Biomarkers and surrogate endpoints: How and when might they impact drug development? · 2019. 8....

Disease Markers 18 (2002) 83–90 83IOS Press

Biomarkers and surrogate endpoints: Howand when might they impact drugdevelopment?

Chetan D. LathiaClinical Pharmacology, Bayer Corporation, West Haven, CT 06516, USATel.: +1 203 812 2768; Fax: +1 203 812 5056; E-mail: [email protected]

Abstract. As the pharmaceutical industry starts developing novel molecules developed based on molecular biology principlesand a better understanding of the human genome, it becomes increasingly important to develop early indicators of activity and/ortoxicity. Biomarkers are measurements based on molecular pharmacology and/or pathophysiology of the disease being evaluatedthat may assist with decision-making in various phases of drug development. The utility of biomarkers in the development ofdrugs is described in this review. Additionally, the utility of pharmacokinetic data in drug development is described. Developmentof biomarkers may help reduce the cost of drug development by allowing key decisions earlier in the drug development process.Additionally, biomarkers may be used to select patients who have a high likelihood of benefit or they could be used by cliniciansto evaluate the potential for efficacy after start of treatment.

1. Introduction

Discovery and development of new molecular enti-ties (NME) or analogs of existing chemical entities ischallenging. For the sake of the patients as well as tokeep the cost of this complex process as low as pos-sible, pharmaceutical scientists must use every tool attheir disposal to increase the speed and efficiency ofdrug development. By some accounts, approval of newmolecules can take up to 10 years from initial discov-ery to first clinical approval and cost as much as $750million dollars per compound.

Perhaps one of the reasons for this complexity andcost is the lack of appropriate tools to help guide keydecisions and reduce cost during development. Forexample, the choice of molecules to move forwardfrom early preclinical or early clinical development intofull-scale clinical development is currently made basedupon pre-clinical experiments whose relevance to thehuman condition is imperfect. For this reason manyagents go through lengthy clinical evaluations beforeits development is terminated due to lack of clinicalbenefit. Early indicators of the activity or toxicity as-

sociated with a molecule could be potentially utilizedto make decisions about further development or earlytermination.

Once a molecule is in clinical development, methodsof selecting patients who might truly benefit from theexperimental treatment or for monitoring clinical ben-efit during treatment may greatly simplify drug devel-opment. “Biomarkers” include laboratory assays thatare thought to reflect a given molecule’s mechanism ofaction and/or its pharmacodynamic activity. The hopeis that such biomarkers could be used to direct keydevelopment decisions such as selection of agents forfurther development, selection of dose and/or scheduleand selection of patients.

Unfortunately, biomarker discovery and develop-ment is not risk-free, as the true correlation between aspecific biomarkerassay and clinical benefit may not beconfirmed until after the well-controlled clinical stud-ies are completed. While decisions to use biomarkersin drug development are not without their risks, if theyare made using biomarkers with a physiological, patho-logical, or pharmacological rationale and with support-ive in vivo preclinical evidence, biomarkers may sig-

ISSN 0278-0240/02/$8.00 2002 – IOS Press. All rights reserved

84 C.D. Lathia / Biomarkers and surrogate endpoints

nificantly enhance the cost- and time-efficiency in drugdevelopment. Thus, there are many potential utilitiesand risks of using biomarkers during drug development.The strengths and liabilities of biomarkers, as well asthe process of biomarker discovery and developmentwill be discussed in this review article.

2. The drug development process

In order to understand the utility of molecular mark-ers of a drug’s activity in drug development, it is worth-while to briefly review the process of drug discoveryand drug development. The modern process of drugdiscovery entails identifying a biological target such asa receptor/protein to which endogenous molecules orxenobiotics could bind to alter the secretion of a pro-tein and/or alter the function of a cell, tissue or organ,thereby altering the progression of disease. Early dis-covery screening cascades are designed to screen can-didate molecules for preclinical research. Using tech-niques of combinatorial chemistry and high throughputscreening, early candidates of preclinical research areselected.

