# Presentation: 856019

##  Microbiological Surrogate Endpoints in Clinical Trials of Infectious Diseases

**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

**Differentiating clinical practice guidelines and clinical trials**
**Definitions of endpoints, clinical endpoints, surrogate endpoints, and biomarkers**
**Utility of surrogate and differentiating risk factors from surrogate endpoints**
**Strengths and limitations of surrogate endpoints**
**Surrogates in the setting of topical antiseptics**
**Conclusions**

## Clinical Practice and Clinical Trials

**Clinical practice**
**use of drug products already proven to be safe and effective**
**not concerned with causality of outcomes**
**treatment guidelines describe use of products based on best available evidence (optimally based on clinical trials)**
**Clinical trials**
**experiments in humans to determine if drugs products are safe and effective**
**determine causality of outcomes related to interventions**
**provide evidence for formulation of practice guidelines (not usually  vice versa)**
**need “yardstick” for determining if products are safe and effective**

## Definitions

***Endpoint *****- measure of the *****effect***** of an intervention on outcome (e.g. success or failure) in a clinical trial in treating or preventing a **_**disease**_
**Several implications:**
***WHAT to measure - ***** should be clinically relevant to the disease in question**
***HOW to measure it - *****should be able to measure differences between therapies should they exist i.e. developing a “yardstick” to differentiate effective from ineffective drugs**
***WHEN to measure it (timing) *****should be clinically relevant to the disease **
***HOW MUCH***** to measure**** ****(*****magnitude)***** should correlate with clinical outcomes that are *****meaningful to patients***
***HOW TO ANALYZE****** *****results  as method may affect conclusions**

**GI symptoms**
**bother me**

**I’m worried**
**and concerned**

**I cannot bend over or exercise**

**I cannot eat and **
**drink whatever**
**I like**

**My whole life is affected**

**Heartburn**
**disturbs my sleep**

## Definitions

***Disease***
**a constellation of signs and symptoms experienced by the patient**
**infectious diseases **_**caused**_** by pathogenic organisms with resultant host response causing symptoms**
**Koch’s postulates relate to proving *****cause***** of disease, not *****effect***** of an intervention**
***cause***** and *****effect***** are separate considerations**
**Patients seek the care of clinicians because of symptoms, not because of presence of organism**
**Verheij TJ et al. Fam Pract 1990;7:175-80.**
**In prevention trials, seek to prevent symptoms from occurring**
**Powers JH Clin Infect Dis 2004;39:S211-17.**

## Definitions

***Clinical endpoint***** = direct measure of how a patient feels, functions or survives**
**mortality**
**resolution or prevention of symptoms of disease**
***Surrogate endpoint***** = laboratory measurement or physical sign used as a substitute for clinical endpoint**
**culture results, radiological testing, histology**
**other data like PK-PD predicts effect on organism**
**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.**
**International Conference on Harmonization, ICH E9 document **

## Definitions

**Biomarkers**** are analytical tools used to assess biological parameters **
**Biomarkers are useful for purposes other than surrogate endpoints in trials**
_**1) diagnostic tool**_** - use of test as an inclusion criteria to define the disease based on presence of organism (increases specificity of diagnosis)**
_**2) describe mechanism of action of drug**_** - effect on organisms is mechanism, not goal of therapy**
_**3) risk factor for acquisition of disease**_** - colonization with particular organisms may be risk factor**
_**4) risk factor for outcome - **_**indicator of disease prognosis   (HIV viral load  and CD4 in HIV)**
**Sande MA et al. NIH Consensus Conference on HIV, JAMA 1993;270:2583-89.**
_**5) surrogate endpoints**_

## Definitions

**Surrogate**** - Etymology: ****Latin *****surrogatus, *****past participle of *****surrogare *****to choose in place of another, substitute, from *****sub- + rogare *****to ask : to put in the place of another: **
- Merriam-Webster Dictionary
***Surrogate endpoint***** is substituting **_**microbiological**_** outcomes for **_**clinical**_** outcomes (both success AND failure) of disease in pivotal  clinical trials to prove drug efficacy**
**Surrogate endpoints very useful in early drug development as proof of principle of drug efficacy and selecting candidate drugs**

## Utility of Surrogates

**Useful in phase 3 trials when surrogate endpoint can be measured sooner than clinical endpoint**
**When clinical endpoint events are more rare, can complete trial with smaller sample size**
**Examples of successful surrogates:**
**lowering cholesterol to prevent CV disease**
**lowering blood pressure to prevent CV disease**
**suppression of HIV viral load as surrogate endpoint in treatment of HIV/AIDS**

