Surrogate endpoints in clinical trial

GCP course material

1. Surrogate Endpoints
DR. AMOL PATIL
ASSISTANT PROFESSOR
DEPARTMENT OF PHARMACOLOGY
POST GRADUATE INSTITUTE OF MEDICAL EDUCATION AND RESEARCH
CHANDIGARH

2. Directed byS. S. Rajamouli
Produced by•Shobu Yarlagadda Prasad Devineni
Screenplay byS. S. Rajamouli
Starring
•Prabhas, Anushka Shetty
•Rana Daggubati
[1]
, Tamannaah
Music by M. M. Keeravani
Cinematograph
y
K. K. Senthil Kumar
Edited by Kotagiri Venkateswara Rao
ProductionArka Media Works
Release date28 April 2017
[2]
Country India
Language
Telugu
Tamil
Budget ₹2 billion
[3]

3. Why we need surrogate endpoint?
Advantages
•Measured earlier
•Measured more frequently
•Less invasive
•More efficient
Reduce sample size and time

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Clinical pharmacology & therapeutics | VOLUME 86 NUMBER 1 | JULY 2009
Numbers of US Food and Drug Administration– approved products

5. How it differ from other endpoints….
Biomarker: – A characteristic that is objectively measured and evaluated as an indicator of
normal biological processes, pathogenic processes, or pharmacologic responses to a[n] . . .
intervention.
Example: cholesterol level
Clinical Endpoint: – A characteristic or variable that reflects how a patient [or consumer]
feels, functions, or survives.”
Example: death
Composite Endpoint: –a set of endpoints that is intended to increase trial’s sensitivity or
statistical power by covering number of experiences of patient in time to event setting.
Example : PROactive clinical trial, EXULT-A and B clinical trial

6. Surrogate end points
A surrogate end point, or marker, is a laboratory measurement or
physical sign that is used in therapeutic trials as a substitute for a
clinically meaningful end point that is a direct measure of how a
patient feels, functions, or survives and that is expected to predict the
effect of the therapy.
- US Food and Drug Administration
Example: blood pressure for trials antihypertensive drugs

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8. Hierarchy of Surrogates…
1.A true clinical efficacy measure (evidence establishing risk is acceptable in the context of
evidence of benefit)
2.A validated surrogate for a specific disease setting and class of interventions (interventions
are safe, with strong evidence that risks from off target effects are acceptable

3.A non-validated surrogate, yet one established to be ‘reasonably likely to predict clinical
benefit’ for a specific disease setting and class of interventions (interventions are safe, with
evidence that risks from off target effects are acceptable)
4.A correlate that is a measure of biological activity, but not established to be at a higher
level

9. Appropriate situation for surrogate
The setting that provides the greatest potential for the surrogate endpoint to be valid
Fleming & DeMets, 1989

10. Reasons for failure of surrogate
endpoint
A.Maternal to fetal HIV transmission prevention studies
B.CAST trial, PROMISE study

11. 1.Finasteride in chemoprophylaxis of Prostate carcinoma
2.Aggressive erythropoietin therapy in ESRD patients

13. Chronic granulomatous disease
Background
–Childhood disease, disorders in immune system
–Phagocytes ingest microorganism but fail to kill them
International CGD Cooperative Group
–Randomized patients between interferon-gamma and placebo in a double-blind fashion
–Superoxide measurements and bacterial killing can be used as surrogate endpoints
–After a lengthy debate, rate of infection was finally used as primary endpoint

–Individual follow-up extended from 1-month to 1-year

14. Results
–Interferon-gamma significantly reduced the rate of recurrent of serious infections at interim
analysis
–FDA approved the use of Interferon-gamma in CGD patients
–There were no significant differences between treatment arms on surrogate biological
markers, superoxide measurements and bacterial killing
Reliance on surrogate markers led to false negative conclusion

15. Vandetanib
Situation
Indication : Metastatic Medullary thyroid Carcinoma
Clinical Endpoint : Overall Survival (OS)
Surrogate Endpoint : Progression free survival (PFS)
Approval status
Conditional approval by EMA with orphan drug status
2012 : G-BA decided no additional benefits
2013 : G-BA decided minor additional benefit based on pain progression and PFS (PFS no
surrogate for OS but individual morbidity endpoint)

16. strength of the evidence of surrogate
endpoints
Boceprevir and Telaprevir assessments
– SVR is valid, but not formally validated
– No formal validation possible for ethical reasons
Consequence: IQWiG downgraded the products’ additional benefits to “not quantifiable“

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18. validation of surrogacy: prentice’s criteria

19. Validation of surrogacy: prentice’s
criteria
Validation of surrogacy: prentice’s criteria Prentice criteria can be summarized in two parts:
1.correlation
2.capture
•Under correlation, the surrogate endpoint must be statistically correlated to the clinical
endpoint.
–should have prognostic value relative to the clinical endpoint.
•Under capture, an intervention’s entire effect on the clinical endpoint should be explained
by the intervention’s effect on the surrogate endpoint.
Desai et al., 2006; Prentice, 1989.

20. Issues in validation
The requirement that the surrogate endpoint fully capture the effect of treatment on the true
endpoint
–It is so restrictive that this condition rarely holds in clinical application
–even when data on a certain treatment allow us to view a biomarker as a valid surrogate for
treatment, we cannot extrapolate this to a new treatment

21. meta-analytic validation
•Using data from several trials, a model is derived that can predict the magnitude of the
treatment effect on the true endpoint, from the treatment effect observed on the surrogate
endpoint.
•A surrogate is valid if the prediction is sufficiently precise.

22. meta-analytic
validation The association between the
treatment effects on the true endpoint
and the corresponding effects on the
surrogate endpoint is then modeled
in a way similar to standard linear
regression, although mathematically
more sophisticated.
•The strength of the association is
measured by the squared correlation
coefficient (R2trial) that also
indicates the precision with which
the treatment effect on the true
endpoint can be predicted from the
observed effects on the surrogate.

23. Generalizability???
Can a surrogate be established based on a single study or only based on a meta-analysis?
Does the surrogate generalize
◦to other studies?
◦to other populations?
◦to other devices?
◦to other companies?
◦to other diseases?
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25. Current regulatory scenario on
surrogate endpoints…
FDA is considering development of these concepts as part of its “Critical Path”
Initiative.
Development would include process for refining general framework as well as
individual projects on surrogate endpoint development

26. Thank
You…