Opportunities and Challenges of Safety BiomarkerQualification: Perspectives from the Predictive Safety
Testing ConsortiumEslie H. Dennis,1 Elizabeth G. Walker,1* Amanda F. Baker,1 and Richard T. Miller2
1Predictive Safety Testing Consortium, Critical Path Institute, Tucson, Arizona2GlaxoSmithKline, Research Triangle Park, North Carolina
Strategy, Management and Health Policy
Preclinical DevelopmentToxicology, FormulationDrug Delivery,Pharmacokinetics
Clinical DevelopmentPhases I-IIIRegulatory, Quality,Manufacturing
ABSTRACT Biomarkers hold tremendous promise to improve the drug development and evaluationprocess, advance patient care, and reduce health-care costs. However, understanding the characteristicsof novel biomarkers and developing the robust evidentiary packages to support incorporating them intodrug development and clinical practice is an enormous undertaking requiring significant resources andcommitment from a wide range of stakeholders, including regulators, the biopharmaceutical industry,academia, governmental agencies, patients, and payors. The Predictive Safety Testing Consortium (PSTC)is a unique publicprivate partnership formed by Critical Path Institute (C-Path) in collaboration with theUnited States Food and Drug Administration (FDA) to identify new and improved drug safety testingmethods and submit them for formal regulatory qualification by the FDA, the European Medicines Agency,and the Japanese Pharmaceuticals and Medical Devices Agency. In 2008, the PSTC obtained the firstregulatory qualification of seven urinary renal preclinical safety biomarkers for use in rodent studies andon a case-by-case basis for inclusion into clinical development programs. These qualified biomarkers arenow successfully informing drug discovery and development decisions. PSTC has expanded their quali-fication efforts into dogs, nonhuman primates, and humans and focuses on six areas of organ toxicity. Thecollaborative effort of multiple stakeholders through PSTC has resulted in significant cost savings and morerapid scientific consensus, leading to greater acceptance of these biomarkers by health authorities andpharmaceutical companies. Regulatory qualification of a biomarker for a defined context of use providesscientifically robust assurances to sponsors and regulators that should accelerate appropriate adoption ofbiomarkers into drug development and, ultimately, clinical practice. Drug Dev Res 74 : 112126,2013. 2013 Wiley Periodicals, Inc.
Key words: regulatory science; biomarker; qualification; drug development tool; novel methodology; Critical PathInstitute; Predictive Safety Testing Consortium
Without a doubt, pharmaceutical products, espe-cially drugs, have had a significant impact on improvingpublic health and increasing longevity [Lichtenberg,2005]. Death rates for all malignant cancers havedecreased substantially. The 5-year relative survival ratefor all cancers diagnosed between 2001 and 2007 was aremarkable 67%, increased from 49% in 19751977[American Cancer Society, 2012], with an estimated
Funding/Support Information: Science Foundation Arizona;grant number: SRG 0335-08; grant sponsor: US Food and DrugAdministration; grant number: U01FD003865.
*Correspondence to: Elizabeth Walker, Predictive SafetyTesting Consortium, Critical Path Institute, 1730 E. River Road,Tucson, AZ 85718.E-mail: email@example.com
Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ddr.21070
DRUG DEVELOPMENT RESEARCH 74 : 112126 (2013)
2013 Wiley Periodicals, Inc.
13.7 million cancer survivors in 2012; those numbersare expected to rise [Siegel et al., 2012]. A study by Sunet al.  demonstrated that, between 1988 and2000, overall survival for all cancers increased by 3.9years, with treatment accounting for 8186% of survivalimprovements. With successes in increasing survivor-ship, there is heightened focus to reduce the toxicitiesof therapies, which can affect every organ system,increasing morbidity and treatment-related mortality.For example, cardiac toxicity, a growing area of concernwith several highly efficacious cancer treatment regi-mens, has resulted in the risk of cardiovascular deathnow being higher than the actual risk of tumor recur-rence [Cardinale and Cipolla, 2011], with a sevenfoldhigher cardiac mortality in childhood cancer survivors[Mertens et al., 2008]. Pharmaceuticals have trans-formed fatal diseases such as human immunodeficiencyvirus into chronic medical conditions. However,chronic diseases require the commitment of patients tolong term if not lifelong treatment with increasingconcern regarding the impact of drug toxicities, andgreater need to predict which patients are at risk, inorder to appropriately manage treatment regimens andadditionally identify adverse events as early as possiblefor effective intervention. As we live longer and have agreater number of chronic conditions treated with mul-tiple drugs, adverse drug reactions (ADRs) are likely toincrease. Among American adults 65 years of age orolder, 57%/59% (women/men) take more than fivemedications and 17%/19% take 10 or more [SloneEpidemiology Center 2006].
Toxicities may be first identified at any stage ofdiscovery or development or may only be identifiedafter marketing approval. Identification is obviously lessdesirable in latter stages of clinical development, par-ticularly once the product is marketed. Toxicitiesrelated to therapeutic treatment are classified andtracked in a number of ways and significantly affectpatient and public health. Type A reactions are predict-able by the mode of pharmacological mechanisms andare often dose dependent. In contrast, type B reactions,which account for about 15% of ADRs, are historicallyreferred to as unpredictable, dose-independent, idio-syncratic reactions [Rawlins, 1981]. ADRs are increas-ing in frequency. ADR-related visits to outpatientclinics in the United States almost doubled between1995 and 2005 [Bourgeois et al., 2010]. Serious ADRsare those that result in death, are life threatening,require inpatient hospitalization or prolong an existinghospitalization, result in persistent or significant disabil-ity or incapacity, or are related to congenital anomaliesor birth defects. Important medical events that may notbe immediately life threatening but jeopardize thepatient or require intervention to prevent one of the
other outcomes listed may also be considered serious[FDA, 2010c]. Serious ADRs accounted for 6.7% ofhospitalized admissions with 106 000 fatalities in 1994,ranking ADRs between the fourth and sixth leadingcause of death in the United States [Lazarou et al.,1998]. Thus, ADRs pose significant risks to patients,increasing morbidity and mortality and can incur sub-stantial health-care costs.
ADRs are an increasing challenge for the pharma-ceutical industry. Although the safety evaluation per-formed during drug development and submitted forregulatory approval is extensive, there remains a safetyuncertainty when a drug enters the marketplace withexposure to larger and more diverse populations.Serious but rare adverse events may not be identified inclinical trials because it is impractical to include a suf-ficient number of patients to detect very infrequentevents, e.g. 1/100 000. In addition, physicians may alsoprescribe drugs off label in patient populations thathave never been studied during drug development.Thus, many ADRs are only identified postapproval and,if serious, require regulatory action ranging from labelchanges to mandated Risk Evaluation and MitigationStrategies (REMS) and Risk Management Programs towithdrawal. There are currently 72 Food and DrugAdministration (FDA) approved REMS [FDA, 2012a].From 1976 to 2011, there have been over 30 newmolecular entities (NMEs) withdrawn from the U.S.market for safety reasons [FDA, 2005, 2010b, 2012d,Wysowski and Swartz, 2005]. Over this same timeframe, many more drugs in development have beenterminated during clinical trials due to safety issues, inaddition to many that were terminated due to toxicity inpreclinical species.
Consequent to the growing awareness and extentof drug-related safety issues, there has been increasedscrutiny of compounds in drug development, with adecreased tolerance of uncertainty. The disease, theunmet medical need, and the efficacy of a specific com-pound influence the benefit-risk assessment and thusthe level of uncertainty that can be accepted. Healthauthorities are constantly challenged to balance theirobligations to protect public health and safety while atthe same time facilitating patient access to new drugswith favorable benefit-risk profiles more rapidly. Thishas resulted in the regulatory bar being raised duringeach of the past four decades [Woodcock, 2010] withadditional testing requirements and more stringentmandates for safety monitoring and reporting. Drugdevelopers today face a much more prolonged, expen-sive, and rigorous development program that may stillnot identify serious adverse events. At the same time,promising new compounds that could significantlyaddress an unmet medical need are frequently lost to
VALUE OF SAFETY BIOMARKER QUALIFICATION 113
Drug Dev. Res.
development in preclinical studies, before they are evenbrought forward for discussion with a regulatoryauthority, because of toxicities that are currentlyunmonitorable or of uncertain relevance to humanstwo gaps that could be addressed with improved pre-dictive tools, beginning in early discovery. There areconcerns that the costs of this increased magnitude andduration of investment in a drug development programare unsustainable [Woodcock, 2012]. Therefore, apressing need exists for a much more efficient andeffective approach to drug development. Predictivetools are urgently needed to help confidently identifythose compounds likely to have favorable benefit-riskprofiles that can be progressed and identify those com-pounds with unfavorable benefit-risk profiles that canbe appropriately terminated early in development.Additionally, it is imperative to improve the ability topredict, identify, and monitor those patients who domanifest adverse drug events.
