Efficacy Biomarkers

Efficacy biomarkers range from pharmacodynamic (PD) biomarkers, markers quantifying drug-target interaction, and markers reflecting the underlying pathology of the disease to those with established links to clinical outcomes accepted as surrogate endpoints for regulatory approval. Effect of a pharmaceutical in development on a biomarker associated with efficacy is guaranteed to generate enthusiasm and momentum in the team.

PD biomarkers have a long history in pharmaceutical development and form one of the cornerstones of hypothesis-driven approaches to drug discovery and development. These biomarkers are commonly generated as part of the discovery process. The biomarker may fulfill multiple key criteria in in vitro or animal models: (1) it may be used to characterize the pharmacology models; (2) it may be used in knock-out or knock-in genetic models to further validate the target; and (3) it may demonstrate a characteristic PD/pharmaco-kinetic (PK) relationship with the drug under development. The changes reflecting underlying pathology range from largely unknown to those clearly indicative of potential market impact. An example of the latter is atrovastatin administration, resulting in decreases in serum triglycerides in normolipidemic subjects in clinical pharmacology studies [12,13] . This is more an exception than the norm. Typically, interpretation of the clinical significance and potential market impact of a biomarker is less certain, particularly if the pharmaceutical is (1) acting by a novel mechanism of action and (2) targeting a chronic progressive disease where disease modification rather than cure is the outcome anticipated.

The rationale for including PD biomarkers is generally easy to articulate to management, and particularly for smaller companies, these biomarkers may be essential for attracting investment. While enthusiasm and willingness to include these types of markers is generally not the issue, they are not without significant challenges in implementation and interpretation in the pharmaceutical development paradigm:

• Technical aspects

• Stability of the biomarkers

• Technical complexity of the assay

• Assay robustness, sensitivity, specificity

• Throughput of the assay

• Biological samples

• Access to matrices that can or should be assayed

• Sample collection volume or amount and timing in relation to dosing

• Feasibility, cost, and resolution capabilities for imaging modalities for interactions with targets in the central nervous system, testis, poorly vascularized tumors, etc.

• Data interpretation

• Normal values; inter- and intraindividual variability

• Values in disease versus healthy conditions

• Diurnal and environmental effects in animals

• Effects of diet, lifestyle, concomitant medications in humans

• Impact on development of no change or unexpected changes in bio-markers in the continuum from discovery to clinical

Patient Stratification Biomarkers

The use of patient stratification biomarkers in pharmaceutical development and medical practice forms the foundation of what has been called personal ized, individualized, or stratified therapy. Patient stratification biomarkers focus on patients and/or underlying pathology rather than on the effect of the pharmaceutical on the target. For small-molecule drugs, genotyping for polymorphic drug-metabolizing enzymes responsible for elimination or activation/ inactivation of the compound is now an established practice in clinical trials. Results about potential effects attributed to certain genotypes may be reflected in labeling recommendations for dose adjustments and/or precautions about drug-drug interactions [14]. A priori determination of genotype for polymorphic metabolizing enzymes are now included on the labels for irinotecan [15] and was recently added for warfarin [16] to guide selection of dosing regimen.

Targeted therapy in oncology is the best established application of patient stratification biomarkers. The development of Herceptin, the monoclonal antibody trastuzumab, with an indication restricted to breast tumors overex-pressing HER2/neu protein [17], is a clinical and commercial success story for this approach. Oncology indications also include examples of the potential of using serum proteomics to classify patients according to the highest potential for clinical benefit. For example, Taguchi et al. [18] used matrix-assisted laser desorption ionization (MALDI) mass spectroscopy (MS) analysis to generate an eight-peak MALDI MS algorithm of unidentified proteins to aid in the pretreatment selection of appropriate subgroups of non-small cell lung carcinoma patients for treatment with epidermal growth factor receptor inhibitors (erlotinib or gefitinib).

As illustrated by the examples above, patient stratification biomarkers encompass a wide range of technologies, including algorithms of unknown proteins. Challenges for the development team are to understand and identify the potential for including patient stratification biomarkers either as part of or as the major thrust in the development process. This is often a major challenge, since the technologies may lie outside the core knowledge areas of the team members, making it difficult to articulate and discuss their value within the team and to communicate effectively to management. These challenges can be particularly pertinent for some of the "omics" technologies, which can be highly platform dependent and rely on complex statistical methodologies to analyze large sets of data to principal components. The results often have little intuitive inference in the underlying targeted disease pathology and may be one of the reasons that these powerful methodologies are not used more commonly. Some considerations for including patient stratification biomark-ers are summarized as follows:

• Strategic issues

• What is the purpose of including the patient stratification biomarker?

• Will it be helpful in reaching go/no go decisions?

• Is it required for registration purposes?

• What will the implications be for marketing and prescribing practices?

• Practical considerations

• Is the biomarker commercially available and accessible?

• If a diagnostic biomarker is essential to the development of the pharmaceutical, should co-development be considered?

• Are there IP and marketing restrictions?

• What are the implications of the biomarker technology on the conduct of the clinical trial?

Safety Biomarkers

The considerations for safety during development are paramount; not surprisingly, it is one of the most regulated aspects of pharmaceutical development. Safety biomarkers have spurred on interesting and innovative regulatory and industry initiative and collaborations to develop and qualify novel biomarkers. Examples are the guidance of the U.S. Food and Drug Administration (FDA) for voluntary submissions of genomic data [19] and partnerships among government, academia, and industry for qualification of safety biomarkers [20] . Data qualifying the interpretation and significance of changes in safety bio-markers are needed to guide pharmaceutical development as well as evaluation of risk to patients or healthy volunteers in clinical trials. The purpose of safety biomarkers in clinical trials can be (1) to exclude patients at risk of developing adverse effects, (2) to increase sensitivity of the adverse event monitoring, and (3) to evaluate the clinical relevance of toxicity observed in the preclinical studies. Introducing novel or more uncommon biomarkers into a development project to address any of these aspects will not be embraced universally. There may be concerns not only about the added testing burden but also about the sensitivity and specificity of the biomarker, its relevance, and its relationship to well- established biomarkers. Nevertheless, including novel or uncommon biomarkers may be a condition for the conduct of a clinical trial as mandated by either regulatory bodies or institutional review boards. For example, there may be requirements to include sperm analysis in healthy volunteers and adapting experimental genotoxicity assays to humans to address effects observed in preclinical safety studies on the male reproductive tract and in genotoxicity evaluation, respectively. These will directly affect the conduct of the trials, the investigator, his or her comfort level with the assay, and the ability to communicate the significance of baseline values and any changes in the biomarkers to the clinical trial participant. However, novel and uncommon biomarkers will also have strategic and practical implications for the overall development program:

• Strategic issues

• Will including the safety biomarker be a requirement for the entire pharmaceutical development program?

• Are the efficacy and/or PK properties sufficiently promising to warrant continued development?

• Can the identified safety concern be managed after approval?


• Practical considerations

• What are the implications for the clinical trial program, locations of trials, linking to testing laboratories?

• Will additional qualification of the biomarker assay be required as the development advances and for regulatory approval?

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