In vitro screening usually includes some type of bind-ing to a specific receptor or cell surface proteins. Subse-quently, these candidates are usually evaluated for theiractivity in preclinical in vivo models of efficacy and si-multaneously evaluated for their pharmacokinetic andformulation properties. The preclinical research team,in conjunction with clinical scientists, then chooses alead candidate, with back-ups, for exploratory devel-opment.

Toxicology, pharmacokinetic and formulation eval-uations are conducted in exploratory development toallow the start of Phase I and Phase IIA or proof-of-concept studies in man. If the safety, tolerability andpharmacokinetics of a compound are favorable in earlyclinical development, proof-of-concept/PhaseIIA eval-uations are generally started to determine the potentialfor a full-scale clinical development in expanded PhaseIIB and III trials.

Full scale clinical development involves intense ef-forts from many physicians and scientists. It takesmany years and costs many millions of dollars in theconduct of labor-intensive toxicology, clinical phar-macology and clinical trials. A package containingthe appropriate clinical and preclinical data as well asthe chemistry and manufacturing data is submitted forregulatory approval. Special Phase IV post-marketingstudies are occasionally conducted to support addi-

tional indications or to provide additional safety orpharmacokinetic data for the product.

Various stages of development, from the pre-clinicaldiscovery to the clinical trials in patients, are typicallyconducted with only limited attention to the direct bi-ological activity of the compound. Often the choiceof dose and schedule for further development is madebased upon limited clinical data. As such, it is notuncommon for clinical investigators to restart PhaseII and III studies when additional clinical data insti-gate revision of the dosing strategies. Furthermore,the primary endpoint of the animal and patient trials isto quantify and characterize the clinical benefit (e.g.,pain reduction for analgesics, survival prolongation foranti-cancer agents) and not to quantitate the impact ofa given agent on it’s direct biological target. As such,clinical studies are large (e.g., up to several thousandpatients) and long (e.g., several years). The true clin-ical benefit of a given experimental agent is fully un-derstood and full regulatory approval is granted aftermany years.

This review will examine the utility of biomarkersof biological activity as potential tools for streamliningthe various phases of drug development. An excellentreview of the use of biomarkers and surrogate endpointsin drug development and regulatory decision-makingwas recently published [11].

3. Definitions

The Biomarkers Definitions Working Group recentlypublished a paper to provide a framework for conduct-ing future research [2]. These definitions are not pro-vided here verbatim. Instead, working definitions areprovided and in some instances elaborated with exam-ples.

3.1. Biomarker

Biomarker is a measurable property that reflects themechanism of action of the molecule based on its phar-macology, pathophysiologyof the disease or an interac-tion between the two (Fig. 1). A biomarker may or maynot correlate perfectly with clinical efficacy/toxicity butcould be used for internal decision-making within apharmaceutical company.

C.D. Lathia / Biomarkers and surrogate endpoints 85

Disease New MolecularEntity or

intervention

Clinical outcome

BiomarkerUnknown factors

Fig. 1. A New Molecular Entity (NME) or an intervention helps slow the progression of a disease leading to an improvement in clinical outcome.A biomarker which has a strong association with the disease state and is affected by the NME to alter the clinical outcome may become a surrogateendpoint if it accounts for a large portion of the clinical outcome and does not appreciably predict other undesirable or unpredictable outcomes.

3.2. Predictive assays

Predictive assays are a category of biomarkers thathelp identify potential responders to therapy. These arelaboratory-based evaluations that predict the activity ofa NME in a given disease for a given set of patientcharacteristics. For example, breast cancer patientswith elevated levels of serum HER-2 concentrationsare more likely to derive clinical benefit from treatmentwith trastuzumab, than are those patients who do not.Trastuzumab is a monoclonal antibody that putativelyblocks the HER-2 neu receptor [13]. It is interestingto note that only 20% of patients identified by thisbiomarker have responded [15].