The biopharmaceutical industry has increasedinvestment in drug development from $2 billion in 1980to $50 billion in 2010 [PhRMA, 2012]. In spite of thishuge financial commitment, the rate of new drug appli-cations and new drug approvals has remained relativelyconstant for several decades [FDA, 2011a], with signifi-cant challenges and uncertainties remaining. Attritionrates for compounds in drug development have risensharply, particularly in late phase trials [Mervis, 2005;Pammolli and Riccaboni, 2008; Pammolli et al., 2011],with the clinical approval success rate from the time ofentering clinical testing being a mere 19% [DiMasiet al., 2010]. Drug development timelines still spanbetween 10 and 15 years with the average cost to bringa product to market estimated at $1.2 billion in the early2000s, likely around $4 billion today, and may even beas much as $11 billion [Herper, 2012].
Most recently, the Presidents Council of Advisorson Science and Technology (PCAST) has issued asobering report on Propelling Innovation in Drug Dis-covery, Development, and Innovation [PCAST, 2012].The PCAST report highlights the significant limitationsof the current trial and error approach in drug devel-opment and the challenges in predicting whethermodulating a particular target will actually ameliorate adisease in humans and if a particular molecule will havetoxic side effects. PCAST has boldly challenged theUnited States to double the current annual output ofinnovative new medicines for patients with importantunmet medical needs while increasing drug efficacy andsafety, through industry, academia, and governmentworking together to decrease clinical failure, clinicaltrial costs, time to market, and regulatory uncertainty.PCAST believes that this goal is attainable over the next1015 years. This report and recommendations are to
be commended and support the current mission ofregulatory science and collaborations such as CriticalPath Institute (C-Path). Many regulators globally haverecognized the key role they play, together with publicprivate partnerships, in championing and facilitatinginnovative research that will impact the drug develop-ment process and improve their ability to fulfill theirmission of protecting the public while enabling new,life-saving drugs to reach patients in need [Ichimaruet al., 2010; Manolis et al., 2011; Woodcock, 2012].
REGULATORY SCIENCE AND QUALIFICATION OFDRUG DEVELOPMENT TOOLS
Regulatory science is the term used by the FDA,European Medicines Agency (EMA), and JapanesePharmaceutical and Medical Devices Agency (PMDA)to describe the knowledge, tools, standards, andapproaches necessary to assess the safety, efficacy,quality, and performance of regulated products [FDA,2011b; EMA, 2012]. These tools include reliable biom-arkers, which can provide more information about drugsafety and efficacy and reduce the level of uncertainty indrug development decision making.
The National Institutes of Health working groupdefinition of a biomarker is a characteristic that is objec-tively measured as an indicator of normal biologicalprocesses, pathogenic processes, or a pharmacologicalresponse to a therapeutic intervention [BiomarkersDefinitions Working Group, 2001]. The FDA catego-rizes biomarkers that can be applied to the process ofdrug development as prognostic, predictive, pharmaco-dynamic, and surrogate biomarkers. These categoriesare not mutually exclusive [FDA, 2010a]. Table 1 pro-vides descriptions of each of these categories.
One recent advance for regulatory science is thecreation of formal processes within the FDA, EMA, andPMDA to review and evaluate data that will support theformal regulatory qualification of drug developmenttools as outlined in the FDA Draft Guidance for Indus-try Drug Development Tool Qualification and theEMA guidance Evaluation of Novel Methodologies forUse in Drug Development: Guidance to Applicants[EMA, 2009; FDA, 2012c]. The PMDA has also estab-lished a process for the submission and review of datasupporting adoption of novel methodologies [PMDA,2012]. These regulatory pathways provide a frameworkto evaluate and adopt new tools into regulatory decisionmaking in drug development, increasing the efficiencyfor achieving consensus science around the appropriatecontext of use (CoU) for a new tool in a drug develop-ment program. The qualification process invites the vol-untary submission of data to support the use of a noveldrug development tool or methodology; these are
DENNIS ET AL.114
Drug Dev. Res.
defined slightly differently at each International Con-ference on Harmonisation (ICH) agency but includebiomarkers, animal models, and clinical reportedoutcome instruments. Qualification at all agencies con-sists of both a consultation and advice phase and areview phase that precedes the release of a formal regu-latory opinion regarding the new qualified tool. Thequalification procedure begins with the submission of aLetter of Intent that describes the characteristics ofthe tool to be qualified, the methodology or measure-ment science to quantify and interpret the results, andthe proposed use of the tool to advance decision makingin a drug development program. The CoU for the tool isa comprehensive and clear statement of the mannerand purpose of use, including how to apply results todecision making and the impact on drug development.It is a central concept that helps sponsors and regulatorsunderstand the role for the new tool to enable a par-ticular aspect of drug development, as well as deter-mine what specific types and how much evidence mustbe provided in the qualification submission to supportthe proposed CoU. Once the Letter of Intent isaccepted, the regulators invite the submission of aBriefing Package that describes the research planand/or data supporting the submission in greater detailand forms the substrate for discussion with a reviewteam at the agency. As needed, iterative rounds of dis-cussion are intended to produce a scientifically robust
data package that supports a refined CoU with potentialto significantly impact the intended area of drugdevelopment.
The qualification process is relatively new with 16unique biomarkers qualified by at least one of the ICHagencies. These biomarkers include urinary proteins tomonitor drug-induced nephrotoxicity in rodents, circu-lating cardiac troponins for detection of drug-inducedstructural cardiac damage in rodents and dogs, as wellas cerebrospinal fluid and imaging biomarkers for clini-cal trial enrichment in Alzheimers disease. It is impor-tant to note that the qualification of a biomarker isdistinctly different than diagnostic device regulatoryclearance. Biomarker qualification focuses on under-standing the appropriate biological context and inter-pretation of an endpoint, while diagnostic clearancefocuses on the analytical validity of the measurementmethod. Regulatory qualification is a lengthy andresource-intense process that is likely most appropriatefor roadblocks in particular therapeutic areas (i.e. neu-rodegenerative disease) or aspects of drug development(safety) where there is pressing public health need andwhere cooperation between drug companies and otherentities is imperative for significant advancement.There are currently many similarities between the pro-cesses at the FDA, EMA, and PMDA, and indeed theagencies work closely together on qualification activi-ties, but, ideally, a truly harmonized approach would bethe most efficient and effective means to achieve globalscientific and regulatory consensus while recognizingthe need for each health authority to be bound by theirspecific legal requirements. Harmonization would beextremely valuable for all stakeholders and would createan aligned global approach to defining the evidentiarystandards required for a specific qualification project,developing research plans, and coordinating communi-cations and interactions. Each agency currently main-tains separate qualification processes, although the ICHagencies have a confidentiality agreement that allowsthe sponsor to meet with more than one agency simul-taneously [Manolis et al., 2011]. However, there arepractical challenges with scheduling simultaneousmeetings to allow for equal input from all agencies, andeach agency conducts its own independent review andassessment. Biomarker qualification is a demandingprocess for regulators, requiring multidisciplinaryexpertise in the regulatory qualification teams [Manoliset al., 2011], as well as for sponsors. These biomarkersare intended to be applied to global drug developmentprograms, and it is important for sponsors individuallyand consortia collectively to have confidence that thereis consistency in how regulators will interpret andrespond to changes in these biomarkers. Therefore, anyeffort to improve efficiencies and gain global regulatory
TABLE 1. Description of Biomarker Categories [FDA, 2010a]
A baseline patient or disease characteristic thatcategorizes patients by degree of risk fordisease occurrence or progression; informsabout the natural history of the disorder inthat particular patient in the absence of atherapeutic intervention.
A baseline characteristic that categorizespatients by their likelihood for response to aparticular treatment; used to identify whethera given patient is likely to respond to atreatment intervention in a particular way.May predict a favorable or an unfavorableresponse.
A dynamic assessment that shows a biologicalresponse has occurred in a patient afterhaving received a therapeutic intervention;may be treatment specific or more broadlyinformative of disease response.
A biomarker intended to substitute for a clinicalefficacy endpoint and is expected to predictclinical benefit (or harm, or lack of benefit orharm). Surrogate endpoints are a subset ofpharmacodynamics biomarkers.
