Calculation Of Clinical Starting Dose

The currently accepted algorithm for calculating a starting dose in clinical trials with oncology drugs is to use one-tenth of the dose that causes severe toxicity (or death) in 10 of the rodents (STD10) on amg m2 basis, provided that this starting dose (i.e., 1 10 the STD10) does not cause serious, irreversible toxicity in a nonrodent species (in this case, the dog) (DeGeorge et al., 1998). If irreversible toxicities are induced at the proposed starting dose in nonrodents or if the nonrodent...

Structure Of The Sbir Grant Proposal Phase I Application

The SBIR grant application process proceeds in two steps. The initial step is the phase I application. The application is (relatively) small and uncomplicated. The 15-page work plan introduces the overall research goal of the project, provides a rationale for doing the research, suggests feasibility, and outlines a series of experiments that (if successful) will support feasibility. Phase I funding provides up to 100,000 to demonstrate the merit of the investigation proposed. The length of...

Drug Targets Historical Perspectives

Drugs are natural or designed substances used deliberately to produce pharmacological effects in humans or animals. Drugs have been part of human civilizations for millennia. However, until the very recent modern era, drugs have been introduced to humans by empiricism and largely by serendipitous events such as encounters with natural products in search of food or by avoiding hazardous plants and animal products. The emergence of the scientific era in drug discovery evolved alongside the...

Proficiency Testing

Proficiency testing (PT) is one external measure by which a laboratory's performance can be judged. In a PT program, laboratories are sent samples for analysis and return their results to the PT program organizers. The correct result (or range of results) for these programs is determined by the organizers based on a comparison of participant results with results obtained by reference laboratories (accuracy-based grading), or by comparison with other laboratories that use the same analytical...

Biomarker Validity And Validation The Regulatory Perspective

The FDA's Guidance for Industry Pharmacogenomic Data Submission, published in 2005, has helped introduce and define exploratory and valid biomark-ers. The FDA defines a valid pharmacogenomic biomarker as one that is measured in an analytical test system with well-established performance characteristics and for which there is an established scientific framework or body of evidence that elucidates the toxicological, pharmacological, or clinical significance of the test result. The FDA further...

Mechanisms Of Antibody Induction

There are two main mechanisms by which antibodies are induced by therapeutic proteins (Table 1). If the proteins are of completely of foreign origin, such as asparginase or streptokinase, and the first generation mAbs derived from murine cells or partly foreign such as chimeric or humanized mAbs, the antibody response is comparable to a vaccination reaction. Often a single injection is sufficient to induce high levels of neutralizing antibodies, which may persist for a considerable length of...

Practistical Magic Which Witch Is Which

During my time as a contract research organization scientist, I was astonished at the frequency of requests from pharmaceutical and biotechnology clients to perform inappropriate statistical treatment of the results it seems that in the drug development industry at least, there is an appreciable level of confusion over when particular tests are appropriate and what underlying assumptions must be met for them to be valid. Accordingly, some refresher basic statistics background is summarized...

Essential Characteristics of Imaging Biomarkers

Earlier we highlighted the use of imaging in biological research. In such studies, when a correlation is demonstrated between an image-based measurement and a particular physiological characteristic or disease process, it is tempting to identify that measurement as an imaging biomarker. However, this is not always useful. Here we identify several additional characteristics of imaging biomarkers that will generally become essential as an image-based functional measure progresses through the...

Uroscopy

Because of its easy availability for inspection, urine was for many centuries the focus of attention. The foundation of the science of uroscopy is generally attributed to Hippocrates (460-355 b.c . ), who hypothesized that urine was a Biomarkers in Drug Development A Handbook of Practice, Application, and Strategy, Edited by Michael R. Bleavins, Claudio Carini, Malle Jurima-Romet, and Ramin Rahbari Copyright 2010 John Wiley & Sons, Inc. filtrate of the humors, taken from the blood and...

Introduction

Across many segments of the biomedical research enterprise and the health care delivery sectors, the impact of biomarkers has been transforming in many ways from business and economics to policy and planning of disease management. The pace of basic discovery research progress has been profound worldwide, with the intertwining of innovative technologies and knowledge providing extensive and comprehensive lists of biological factors now known to play integral roles in disease pathways. These...