## HIV Viral Load and CD4 as Risk Factors

## Risk Factor and Endpoints Differ

**Level of HIV viral load and CD4 count both are *****risk factors***** for disease progression in HIV/AIDS**
**HIV viral load functions well as *****surrogate endpoint***** but CD4 count not as useful as endpoint in clinical trials**
**7 of 8 trials in with positive effect on CD4 showed positive effect on progression to AIDS/death**
**BUT effect on CD4 positive in 6 of 8 trials with negative effect on AIDS progression/death**
**CD4 count may not change fast enough over time course of trial**
**Fleming TR. Stat Med 1994;13:1423-35.**

## Strengths and Limitations

**The “logic string” for topical antiseptic products**
**colonization with organisms precede infection (risk factor)**
**organisms can cause infection and resulting host response**
**since organisms cause infection, eliminating or decreasing organisms *****should***** results in positive clinical outcomes for patients**
**So logical, so “objective”.....but is it correct?**
**DeGruttola V et al. Ann Intern Med 1997;175:237-46.**
**Deductive, not inductive reasoning**
**Need to test this logic to see if it is true**
**Prentice RL Stat Med 1989;8:431-440.**

## Strengths and Limitations

**Reasons why surrogate may not accurately predict clinical outcomes:**
** ****unmeasured harms caused by intervention**
** ****unmeasured benefits caused by intervention**
** ****other mechanisms of disease other than those affected by intervention**
** ****issues with measuring surrogate**
** ****issues with measuring clinical outcomes**

## Strengths and Limitations

** ****Surrogate may not take into account unmeasured**
**benefits and harms of treatment (not just “correlate”)**
** ****Knowledge about how a drug achieves clinical results may be incomplete**
** ****Conservation of processes in human body**

## Strengths and Limitations

**Unmeasured benefits**
**effects of drug other than “eradication” of organisms**
**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 harms**
**deleterious effects on host that may promote infection**
**replacement of one organism with another that may cause infection**
**other sources of infection other than those affected by drug**

## Strengths and Limitations

**Unmeasured benefits**
**rifaximin approved for treatment of travelers diarrhea**
**drug have similar rate of positive cultures for pathogens in stool compared to placebo**
**drug still decreased time to resolution of diarrhea compared to placebo (for some, not all organisms)**
**Steffen R et al. Am J Gastroenterol 2003;98:1073-8.**
**Unmeasured harms**
**dose escalation trial of clarithromycin for disease due to *****Mycobacterium avium-intracellulare***** in patients with AIDS**
**higher doses had higher rates of negative blood cultures (microbiological outcomes) but also higher mortality (clinical outcomes)**
**Chaisson et al.  Ann Intern Med 1994;121:905-911**

## Strengths and Limitations

**Intervention may affect one pathway of disease and **
**not other pathways that are as important**
**or more important in resulting clinical outcomes**

## Strengths and Limitations

**Other mechanisms of disease not affected by intervention**
**several trials show decreased rates of colonization with *****S. aureus***** (microbiological outcome) with intranasal mupirocin**
**prevention of infections (clinical outcome) in patients not lower than placebo**
**Kalmiejer MD et al. Clin Infect Dis 2002;35:353-8.**
**Perl TM et al. N Engl J Med 2002;346:1871-7.**
**Wertheimer HF et al. Ann Intern Med 2004;140:419-25.**
**May be due to infection caused by sources of *****S. aureus***** other than the nose**

## Strengths and Limitations

** ****Issues with accuracy of how surrogate is measured**
**it may be reproducible (precision) but is it telling**
**us the correct inference (accuracy)?**
**what, when, how and magnitude of what is measured**

## Strengths and Limitations

**Culture techniques based on methodology from late 1800’s with inherent error (same organisms can give MIC one to tube dilutions different on serial testing)**
**Issues with microbiological outcomes**
**patient population sampled**
**sampling technique**
**culture methodology**
**when culture is performed (“on therapy”) and follow-up period**
**frequency of sampling**
**criteria applied for classification (“all or nothing” vs. quantitative)**

## Strengths and Limitations

- Microbial load

- Time

- level of detection

- Patient 1

- Patient 2

- baseline

- end of study

- on therapy

**Suppression **
**vs.**
**“****Eradication”**

## Strengths and Limitations

** ****Measurement of clinical endpoint may not**
**	****be relevant based on natural history of disease**
** ****inaccurate measurement of clinical endpoint does not**
**justify use of unvalidated surrogate**