VALUE OF SAFETY BIOMARKER QUALIFICATION 115
Drug Dev. Res.
consensus would be a welcome evolution for the biom-arker qualification process.
BIOMARKERS IN DRUG DEVELOPMENT
The ability of biomarkers to improve treatmentand reduce health-care costs is considered potentiallygreater than in any other area of current medicalresearch [Poste, 2011]. Technologies such as proteom-ics and DNA microarrays have contributed to the vastliterature of hundreds of thousands of papers docu-menting thousands of putative biomarkers, but very fewof these have been validated and incorporated intoroutine clinical practice [Poste, 2011]. Most biomarkerdiscovery is conducted in academic laboratories equip-ped with specific expertise and technology platforms.However, in order to establish robust correlationsbetween biomarkers and outcomes or responses totreatments, greater resources and multidisciplinaryexpertise are needed. Most individual pharmaceuticalcompanies lack the resources to adequately develop therobust evidentiary packages to support a biomarkerqualification that is universally applicable for anysponsor with any NME. Understanding the character-istics of these novel biomarkers and developing consen-sus recommendations on how to interpret changes inorder to incorporate them into drug development and,subsequently, clinical practicum is a massive undertak-ing requiring significant resources and commitmentfrom a wide range of stakeholders and experts. A disci-plined, comprehensive, systematic evaluation of allavailable evidence is needed, followed by the develop-ment and execution of a coordinated research plan toaddress knowledge gaps. Success requires multiteamcollaborations rather than fragmented efforts of small,opportunistic studies [Ioannidis, 2013] underscoringthe value of a consortium-based approach to biomarkerqualification.
Translational biomarkers are particularly valuablein early drug development when assessing compoundsin preclinical studies. Translational safety biomarkers(TSBs) can improve drug candidate selection, doseselection, and monitorability of potential toxicities. Fur-thermore, they may enable progression of promisingcompounds into first-in-human (FIH) studies and clini-cal development by providing greater confidence in theability to monitor and detect potential toxicities earlierwhen these effects are still reversible or provide supportfor determinations that toxicities are specific to preclini-cal species. Conversely, biomarkers may enable morerapid determination that a development programshould be terminated, preserving resources and allow-ing sponsors to make wiser investment decisions[Sistare and DeGeorge, 2011].
As described in the previous section, regulatoryqualification offers a framework for the systematicevaluation of the utility of new biomarkers that accel-erates their application and ongoing learning in real-world situations, including preclinical studies, clinicaltrials, and clinical practice. In the absence of qualifica-tion, it has taken decades to reach scientific consensusregarding the utility of important and useful biomark-ers, such as cardiac troponins, and continuous contro-versy has dominated. An example is prostate-specificantigen (PSA) that was recommended for routinescreening for prostate cancer in 1993 [Woolf, 1995].After decades of debate and uncertainty regarding thevalue of the PSA test, the U.S. Preventive Services TaskForce recently published their assessment and recom-mendation against PSA-based screening for prostatecancer in all age groups [Moyer, 2012]. The conclusionstated that there is moderate certainty that the benefitsof PSA-based screening for prostate cancer do not out-weigh the harms settled against routine screening usingthis marker. New biomarkers thus need to be rigorouslyand objectively assessed on an ongoing basis. Each newbiomarker will ultimately be a critical, individual pieceof larger data sets to be interpreted in context of thedrug development program. This will facilitate thegrowth of an ever-richer cadre of tools and technologiesto help bring newer and safer medicines to patients.
Dr. Margaret Hamburg, Commissioner of theFDA, has eloquently stated: As we work to accelerateinnovation and strengthen regulatory science, it isincreasingly clear that our most effective strategies aregrounded in partnership [Hamburg, 2011]. Numerouscollaborations and publicprivate partnerships havebeen created to address the critical challenges in drugdevelopment, including C-Path.
C-Path is a nonprofit, publicprivate partnershipcreated by Dr. Raymond Woosley in 2005 and estab-lished as collaboration between the FDA, the Univer-sity of Arizona, and SRI International, with fundingfrom Science Foundation Arizona, federal grants,private philanthropy, and the FDA [Critical PathInstitute, 2006]. The mission of C-Path is to improvehuman health and well-being by developing new tech-nologies and methods to accelerate the developmentand review of medical products. C-Path is a neutral,precompetitive ground for scientists from academia,industry, and government to test ideas that will result inoptimal (safe, effective, and timely) drug developmentprocesses in the support of the FDAs Critical PathInitiative [FDA, 2012b; Woosley, 2012]. C-Path andits partners work to establish the scientific basis for
DENNIS ET AL.116
Drug Dev. Res.
new standards, tools (including biomarkers), patient-reported outcome instruments, and disease models andto contribute to best practices and FDA guidance docu-ments that impact drug development. C-Path operatesa consortium-based model with six established consor-tia addressing key unmet drug development needs.These consortia are the Predictive Safety Testing Con-sortium (PSTC), the Patient-Reported Outcome Con-sortium, the Electronic Patient-Reported OutcomeConsortium, the Coalition Against Major Diseases, thePolycystic Kidney Disease Outcomes Consortium, andthe Critical Path to TB Drug Regimens Consortium. AllC-Path consortia develop evidence-based proposals onthe utility of new drug development tools, such asprotein and imaging biomarkers for selecting patientsinto trials for Alzheimers disease and polycystic kidneydisease, and patient-reported outcome instruments forpain, with formal regulatory qualification as a major goal[Woosley et al., 2010]. This paper will specifically utilizethe work of the PSTC to elaborate the value propositionfor collaborative efforts supporting regulatory qualifica-tion of safety biomarkers in drug development.
The PSTC was the first C-Path consortium,formed in 2006. This collaboration between C-Path, theFDA, and five initial pharmaceutical companies wasannounced as an unprecedented sharing of potentialearly indicators of clinical safety that could streamlinethe cost and greatly reduce the duration of preclinicaldrug safety evaluation [FDA, 2006a]. The mission ofPSTC is to identify new and improved safety testingmethods and submit them for formal regulatory quali-fication by global health authorities. The panel of safetybiomarkers that is currently used to support drug dis-covery and development decisions in preclinical studiesand to ensure patient safety in clinical trials has notchanged in decades. Collectively, there are significantdeficiencies in the sensitivity, specificity, and predictiveabilities of currently used biomarkers [Mattes andWalker, 2009]. In addition, these biomarkers providelittle, if any, mechanistic understanding of underlyingtissue effects or do they provide insight regardingpotential species specificity. These deficiencies, as iden-tified by PSTC members, are believed to be in largepart responsible for high drug development attritionrates, additional animal testing, and uncertainty-baseddelays and program termination decisions. Since 2006,PSTC has grown to 18 pharmaceutical and biotechnol-ogy company members with participation of more than250 industry and academic scientists and clinicians whoshare and validate innovative safety testing methodsunder advisement of the FDA, EMA, and PMDA.
The initial focus in PSTC is on improving predic-tive toxicology and preclinical biomarkers. Much hasbeen written about the current limitations of animalmodels as predictors of responses in humans. A pivotalstudy by Olson et al. demonstrated a true positivehuman toxicity concordance rate of 71% for rodent andnonrodent species, with nonrodents alone being predic-tive for 63% of human toxicities and rodents alone for43% [Olson et al., 2000]. Animal toxicology studiesprovide guidance regarding what safety concerns couldbe anticipated in clinical studies, but they are imperfect[Sistare and DeGeorge, 2011]. Yet preclinical proof-of-concept studies are critical elements of drug develop-ment and translational research that are regularly usedas stage gates in the advancement of potential thera-peutics to the clinic depending on the results of theanimal studies [Unger, 2007]. Well-conceived anddesigned preclinical investigations, incorporating rel-evant, translatable endpoints, strengthen the founda-tion for clinical investigation. The qualification ofpreclinical safety biomarkers with the ability to anchorchanges in biomarker levels with histological changesforms the foundation for the progressive qualification ofclinical biomarkers. All PSTC research programs have astrong translational focus to select new biomarkers thatare applicable across the drug development spectrum.
