TUESDAY, 6 NOVEMBER 2007

07:30-08:00 Morning Coffee

BIOMARKERS FOR EARLY CLINICAL TRIALS

08:00-08:05 Chairperson’s Opening Remarks

08:05-08:35 Biomarkers in Early Oncology Clinical Trials
Michael Lahn, Ph.D., Medical Advisor, Lilly Deutschland GmbH
With the advent of novel and molecularly targeted agents, the clinical design in early oncology trials has included the use of biomarkers. Today, the use of biomarkers is not primarily focused on safety assessments, but also to determine early proof-of-concept. The presentation will provide an overview on how biomarkers have been used in the early stages of clinical development and their potential of identifying novel and attractive compounds. Finally, the development of novel biomarkers for the development of TGF-beta inhibitors will be presented.

08:35-09:05 Biomarkers as Key Drivers of a Question-Based Pharmaceutical R&D Process
Alain J. van Gool, Ph.D., Director, Genomics & Proteomics; Chair, Biomarker Platform, N.V. Organon
Organon’s translational approach is based on a question-based approach covering early research to Proof-of-Concept in man. The questions address proper exposure, efficacy and safety characteristics of novel drugs, whereas the answers to these questions are provided by key biomarkers. Through parallel application of diverse bio-marker discovery methodologies, facilitated by Organon’s biomarker platform, therapeutic teams use this approach to identify and validate biomarkers enabling them to make the right decisions on which drugs to progress. Examples from various therapeutic areas will be discussed.

09:05-09:35 Biomarkers in Early Clinical Trials for Dementia
Vincenzo Libri, M.D., Ph.D., Head, Translational Clinical Science, Clinical Pharmacology & Discovery Medicine, Neurology and Gastro-Intestinal Centre of Excellence in Drug Discovery, GlaxoSmithKline
Trials designed to evaluate clinical outcomes based upon conventional testing are of long duration, highly subjective and variable and, therefore, expensive. This is particularly true for chronic diseases such as Alzheimer’s disease. While markers endpoints may not be the true predictor of a real clinical endpoint, they may provide initial indication on whether the intervention is sufficiently promising to justify the conduct of larger-scale, and longer-term, clinical trials for demonstration of either symptomatic action or disease-modification. In early clinical trials for dementia (as for other diseases) markers endpoints should either correlate to the causal pathway of the disease process (disease-based surrogate marker) and so they can be used as substitute of the conventional clinical endpoint, or recognize the mechanism of action of a potential new therapy, and therefore be of use in determining central penetration and/or optimal dose (mechanism-based or pharmaco-dynamic markers). A rigorous process of marker validation is required to support Go/No Go decisions at early stages of drug development.

09:35-10:30 Coffee Break with Poster and Exhibit Viewing

10:30-11:00 Lost in Translation
Mark Fidock, Ph.D., Associate Research Fellow, Biomarkers and Translational Biology, Pfizer Global Research and Development 
An industry-wide problem is that a significant number of new chemical entities (NCEs) fail in clinical studies due to a lack of efficacy. This presentation will discuss possible reasons and illustrate the need to have validated proof-of-pharmacology biomarkers during all phases of the drug discovery process that will facilitate informed decision making for a favorable clinical outcome. 

11:00-11:30 The Application of Biomarkers in Early (Phase I) Clinical Development 
Georg Wensing, Ph.D., Head, Pharmacodynamics, Clinical Pharmacology, Global Drug Discovery, Bayer HealthCare AG
Selecting, evaluating and applying biomarkers in early clinical (phase I) drug development can substantially shorten the time to reach a critical decision point. The use of biomarkers in phase I studies helps to determine whether the drug is reaching the molecular target in humans or affecting a meaningful measurable endpoint that predicts desired or undesired clinical effects. Critical decisions such as candidate selection, early proof of mechanism or proof of concept, and dose ranging can be based on measurement of appropriate biomarkers. Linking pharmacodynamic to pharmacokinetic information may help to predict drug response and to assess safety risks. Preclinical and phase I development plans should be focused to support an early sd or md biomarker study in healthy volunteers or mildly diseased patients, thus saving both resources and time. Examples of using biomarkers in early clinical development are given.

