Surrogate Markers and its role in the Drug Development Process

1
Surrogate Markers and its role in the Drug
Development Process

• Aloka G. Chakravarty, Ph.D.
• Director,
• Biologics Therapeutics Statistical Staff
• chakravarty_at_cder.fda.gov
• The 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 Issues
• Case Examples
• Conclusion

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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)

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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

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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

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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/(ac) and specificity
  SP d/(bd)
• Attributable proportion defined as
  APSE/1-(RR)-1 should be close to 1, where
  RRa(cd)/c(ab)

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RelationshipSurrogate 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.

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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

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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

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Biomarkers Surrogate Endpoints- A Conceptual
Model
Clinical endpoints (for Efficacy)
Surrogate Endpoints (for Efficacy)
Evaluate Patient Benefit
Biomarkers (for Efficacy)
Conduct provisional integrated evaluation
Establish linkage of biomarker with Clinical
Endpoint
Global Intervention Assessment
Evaluate Patient Risk
Surrogate Endpoints (for Toxicity)
Biomarkers (for Toxicity)
Clinical endpoints (for Toxicity)
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Biomarkers as Surrogate Endpoints - Possible
Relationships
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Biomarkers as Surrogate Endpoints - Possible
Relationships (contd.)
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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

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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

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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

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Scheme to determine Fast Track
Condition serious or life-threatening?
No
Yes
Any approved treatment for the condition?
Yes
Not fast track
No
No
Unmet Medical needs?
Yes
Fast track designation
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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 drugs 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.

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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

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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

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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

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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)

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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

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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

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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

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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.

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Accelerated to Traditional ApprovalTime and
Endpoints
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Endpoints used in approval of Anti-HIV Drugs
DP or 50 drop of CD4
CD4
Didanosine(ddI)
Dideoxycytidine (ddC)
DP
CD4
stavudine (d4T)
DP or 50 drop of CD4
DAVG16 of CD4
lamivudine (3TC)
DP
CD4, HIV, p24
DP
CD4 and HIV RNA
Saquinavir mesylate
Change of HIV, CD4 DP
DAVG of HIV, DP
Ritonavir
Survival
DAVG CD4, DAVG HIV
Indinavir sulfate
Time to HIV failure
Change of CD4 and HIV RNA
Nevirapine
lt400 for HIV Week 48
DAVG CD4 and HIV RNA
Nelfanivir mesylate
Time to HIV failure
DAVG CD4 and HIV RNA
Delavirdine mesylate
Time to HIV failure
lt400 for HIV at Week 24
Efavirenz
Time to HIV failure
lt400 for HIV at Week 16
Abacavir
Time to HIV failure
lt400 for HIV at Week 24
Amprenavir
Time to HIV failure
lt400 for HIV at Week 24
Lopinavir
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
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Endpoints used for Anti-Viral approvals
Accelerated Accelerated Traditional Traditional
Time Endpoint Time Endpoint
lt 1995 Change in CD4 count or time-averaged change of CD4 (DAVG) lt 1997 Clinical progression
1995-1998 HIV RNA load (change from baseline, DAVG, lt threshold) gt 1997 HIV RNA lt 400 copies /mL or time to virologic failure
gt 1998 HIV RNA lt 400 and/or lt50 copies /ML
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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

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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 gt10 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.

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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
  (p0.0001).
• 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.

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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