Surrogate Markers and its role in the Drug Development Process

Aloka G. Chakravarty, Ph.D. Director,

Biologics Therapeutics Statistical Staff chakravarty@cder.fda.gov

The opinions expressed are those of the author and do not necessarily reflect those of the FDA

Outline

Definition and motivation Biomarkers and Surrogate Endpoints – are

these terms interchangeable? Regulatory Issues Case Examples Conclusion

Surrogate Marker Working Definition

A laboratory or physical sign that is used in therapeutic trials as a substitute for a clinically meaningful endpoint that is a direct measure of how a patient feels, functions, or survives and that is expected to predict the effect of the therapy

(Temple, 1999)

Regulatory Motivation

Replace a distal endpoint with a more proximal one, – can be measured earlier– Can be measured more easily or frequently – Can be measured with higher precision, or less subject

to competing risks May be less affected by other treatment modalities Reduced sample size requirements ? Possibility of faster decision making

Surrogate Endpoints at various phases of drug development

Will focus this talk on effect of Surrogate Endpoints in Phase III clinical trials – a possible FDA Critical Path Initiative

Other uses: – Can be used to integrate data across all phases to build an

evidence base, including validation (Phase II Learn and Confirm strategy)

– Can be linked with external sources of information - of disease, of other treatments

– Can be mined for relationships of SEPs to disease, other markers, patient covariates and treatment as well as for signs of possible toxicity

Relationship: Surrogate Endpoint and Disease Need to establish strength of relationship of SEP

with the disease, not just a correlation factor “A correlate does not a surrogate make” (Fleming)

Need high sensitivity SE= a/(a+c) and specificity SP= d/(b+d)

Attributable proportion defined as AP=SE/[1-(RR)-1] should be close to 1, where RR=a(c+d)/[c(a+b)]

CE good CE poor TotalSEP good a b a+bSEP poor c d c+d

a+c b+d N

Relationship:Surrogate Endpoint and Treatment Evaluate treatment action plans on SEPs, or

identify safety concerns based on SEPs Select appropriate metric to characterize treatment

response, the choice depends on biological considerations as well as statistical

Rank possibly useful SEPs based on AP Use SEPs to study dose response, subgroup of

responders etc.

Biomarker - Definition

A characteristic that is objectively measured and evaluated as an indicator of normal biologic or pathogenic processes or pharmacological responses to a therapeutic intervention

Biomarkers can be measurements thought to be directly related to clinical outcomes – blood pressure, blood pressure - RNA

viral load – total lipids, lipid fractions - CD4 count – coronary artery occlusion - tumor size

Biomarker – what to consider

Effects on Binding – early effects such as intracellular, membrane or circulating receptor e.g.

binding to ACE of ACE-Is was an early clue that the effects will be relatively prolonged than their blood level half life

Effects on activity of an intrinsic or externally induced molecule – Effect on an externally induced enzyme, hormone or cytokine is the

effect examined e.g. inhibition of infused isoproterenol as a measure of

beta blockade Effect on etiologic agents or anatomical features

– infectious agent – pathological hallmarks of neurologic disease e.g. arteriosclerotic plaque

structure

Biomarkers & Surrogate Endpoints- A Conceptual Model

Establish linkage ofbiomarker with

Clinical Endpoint

Evaluate Patient Benefit

Evaluate Patient Risk

GlobalInterventionAssessment

Clinical endpoints (for Toxicity)

Clinical endpoints(for Efficacy)

Surrogate Endpoints

(for Efficacy)

Biomarkers (for Toxicity)

Biomarkers (for Efficacy)

Conduct provisionalintegrated evaluation

Surrogate Endpoints (for Toxicity)

Biomarkers as Surrogate Endpoints - Possible RelationshipsType ofRelationship

Value of theBiomarker

Example

A. Unreliableinteraction betweenbiomarker and thetreatmentintervention

Biomarker of no valueas a surrogate endpoint

Prostrate-specificantigen is a usefulbiomarker for prostratecancer detection butunreliable as anindicator of treatmentresponse.

B. The full effect ofthe intervention isobserved throughthe biomarkerassessment

Biomarker is an idealsurrogate endpoint

None known at present

Biomarkers as Surrogate Endpoints - Possible Relationships (contd.)Type ofRelationship

Value of theBiomarker

Example

C. Intervention affectsthe endpoint andmarker independently,only a proportion of thetreatment effect iscaptured by the SEP.