11:30-12:00 Biomarker-Based Quantitative Risk Assessment for CYP3A Induction DDI in Early Clinical Development 
Karthik Venkatakrishnan, Ph.D., Associate Director, Clinical Pharmacology, Pfizer Global Research and Development
This presentation is intended to offer a quantitative framework to permit objective utilization of cytochrome P450 3A (CYP3A) induction biomarker data in early clinical development for drug-drug interaction (DDI) risk assessment and understanding of the associated therapeutic index. The urinary 6-beta hydroxycortisol: corti-sol metabolic ratio (CMR) has been widely used as a biomarker for diagnosis of CYP3A induction, although its relationship to clinical pharmacokinetic correlates of CYP3A induction DDI magnitude is currently not established. Additionally, the lack of an established classification of CYP3A inducers has precluded the utilization of CMR as an objective biomarker for quantitative DDI risk assessment in early clinical development. We have collated literature data on eight prototypic CYP3A inducers including in-house data on compounds in clinical development and developed a mathematical model relating the fold-increase in CMR to the percent de-crease in total exposure of the orally administered CYP3A index substrate midazolam using a Bayesian analysis approach. A case study describing application of this model will be presented in context of a proposed classification of CYP3A inducers to illustrate early forecasting of DDI risk from dose-response modeling of CMR data collected in a multiple dose toleration study.

LUNCHEON TECHNOLOGY SOLUTIONS SHOWCASE

12:15-12:30 Biomarker Discovery by Antibody Mediated Proteomics 
William Hempel, Ph.D., Scientific Director Biology, BioSystems International
Discovery and utilization of new, disease-specific protein biomarkers will forward clinical diagnostics and treatment, as well as accelerate the complex drug discovery and validation process. In this presentation, a novel biomarker discovery strategy will be described, that combines high-throughput monoclonal antibody-based global disease-specific plasma screening technology via 10,000 mABs in an experiment. The availability of disease-specific mABs at this scale with proven diagnostic poten-tial significantly cuts the transition time from biomarker discovery to clinical diagnostics. 

12:30-13:45 Key Features in Evaluating Potential Clinical Biomarkers
Sabine Küsters, Ph.D., Director of European Operations, Rules-Based Medicine Inc.
It is well accepted that using multiple biomarkers simultaneously to characterize disease and measure drug safety and efficacy are far superior to single analyte measurements. Only through the stacking of multiple markers can sensitivity be raised without sacrificing specificity and vice versa. In a clinical situation one of the difficulties of this approach, however, is whether a sophisticated algorithm is necessary to analyze the data as opposed to the more traditional method of using cut-offs. Sample type is also a critical issue in the identification and validation of biomarkers. Case studies will be shown of the different methods of data analysis as well as the importance of sample type.

12:45-13:00 Translating Tissue Based BioMarkers from Discovery through Pre-Clinical to Clinical Trials
Steven J. Potts, Ph.D., MBA, Director, Biopharma, Aperio Technologies, Inc.
While there is strong interest in biomarkers in circulation, tissue-based biomarkers still provide the best indication of the local tumor environment. The challenge for the pharmaceutical industry is the development of tissue biomarkers that both provide an accurate protein measurement, and yet still preserve the local tissue environment. This becomes even more important when they are used in preclinical or clinical trials, to allow their measurement in a format familiar to histopathologists. I will discuss two examples, the measurement of dual colocalized proteins (e.g. membrane, cytoplasm, and nuclear), and the measurement of angiogenesis.

BIOMARKERS FOR SAFETY ASSESSMENT

14:00-14:30 Biomarkers of Nephrotoxicity in Toxicology and the Clinic 
Graham Betton, Ph.D., Senior Principal Scientist, Safety Assessment, AstraZeneca Pharmaceuticals
Currently, ICH recommendations for nephrotoxicity biomarkers are just for relatively insensitive and non-specific markers (urea, creatinine). A number of emerging new urinary biomarkers are under evaluation in pharma consortia and are under consideration for regulatory acceptance. The next challenge is to apply these in the clinic. The presentation will overview the utility of urinary biomarkers in animals and man.

