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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

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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

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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

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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?

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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)

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• 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

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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

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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?

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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

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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)

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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Shape of the Surrogate - Clinical Relationship

Clin

ical

Sta

tus

Biomarker

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Clinical – Biomarker Relationship

C1

Good

BiomarkerLow High

Poor

C2

C3

C4 C5

C6

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Clinical Effects of Biomarker Change

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Clinical – Biomarker Relationship

C1

Good

BiomarkerLow High

Poor

C2C3

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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

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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