Identifying Biomarker Patent Infringement Risks

Patents give the patent owner the right to exclude others from practicing the patented invention. The patent, however, does not provide the patent owner with an affirmative right to practice the invention. For example, the owner of a patent that claims a method of using a biomarker can exclude others from the use of that biomarker. If another party owns a composition of matter patent on the biomarker (i.e., a patent to the biomarker itself), the owner of the method of use patent would not be...

Case Study 3 Clinical Modeling of Brain D2 Receptor Occupancy Plasma Concentration Relationships with a Novel

PK PD modeling using functional imaging methodology such as positronemission tomography (PET) may be a very useful tool for early clinical development of antipsychotic compounds, especially in suggesting initial doses for further clinical studies. The purpose of this study was to assess PK PD relationships of YKPi358 to guide decisions for further clinical study designs. YKPi358 is a novel serotonin (5-HT2A) and dopamine (D2) antagonist that

Brief History Of Biomarker Research 19982008 The First Decade

During the last decade of the twentieth century, biomedical research underwent one of the most dramatic periods of change in history. Influenced by a multitude of factors some scientific, others economic, and still others of policy new frontiers of science emerged as technology and knowledge converged, and diverged bringing new discoveries and hope to the forefront of medicine and health. These capabilities came about as a generation 's worth of science that brought to the mainstream of...

Analytical Performance

Describing and characterizing analytical performance is very much oriented toward metrology. The general conventions and standards to consider include precision, trueness, and accuracy, along with a number of other more technical characteristics that describe the performance of a test. Analytical Precision and Imprecision Precision is a measure of the random error or variability observed in measurement results and is a product of the sample handling and analytical process. Precision is...

Parametric vs Nonparametric

Parametric tests are so named because they use parameters, such as mean and standard deviation, in their computations. Student's t-test and the analysis of variance (ANOVA) are examples of this type of test. Parametric tests assume that the data sets are normally distributed and that the various groups have roughly equivalent variance between members of the group. They are prone to falsely indicating a significant difference between the groups if these assumptions are not met. In that case,...

References

Ally S, Clair T, Katsaros D, et al. ( 1989 ). Inhibition of growth and modulation of gene expression in human lung carcinoma in athymic mice by site-selective 8-Cl-cyclic adenosine monophosphate. Cancer Res, 49 5650 - 5655 . Block GA ( 2000 ). Prevalence and clinical consequences of elevated Ca x P product on hemodialysis patients. Clin Nephrol, 54(4) 318-324. Bone Care International, Inc., (1999). Package insert, Hectorol (doxercalciferol) capsules. June 9. Brown AP, Morrissey RL , Smith AC,...

Consequences Of Antibodies To Therapeutic Proteins

In many cases the presence of antibodies is not associated with biological or clinical consequences. The effects that antibodies may induce depend on their level and affinity and can be the result of antigen-antibody reaction in general or of the specific interaction. Severe general immune reactions as anaphylaxis associated with the use of animal antisera have become rare because the purity of the products increased substantially. Delayed-type infusion-l ike reactions resembling serum sickness...

Limitations Faced In Preclinical Safety Assessment

A critical problem faced by nonclinical safety assessment groups in pharmaceutical drug development is the disparity of responses sometimes seen between the two nonclinical test species in the tools used to assess these responses. Historically, microscopic histopathology is used as a primary tool for identifying compound--nduced damage. When damage is identified only at exposures far exceeding those expected in clinical studies, clinical safety is expected. However, microscopic histopathology...

Population Biobanks And The Challenge Of Harmonization

The banking of human biological samples for research is not a twenty-first century phenomenon. Human tissue has been gathered and collected for at least 100 years. According to the U.S. National Bioethics Advisory Committee, by 1999, a total of 282 million unique tissue specimens were being held in the United States 27 . The term biobank, however, is relatively new. It appeared in PubMed for the first time in 1996 28 and was not common nomenclature until the end of the decade. The sequencing of...

Team Dynamics Pharmaceutical Project Teams

The development team has members with complementary technical skills. The management of the complex process of pharmaceutical development requires that these highly skilled knowledge workers engage, relate, and commit to a shared goal with defined milestones. These team interactions have to occur in a dynamic environment where (1) studies and experiments continually generate results that may fundamentally change the course of development, (2) management support and priority may be low compared...