A unique strength of PSTC is the effective dia-logue and partnership established between preclinicalscientists and clinicians to identify and address the keyresearch needs for the most frequent and concerningorgan toxicities: kidney, liver, skeletal muscle, vascula-ture, heart, and testes. With all drug-induced toxicities,there is a need for identification as early as possible topermit effective intervention or deselection [Matteset al., 2010; Sistare et al., 2010]. Traditional safetybiomarkers and measures for these organ toxicities havesignificant limitations, and for some organ toxicities,there are no biomarkers available. For example, typicalstandards to measure renal toxicity, which includeserum creatinine (sCr) and blood urea nitrogen (BUN),only show changes when at least 50% of kidney functionis lost due to significant renal reserve [Coca et al., 2008;Ronco and Rosner, 2012]. In addition, sCr is influencedby several nonrenal factors such as body weight, race,age, gender, total body volume, drugs, muscle metabo-lism, and protein intake [Tomlanovich et al., 1986]. Forskeletal muscle toxicities, a common side effect ofseveral drug classes, including statins and fibrates, thetraditional biomarkers creatine kinase activity andaspartate aminotransferase activity (AST) are bothinsensitive and nonspecific [Vasallo et al., 2009]. Drug-induced liver injury (DILI) is the leading cause of acuteliver failure, exceeding all other causes combined [Leeet al., 2011; FDA, 2012c], and has been linked to nearly
VALUE OF SAFETY BIOMARKER QUALIFICATION 117
Drug Dev. Res.
1000 drugs [Abboud and Kaplowitz, 2007]. DILI is aleading cause of drug failures in clinical developmentand withdrawals from the market [Chen et al., 2011].The standard DILI biomarkers lack specificity and sen-sitivity. Of particular concern is the lack of predictivebiomarkers for idiosyncratic DILI. Drug-inducedinjury to the vasculature (DIVI), typified by injuryobserved in rats and dogs by phosphodiesterase inhibi-tors, is currently considered unmonitorable whenobserved in nonclinical studies [Louden et al., 2006],nearly always leading to discontinued developmentof the investigational compound. Uncertainties as towhether nonclinical findings of vascular injury are ofrelevance to humans and whether biomarkers canprovide insights for potential vascular damage anddisease are areas of research within PSTC that seek topromote more informed risk assessment of DIVI innonclinical species. PSTC is also looking to qualify apreclinical predictive biomarker of hemodynamic stressand cardiac toxicity to assist in compound selection, aswell as trigger additional monitoring of patients in clini-cal trials. A significant gap also exists for circulatingmarkers of testicular toxicity, another area of activity forPSTC.
The organizational structure and membership,established project phases of PSTC working groups,project management oversight, and database expertiseall contribute to ongoing maintenance of rigorousresearch programs and a compelling value propositionfor participation. PSTC working groups address indi-vidual organ toxicities while leveraging synergies, forexample, between the hepatotoxicity and skeletalmuscle working groups where the lack of specificityof AST challenges the diagnosis and monitoring ofboth target organs. There are four phases of PSTCbiomarker activities: (i) literature review and candi-date biomarker nomination; (ii) research/discovery; (iii)proof-of-concept studies; and (iv) regulatory qualifica-tion and subsequent publication. It is the intent ofPSTC to publish all biomarker research, even if quali-fication submission is not attained.
The impact of the work of PSTC however goeswell beyond qualification and publication. Its member-ship and precompetitive structure provide a uniqueforum for driving innovation through open dialogue,sharing of expertise and data, and the ability to reachscientific consensus. Through PSTC, best practicedocuments and histology lexicons are created andendorsed by the membership to enhance shared learn-ing and a standardized approach to common practicesand assessments. This ensures consistency when com-bining data sets and performing analyses. This col-laboration enhances the knowledge of comparativepathophysiology for risk assessment and accelerates the
functional understanding of target organ biology andpathophysiology. Innovation within PSTC shapes andinfluences the most current thinking on the utility ofthese drug development tools by continuously anditeratively building cutting-edge scientific knowledgeabout biomarkers, both old and new, as well as thetarget organs they reflect. In addition, PSTC has theopportunity to dialogue, debate, share experiences, andpartner with the FDA, EMA, and PMDA as these new,innovative approaches are pioneered and developed forbroader use. These collaborations with health authori-ties have helped to shape regulatory approaches andhave resulted in guidance documents to improve drugdevelopment.
In 2008, seven preclinical (rat) urinary renalsafety biomarkers were submitted by the PSTC andqualified by FDA and EMA. This was the first-everregulatory biomarker qualification decision under theFDAs and EMAs joint pilot Biomarker QualificationProgram. In 2010, the PMDA followed with theirqualification of these biomarkers [PMDA, 2010]. Theunprecedented collaboration and alignment betweenthese three agencies was a significant accomplishmentfor PSTC and all its stakeholders. This initial qualifica-tion process contributed to the FDAs new Draft Guid-ance for Industry on the Qualification Process for DrugDevelopment Tools, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM230597.pdf, issued in October 2010.To create the qualification submission, consortiummembers shared existing or already planned andongoing study samples to minimize animal, human, andfinancial resources. A final inventory of studies evaluat-ing over a dozen candidate nephrotoxicity biomarkersinvolving over 30 kidney toxicants and over 20 kidneynontoxicants was compiled and formed the basis of thequalification submission. It was estimated that the costsavings through this collaboration exceeded $4 million[Sistare et al., 2010]. The FDA qualification stated thatthe urinary kidney biomarkers (KIM-1, albumin, totalprotein, b2-microglobulin, cystatin C, clusterin, andtrefoil factor-3) are acceptable biomarkers for thedetection of acute drug-induced nephrotoxicity in ratsand can be included along with traditional clinicalchemistry markers and histopathology in toxicologystudies. They provide additional and complementaryinformation to BUN and sCr that correlates with histo-pathological alterations, which are considered to be thegold standard. The receiver operating characteristicanalyses showed that some of these biomarkers havebetter sensitivity and specificity than BUN and creati-nine when tested with a discrete number of nephro-toxic and control compounds. The FDA concludedthat while further studies are needed to qualify the
DENNIS ET AL.118
Drug Dev. Res.
biomarkers for broader use, the data were sufficient tosupport the voluntary use in safety assessment testing,in addition to traditional safety markers. The recom-mended application contexts of used statements are thefollowing [FDA, 2008]:
KIM-1, albumin, clusterin, and trefoil factor-3 can beincluded as biomarkers of drug-induced acute kidneytubular alterations in Good Laboratory Practice(GLP) rat studies used to support clinical trials.
Total protein, b2-microglobulin, and cystatin C canbe included as biomarkers of acute drug-inducedglomerular alterations/damage and/or impairment ofkidney tubular reabsorption in GLP rat studies usedto support clinical trials.
Since this early qualification, the FDA has evolvedthe concept and standards for supportive evidence for agiven CoU, moving toward more narrow contexts of usealigned with a conservative interpretation of the sup-portive data. For example, the FDA has proposed that ifbiomarker studies to support a safety biomarker did notextend beyond 7 days, then the CoU must restrict use innonclinical safety assessment to 7-day studies, even ifthe specific injury the biomarker has been demon-strated to monitor may conceivably be produced instudies of longer duration. PSTC workgroups haveadopted their target CoU statements to reflect this evo-lution. For example, instead of proposing that a novelbiomarker may monitor (i.e. detect, track progression,and reversibility) testicular toxicity in rodents, theworking groups research aims to demonstrate that anovel biomarker can detect drug-induced damage tothe seminiferous epithelium of the testis resulting ingerm cell death in rats; additional information is pro-vided to define the conditions for use of the biomarkerrelated to measurement methodology, species strain,sex, age, duration of study, etc. In the current climate ofrestrained resources, each working group strives to gen-erate the information considered most useful to futuredrug development programs.
