# Presentation: 534302

##  Surrogate Endpoints in Infectious Diseases Trials:FDA Perspective

**John H. Powers, MD**
***Lead Medical Officer***
***Antimicrobial Drug Development and Resistance Initiatives***
***Office of Drug Evaluation IV***
***Center for Drug Evaluation and Research***
***U.S. Food and Drug Administration***

## Introduction

**Definition of clinical endpoints and surrogate endpoints**
**Strengths, limitations and utility of surrogates endpoints in drug development**
**Regulatory considerations with the use of surrogate endpoints**
**Validating a surrogate endpoint**

## What’s Important to Patients?

## Definitions

_**Clinical endpoint**_** = direct measure of how a patient feels, functions or survives**
**mortality**
**resolution of symptoms of disease**
_**Surrogate endpoint**_** = laboratory measurement or physical sign used as a substitute for clinical endpoint**
**Surrogate endpoint by itself does not confer direct clinical benefit to the patient**
**NIH Biomarkers Definitions Working Group, Clin Pharmacol Ther;2001;69:89-95.**

## Definitions

**Examples of surrogate endpoints**
**measurement of organism (e.g.culture or viral load)**
**results of antigen testing**
**changes in x-ray, CT scan, endoscopic appearance**
**histological changes**
**“****Surrogate of a surrogate”**
**changes in cultures associated with histological changes**
**presence of organisms on catheter tip**
**elimination of organisms in a population without the disease (e.g patients with asymptomatic bacteruria as a surrogate for patients with uncomplicated UTI)**

## Definitions

**Surrogate endpoints are a subset of **_**biomarkers**_
**Biomarkers are useful for purposes other than endpoints**
_**diagnostic tool**_** - use of test as an inclusion criteria to define the disease based on presence of organism (increases specificity of diagnosis)**
_**risk factor for disease**_** - neutropenia (WBC) in a patient with hematological malignancy**
_**indicator of disease prognosis**_** - risk factor for outcome  (HIV viral load  and CD4 in HIV)**
**Sande MA et al. NIH Consensus Conference on HIV, JAMA 1993;270:2583-89.**

## Biomarkers as Prognostic Indicators

**CS = clinical success, CF = clinical failure**

**Microbiological Success**

**CS**

**CS**

**CS**

**CS**

**CS**

**CS**

**CS**

**CS**

**CS**

**CS**

**CS**

**CS**

**CS**

**CF**

**CF**

**CS**

**CS**

**CS**

**CS**

**CS**

**Microbiological Failure**

**CS**

**CS**

**CS**

**CS**

**CS**

**CS**

**CS**

**CS**

**CS**

**CS**

**CS**

**CS**

**CF**

**CF**

**CF**

**CF**

**CF**

**CF**

**CF**

**CF**

## Biomarkers as Surrogate Endpoints

**Microbiological Outcomes**

**Clinical Outcomes**

**MS**

**CF**

**CF**

**CF**

**CF**

**MS**

**MS**

**MS**

**MS**

**MS**

**CS**

**CS**

**CS**

**CS**

**CS**

**CS**

**CS**

**CS**

**CS**

**MS**

**MF**

**MS**

**MF**

**MF**

**MS = micro success**
**MF = micro failure**

**CS = clinical success**
**CF = clinical failure**

## Biomarkers as Surrogate Endpoints

**Micro**
**Outcomes**

**Clinical **
**Outcomes**

**Micro**
**Outcomes**

**Clinical **
**Outcomes**

**Good**
**Overlap**

**Not-So-Good**
**Overlap**

## Strengths of Surrogate Endpoints

**Reproducible**
**Standardized (in some cases)**
**Objective**
**Can be dichotomous (yes/no)**
**Can lower sample size when success rate is higher higher success rates**
**In chronic diseases, can measure earlier than clinical endpoint**

## Sample Size per Arm - 80% power

- 

## Utility of Surrogate Endpoints

**Early clinical development**
**Mechanistic understanding/pathogenesis of disease**
**Knowledge about clinical pharmacology**
**Guidance in dose selection**
**“****Proof of principle” of efficacy in phase 2 trials**
**Basis for selecting compounds for phase 3 testing**
**Later stages of drug development**
**Bring treatment benefits to patients earlier than with trials with clinical outcomes when surrogate endpoint precedes clinical endpoint by significant amount of time (e.g. HIV infection)**

## Limitations of Surrogate Endpoints

**Smaller trial may not provide enough data to analyze safety of drug**
**absence of an adverse event in a safety database of 300 patients will rule out risk of only 1 in 100 (1%)**
**Benefit in terms of surrogate endpoint may overestimate benefit on true endpoint**
**in prophylaxis trial high rate of decolonization may predict only small benefit in prevention of infection**
**in treatment trial rate of culture negativity may overestimate clinical cure rate**
**Surrogate endpoint may not predict clinical benefit**

