation – Disease Related
• Do we know the underlying primary cause?True single etiology or multiple closely related etiologies or
syndrome with (potentially) different etiologies? • How well do we understand the complete
pathophysiology from primary cause to meaningful clinical outcome?How detailed is the knowledge?How strongly do we believe our “knowledge” (interpretation
of scientific observations) is complete and correct? • What is nature of variation in disease?
Homogeneous / broadly heterogeneous / heterogeneous with distinct, homogeneous, phenotypes?
How well understood is the basis for the variation?
5
Questions to Consider – Biomarker Focus
• What is the physiologic concept thought related to clinical outcome?
• How should that concept be measured?The biomarker is this measurement
• What clinical outcome is it expected to predict?• When is the clinical outcome expected?
Relative to the measurement of the biomarker• Is the biomarker in the direct pathophysiologic
pathway leading to that clinical outcome?Versus a side branchHow confidently understood? (refer to ‘disease
related’ issues)
6
• Is it in a unitary part of the pathophysiologic pathway leading to the clinical outcome?Versus in one of several parallel pathologic pathways
• Where in the sequence of pathophysiologic steps does the biomarker occur?
• Do we know the anatomic location where the biomarker functions in the disease process?
• Is the biomarker being sampled at the site where it functions in the pathophysiology?If not, how do measurements at the site of sampling
relate to effects at the site of function?
Issues for Evaluation – Biomarker Focus
7
Issues for Evaluation – Biomarker Focus
• How close in the pathopysiologic sequence is the biomarker to the intended clinical outcome?
• What is the shape of the biomarker – clinical outcome relationship?Does the change observed in the biomarker lead
to a meaningful change in the clinical outcome?Amount of change in eachLocation of that change within the full scale of the
biomarkerMajor question
Dynamic range of biomarker
8
Questions to Consider – Drug-related
• How certain are we of the mechanism of drug action?• Where in the pathophysiology sequence does the
drug act?Relationship to biomarker’s location in the
pathophysiology• What is known about the time course relationship of
drug administration (or readministration) and effects on the biomarker?When should the biomarker be sampled?
• What are the assumptions about drug effect over time between biomarker sampling and clinical outcome?
9
Additional supportive information
• Other biomarkersMeasure steps in pharmacology/
pathophysiology prior to or after primary biomarker
Are effects on those biomarkers consistent with expected relationships
• Clinical effect observationsClinical effects of uncertain meaningfulnessUnderpowered meaningful clinical endpoints
with concurrent trend in outcome
10
Potential Sources of Information
• Clinical trials of specific drug candidateBiomarker – Clinical relationship
• Clinical trials of other interventionsSame or different mechanism
• Understanding of disease pathophysiology and relationship to clinical course – Natural history
• Understanding of normal human physiology• Information from related diseases• Animal models of the disease
PathophysiologyBiomarker relationshipTreatment effects on biomarker and clinical measuresPhenotype relevance of the model(s)
11
Potential Hazards of Relying on Surrogate Endpoint
• Failure of surrogate’s predictionFalse indication of presence of benefitMisleading prediction of amount of benefit
• Limited safety experience may be inadequateDataset often more limited than with clinical
endpoint studiesReal risks of drug may not be observed“Off-target” effects of drug may occur later
than biomarker measurement• Potential use of a drug with an unfavorable
benefit-risk comparison
12
Accepting a Biomarker as a Surrogate
• Consider all issuesMultiple issues Importance of each varies case to case
• Consider all available relevant informationMultiple kinds of information Strength of different kinds of information variesRelevance to different issues Strengths and weaknesses of available information
• Consider key types of information absent Importance of missing information varies case to case
• Central problem – What makes for a persuasive body of information?Prior cases as guiding examples
13
Informative Examples• Acute MI
Arterial blood flow• Alpha1-antitrypsin Deficiency
Enzyme Levels• Phenylketonuria
Phe blood level• Fabry Disease
Renal capillary endothelial histology• MPS 1
Urinary GAG• Transfusional hemosiderosis
Liver iron content
14
Informative Examples (2)
• Fractures in OsteoporosisBone mineral density with fluoride
• Mortality in Acute MIPVCs with antiarrythmic agents (CAST)
• Stroke, MI, death in Cardiovascular DiseaseHDL with torcetrapib
• Infections in Chronic Granulomatous DiseaseSuperoxide with Interferon gamma
• Arthritis in GoutSerum uric acid with multiple drug classes
15
Acute MI
• Clinical outcome is mortality• Intravenous thrombolytic agent is the treatment• Biomarker is the concept of blood flow (patency)
How and when is blood flow evaluated?• Development of reteplase (R-PA)• RAPID-2 Study
Evaluated biomarker• GUSTO-III Study
Evaluated clinical outcome
16
Acute MI
• R-PA superior to T-PAIrrespective of which amount or when the
concept of blood flow is assessed
RAPID 2 - % of patients achieving flow
TIMI 3 - % TIMI 2&3 - %60 min 90min 60min 90min
R-PA 51 60 82 83T-PA 37 45 66 73
17
Acute MI
• Concept indicating efficacy is blood flowHow and When should it be measured?What is the shape of the relationship?
RAPID 2TIMI 3 - % TIMI 2&3 - % 30 min
60 min 90min 60min 90min TIMI3 TIMI2&3R-PA 51 60 82 83 27 67T-PA 37 45 66 73 39 66
GUSTO-IIIR-PA 7.5 Mortality %
T-PA 7.2
18
Understanding the Surrogate Measure: Idealized
Surrogate
Endpoint
Drug
Intervention
Clinical
OutcomeP1 P2Surrogate
Endpoint
Drug
Intervention
Clinical
Outcome
PathophysiologicProcesses
P1 P2Surrogate
Endpoint
Drug
Intervention
Clinical
OutcomeP1 P2Surrogate
Endpoint
Drug
Intervention
Clinical
Outcome
Order of Processes
PathophysiologicProcesses
P1 P2
19
Understanding the Surrogate: Silent Surrogate
Surrogate
Endpoint
Drug
Intervention
Clinical
Outcome
PathophysiologicProcesses
P1 P2Surrogate
Endpoint
Drug
Intervention
Clinical
Outcome
Order of Processes
PathophysiologicProcesses
P1 P2
20
Understanding the Surrogate: Complexity
Surrogate
Endpoint
Drug
Intervention
Clinical
Outcome
Order of Processes
P1
P2
P3
Surrogate
Endpoint
Drug
Intervention
Clinical
Outcome
P1
P2
P3
21
Shape of the Surrogate - Clinical Relationship
Clin
ical
Sta
tus
Biomarker
22
Clinical – Biomarker Relationship
C1
Good
BiomarkerLow High
Poor
C2
C3
C4 C5
C6
23
Clinical Effects of Biomarker Change
24
Clinical – Biomarker Relationship
C1
Good
BiomarkerLow High
Poor
C2C3
25
Accelerated Approval
• Should be a goal only after careful thoughtPlan how to show “reasonably likely to predict”Plan how to verify clinical benefitDifficulty of verification may be increased in rare
diseases• Mistaken belief in efficacy has disadvantages
Patient burden from treatment without benefitEffort, ‘side effects’ (moderate, common AE), cost
Safety risk without benefitMay be impediment to develop a second
treatment, which might be truly efficacious
26
Confirmatory Study
• Develop plan by mid-way in development programAlso an A&WC study“Usually underway” at time of AA
• Multiple approachesAs extension of primary biomarker studyIn closely related populationDose comparison study