High Throughput Gene Cloning And Expression For The Fabrication Of Proteome Microarrays

The genomics era ushered in a new type of research. For the first time in history the decoded blueprint of life was available for study. The Human Genome Project (HGP) was the first major undertaking of its kind. The HGP was a 13-year project coordinated by the U.S. Department of Energy and the National Institutes of Health that was completed in 2003. The goal was to identify all of the approximately 20,000 to 30,000 genes in human DNA, determine the sequences of the 3 billion chemical base...

Key Advantages of Imaging Biomarkers

As a tool in drug development, imaging biomarkers share several general advantages among all imaging modalities. Imaging biomarkers provide the unique ability to visualize anatomy as well as to spatially localize physiological and molecular function in vivo. Additionally, most imaging modalities have the capability to acquire repeated or temporally resolved images which allow a study of various dynamic biological processes. In vivo image-based evalua tion of disease processes or drug targets...

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...

Imaging

Belgians had decided to bring x-rays into practical use in hospitals throughout the country Nevertheless, it was soon clear that a major new diagnostic tool had been presented to the medical world, and there was little surprise when Roentgen received a Nobel Prize in Physics in 1901. Meanwhile, in March 1896, Henri Becquerel, professor of physics at the Mus um National d'Histoire Naturelle in Paris, while investigating Roentgen's work, wrapped a fluorescent mineral, potassium uranyl sulfate, in...

Why Qualify Biomarkers

More often than not, new biomarkers are judged on the basis of whether they have been subjected to a process of validation. Strictly speaking, validation is a process to establish, or illustrate the worthiness or legitimacy of something 44 . For judgments of biomarker worthiness or legitimacy, an assessment is needed of both (1) the assay or analytical method to measure the biomarker, and (2) the performance against expectations of the biomarker response under a variety of biological or...

Miscellaneous Data

Outliers Within any set of observations it is not unusual to obtain occasional data points that vary substantially from others found in the same group of subjects. These outlier data may be the result of unknown errors or may represent genuine information, and indeed, whether such data should be included or rejected is the subject of much debate. Methods for detecting outlier data and the use of robust methods of statistical analysis to accommodate such data are complex issues, beyond the scope...

Project Management

The following systematic tools and processes approach available for project management 9,10 can be applied to management of biomarker programs Contracts, scope documents Meeting minutes Communication plans RACI (responsible, accountable, consulted, informed) charts Lessons-learned tools Milestone charts review, tracking) charts Work breakdown structures Budget tracking Lean-sigma tools Process mapping with the team is useful to ensure that all aspects of the biomarker project management are...

The Future

Two generalizations may perhaps be drawn from the accelerating history of biomarkers over the last 2700 years. The first is that each new step depends on an interaction between increasing understanding of the biology and technical improvement of the tools leading to a continuous spiral of innovation. The second is the need for an open but cautious mind. Sushustra's recognition of the implications of sweet urine has stood the test of time de Corbeil's Poem on the Judgment of Urines has not. The...

Role Of Biomarkers In Discovery And Preclinical Development

Many companies start evolving a TPP even at the earliest go no go decision gates of drug development. In this way, a common way of thinking is preserved throughout the life of the product. The development program plan is assembled by determining what studies need to be done and their design that would provide information critical to answering the key questions at each go no go decision gate. The value of a solid drug development plan based on a decision gate approach can...

Biomarkers Utilitarian Classification

Biomarkers are the stepping-stones for modern drug discovery and development 1-4 . Biomarkers are defined as biological substances or biophysical parameters that can be monitored objectively and reproducibly and used to predict drug effect or outcome. This broad definition is, however, of little utility to the pharmaceutical process since it carries no qualification for the significance and use of the biomarker. The following classes and definitions of biomarkers are therefore offered 1. Target...

Funding Biomarker Research Through The Sbir Program

The discussion above applies to just about any project for which funding through the SBIR program might be sought. The following discussion relates, more specifically, to funding of biomarker development work. Developing a biomarker is, in many respects, similar to developing a therapeutic product. Both involve a focus on a particular disease or condition. While the therapeutic agent is, obviously, a tangible material that needs to be developed and tested in the laboratory, validated in a...