1. Surrogate Markers and its role in the Drug Development Process
Aloka G. Chakravarty, Ph.D.
Director,
Biologics Therapeutics Statistical Staff
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

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 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

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 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

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 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.

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 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

9. 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

10. 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)

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 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

14. 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

15. 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

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

17. 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.”

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

19. 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

20. 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

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 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)

22. 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

23. 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

24. 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

25. 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.

26. Accelerated to Traditional Approval: Time and Endpoints

27. 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

28. Endpoints used for Anti-Viral approvals
Accelerated
Traditional
Time
Endpoint
< 1995
Change in CD4 count or time-averaged change of CD4 (DAVG)
< 1997
Clinical progression
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
These 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 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

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 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.

31. 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.

32. 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