Presentation on theme: "Surrogate Markers and its role in the Drug Development Process"— Presentation transcript:
1 Surrogate Markers and its role in the Drug Development Process Aloka G. Chakravarty, Ph.D.Director,Biologics Therapeutics Statistical StaffThe opinions expressed are those of the author and do not necessarily reflect those of the FDA
2 Outline Definition and motivation Biomarkers and Surrogate Endpoints – are these terms interchangeable?Regulatory IssuesCase ExamplesConclusion
3 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)
4 Regulatory Motivation Replace a distal endpoint with a more proximal one,can be measured earlierCan be measured more easily or frequentlyCan be measured with higher precision, or less subject to competing risksMay be less affected by other treatment modalitiesReduced sample size requirements ?Possibility of faster decision making
5 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 InitiativeOther 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 treatmentsCan be mined for relationships of SEPs to disease, other markers, patient covariates and treatment as well as for signs of possible toxicity
6 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)]Suppose success is measured with respect to a distal CE as well as a proximal SE. If we can dichotomize based on both the endpoints, we get the following table. A is the number of patients that both the endpoints could pick up as success etc.
7 Relationship: Surrogate Endpoint and Treatment Evaluate treatment action plans on SEPs, or identify safety concerns based on SEPsSelect appropriate metric to characterize treatment response, the choice depends on biological considerations as well as statisticalRank possibly useful SEPs based on APUse SEPs to study dose response, subgroup of responders etc.
8 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 interventionBiomarkers can be measurements thought to be directly related to clinical outcomesblood pressure, blood pressure - RNA viral loadtotal lipids, lipid fractions - CD4 countcoronary artery occlusion - tumor size
9 Biomarker – what to consider Effects on Bindingearly 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 lifeEffects on activity of an intrinsic or externally induced moleculeEffect on an externally induced enzyme, hormone or cytokine is the effect examined e.g. inhibition of infused isoproterenol as a measure of beta blockadeEffect on etiologic agents or anatomical featuresinfectious agentpathological hallmarks of neurologic disease e.g. arteriosclerotic plaque structure
11 Biomarkers as Surrogate Endpoints - Possible Relationships
12 Biomarkers as Surrogate Endpoints - Possible Relationships (contd.)
13 Distinction - Biomarkers and Surrogate endpoints Surrogate endpoints are a subset of biomarkersEarly clue by biomarkers, validation by surrogatesA 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 evidenceNeed to consider all possible effectsCOX-2 selective NSAIDs treat pain, but cardiovascular effects?TPA establishes blood flow but causes hemorrhage strokes
14 Distinction - Biomarkers and Surrogate endpoints (contd.) Surrogate endpoint are primarily endpoints in therapeutic intervention trials, although sometimes in natural history or epidemiologic studiesFor 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
15 Fast track ProgramTo facilitate the development and expedite the review of new drugs that areintended to treat serious or life-threatening conditionsdemonstrate the potential to address unmet medical conditionsGranted for a specific indication of a specific drug/biological product
16 Scheme to determine Fast Track Condition serious orlife-threatening?NoYesYesAny approved treatmentfor the condition?Not fasttrackNoNoUnmet Medical needs?YesFast trackdesignation
17 Accelerated Approval21 CFR (314 and 601) Accelerated Approval Rule, 1992Serious or life-threatening illnessSurrogate or non-ultimate clinical endpointsPost-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.”