Biomarker has value asa SEP but explains onlypart of the treatmenteffect

Most established SEPs(development of OIwith HIV antivirals andmortality)

D. Intervention affectsfavorably on the markerbut unfavorable on thewell-state and disease

Biomarker is of littlepractical use as a SEPbut may have utility inexploratory studies

PVCs as a biomarker offatal arrythmiasfollowing MI (CASTtrials)

Distinction - Biomarkers and Surrogate endpoints Surrogate endpoints are a subset of biomarkers Early clue by biomarkers, validation by surrogates A biological marker is a candidate for surrogate endpoint

if it is expected to predict clinical benefit (or harm, or lack of benefit or harm) based on epidemiologic, therapeutic, pathophysiologic or other scientific evidence

Need to consider all possible effects – COX-2 selective NSAIDs treat pain, but cardiovascular

effects?– TPA establishes blood flow but causes hemorrhage

strokes

Distinction - Biomarkers and Surrogate endpoints (contd.) Surrogate endpoint are primarily endpoints in

therapeutic intervention trials, although sometimes in natural history or epidemiologic studies

For a surrogate to be useful, one must specify the clinical endpoint, class of intervention and population in which substitution of a biomarker for clinical endpoint is considered reasonable

Fast track Program

To facilitate the development and expedite the review of new drugs that are – intended to treat serious or life-threatening

conditions – demonstrate the potential to address unmet

medical conditions

Granted for a specific indication of a specific drug/biological product

Scheme to determine Fast Track

Condition serious orlife-threatening?

Not fast track

Any approved treatment for the condition?

Unmet Medical needs?

Fast track designation

Yes

No

Yes

NoYes

No

Accelerated Approval

21 CFR (314 and 601) Accelerated Approval Rule, 1992– Serious or life-threatening illness

– Surrogate or non-ultimate clinical endpoints

– Post-marketing data required to “verify and describe the drug’s clinical benefit and to resolve remaining uncertainty as to the relation of the surrogate endpoint upon which approval was based to clinical benefit, or the observed clinical benefit to ultimate outcomes.”

Subpart H

Special section of fast track related to surrogate endpoints

Section 112 of the FDAMA of 1997, Chapter V (21 USC 351) – provides for definition, designation, and request for such

– … has an effect either on a clinical endpoint or on a surrogate endpoint that is reasonably likely to predict clinical benefit

– conduct post-approval studies to validate the surrogate endpoint or otherwise confirm the effect on the clinical endpoint

Regulatory Issues

Use of SEPs focus on the treatment effect mediated by a certain pathway, but in reality, multiple pathways or modalities may exist. – All anti-hypertensives lower BP but could have

different (better or worse) effects on endpoints (CHF, renal function, diabetes) because their mechanism of action are different and multiple

They have to be comparatively evaluated as well

Four Roles of Surrogate Endpoints Efficient and improved design of trials Improved understanding of drug effects

– subgroup differences -dose &dose interval– effects over time -withdrawal effect– phramaco-dynamic effects

Efficacy in new settings (e.g. pediatric) Support for results of clinical trials

Improve design of Phase II-III trials Effect (magnitude and time course) on an

“etiologic SEP” can help choose dose range and regimens, titration steps– for large trials give insight into tolerance, first dose

effects, withdrawal effects that need study– this is important for “all at once” Phase III studies, seen

substantial efforts to study regimens that would have had little chance on PK/PD grounds

Potential role in identifying population more or less likely to respond (as a baseline covariate)

Better understanding

Subgroup differences in favorable (or not) responses– sensitivity to QT effects in women or group with

inherited QT abnormalities potential problems may be avoided (orthostatic

effects, anti-cholinergic effects) Better labels (precautions or modified treatment

plan) PD interactions

Efficacy in new settings

Approval is sometimes feasible without new clinical trials where basic effectiveness is established and pathophysiology is clear – ICH E-5 proposes use of PD drug response as a

potential basis for “bridging study” into new regions

– ICH PED guidance discusses PD to bridge adult DR to pediatric population where disease is similar

Depends on understanding of the SEP effect to the clinical effect

Efficacy in new setting

FDA Guidance: Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products – Efficacy of a different dose, regimen or dosage

form (e.g. post-infarction propranalol) Better the understanding of SEP relationship to the

clinical outcome, the better clinical trial design

Case example I - CD4 count as SEP in HIV trials CD4 lymphocyte count widely used and accepted

as a SEP for progression to AIDS ZDV approved in 1987 based on 17 weeks

survival ddI approved in 1991 based on surrogate endpoint

(CD4) with limited indication (in AZT failures) ddC is the first drug approved under accelerated

approval regulation (1992) More than 12 other HIV drugs has been approved

under this regulation since then.