14:30-15:00 The Use of the Safety Biomarker aPTT in a Phase II Clinical Study with a Novel Direct Thrombin Inhibitor in Pa-tients with Atrial Fibrillation 
Joachim Stangier, Ph.D., Senior Principal Scientist, Drug Metabolism & Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co. KG
The oral direct thrombin inhibitor dabigatran etexilate is currently under development for the prevention of stroke in patients suffering from atrial fibrillation. In order to support the first dose-finding trial with this novel oral anticoagulant, correlations of drug plasma concentrations and the blood coagulation parameters pro-thrombin time (INR), ecarin clotting time, and activated partial thromboplastin time (aPTT) were established. APTT was selected as safety biomarker to identify patients at risk for bleeding during treatment. A comprehensive cross validation of the aPTT assays between study sites was performed before initiation of the clinical trial. An algorithm based on repeated aPTT measurements after treatment initiation was developed in order to adjust the dose of the anticoagulant in patients if nec-essary.

15:00-15:45 Refreshment Break with Poster and Exhibit Viewing

BIOMARKER QUALIFICATION AND VALIDATION

15:45-16:15 Biomarker Validation: Why, Which, and How? 
Charles Benson, M.D., Ph.D., Medical Advisor, Exploratory & Program Medicine, Eli Lilly & Co., UK
Criteria are advanced on to select biomarkers for validation (which) and methods to use for this exercise (how). Validation is described as a progressively increasing degree of certainty balanced against risk where the degree of certainty needed in a specific case depends upon many factors such as the product, the therapeutic con-text and risks of validation. In all cases, the progression to validation must always consider the overall benefit/risk ratio.

16:15-16:45 Important Considerations in the Discovery and Qualification of Biomarkers for Clinical Use 
Viswanath Devanarayan, Ph.D., Director, Statistics, Biomarker Research, Abbott Laboratories
Biomarker discovery entails the identification of putative markers for the response of interest, typically from exploratory and/or focused multi-array and other technol-ogy platforms. This is followed by the process of qualification of these biomarkers via additional studies/cohorts to demonstrate their predictive ability for the intended purpose. The quality of statistical thinking and methods used is a major determinant in the successful discovery and qualification of biomarkers. Data normalization and transformation methods can greatly impact the analysis. False discovery rates (q-values) and miss rates are critical for setting meaningful thresholds for identifica-tion. While it is important to analyze each marker individually (e.g., ANOVA), it is also important to keep in mind that a marker useless on its own may be great in a composite. The use of multivariate modeling methods that account for the interactions, similarity and diversity of the markers is essential for the identification of composite biomarkers. The predictive utility of these composite biomarkers should be assessed carefully via appropriate internal cross-validation methods, and further tested in independent cohorts (external validation) to expand and qualify their use in early clinical development.

16:45-17:15 A Cost Effectiveness Approach to the Qualification and Acceptance of Biomarkers 
David E. Slavin, M.D., Ph.D., Head, Business Innovations Unit, Pfizer Global Research and Development
The flow of new medicines to patients and much of the practice of medicine depends on development of new biomarkers and the correct interpretation of existing biomarker signals, yet there are no widely accepted and practically applicable criteria that determine the optimal qualification of biomarkers for these purposes. As a result, case-by-case determinations are based on subjectivity. Biomarker signals, monitoring programs or surrogate endpoints regarded as acceptable by one stakeholder will likely be regarded as unacceptable by others because of subjectivity in ranking importance of different risks. This leads to stagnation, increased costs, and a failure to maximize societal good. Conversely, a cost-benefit approach based on tolerability of risk principles can define acceptable biomarker performance that maximizes benefits and reduces the unintended consequences of precautionary behaviors. This approach is typical in other areas such as occupational medicine and public health. We therefore examined how biomarker qualification could be determined by cost effectiveness assessments and created a set of generalizable principles for the qualification of biomarkers that adapt to incomplete knowledge. Adoption of this approach by regulators and industry would minimize harm to patients, improve their access to medicines, and reduce healthcare costs. This may lead to optimal decisions for patients and reduce the “stagnation” issue identified in the FDAs Critical Path.

17:15-17:45 Panel Discussion with the Speakers: When is a Biomarker “Validated”?
Discussion Questions Include:

• What is “fit-for-purpose” validation? 

• What is biological vs. analytical validation? 

• What is cost/benefit analysis of biomarker acceptance criteria? 

• What are the best practices for validation of multiplex platforms? Do the same rules apply as for single analyte validations? 

• What are the current regulatory guidelines on validation of biomarker assays? 

• What are the strategies to deal with normal variability? 

• What are the differences in biomarker validation criteria for internal drug development decision making vs. diagnostic product? 

17:45 Close of Conference