18 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 benefitconduct post-approval studies to validate the surrogate endpoint or otherwise confirm the effect on the clinical endpoint
19 Regulatory IssuesUse 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 multipleThey have to be comparatively evaluated as well
20 Four Roles of Surrogate Endpoints Efficient and improved design of trialsImproved understanding of drug effectssubgroup differences -dose &dose intervaleffects over time -withdrawal effectphramaco-dynamic effectsEfficacy in new settings (e.g. pediatric)Support for results of clinical trials
21 Improve design of Phase II-III trials Effect (magnitude and time course) on an “etiologic SEP” can help choose dose range and regimens, titration stepsfor large trials give insight into tolerance, first dose effects, withdrawal effects that need studythis is important for “all at once” Phase III studies, seen substantial efforts to study regimens that would have had little chance on PK/PD groundsPotential role in identifying population more or less likely to respond (as a baseline covariate)
22 Better understandingSubgroup differences in favorable (or not) responsessensitivity to QT effects in women or group with inherited QT abnormalitiespotential problems may be avoided (orthostatic effects, anti-cholinergic effects)Better labels (precautions or modified treatment plan)PD interactions
23 Efficacy in new settings Approval is sometimes feasible without new clinical trials where basic effectiveness is established and pathophysiology is clearICH E-5 proposes use of PD drug response as a potential basis for “bridging study” into new regionsICH PED guidance discusses PD to bridge adult DR to pediatric population where disease is similarDepends on understanding of the SEP effect to the clinical effect
24 Efficacy in new setting FDA Guidance: Providing Clinical Evidence of Effectiveness for Human Drug and Biological ProductsEfficacy 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
25 Case example I - CD4 count as SEP in HIV trials CD4 lymphocyte count widely used and accepted as a SEP for progression to AIDSZDV approved in 1987 based on 17 weeks survivalddI 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.
26 Accelerated to Traditional Approval: Time and Endpoints
27 Endpoints used in approval of Anti-HIV DrugsCD4Didanosine(ddI)DP or 50% drop of CD4CD4Dideoxycytidine (ddC)DPDAVG16 of CD4stavudine (d4T)DP or 50% drop of CD4CD4, HIV, p24lamivudine (3TC)DPCD4 and HIV RNASaquinavir mesylateDPDAVG of HIV, DPRitonavirChange of HIV, CD4; DPDAVG CD4, DAVG HIVIndinavir sulfateSurvivalChange of CD4 and HIV RNANevirapineTime to HIV failureDAVG CD4 and HIV RNANelfanivir mesylate%<400 for HIV Week 48DAVG CD4 and HIV RNADelavirdine mesylateTime to HIV failure%<400 for HIV at Week 24EfavirenzTime to HIV failure%<400 for HIV at Week 16AbacavirTime to HIV failure%<400 for HIV at Week 24AmprenavirTime to HIV failure%<400 for HIV at Week 24LopinavirTime to HIV failure199019911992199319941995199619971998199920002001
28 Endpoints used for Anti-Viral approvals AcceleratedTraditionalTimeEndpoint< 1995Change in CD4 count or time-averaged change of CD4 (DAVG)< 1997Clinical progressionHIV RNA load (change from baseline, DAVG, % < threshold)> 1997HIV RNA % < 400 copies /mL or time to virologic failure> 1998HIV RNA < 400 and/or <50 copies /MLThese are the Topics proposed by PhRMA. All these questions are about non-inferiority designs. These questions are:Has DAVDP had experience with non-inferiority trials?Is DAVDP open to drug-specific proposals using this design?Are there any special considerations that would prompt FDA to think about such studies differently than the considerations described in the ICH E9 guideline?
29 Approaches to a better surrogate Week 16 vs. Week 24 for HIV RNAWeek 24 will likely be a better predictor of clinical outcome than Week 16FDA usually ask for Week 24 results in accelerated approval of HIV drugs.Data beyond Week 24 are also requested and reviewedBased 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
30 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 hourReduction in ventricular ectopic contraction used as a SEP for decreased mortalityPrimary endpoint was death or cardiac arrest with resuscitation, either of which due to arrhythmia.
31 CAST trial resultsUnexpected 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.
32 ConclusionsCollection of information on the SEPs should be encouraged, it provides additional insight into the mechanism of actionIt can often provide supportive evidence into reliability of observed associationWhen used as auxiliary information, can provide improvement in trial designNeed to be cautious about association and inferences drawn from it