3.3. Clinical endpoint

A clinical endpoint is the true measure of how thepatient benefits. Clinical endpoints are measured in asufficient number of patients in prospectively designed,controlled clinical trials to reflect the effect of the phar-macological agent or New Molecular Entity (NME) onthe disease process. Using clinical efficacy and safetydata collected in these clinical trials, and, if appropri-ate, comparing these to other approved agents to treatthe same disease, regulatory agencies determine theratio of risk to benefit. This along with other regu-latory considerations generally serves as the basis ofdrug approval. Mortality, morbidity, and survival aresome of the definitive clinical endpoints used to as-sess response to therapeutic interventions. For exam-ple, survival is considered as the gold-standard clini-cal endpoint for anticancer agents and cardiovascularmorbidity is considered a desirable for several antihy-pertensive and anti-atherosclerotic agents. Quality oflife instruments could evaluate how patients feel and,are gaining utility in late-stage clinical trials. Theseinstruments may also help with procuring a desirableprice with a Health Maintenance Organization (HMO)or a regulatory agency.

3.4. Surrogate endpoint

A surrogate endpoint is a biomarker that corre-lates very well with the activity and/or toxicity of themolecule. It is generally an acceptable endpoint forregistration of a molecule with regulatory agencies. Abiomarker qualifies as a surrogate endpoint for a clini-cal endpoint after controlled clinical trials show a sta-tistically and clinically significant correlation betweenthe two. Surrogate endpoints must reliably predict boththe safety and efficacy associated with a pharmacologi-cal agent. Surrogate endpoints are sometimes obtainedfrom studies evaluating the natural history of the dis-ease or epidemiology. There are only a few examplesof a biomarker becoming a qualified surrogate end-point. Blood pressure is an accepted surrogate endpointfor antihypertensive agents as it predicts cardiovasculardisease, heart failure, stroke and kidney failure [4]. Onthe other hand, insufficient evidence of a strong cor-relation between a biomarker and an ultimate clinicalendpoint, would disqualify its use as a surrogate end-point. For example, for several classes of agents bonemineral density has shown to a have good correlationwith fracture rates. However, this has not turned out tobe the case for fluoride [16].

Atkinson [1] has compiled a table of biomarkerswhich have found varying degrees of clinical utility.Tables 1 and 2 present selected examples of biomarkersand surrogate endpoints.

4. Applications of biomarkers in drug discoveryand development

Biomarkers may be utilized in several phases of drugdevelopment. They are useful for in vitro evaluationsof hundreds of candidates that are typically screenedduring drug development. Biomarkers can be use-ful in lead candidate selection during preclinical re-


Table 1Biomarkers/surrogate endpoints that have aided drug development

Biomarker/surrogate endpoint Type of drug Clinical endpoint

Blood pressure Antihypertensives Stroke, athersclerosis, heart failureCholesterol LDL lowering statins Coronary artery disease, heart attacksViral RNA Antiretroviral agents Survival, decrease in infectionsHbA1C, glucose Antidiabetic agents Diabetic neuropathyCD4+ T cells Antiretroviral agents, cytokines Sustained reduction in viral RNAIntraocular pressure Antiglaucoma agents Preservation of peripheral visionBone mineral density (BMD) Antiosteoporotic agents Fracture rateMRI scans Agents for treatment of MS Decrease in rate of progression disease (check PDR)CT scans for tumor size Anticancer agents Survival

Table 2Biomarkers/predictive assays used for diagnostic purposes

Biomarker/predictive assay Disease

Intraocular pressure GlaucomaElectrocardiogram Arrythmic cardiovascular diseaseProstate specific antigen Prostate cancerCT scans/X-rays CancerCarcinoembryogenic antigen Ovarian cancerIncreased serum alpha fetoprotein Hepatocellular carcinomaIncreased viral load HIV infectionIncreased blood glucose DiabetesReduced bone mineral density Osteoporotic diseaseFever InfectionReduced absolute neutrophil count Risk for infectionReduced platelet count Risk of bleedingIncreased PT/PTT Risk of bleedingIncreased AST/ALT/Alkaline phosphatase Damage to the liverIncreased serum creatinine Damage to the kidneyIncreased serum creatinine phophokinase Rhabdomyolysis

search. There is significant value in measuring ap-propriately selected biomarkers in early phase devel-opment of the NME to ensure that it alters the phar-macology/physiology/pathology as desired. A NMEthat does not demonstrate a change in the pathway itis supposed to affect, may have a lower likelihood ofsuccess. The utility of biomarkers will be describedwith examples in the following sections.