IMPACT OF QUALIFIED PRECLINICAL RENALSAFETY BIOMAKERS ON DRUG DEVELOPMENT
Safety biomarkers are applied in drug develop-ment to inform critical decisions about a drug devel-opment program. Preclinical utility includes earlydetection of toxicity, selection of the safest drug candi-date, sensitive safety monitoring in regulatory toxicitystudies, and selection of dosing regimens. Clinically,they can be utilized for translation from preclinical intoFIH studies, safety monitoring in all clinical phases,development of personalized health-care strategies, and
postmarketing safety surveillance [Dieterle et al., 2010].Prior to the establishment of a formal regulatory quali-fication process for biomarkers, individual sponsorswere only able to discuss with regulators, on a case-by-case basis, the incorporation of novel biomarkers intothe drug development program of a specific NME. Thisoption continues to be available. However, an indi-vidual, case-by-case approach limits the ability to applythese biomarkers more broadly and does not allow forgreater scientific consensus and learning. The regula-tory qualification process, however, requires collabora-tion and investment of resources from all stakeholders,with a more rigorous evidentiary standard given theapplicability of a qualified biomarker over a broad,mechanistically diverse set of compounds, instead ofone specific, known NME. It is therefore important forPSTC to evaluate the impact of the regulatory qualifi-cation of these seven preclinical safety biomarkers andto understand the value proposition of these qualifica-tion projects. It is currently still too early to deter-mine the full value of these qualified biomarkers frombeginning to end within the drug development cycle.However, PSTC member companies have emphasizedthat regulatory qualification has provided confidence inhow these biomarkers can be applied to decision makingby both sponsors and regulators. In the absence ofqualification, sponsors have been reluctant to includenovel biomarkers into their drug development programsdue to concerns about broader regulatory agency aware-ness and receptivity versus established biomarkers.Qualification, on the other hand, provides the regulatoryassurance of the interpretation and benefit of thesebiomarkers, and PSTC member companies are increas-ingly incorporating them in their preclinical and clinicaldevelopment programs. As the seven preclinical renalsafety biomarkers are not yet qualified for clinical use,sponsors are required to discuss these with the appro-priate regulatory review groups before they can beincluded in clinical studies. Examples of how the newlyqualified biomarkers have been utilized in preclinicaldevelopment programs at PSTC member companiesinclude candidate molecule prioritization, early safetyreads on efficacy studies and candidate selection, andgo/no go decisions at the pre-investigational new drug(IND) stage. As an added benefit, these biomarkershave decreased animal use and the number of interimtime points to be assessed, with fewer necropsy andpathology endpoints. Clinical utilization examplesinclude demonstrating monitorability in IND-enablingstudies to support FIH study design, including defin-ing stopping criteria for dose escalation in tolerabilitystudies and ensuring sensitive monitoring of neph-rotoxic risk in clinical studies. From the observedimpact on safety assessment of this first pioneering
VALUE OF SAFETY BIOMARKER QUALIFICATION 119
Drug Dev. Res.
qualification, additional safety biomarker qualificationsshould greatly enable more efficient and confidentdecision making in developmental programs to jointlyprotect patients from potential toxicities and enable thedelivery of important new therapies.
TRANSLATIONAL QUALIFICATION OF RENALSAFETY BIOMARKERS
PSTC continues to expand renal biomarker quali-fication activities to enable informed use of these biom-arkers in dogs and nonhuman primates, and in humans,including normal and diseased populations. Key consid-erations in the next phases of nonclinical qualificationare the increased costs but reduced numbers with largeanimal studies as compared with rats and the currentlack of validated assays for novel biomarkers in dogs andnonhuman primates. While greater numbers of serialsamples from the same animal are possible to evaluatebiomarker kinetics with injury progression and revers-ibility, correlating biomarker changes with microscopicobservations in the tissues, which is fundamental tounderstanding the performance of the biomarker andsupporting a given CoU. Thus, a phased research plan isbeing devised to simultaneously enable evaluation ofmany candidate biomarkers but make responsible andefficient use of animal and financial resources. Explor-atory and then advanced assay validation for candidatebiomarkers will proceed in parallel to the toxicologystudies.
To support the clinical qualification of new renalsafety biomarkers, PSTC has conducted a healthy vol-unteer study to determine intersubject and intrasubjectvariability of these biomarkers, as well as any potentialeffect of gender, age, and food intake. The data fromthis and additional healthy volunteer studies conductedby PSTC members will be used to define normal levelsof these biomarkers. In parallel, PSTC is collaboratingwith the Foundation for the National Institutes ofHealth Biomarkers Consortium on a prospective clini-cal project to evaluate the ability of novel kidney biom-arkers to monitor drug-induced kidney injury utilizingtwo known nephrotoxic agents in humans at an esti-mated cost of $3.25 million [Sistare and DeGeorge,2011]. PSTC is also collaborating with the European-based Innovative Medicines Initiative Safer and FasterEvidence-based Translation Consortium on the transla-tional qualification for safety biomarkers of renal,hepatic, and vascular injury. Of course, clinical qualifi-cation requires more complex and resource-intensiveresearch plans. This type of investment for clinicalqualification of biomarkers is unlikely to be sustainable,and alternative approaches are being explored, includ-ing utilizing samples from completed, sufficiently well-
designed clinical studies that have been handled andstored appropriately. Another potentially rich source ofbiomarker evidence is peer-reviewed literature toeither entirely support qualification or to complementqualification submissions. The regulatory consultationphase for the clinical qualification of the kidney biom-arkers will seek to agree upon the appropriate balanceand weight given to published evidence and primarydata.
In the same manner that novel biomarkers areused preclinically to characterize hazards, it is the intentof PSTC that the novel biomarkers, once clinicallyqualified, will be used in conjunction with conventionalbiomarkers, such as sCr and BUN. These novel biom-arkers would be used clinically to monitor for injuryinitially in healthy volunteer studies if the investiga-tional drug has previously demonstrated nonclinicaltoxicology findings of drug-induced injury with changesin the novel biomarkers. The absence of active biomar-ker injury patterns in these healthy volunteer studieswould then permit continued protocol conduct toplanned higher dose levels within that IND study andwould support conducting studies in patient popula-tions. If a clear injury pattern is detected with the novelbiomarkers even in the absence of change in conven-tional biomarkers, then appropriate intervention will beinstituted. Additionally, should the conventional biom-arkers rise without concurrent changes in novel biom-arkers, then the decision to discontinue will be based onthe conventional biomarker data. It is important to rec-ognize that safety biomarkers may also be utilized asefficacy biomarkers. For example, novel nephrotoxicitybiomarkers could be used to risk-stratify patients withacute kidney injury from other causes and could beused to monitor response to intervention [Coca et al.,2008; Endre et al., 2011]. This provides additional moti-vation to invest in the characterization and qualificationof these biomarkers. As more knowledge and confi-dence in the utility of these new biomarkers evolves indrug development and as affordable, robust assaysbecome available, it is anticipated that these biomarkerswill increasingly be incorporated into clinical practice.
CHALLENGES TO BIOMARKER QUALIFICATION
Although the several successfully qualified biom-arkers represent a promising start, the total capacity andefficiency of this regulatory pathway to advance drugdevelopment through more rapid adoption of novelbiomarkers is unknown. However, participants in theprocess submit that there are many opportunities forstreamlining and efficiency gains to the benefit of allparties in a resource-constrained environment. Invest-ments in drug development research must be weighed
DENNIS ET AL.120
Drug Dev. Res.
against sufficient potential or known promise for return.The process to qualify a TSB has evolved to becomemore time-consuming and resource intensive, andthere are concerns that this could become comparableto the development of a NME. Yet the goal of regula-tory qualification to speed adoption of new tools andcreate efficiency across regulatory review necessitates astreamlined and efficient process. The difficulty indetermining the levels of evidence needed to support adefined CoU for a new biomarker and the desire todrive to more rapid scientific consensus will likely con-tinue to evolve.
Other challenging aspects of biomarker qualifica-tion include defining the level of assay validationrequired for each proposed CoU and investing in assaydevelopment and validation in parallel or ahead ofresearch to determine whether a given biomarker willbe truly useful. Unlike diagnostic 510(K) process ofregulatory clearance, qualification is assay/platformindependent. Therefore, it is possible that a qualifica-tion package may contain biomarker performance dataobtained using multiple assays as long as they are allconfirmed to be suitable for its intended use. There aremultiple publically available references and guidancedocuments available from the FDA and ICH address-ing aspects of assay validation, but no specific guidancefor qualification of assays for a proposed clinical ornonclinical CoU has been made available [FDA, 1995,1996, 2001, 2005, 2006b, 2012c; EURACHEMWorking Group, 1998].
Appropriate reference standards and antibodiesare cornerstones of assay development and representfundamental hurdles in novel biomarker assay develop-ment. Although antibodies specific for rat and humanprotein isoforms are commonly commercially available,there are fewer antibodies for canine proteins. Commer-cially available purified human protein standards and/orrecombinant purified proteins can also be lacking. Whenonly recombinant proteins are available, it is difficult topredict how potential differences in protein foldingand posttranslational processing may impact antibodyrecognition. Biological reference samples (positive andnegative controls) are important for understanding thenecessary assay dynamic range and for identification ofmatrix effects. For clinical assays, access to controlsamples can be especially difficult.