Accelerated to Traditional Approval:Time and Endpoints

CD4 ddI DP or 50% drop of CD4

CD4 ddC DP

DAVG16 of CD4 d4T DP or 50% drop of CD4

CD4, HIV, p24 3TC DP

CD4 and HIV RNA SQV DP

DAVG of HIV, DP RTV Change of HIV, CD4; DP

DAVG CD4, DAVG HIV IDV Survival

Change of CD4 and HIV RNA NVP Time to HIV failure

DAVG CD4 and HIV RNA NFV %<400 for HIV Week 48

DAVG CD4 and HIV RNA DLV Time to HIV failure

%<400 for HIV at Week 24 EFV Time to HIV failure

%<400 for HIV at Week 16 ABC Time to HIV failure

%<400 for HIV at Week 24 AMP Time to HIV failure

%<400 for HIV at Week 24 LPV Time to HIV failure

1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001

Endpoints used in approval of Anti-HIV Drugs

CD4 Didanosine(ddI) DP or 50% drop of CD4

CD4 Dideoxycytidine (ddC) DP

DAVG16 of CD4 stavudine (d4T) DP or 50% drop of CD4

CD4, HIV, p24 lamivudine (3TC) DP

CD4 and HIV RNA Saquinavir mesylate DP

DAVG of HIV, DP Ritonavir Change of HIV, CD4; DP

DAVG CD4, DAVG HIV Indinavir sulfate Survival

Change of CD4 and HIV RNA Nevirapine Time to HIV failure

DAVG CD4 and HIV RNA Nelfanivir mesylate %<400 for HIV Week 48

DAVG CD4 and HIV RNA Delavirdine mesylate Time to HIV failure

%<400 for HIV at Week 24 Efavirenz Time to HIV failure

%<400 for HIV at Week 16 Abacavir Time to HIV failure

%<400 for HIV at Week 24 Amprenavir Time to HIV failure

%<400 for HIV at Week 24 Lopinavir Time to HIV failure

1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001

Endpoints used for Anti-Viral approvals

Accelerated Traditional

Time Endpoint Time Endpoint

< 1995 Change in CD4 count or time-averaged change of CD4 (DAVG)

< 1997 Clinical progression

1995-1998 HIV RNA load (change from baseline, DAVG, % < threshold)

> 1997 HIV RNA % < 400 copies /mL or time to virologic failure

> 1998 HIV RNA < 400 and/or <50 copies /ML

Approaches to a better surrogate

Week 16 vs. Week 24 for HIV RNA– Week 24 will likely be a better predictor of clinical

outcome than Week 16– FDA usually ask for Week 24 results in accelerated

approval of HIV drugs.– Data beyond Week 24 are also requested and reviewed

Based on the predicted value of the surrogate, compute what kind of efficacy we will need to reliably predict a significant and meaningful clinical outcome at the end for traditional approval

Case Example II: CAST trial

Cardiac Arrhythmia Suppression Trial (CAST) evaluated effect of encainide, flecainide and moricizine on survival of patients who had MI and had >10 premature ventricular beats per hour

Reduction in ventricular ectopic contraction used as a SEP for decreased mortality

Primary endpoint was death or cardiac arrest with resuscitation, either of which due to arrhythmia.

CAST trial results

Unexpected results: encainide and flecainide arms stopped early : 63 patients died in encainide or flecainide arm compared to 26 in the placebo arm (p=0.0001).

After continuing the trial with moricizine as the only active arm (CASTII), there was excess mortality in moricizine arm alone (17 deaths in 665 patients) as compared to no therapy or placebo group (3 deaths in 660 patients). This study had to be terminated early also.

Points to the fact that surrogate markers may not always be a good predictor and have to be validated extensively before being used in a regulatory setting.

Conclusions

Collection of information on the SEPs should be encouraged, it provides additional insight into the mechanism of action

It can often provide supportive evidence into reliability of observed association

When used as auxiliary information, can provide improvement in trial design

Need to be cautious about association and inferences drawn from it