4.1. Drug discovery

Early in drug discovery, hundreds of molecules areevaluated in a series of experiments to determine ifthey are good candidates for further research. The ra-tional drug discovery process screens these moleculesagainst appropriate targets/receptors/proteins. For ex-ample, LDL lowering statins are screened based ontheir activity against HMG Co A reductase enzyme.The rationale is based on clinical epidemiologic infor-mation showing that the incidence of coronary heartdisease is linked with LDL cholesterol and inhibitingthe HMG Co A reductase enzyme helps as it is a rate-limiting step in the synthesis of LDL cholesterol [9].

ACE inhibitors are evaluated in vitro by their inhibi-tion of angiotensin converting enzyme (ACE). Gener-ally, compounds with the highest in vitro potency andselectivity for the intended pathway are chosen for fur-ther research. Showing that a purported biochemicalpathway is modified in selecting a molecule for furtherresearch makes intuitive sense as it builds confidence inthe mechanism of action of the drug and provides toolsfor biomarker development in preclinical and clinicalin vivo evaluations.

4.2. Lead candidate selection

In vivo animal models are frequently used to fur-ther characterize late-stage research compounds beforebringing them forward into clinical development. Forexample, blood pressure is good marker of cardiovascu-lar morbidity and mortality. Compounds which lowerblood pressure in appropriate animal models are likelyto show similar antihypertensive activity in clinical tri-als. From a toxicologic standpoint, a molecule whichshows prolongation of QT interval in appropriate an-imal models is also likely to do so in man. ACAT


inhibitors act by inhibiting the ACAT enzyme therebyreducing the formation of atherosclerotic lesions in ar-teries [17]. Preclinical proof-of-conceptdata were gen-erated by evaluation of ACAT inhibition in monocytesturned macrophages in arterial lesions in rabbits dosedwith an ACAT inhibitor [3]. Similarly, angiotensin IIinhibitors have been evaluated in preclinical in vivomodels by measurement of angiotensin II and aldos-terone in animals in addition to the measurement ofblood pressure.

4.3. Early clinical development

To increase the efficiency and quality of clinical de-velopment, pharmaceutical companies seek to improvetheir screening processes for NMEs by making criti-cal go/no go decisions early in drug development. Ifthe NME does not demonstrate the proof-of-conceptin an appropriatedly designed early clinical trial, de-velopment should be terminated. This is particularlyuseful in therapeutic areas where biomarkers may havefound some predictive value for efficacy or patient ben-efit. For example, successful lipid lowering HMG Co-A reductase inhibitors such as statins may show earlyevidence of cholesterol lowering in otherwise normal,mild to moderate hypercholesterolemic patients in earlyPhase I or II trials in a 3- to 4-week multiple dose study.If such a study is designed as a dose-ranging, placebocontrolled, randomized, double-blind trial it may beable to help in the selection of doses for future Phase IItrials. Similarly, a Phase 1 multiple dose study with ananticancer agent in a focussed patient population whichshows antitumor activity may help with dose-selectionof an anticancer agent in Phase II trials. For evalu-ation of an agent to treat asthma, one may measureFEV1 (Forced Ejection Volume in 1 second) and/orFVC (Forced Vital Capacity) in asthmatic patients todetermine the appropriate Phase II dose. In the ab-sence of these more predictive markers, pharmaceuticalcompanies may choose to measure other biomarkers,including plasma concentration-time profiles, to assistwith go/no go decisions. Small and mid-size biotech-nology companies often develop molecules by alter-ing a few amino acids in a peptide/protein moleculeto block a receptor/pathway in a known pathophysi-ologic pathway. Measurement of a protein moleculewhose concentration in serum/plasma changes down-stream from the blocked receptor/pathway may serveas a useful tool in determining if the molecule worksthrough the putative mechanism of action. In theirproof-of-concept studies, these companies may choose

to look at that downstream protein or its mRNA to makea go/no go decision with regards to its mechanism ofaction. The extent of ACE inhibition, even though itmay not have clear and distinct relationship with clini-cal outcome, has been used by pharmaceutical compa-nies to evaluate their NME with that of other pharma-ceutical companies before moving their compound fur-ther in drug development. It is well known, for exam-ple, that pharmaceutical companies may terminate thedevelopment of a poorly absorbed compound if, withtheir best dosage form, exposures comparable to thoseleading to preclinical efficacy are not observed.