Choosing the optimal assay platform can be dif-ficult. Multiplex antibody-based assays and proteomictechniques offer economical approaches for safetyscreening and require smaller sample volumes com-pared with singleplex immunoassays. However, thereare many validation issues that are unique to multiplexassays. These were recently discussed at a workshophosted by the National Cancer Institute and FDA in
2010 [Rodriguez et al., 2010]. For clinical studies,rapid analysis times may be important and therebyinfluence selection of assay platform. In many situa-tions, the sponsor of a qualification package is separatefrom the company developing the assay being used.Therefore, it is critical to work closely with the diag-nostic company or companies to produce and provideassay validation documentation that meets regulatoryexpectations.
Defining and implementing best practices for pre-analytical handling and processing, shipping, andstorage of samples can be difficult. For many newlyidentified biomarkers, information about the impact ofpre-analytical variation on analysis readouts is not avail-able in the literature or from commercial assay vendors.Factors that must be considered include stability atroom temperature, freeze-thaw stability, necessity forand force of centrifugation of liquid samples (urine,plasma, and serum), type of collection tube, necessityfor stabilizing buffers or enzyme inhibitors, tempera-ture for long-term storage, long-term storage stability,and interference of matrix components (platelet con-tamination and hemolysis). Reproducibility studiesshould carefully consider the impact of pre-analyticalfactors. Analytically robust biomarkers are highly desir-able to decrease the risk of false negative signals.
Building confidence that a novel biomarker isuseful across a diversity of mechanisms, species,genders, and different settings brings additional com-plexities that include determining the sufficient numberof toxicants representing these mechanisms and typesof injury and identifying sufficient but practical studydesigns to support understanding biomarker kineticswith injury progression and reversibility. There arelikely to be differences in the magnitude and timecourse of biomarker expression depending on the sever-ity of injury, and these differences need to be charac-terized. For clinical qualification, it will be important toestablish that the biomarkers have similar performancecharacteristics across multiple toxicants of differenttypes and across nonclinical and clinical settings, at leastfor well-studied toxicants. Biomarkers that translatewell from preclinical studies to clinical studies are likelyto be most useful. However, some biomarkers that maybe useful in a clinical setting are not physiologicallyrelevant in the rat (e.g. liver-type fatty acid-bindingprotein [L-FABP]). This should not preclude thesebiomarkers from being clinically useful. Similarly,biomarkers that elucidate mechanisms and clarifyunderlying pathophysiology in preclinical species,regardless of translatability, are valuable for thoroughlycharacterizing the hazard for clinical progression andinforming the monitoring approach, as well as enhanc-ing the overall risk assessment.
VALUE OF SAFETY BIOMARKER QUALIFICATION 121
Drug Dev. Res.
An essential topic for clinical qualification, wherecomparison of novel biomarker changes to histopathol-ogy is only rarely possible due to the extreme limitationsof biopsy, is defining thresholds of injury for novelbiomarkers benchmarked to the imperfect traditionalstandard biomarkers they are meant to eclipse, espe-cially in light of the fact that such thresholds are oftenpoorly defined for traditional biomarkers. Cutoff valuesand algorithms need to be established for each biomar-ker. The approach to defining these threshold valuesmay vary from biomarker to biomarker. Some may bestbe set by an absolute cutoff value defined by a popula-tion upper limit of normal, some by a fold change fromeach individuals baseline, some by a fold change abovean upper limit of normal, and others by a combination.The current focus of biomarker qualification is on singlebiomarkers, but in many cases, it may be the combina-tion of several biomarkers constituting a biosignaturethat may be most impactful. The approach to the quali-fication of biosignatures is currently under discussionand examples such as the combination of alanine ami-notransferase (ALT) and bilirubin as interpreted bysoftware such as evaluation of drug-induced serioushepatotoxicity can provide guidance [Guo et al., 2008].
Translating biomarkers for clinical drug develop-ment will also require not just confident understandingof their response to drug-induced injury but also theimpact of potentially confounding factors such as con-comitant medication use, comorbidities, age, gender,ethnicity, food, tobacco use, and potential diurnal varia-tions. However, the cost of prospective clinical studiesto address all these potential confounders is likely to beprohibitive. More pragmatic approaches will need to beconsidered such as leveraging stored samples fromclinical trials that have already been completed in spe-cific, well-characterized patient populations or the col-lection of additional biospecimens in planned clinicaltrials. However, it would be critical to ensure a solidunderstanding of how pre-analytical variables, includ-ing time, temperature, processing, and handling condi-tions, can change molecular composition and quality.The challenges of pre-analytical variations can limitoverall reproducibility and sensitivity of biomarkermeasurements. Clearly, considerable resources arerequired to address all these considerations; however,there is a paucity of funding for this type of research.Patient safety is a societal concern and investment inthis area is a key to advancing public health. Optionsinclude supporting federal funding initiatives as well asexploring economic incentives to promote innovativeresearch as proposed in the PCAST  report.
An important consideration for the adoption ofnovel biomarkers as standard drug development tools iscost effectiveness. While a rigorous economic evalua-
tion of qualified TSBs has not been conducted byPSTC, a recent publication provided a business case forthese biomarkers based on cost reviews [Sistare andDeGeorge, 2011]. The authors estimated that if a newlyqualified TSB with improved performance over conven-tional endpoints could eliminate the need for just onephase II study by providing a convincing safety signal atrelevant exposure margins from phase I study sampleswhere conventional biomarkers fail, the savings couldexceed $42 million. In another example from Sistareand DeGeorge, if a toxicity is identified for the first timein a longer-duration animal study that is unmonitorablewith conventional endpoints but demonstrated to bemonitorable with the novel translatable safety biomar-kers, then these biomarkers are appropriate for FIHmonitoring and could help establish that the toxicityis not relevant to humans if no changes are observedin those FIH studies. This would allow progression ofthe compound with savings of an additional $31 mil-lion in phase I that would have been required todevelop a backup molecule. However, in an increas-ingly resource-constrained environment, sponsors needmore robust assurances regarding the cost effective-ness of integrating these novel biomarkers into theirprograms.
To be relevant for sponsors, regulatory qualifica-tion must balance the desire for certainty and perfectknowledge with acknowledgment of the imperfectionsand lack of knowledge about current biomarker stan-dards, such as ALT, sCr, and cardiac troponins. Thecontinuing dialogue with the FDA regarding their guid-ance for the clinical evaluation of DILI is a goodexample of the knowledge limitations of biomarkersthat are routinely used as gold standards. If the publichealth impact and enabling potential of novel biomark-ers to advance safe and effective therapies can be con-sidered along with scientifically rigorous evidence, atruly successful regulatory process can be achieved.Qualification may also inspire the development of clini-cally accepted diagnostic assays that can be used inroutine clinical practice, which will contribute toincreasing the clinical knowledge base.
Ultimately, safety biomarker identification andqualification are long-term endeavors. This is a never-ending process of incremental knowledge gain, whichincludes those biomarkers now considered routine.Stepwise or progressive qualification should thereforebe encouraged to expand the knowledge gained fromreal-world use, which is the most enlightening.
Limitations of the current standard biomarkersand lack of more sensitive, specific, and easily accessible
DENNIS ET AL.122
Drug Dev. Res.
safety biomarkers for use in drug development andclinical practice underscore the need for well-characterized novel safety biomarkers with robust fitfor purpose validated assays. Through biomarkerresearch, a greater understanding of the molecular basisof toxicity, as well as the pathophysiology of disease anddisease progression, can play a major role in drug devel-opment outcomes.
The regulatory qualification process is highlyvaluable in providing confidence in the utility of novelsafety biomarkers to strengthen evidence-based drugdevelopment decision making, leading to the incorpo-ration of these biomarkers in increasing numbers ofstudies and thereby adding to the ongoing understand-ing of their specific and practical utilities. The review ofPSTCs preclinical nephrotoxicity dataset and qualifica-tion by the FDA, EMA, and PMDA provides a quickerand much greater level of acceptance and use of thesenovel biomarkers than would have been achievedthrough solely peer-reviewed scientific publication.Progressive qualification, starting with a limited pre-clinical CoU, directly encourages the safe advancementof potential new drugs to clinical development thatwould have previously been terminated due to inabilityto monitor potential nephrotoxic liability. These newtools can also be used to deselect unsafe drug candi-dates earlier in development, thus allowing focus onthose candidates more likely to benefit patients with amore positive safety profile. Additionally, qualificationstimulates the generation of data to expand the quali-fication context to additional preclinical species andhumans while simultaneously broadening our knowl-edge of target organ toxicity. A full understanding ofsafety biomarker performance and utility will continueto evolve over time alongside the evolving understand-ing of comparative biology, predictive toxicology, anddisease. All of PSTCs safety biomarker qualificationprograms were initiated because of organ-specific tox-icitiescurrently considered to be unmonitorable dueto insensitive and nonspecific biomarkersthat regu-larly cause promising potential therapeutics to bedropped from development without opportunity tosafely assess whether toxicities observed in animalstudies are of any relevance to humans at therapeuticdoses. Better biomarkers exist and are actively and rig-orously evaluated within PSTCs working group processprior to submission to the FDA as candidates for pre-clinical qualification. In the areas of focus for PSTCrenal, skeletal muscular, hepatic, vascular, cardiac, andtesticularqualification for a preclinical CoU willdirectly enable safer, promising potential therapeu-tics to be brought forward, as well as stimulate furthergeneration of information about the biomarkers fullutility.