## Surrogate Endpoints

** ****Surrogate endpoints must be on causal path of disease**
** ****Surrogate must capture **_**full benefit**_** of treatment effect**
** ****Assumes no other pathway of mechanism of drug effect**
** ****Mechanism of action different from effect of drug**

## Surrogate Endpoints

** ****Surrogate may not take into account unmeasured**
**benefits and harms of treatment**
** ****Knowledge about how a drug achieves clinical results**
**may be incomplete**

## Surrogate Endpoints

**Unmeasured benefits**
**effects of drug other than “eradication”**
**sub-inhibitory effects of antimicrobials on organisms**
**bactericidal therapy not necessary in many infections**
**direct effects of antimicrobials on host immune system**
**Labro MT et al. Curr Opin Investig Drugs 2002:3:61-8.**
**Nau R et al. Clin Micro Rev 2002;15:95-110.**
**Unmeasured harm**
**lysis of organisms may have effect on inflammatory cascade and resultant effect on clinical outcomes**
**replacement of one organism with another**
**other sources of infection other than that affected by drug**

## Surrogate Endpoints

** ****Issues with accuracy of how surrogate is measured**
**it may be reproducible (precision) but is it telling**
**us the correct inference (accuracy)**

## Limitations of Surrogate EndpointsReasons why Surrogates Fail

** ****Measurement of clinical endpoint may not**
**	****be relevant based on natural history of disease**
** ****fixed time points beyond time of natural resolution**

## Endpoints and Timing

**Nicholson KG et al. Lancet 2000;355:1845-1850.**

## Validating SurrogatesCorrelation/Concordance

**A**

**B**

**C**

**D**

**Surrogate success**

**Surrogate failure**

**Clinical success**

**Clinical failure**

**Kappa coefficient of correlation**
**	**** **0 _<_  _<_ 0.4  = marginal (or no) agreement
- 0.4 _<_   < 0.75 = good agreement
-  _>_ 0.75 = excellent agreement
- 	Kraemer HC Stat Med 2002:21:2109-29

## Validating Surrogates

** ****Surrogate must measure effects similarly for**
**all drugs studied**

**% success with surrogate**

**% clinical success**

## Validating Surrogates

** ****Surrogate should accurately reflect clinical outcomes**

**% success with surrogate**

**% clinical success**

## Validating SurrogatesDouble-Tympanocentesis Trials in AOM

** ****Surrogate must measure effects similarly for**
**all drugs studied**

**% success with surrogate**

**% clinical success**

**0.14**

**0.28**

**0.32**

**0.34**

**0.37**

**0.42**

**0.62**

**Surrogate and clinical on day 4-6**

## Validating Surrogates

** ****Surrogate must measure effects similarly for**
**all drugs studied**

**% success with surrogate**

**% clinical success**

## Validating Surrogates

** ****Surrogate must measure effects similarly for**
**all drugs studied**

**% clinical success**

**% success with surrogate**

## Regulatory Perspective

**Traditional approval based on surrogate endpoints only in cases where endpoint **_**already**_** validated to predict clinical endpoint**
**Accelerated approval based on surrogate endpoints (Subpart H, 21 CFR 314.800)**
**serious and life threatening disease**
**requires confirmatory post-approval trial based on clinical endpoint**
**usually from a trial that is already ongoing**

## Regulatory Perspective

**HIV trial**

**Surrogate**
**endpoint**

**Clinical**
**endpoint**

**Acute bacterial disease trial**

**time**

**Trial complete so requires initiation of second trial**

## Conclusions

**Surrogate endpoints can be useful in clinical trials in both early and later development**
**examine risk/benefit of use of surrogate e.g. long term illness, serious and life threatening disease**
**Use of surrogates requires validation **_**prior**_** to using as endpoint in clinical trial**
**validation specific for disease and population**
**Accelerated approval requires confirmatory trial**
**Validation of surrogate requires meta-analysis of correlation AND capture full treatment effect**

**“****Far better an approximate answer to the right question, which is often vague,  than an exact answer to the wrong question, which can always be made precise.”**
**	****	****	****	**
**	****	****	****	****John W. Tukey (1962)**
**	****	****	****	****Annals of Mathematical Statistics**
**	****	****	****	****1962;33:1-67.**

## Questions

**In what situations and in what kinds of diseases would surrogate endpoints be most useful?**
**How can one obtain the information necessary to validate surrogate markers? **
**What are the issues with obtaining the validation of a surrogate necessary for fulfillment of Subpart H in more acute diseases?**