A bridging strategy to move a compound from PhaseI to limited Phase II development in Japan is often re-quired. For a cytotoxic anticancer agent under devel-opment exposure-toxicity relationship can be used. Forexample, if thrombocytopenia is the dose-limiting tox-icity and occurs in a predefined range of exposures inclinical trials in North America or Europe, and a similarexposure-toxicity relationship is observed in Caucasianand Japanese patients, it may provide assurances to thepharmaceutical company and to the regulatory author-ity about similarity between Caucasian and Japanesepatients. This may allow start of Phase II/III clini-cal trials with limited number of patients in Japan forevaluating similarity in efficacy and toxicity in thesepatients.

By developing a hypothesis and a clear decision-treebased on the outcome of these early development clin-ical trials, pharmaceutical companies may be able tomake good decisions with regards to taking their bestNME candidates forward in development. Early proof-of-concept trials not only help in making go/no go de-cisions but could also help in selecting an appropriatedose and exposure to move forward in future clinicaltrials.

4.4. Full-scale clinical development

A large amount of human resources as well asmonies are spent on full-scale development clinical tri-als. Dose-ranging Phase II studies as well as full-fledged Phase III trials could be conducted and po-tentially bridged with the use of biomarkers. HIV-1RNA concentrations and CD4+ T-lymphocyte countshave been shown to be independent prognostic markersof clinical progression in patients receiving antiretro-viral therapy for HIV related disease [12]. A suffi-cient change in these markers from baseline has led toaccelerated approval [6] of a number of antiretroviralagents. However, the FDA and other regulatory agen-


cies would subsequently ask the pharmaceutical com-pany to provide data demonstrating clinical benefit infuture clinical trials [6].

Bone mineral density (BMD) as measured by DualEnergy X-ray Absorptiometry (DEXA) may allowbridging Phase III trials from one indication (hip frac-ture) to another indication (vertebral fracture) for amolecule under development if BMD is correlated withfracture rate for the first indication. Demonstration ofa clinically significant increase in BMD in vertebralbones over a period of sufficient duration may be ad-equate for regulatory approval of the agent for the in-dication of vertebral fracture. With Fosamax, the FDAallowed approval of a sustained release once-weeklyformulation based primarily on BMD data. The thera-peutic equivalence of once-weekly Fosamax 70 mg andFosamax 10 mg daily was demonstrated in a one-yearstudy of postmenopausal women with osteoporosis.The two treatment groups were also similar with regardto BMD increases at other skeletal sites [14]. However,if for a particular molecule, increases in BMD do notcorrelate with fracture rate, changes in BMD may notserve as a useful measure to evaluate its efficacy. BMDmeasurements in clinical studies with fluoride did notreflect decreases in patient fracture rates [16].

Magnetic resonance imaging, along with appropri-ate clinical evaluations (disease progression based ona clinical score or annual exacerbation rate), is a puta-tive secondary endpoint for the evaluation of multiplesclerosis (MS). It is conceivable that, if a good corre-lation is shown between the clinical endpoint and MRIin patients with secondary progressive MS, MRI maybe used to explore the clinical benefit of that NME in adifferent MS population.

Investigators have evaluated compounds which pu-tatively change the morphology of an atheroscleroticplaque using MRI in rabbit models of atherosclero-sis [10]. MRI could be a sensitive tool to evaluate thechange in plaque morphology from baseline in patientswith atherosclerotic plaque [5]. If preclinical evalu-ations are conducted to show that change in plaquemorphology from baseline is measurable using MRI, apharmaceutical company may choose to evaluate MRIas a biomarker for atherosclerotic disease progressionto evaluate further development.