Regulatory qualification for a preclinical CoU ofthe kidney biomarkers has been critical to their markedincrease in application to drug development programsto help understand potential kidney liabilities. Thequalification for preclinical use has been successful ingiving sponsors and regulators more confidence toengage in dialogue around how novel kidney biomarkerdata inform the understanding of a safety profile of apotential new drug. Clinical programs for promisingnew therapies have directly been made possible, moredata to understand the biomarkers totality of behaviorin animals and humans have been generated, and deci-sion making around potential kidney toxicities has beenvastly improved. However, the qualification processmust be streamlined with a sense of urgency to remainviable.
The success of PSTC demonstrates the power ofmultistakeholder collaboration, including regulators,industry, and academia. This model serves to supportthe commendable efforts of global health authorities aschampions of regulatory science and provides a success-ful framework to respond to the recent PCAST call toaction to double the current annual output of innovativenew medicines for patients by improving the efficiencyof drug development and regulatory uncertainty.
PSTC members, which include Abbott, Amgen,Inc., AstraZeneca Pharmaceuticals LP, BoehringerIngelheim, Bristol-Myers Squibb Company, CelgeneCorporation, Daiichi Sankyo, Eli Lilly and Company,Genentech, GlaxoSmithKline, Hoffmann-La Roche,Inc., Johnson & Johnson Pharmaceutical Research andDevelopment, LLC, Merck and Co., Inc., Millennium:The Takeda Oncology Company, Mitsubishi TanabePharmaceutical, Novartis Pharmaceutical, Pfizer, Inc.,Sanofi, and SRI International, are thanked for theirfinancial and in-kind contributions.
C-Path contributions to this work are supportedby Grant No. U01FD003865 from the United StatesFood and Drug Administration and by Science Foun-dation Arizona under Grant No. SRG 0335-08. Bothorganizations are gratefully acknowledged.
Mr. Nicholas King and Mrs. Krystal Elms arethanked for their technical and editorial assistance andassistance with references.
REFERENCESAbboud G, Kaplowitz N. 2007. Drug-induced liver injury. Drug Saf
American Cancer Society. 2012. Cancer facts and figures 2012.Atlanta: American Cancer Society. http://www.cancer.org/acs/
VALUE OF SAFETY BIOMARKER QUALIFICATION 123
Drug Dev. Res.
groups/content/@epidemiologysurveilance/documents/document/acspc-031941.pdf Accessed 24 September 2012.
Biomarkers Definitions Working Group. 2001. Biomarkers and sur-rogate endpoints: preferred definitions and conceptual frame-work. Clin Pharmacol Ther 69:8995.
Bourgeois FT, Shannon MW, Valim C, Mandl KD. 2010. Adversedrug events in the outpatient setting: an 11-year national analysis.Pharmacoepidemiol Drug Saf 19:901910.
Cardinale D, Cipolla CM. 2011. Assessment of cardiotoxicity withcardiac biomarkers in cancer patients. Herz 36:325332.
Chen M, Vijay V Shi Q, Liu Z, Fang H, Tong W. 2011. FDA-approved drug labeling for the study of drug-induced liver injury.Drug Discov Today 16:697703.
Coca SG, Yalavarthy R, Concato J, Parikh CR. 2008. Biomarkers forthe diagnosis and risk stratification of acute kidney injury: a sys-tematic review. Kidney Int 73:10081016.
Critical Path Institute. 2006. Critical Path Institute annual report20052006. http://c-path.org/pdf/Annual%20report%20final%202006.pdf Accessed 21 September 2012.
Dieterle F, Sistare F, Goodsaid F, Papaluca M, Ozer JS, Webb CP,Baer W, Senagore A, Schipper MJ, Vonderscher J, et al. 2010.Renal biomarker qualification submission: a dialog between theFDA-EMEA and Predictive Safety Testing Consortium. Nat Bio-technol 28:455462.
DiMasi JA, Feldman L, Seckler A, Wilson A. 2010. Trends in risksassociated with new drug development: success rates for investi-gational drugs. Clin Pharmacol Ther 87:272277.
EMA. 2009. Qualification of novel methodologies for drug develop-ment: guidance to applicants. http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004201.pdf Accessed 25 September 2012.
EMA. 2012. European Medicines Agencyspecial topicsregula-tory science. European Medicines Agency. http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000479.jsp&mid=WC0b01ac058026369cAccessed 20 September 2012.
Endre ZH, Pickering JW, Walker RJ, Devarajan P, Edelstein CL,Bonventre JV, Frampton CM, Bennett MR, Ma Q, Sabbisetti VS,et al. 2011. Improved performance of urinary biomarkers of acutekidney injury in the critically ill by stratification for injury durationand baseline renal function. Kidney Int 79:11191130.
EURACHEM Working Group. 1998. The fitness for purpose ofanalytical methods: a laboratory guide to method validation andrelated topics. http://www.eurachem.org/images/stories/Guides/pdf/valid.pdf Accessed 19 September 2012.
FDA. 1995. Guideline for industry: text on validation of analyticalprocedures ICH-Q2A. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073381.pdf Accessed 20 September 2012.
FDA. 1996. Guidance for industry: Q2B validation of analytical pro-cedures: methodology. http://www.fda.gov/downloads/Regulator%20yInformation/Guidances/UCM128049.pdf Accessed 20 Sep-tember 2012.
FDA. 2001. Guidance for industry: bioanalytical method validationICH-Q2A. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073381.pdfAccessed 20 September 2012.
FDA. 2005. Class II special controls guidance document: instrumen-tation for clinical multiplex test systemsguidance for industry
and FDA staff. http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm077819.htmAccessed 20 September 2012.
FDA. 2006a. FDA and the Critical Path Institute Announce Predic-tive Safety Testing Consortiumconsortium will share tests tounderstand safety of potential new drugs earlier. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108617.htm Accessed 20 September 2012.
FDA. 2006b. Manual of policies and procedures: requestingmethods validation for abbreviated new drug applications. March29. http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ManualofPoliciesProcedures/ucm079777.pdf Accessed 20September 2012.
FDA. 2008. Seven biomarkers of drug-induced nephrotoxicity in therat. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/UCM285031.pdf Accessed 20 September 2012.
FDA. 2010a. Guidance for industry: qualification process for drugdevelopment tools. Silver Spring, Maryland: U.S. Food and DrugAdministration. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM230597.pdfAccessed 20 September 2012.
FDA. 2010b. Public health advisories (drugs). Silver Spring,Maryland: U.S. Food and Drug Administration. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/default.htm Accessed 20September 2012.
FDA. 2010c. FDA guidance for industry and investigators:safety reporting requirements for INDs and BA/BE studies. SilverSpring, Maryland: U.S. Food and Drug Administration. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM227351.pdf Accessed 20 September2012.
FDA. 2011a. Nmes approved by CDER (20062010). Silver Spring,Maryland: U.S. Food and Drug Administration. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/UCM242695.pdf Accessed 20 September 2012.
FDA. 2011b. Strategic plan for regulatory science: advancing regula-tory science at FDA. Silver Spring, Maryland: U.S. Food and DrugAdministration. http://www.fda.gov/ScienceResearch/SpecialTopics/RegulatoryScience/ucm267719.htm Accessed 20 Septem-ber 2012.
FDA. 2012a. Postmarket drug safety information for patients andprovidersapproved risk evaluation and mitigation strategies(REMS). Silver Spring, Maryland: U.S. Food and Drug Adminis-tration. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htmAccessed 20 September 2012.
FDA. 2012b. Critical path initiative. Silver Spring, Maryland:U.S. Food and Drug Administration. http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative Accessed 20 Sep-tember 2012.
