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10.1586/14737159.7.6.759 © 2007 Future Drugs Ltd ISSN 1473-7159 759
Meeting Report
Clinical Biomarkers Forum: harnessing the potential of biomarkers from translational research throughout clinical trials13–14 September, 2007, Prague, Czech Republic
Martin ShawBiotrin International, Dublin, Ireland; Tel.: +353 1 283 1166; Fax: +353 1 283 1232 ; [email protected]; www.biotrin.com
Expert Rev. Mol. Diagn. 7(6), 759–760 (2007)
With average drug development costsnearing US$1 billion and a decreasing pro-ductivity, biomarkers are seen as onemeans of reducing development costs andstreamlining drug development [1]. Despitethe encouragement of regulatory authori-ties with, for example, the C-Path initiative[2] and cross-industry consortia such as theInternational Life Sciences Instituteprojects on biomarker validation [3], theintroduction of novel biomarkers intoclinical trials, the final and most expen-sive part of drug development, has beenslow. One reason is that the further aproject has progressed, the more difficultit is to introduce new biomarkers, becausethere will be no history linking them todata obtained earlier in the developmentprocess. The Clinical Biomarkers Forumdrew together presentations by research-ers from academia, pharmaceuticalindustry and biomarker platform provid-ers to discuss the introduction and utili-zation of novel biomarkers. Two comple-mentary themes were presented at themeeting; biomarker platforms and theutilization of biomarkers as an aid todecision-making in drug development.
Biomarker platformsSeveral methods of identifying genomicpatterns were presented, including a pres-entation by David Bol, Vice President ofProduct Development of Avalon Pharma-ceuticals, Inc., who claimed that their
system could be better at detecting off-target effects of compounds by analyzingthe patterns of gene activations resultingfrom administration of the drug. Thiswas exemplified by the presentation ofbiomarker changes in preclinical andclinical studies with an anticancer com-pound. Changes in gene expression cor-related with biological activity and coulddistinguish between subjects with stableor progressive disease.
Dirk van Bockstaele of Esoterix pre-sented the use of flow cytometry as abiomarker platform, introducing the con-cept of ‘cellomics’. According to a studyquoted by Bockstaele (Boston BiomedicalConsulting, Inc., 2002) 50% of pathol-ogy testing could be on cells or cell prod-ucts by 2010. The merits of studying cellsurface receptors are that the expressionof surface protein receptors in disease andtheir changes as a result of therapeuticinterventions can be studied on an easilyavailable sample. Binding of active sub-stances to surface receptors can also bequantified. This could be especially usefulin the study of the effects of compoundsthat affect (directly or indirectly) theexpression of proteins on the cell surface.
Martin Shaw, Senior Scientific Officerat Biotrin International, presented dataon the discovery of novel renal biomark-ers by immunohistological screening(Histomics®) and their use in monitor-ing renal injury from cell culture through
to human clinical studies. The biomark-ers are not only more sensitive and spe-cific than traditional biomarkers, but canbe translated from one stage of the drugdevelopment process to the next.
Patrick Mueller of RCC Ltd (Switzer-land) reviewed the literature on organ-specific biomarkers for the kidney, liver,heart and gonads. He presented somenovel data on the use of α-glutathioneS-transferase in hepatotoxicity where itshowed injury more clearly than tradi-tional liver biomarkers, inhibin in ovariantoxicity and troponin in canine hepato-toxicity. He quoted from a study onNGAL (neutrophil gelatinase-associatedlipocalin) in cisplatin toxicity, where itwas more sensitive than N-acetyl β-gluco-samidase (NAG). The data on troponinin canine cardiotoxicity sparked a discus-sion regarding the relative sensitivity ofdifferent troponin assays in canine sam-ples and how they can be compared.
Use of biomarkers in drug developmentPresentations from the pharmaceuticalindustry stressed the use of biomarkers toobtain information earlier in the drugdevelopment process and, therefore,reduce late-stage attrition.
Magnus Sjögren, Director of ClinicalResearch of Organon and Senderovitz,Vice President Global ExploratoryDevelopment UCB presented strategiesof drug development where increasedaccumulation of knowledge early indevelopment, including biomarkers,could reduce late-stage failures. Sjögrencalls the strategy at Organon ‘question-based drug development’.
Stefan Sultana, working on genito-urinary medicine at Pfizer Inc., discussedthe use of different types of biomarkers;including, proof of pharmacology, proofof mechanism and proof of concept (isthe compound likely to work in apatient?), and how they could be used toreduce the total cost of drug developmentby enabling less promising compounds tobe detected earlier. Sultana presented datademonstrating that while the cost for
Shaw
760 Expert Rev. Mol. Diagn. 7(6), (2007)
developing an individual drug may beincreased, the total cost for a programwill be lower due to reduced expenditureon failed compounds.