5. Use of plasma concentration-time data as abiomarker for efficacy [8]

If the exposure-response relationship is adequatelyevaluated in placebo-controlled dose-ranging clinical

trials and the relationship is characterized well, this re-lationship may be used to support new dosing regimens,new or modified dosage forms or formulations, or a dif-ferent route of administration. If a dosing regimen thathas not been evaluated in clinical trials is evaluated ina pharmacokinetic (PK) trial and found to be advanta-geous, and if the relationship between exposure and re-sponse is well-characterized, this information could beused to extrapolate from previous clinical results. Simi-larly, if the pharmaceutical company chooses to developa modified release dosage form, a known exposure-response relationship could be used to seek approval.An example of approval of Fosamax 70 mg was pro-vided earlier. Procardia XL tablets appear to have re-ceived regulatory approval based on a known exposure-response relationship between nifedipine concentra-tions and blood pressure/angina and additional sup-portive clinical pharmacology data for these modified-release tablets. In limited circumstances, if it can bedemonstrated that changing the route of administrationdoes not alter the metabolic profile or the exposure-response relationship of a compound, further develop-ment of the approved agent, using a new route of ad-ministration may be warranted. Exposure-response re-lationship data can also be used to support a changein an existing formulation which may in turn changeits pharmacokinetics. Bioequivalence testing is usu-ally sufficient to demonstrate that a new formulation isequivalent to that used to generate the primary efficacyand safety data. In such a situation, the 90% confidenceinterval of ratio of the geometric means of Cmax andAUC values of the new formulation to the referenceformulation is required to be within 80–125%. If theratio of new formulation falls outside this confidenceinterval and if the pharmaceutical company has datashowing that a wider confidence interval is acceptablebased on available clinical data, the FDA may considerthese two products to be bioequivalent. In other caseswhere bioavailability of the new formulation is altered,the FDA may allow altering the strength of the productso that the bioavailability of the altered formulation issimilar to that of the marketed product.

6. Risks of using biomarkers

As with any new tool, the use of biomarkers may beassociated with risks. These risks have been describedby Lesko and Atkinson [11] and could possibly arisebecause of the following reasons:


1. The NME affects the biomarker but does notaffect the clinical outcome. In this case, thebiomarker is non-specific. If such a biomarker ischosen in early phase clinical development, thepharmaceutical company could end up wasting alot of money on clinical development relying onan inappropriate biomarker.

2. The NME affects the biomarker and clinical out-come to a different extent. In this case, there willbe some correlation between biomarker and clin-ical outcome but the biomarker will not be able tofully account for the effect on clinical outcome. Ifthe chosen biomarker accounts for a small portionof the clinical benefit, the pharmaceutical com-pany could make a wrong decision to discontinuethe development of a good drug.

3. The biomarker may be associated with only a por-tion of the effects on clinical outcome. For exam-ple, quinidine was found to suppress cardiac arry-thmias leading to normalization of sinus rhythm.However, it also caused premature deaths [7].

7. Conclusions

It is expensive and time consuming to tackle thechallenges of discovering and developing new molec-ular entities without the use of well-defined biomark-ers. The use of biomarkers could not only help withreducing the cost of drug development but also de-velop a better understanding of the disease process andpossibly improve patient care. Many validated andunvalidated biomarkers are currently in clinical use.However, there are many, many untapped opportuni-ties in enhancing drug development. Drug develop-ment could substantially benefit by making judiciousdecisions using biomarkers. Biomarkers have theirutility in all phases of a drug’s life-cycle. Perhaps,they are most valuable in terminating development ofmolecules, before a vast amount of resources are ex-pended in expensive Phase 3 clinical trials, which don’texhibit their proof-of-principle based on the putativemechanism of action. From a clinician’s standpoint,validated biomarkers which preselect a patient popula-tion or track the course of a disease (or lack thereof)may add significant value. Clearly, the use of biomark-ers is not without risks. If these risks are adequatelyunderstood and quantified, decision-making in moderndrug development may be significantly accelerated andenhanced by the use of carefully selected biomarkers.

Acknowledgements

The author thanks Rachel Humphrey, MD for a thor-ough review of this document and Pavur Sundaresan,MD, PhD, for his encouragement and support and toGeraldine Tomassi for helping format this document.

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