FDA. 2012c. Additional research areasdrug-induced liver toxicity.Silver Spring, Maryland: U.S. Food and Drug Administration.http://www.fda.gov/drugs/scienceresearch/researchareas/ucm071471.htm Accessed 20 September 2012.
FDA. 2012d. Drug safety and availabilitydrug safety com-munications. Silver Spring, Maryland: U.S. Food and Drug
DENNIS ET AL.124
Drug Dev. Res.
Administration. http://www.fda.gov/Drugs/DrugSafety/ucm199082.htm Accessed 20 September 2012.
Guo T, Gelperin K, Senior J. 2008. A tool to help you decide: detectpotentially serious liver injury. March 26. http://www.fda.gov/downloads/Drugs/ScienceResearch/ResearchAreas/ucm076777.pdf Accessed 20 September 2012.
Hamburg M. 2011. Moving new drugs from discovery to delivery.http://www.fda.gov/NewsEvents/Speeches/ucm279777.htmAccessed 20 September 2012.
Herper M. 2012. The truly staggering cost of inventing new drugsForbes. Forbes. http://www.forbes.com/sites/matthewherper/2012/02/10/the-truly-staggering-cost-of-inventing-new-drugs/Accessed 25 September 2012.
Ichimaru K, Toyoshima S, Uyama Y. 2010. PMDAs challenge toaccelerate clinical development and review of new drugs in Japan.Clin Pharmacol Ther 88:454457.
Ioannidis JP. 2013. Biomarker failures. Clin Chem 59:202204.
Lazarou J, Pomeranz BH, Corey PN. 1998. Incidence of adversedrug reactions in hospitalized patients: a meta-analysis of prospec-tive studies. JAMA 279:12001205.
Lee JY, Garnett CE, Gobburu JV, Bhattaram VA, Brar S, Earp JC,Jadhav PR, Krudys K, Lesko LJ, Li F, et al. 2011. Impact ofpharmacometric analyses on new drug approval and labelling deci-sions: a review of 198 submissions between 2000 and 2008. ClinPharmacokinet 50:627635.
Lichtenberg FR. 2005. The impact of new drug launches on longev-ity: evidence from longitudinal, disease-level data from 52 coun-tries, 19822001. Int J Health Care Finance Econ 5:4773.
Louden C, Brott D, Katein A, Kelly T, Gould S, Jones H, Betton G,Valetin JP, Richardson RJ. 2006. Biomarkers and mechanisms ofdrug-induced vascular injury in non-rodents. Toxicol Pathol34:1926.
Manolis E, Vamvakas S, Isaac M. 2011. New pathway for qualifica-tion of novel methodologies in the European Medicines Agency.Proteomics Clin Appl 5:248255.
Mattes WB, Walker EG. 2009. Translational toxicology and the workof the Predictive Safety Testing Consortium. Clin Pharmacol Ther85:327330.
Mattes WB, Walker EG, Abadie E, Sistare FD, Vonderscher J,Woodcock J, Woosley RL. 2010. Research at the interface ofindustry, academia and regulatory science. Nat Biotechnol28:432433.
Mertens AC, Liu Q, Neglia JP, Wasilewski K, Leisenring W, Arm-strong GT, Robison LL, Yasui Y. 2008. Cause-specific late mortal-ity among 5-year survivors of childhood cancer: the childhoodcancer survivor study. J Natl Cancer Inst 100:13681379.
Mervis J. 2005. Productivity countsbut the definition is key.Science 309:726.
Moyer VA. 2012. Screening for prostate cancer: U.S. PreventiveServices Task Force recommendation statement. Ann Intern Med157:120134.
Olson H, Betton G, Robinson D, Thomas K, Monro A, Kolaja G,Lilly P, Sanders J, Sipes G, Bracken W, et al. 2000. Concordanceof the toxicity of pharmaceuticals in humans and in animals. RegulToxicol Pharmacol 32:5667.
Pammolli F, Riccaboni M. 2008. Innovation and industrial leader-ship: lessons from pharmaceuticals. Washington, DC: Center forTransatlantic Relations.
Pammolli F, Magazzini L, Riccaboni M. 2011. The productivitycrisis in pharmaceutical R&D. Nat Rev Drug Discov 10:428438.
PCAST. 2012. Report to the president on propelling innovationin drug discovery, development, and evaluation. http://www.whitehouse.gov/sites/default/files/microsites/ostp/pcast-fda-final.pdf Accessed 20 September 2012.
PhRMA. 2012. Key industry and PhRMA facts. PhRMA. http://www.phrma.org/news-media/related-resources/key-industry-factsabout-phrma Accessed 21 September 2012.
PMDA. 2010. Japanese Pharmaceutical Manufacturing and DevicesAgency. Special consultation for biomarker qualification. http://www.pmda.go.jp/operations/shonin/info/consult/file/pbm-kiroku-e.pdf Accessed 20 September 2012.
PMDA. 2012. Japanese Pharmaceutical Manufacturing and DevicesAgency. Special consultation for biomarker qualification. http://www.pmda.go.jp/operations/shonin/info/consult/file/0928001-betten03.pdf Accessed 20 September 2012.
Poste G. 2011. Bring on the biomarkers. Nature 469:156157.
Rawlins MD. 1981. Clinical pharmacology. Adverse reactions todrugs. Br Med J (Clin Res Ed) 282:974976.
Rodriguez H, Rivers R, Kinsinger C, Mesri M, Hiltke T, Rahbar A,Boja E. 2010. Reconstructing the pipeline by introducing multi-plexed multiple reaction monitoring mass spectrometry for cancerbiomarker verification: an NCI-CPTC initiative perspective. Pro-teomics Clin Appl 4:904914.
Ronco C, Rosner MH. 2012. Acute kidney injury and residual renalfunction. Crit Care 16:144.
Siegel R, Naishadham D, Jemal A. 2012. Cancer statistics, 2012. CACancer J Clin 62:1029.
Sistare F, DeGeorge JJ. 2011. Promise of new translational safetybiomarkers in drug development and challenges to regulatoryqualification. Biomark Med 5:497514.
Sistare FD, Dieterle F, Troth S, Holder DJ, Gerhold D,Andrews-Cleavenger D, Baer W, Betton G, Bounous D, Carl K,et al. 2010. Towards consensus practices to qualify safety biomar-kers for use in early drug development. Nat Biotechnol 28:446454.
Slone Epidemiology Center, Allen A, Mitchell AA, Kaufman DW,Rosenberg L, Kelly J, Anderson T. 2006. Patterns of medicationuse in the United States. A report from the Slone Survey. http://www.bu.edu/slone/SloneSurvey/AnnualRpt/SloneSurveyWebReport2006.pdf Accessed 17 September 2012.
Sun E, Jena AB, Lakdawalla D, Reyes C, Philipson T, Goldman D.2010. The contributions of improved therapy and early detectionto cancer survival gains, 19882000. Forum Health Econ Policy13:120.
Tomlanovich S, Golbetz H, Perlroth M, Stinson E, Myers BD.1986. Limitations of creatinine in quantifying the severity ofcyclosporine-induced chronic nephropathy. Am J Kidney Dis8:332337.
Unger EF. 2007. All is not well in the world of translational research.J Am Coll Cardiol 50:738740.
Vasallo JD, Janovitz EB, Wescott DM, Chadwick C, Lowe-KrentzLJ, Lehman-McKeeman LD. 2009. Biomarkers of drug-inducedskeletal muscle injury in the rat: troponin I and myoglobin. ToxicolSci 111:402412.
Woodcock J. 2010. Precompetitive research: a new prescription fordrug development? Clin Pharmacol Ther 87:521523.
VALUE OF SAFETY BIOMARKER QUALIFICATION 125
Drug Dev. Res.
Woodcock J. 2012. Evidence vs. access: can twenty-first-centurydrug regulation refine the tradeoffs? Clin Pharmacol Ther 91:378380.
Woolf SH. 1995. Screening for prostate cancer with prostate-specificantigen. An examination of the evidence. N Engl J Med 333:14011405.
Woosley RL. 2012. Is it possible for FDA regulatory scientists andindustry scientists to work together? Clin Pharmacol Ther 91:390392.
Woosley RL, Myers RT, Goodsaid F. 2010. The Critical Path Insti-tutes approach to precompetitive sharing and advancing regula-tory science. Clin Pharmacol Ther 87:530533.
Wysowski DK, Swartz L. 2005. Adverse drug event surveillance anddrug withdrawals in the United States, 19692002: the importanceof reporting suspected reactions. Arch Intern Med 165:13631369.
DENNIS ET AL.126
Drug Dev. Res.