## Strengths and Limitations

**Example**
**Catheter tip decolonization claimed to be “validated” as surrogate endpoint for clinical trials in prevention of catheter-related bloodstream infections (BSI) based on “correlation” of two endpoints**
**Rijnders BJA et al. Clin Infect Dis 2002;35:1053-8.**
**Definition of “bloodstream infection” in some of these studies is positive blood culture AND a positive culture of a catheter tip**
**“**residual antimicrobial activity in the removed catheter sufficient to prevent growth from the cultured catheter segments would substantially reduce the *apparent* rate of catheter-related bloodstream infections.... could it be that use of minocycline–rifampin impregnation prevents growth from catheters in the microbiology laboratory but does not eliminate the clinical syndrome of catheter-related bloodstream infection?”
**Paterson DL N Engl J Med 1999;340:1761.**
**Studies submitted to FDA show no effect on BSI relative to placebo despite effect on decolonization**

## “Correlating” Surrogates

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

**% success with surrogate**

**% clinical success**

## “Correlating” Surrogates

** ****Surrogate must measure effects similarly for all drugs studied**
**adapted from Baker**** ****SG et al. BMC Medical Research Methodology 2003;3:16.**

**% clinical success**

**% success with surrogate**

## Regulatory Issues

**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 314.510)**
**serious and life threatening disease**
**surrogate endpoint reasonably likely to predict clinical outcome**
**requires confirmatory post-approval trial based on clinical endpoint (usually from a trial that is already ongoing)**
**TFM predates these regulations**

## Surrogates and Topical Antiseptics

**Unmeasured harms**
**unintended effects on microscopic breakage in skin may result in greater infection rate (example of shaving and peri-operative infections)**
**Seropian R et al. Am J Surg 1971;121:251-4.**
**effects on common pathogens may be less than that on marker organisms in skin**
**selection of resistance to systemic antimicrobials?**
**Unintended benefits**
**some products may have positive effects other than those on organisms**
**effects on common pathogens may be greater than that on marker organisms used to contaminate skin**

## Surrogates and Topical Antiseptics

**Other mechanisms not affected by intervention**
**data obtained on surrogate endpoint is from most superficial layer of skin (stratum corneum of epidermis) **
**source of organisms causing infection may not be the same as site measured by surrogate**
**“****skin stripping” experiments using cellophane tape**
**12 different sites on body had variable colony counts of coagulase negative staphylococci**
**top 5 layers of stratum corneum had higher colony counts and next 20 layers with stable counts**
**return of same organisms 18 hours post-sterilization with alcohol indicates reservoir of normal skin flora may be below stratum corneum in hair follicles/glands in dermis**
**Brown E et al. J Infect Dis 1989;160:644-50.**

## Skin Anatomy

## Skin Anatomy

## Surrogates and Topical Antiseptics

**Issues with measurement of surrogate**
**Population in whom surrogate is measured may be different from actual use population in unmeasured ways**
**Organisms measured not necessarily those that cause infection**
**Is timing of measurements relevant to disease process?**
**Are conditions of testing same as those that would be encountered in real life situations?**
**Does variations in methodology (vigor of scrubbing, use of neutralizers) affect consistency of results?**
**What log reduction is clinically significant? How to analyze numbers obtained on log reductions? Changing method of analysis may change clinical conclusions**

## Surrogates and Topical Antiseptics

**Clinical endpoints**
**What is data showing correlation of reduction in bacteria with decrease in infection rates?**
**What does dose response curve look like for infection rates and numbers of bacteria? Is this a threshold effect (lower infection rates below some amount of bacteria) or a continuous variable?**
**Are correlations the same for all types of products? **

## Surrogates and Topical Antiseptics

- Rate of infection

- Change in numbers of bacteria on skin

- “Dose Response” of Numbers of Skin Bacteria and Infection Rates

## Surrogates and Topical Antiseptics

- Rate of infection

- Change in numbers of bacteria on skin

- “Dose Response” of Numbers of Skin Bacteria and Infection Rates

## Surrogates and Topical Antiseptics

## Conclusions

**Surrogate endpoints must not only “correlate” with clinical outcomes but must also take into account :**
**unmeasured harms and benefits**
**methodology and uncertainties in measuring surrogate**
**appropriate measurement of clinical endpoint**
**Clinical endpoint for efficacy of topical antiseptic products would be prevention of infections**
**condition of testing today are not those of Semmelweis**
**Further discussion today on what is known about surrogates in setting of topical antiseptics**

**“****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.**