Stefan Scherer, Biomarker ProgrammeLeader, Roche, presented the co-develop-ment of biomarkers and therapeutics incancer. Since only 25% of cancer patientsrespond to therapy, identifying thosewho will or will not respond will improvesuccess rates in trials while reducing costsand side effects. At Roche, all drug devel-opments have a biomarker strategy. Therelationship between the use of the drugHerceptin® and the expression of theHER2 receptor was given as an exampleof this. Breast cancers expressing HER2show a much stronger response to Her-ceptin, but only approximately 20–30%of them express it. Testing for HER2prior to therapy makes it more cost-effec-tive and reduces unnecessary patienttherapy.
Biochemical and omics biomarkers stillhave to be used alongside traditionalbiomarkers, and the power of the combi-nation was shown in a presentation byLouden Calvert of AstraZeneca. He pre-sented a study where by combining heartrate and blood pressure measurementswith troponin, it could be shown that theapparent cardiac effects of a compoundwere due more to increased cardiac workload resulting from peripheral hyper-tension, rather than direct effects of thecompound on the heart.
The results extrapolated from a studyare only as good as the data on which theyare based, and Huss, Head of GlobalClinical Pharmacology Data Managementof Bayer, presented the problems of ensur-ing top-quality data for biomarkers. Novelbiomarkers may be assayed by scientificexperts who are inexperienced in the rig-orous standards that are required for data-quality control in the pharmaceuticalindustry. The sponsor should have exper-tise on biomarkers within the data man-agement unit, plus the supplier of thebiomarker service must ensure that theyare fully informed about what is required.Apparently small changes in assay calibra-tion at one center can make multicenterdata comparison more difficult andcomplicate the interpretation of a study.
Data that are submitted in support of adrug submission are interpreted againstthe background of society and how thevarious stakeholders in drug approvaland use perceive the risks and benefits ofapproving the substance. Against thisbackground, David Slavin of the Busi-ness Innovations unit of Pfizer, discussedbiomarkers in the context of risk percep-tion and how it influences people’s will-ingness to accept new tests. There is pres-sure on regulators to be very cautiousregarding drug toxicity, as it can beregarded as a product defect, rather thanunavoidable side effect of the benefit thatthe substance provides. Surrogate endpoints have driven health improvements(e.g., LDL and stroke and myocardialinfarction), because they can reduce thecost of screening drugs in humans. Otherdata have shown that studies based onsurrogate end points may provide evi-dence of benefit more frequently thanstudies relying on clinical end points,indicating the continued need to confirmsurrogate end pints by clinical benefit.Different stakeholders may also viewbiomarkers in different ways, due to theirdifferent perspectives. A false-positivetoxicology result could lose a valuablecompound, leading to loss to the devel-oper and loss of patient benefit. A false-negative result could lead to injury topatients and criticism of the regulator.These two risks must be balanced to givemaximum patient benefit.
Concluding remarks My opinion on the presentations is thatbiomarkers are now moving into themainstream. The presentations from thepharmaceutical industry were very prac-tically orientated about how to incorpo-rate biomarkers into the decision-makingprocess, rather than research on thedevelopment of new biomarkers. Unfor-tunately, very few of the data presentedwere from human clinical trials wheredevelopment of the substance was dis-continued; many of the data were fromanimal studies or from human clinicalstudies where there was a positive out-come. The presentations showed how, bythe use of biomarkers earlier in develop-ment, unsuccessful compounds can be
removed from the development pipelineand clinical trials can be better plannedwith a reduced risk of failure. Many ofthe data from preclinical studies was ontoxicology, while those from humanstudies tended to be on biomarkers ofeffect. This reflects the general literaturewhere few biomarker data are publishedfrom negative clinical trials. Successfulclinical trials with successful clinical endpoints will tend to show positive data forbiomarkers of risk and response. Withonly one in ten compounds that enterPhase I trials being finally approved asdrugs, there must be a vast amount ofdata in the files of companies that couldbe used to validate and streamline theintroduction of biomarkers. An industry-wide agreement on the release of bio-marker data on these substances wouldbe very valuable.
Financial & competing interests disclosureMartin Shaw works for Biotrin Inter-national, which is a company that developsand promotes Biomarker assays. The authorhas no other relevant affiliations or finan-cial involvement with any organization orentity with a financial interest in or finan-cial conflict with the subject matter ormaterials discussed in the manuscript apartfrom those disclosed.
No writing assistance was utilized in theproduction of this manuscript.
Websites
1 Crawford LM. Acting commissioner of the FDA’s speech to the drug information association (2004)www.fda.gov/oc/speeches/2004/dia1026.html
2 The Critical Path Institutewww.c-path.org
3 ILSI: Development and Application of Biomarkers of Toxicitywww.hesiglobal.org/Committees/TechnicalCommittees/Biomarkers
Affiliation
• Martin ShawSenior Scientific Officer, Biotrin International, Dublin, IrelandTel.: +353 1 283 1166Fax: +353 1 283 [email protected]
