Biomarkers: where are we and where are we going?

Skeptics argue that biomarkers are not a basis or stimulus for the next generation of new drugs, rather the term is just a novel word for basic tools to probe biology. Biomarkers are not new. Assessing physiological status by determining blood pressure and measurement of serum cholesterol as risk factors for disease is not debatable and has long been part of good clinical preventative and diagnostic practice. More controversial is the expansion of the concept of biomarkers to improve the low success rate encountered in development of new drugs and biologics, particularly in early clinical development, and guide treatment decisions based on genotype and phenotype in personalized medicine. The types of biomarkers for these applications are often technically sophisticated, expensive and localized to a few large university/hospital settings. Large datasets generated using gene array and proteomic technologies require sophisticated statistical treatments and interpretations in order to contribute to biological/clinical decision making.

Despite the challenges of accurately defining biomarker science and accessing relevant emerging technologies, the use and concept of biomarkers have had some recent successes in terms of regulatory approvals. Biomarkers development forms one of the corner stones of a new working paradigm in the pharmaceutical industry by increasing the importance of linking diagnostic technologies with the use of drugs. The position of the FDA is rather clear on this. Biomarkers are crucial to generate safe and efficacious drugs. Biomarkers are essential for deciding what patients should receive which treatment.

It appears likely that development of pharmaceuticals will also drive the development of biomarkers as diagnostic probes for clinical decisions and stratification of patients. Biomarker science is a field that is advancing rapidly. It can even be said that companies that do not include a biomarker strategy in their development paradigm will probably do so at their peril.

Biomarkers and decision-making

Historically biomarkers referred to analytes in biological samples, or any measurement that predicts a disease state or response to a specific drug therapy. Biomarkers are valuable drug development tools that provide more accurate or more complete information regarding drug performance and disease progression. The biomarker concept has evolved over time from a single physiological entity (blood pressure, cholesterol) parameters to highly complex multi-marker genomic/proteomic panels and sophisticated imaging technologies. However, while most researchers still focus on more accessible matrices, like blood, saliva, urine, synovial fluid for rather simple analytes, enthusiasm for complex and expensive technologies is growing that provide high information content.

Developments in genomics, genetics, and proteomics have renewed the interest in biomarkers as useful clinical indicators. While the speed of developing these technologies has been impressive, the interpretation of data has not reached maturity. Often the time required to characterize and validate new biomarkers is lagging behind the rapidly evolving technologies. For specific biomarker panels, there is the risk that by the time a biomarker or a panel of markers is validated, it may be too late in the process to be of value in decision-making. Nevertheless, biomarkers constitute a rationale approach that at its optimal level reflects the biology of the disease and the effect of the drug candidate. Proper incorporation of biomarkers in drug development strategy can enable the concept of ‘fail fast, fail early’, facilitate the choice of the proper critical path toward approval, and even differentiate approved products in a competitive marketplace. The challenge therefore is to identify relevant biomarkers early enough to implement them for ‘go, no-go’ decisions at critical stages throughout the development process.

Breaking down the silos

Basic research and clinical practice of medicine often works in silos hardly communicating with each other. Drugs were developed independently of the clinical needs, and often the first contact with the clinic was to be tested for safety and efficacy in clinical trails. The recent move towards Translational Medicine is focused to remove these silos, and stimulate exchange of ideas and understanding of the possibilities of the basic research in clinical practice, true ‘bench to bedside’ research. One of the most tangible problems that scientists have been facing, in recent years, is finding biomarkers that are predictive or ‘translate well’ from animal models to humans. For example, inhibiting an enzyme in animal models can have a dramatic effect in the animal, whereas inhibiting the same enzyme in human could have very limited or no clinical impact. The reasons for the lack of correlation are many and varied:

1. the therapy can change a biomarker but be irrelevant to the disease;
2. the biomarker may not reflect clinically important effects of the treatment;
3. in humans a drug may work through several different pathways not reflective in animal models. Thus, the fundamental challenge for a biomarker is not to unravel sophisticated pathogenetic mechanisms, but rather to understand how the biomarker reflects the biology of the disease. A drug should ‘treat a disease, not a biomarker’. If you do not understand the biology of the disease; it is difficult to figure out what is the right biomarker to be chosen. Proper biomarkers evolution requires close dialogue between biomarker scientists and practicing physicians and this can be accomplished under the banner of ‘Translational Medicine’.

Translational Medicine: bridging biomarkers to clinical outcomes

The ideal situation for pharmaceutical and diagnostic companies would be to have the tools to establish and characterize who has the disease, which patient will benefit from what drug at what doses, and whether a drug will have adverse effects. Compare this to the current paradigm of waiting for years, and studying thousands of patients to determine the efficacy and safety of a new pharmaceutical.

To be considered predictive, a biomarker should in most cases satisfy two criteria: a) it must be associated with the biological mechanisms within a disease or treatment; and b) must correlate statistically to clinical outcomes. Early clinical assessment of the potential value of biomarkers in decision making, either for product development or patient selection, is the focus of Translational Medicine. Deployment of a well-designed biomarker strategy within the paradigm of Translational Medicine provides a significant opportunity to enhance and streamline clinical development programs through accurate measurements of patient response or predisposition to therapeutic intervention.

It is still too early to evaluate the impact of biomarker strategies on marketing approvals of new drug products. It is evident from recent approvals that several new products included novel biomarkers to aid the drug development decision-making process.

Putting biomarkers to work and the role of contract research organizations

One must consider the time and money spent or saved versus the confidence gained from the use of biomarkers in ongoing drug development. There is a significant opportunity to enhance and streamline clinical development programs through accurate measurements of patient response or predisposition to therapeutic intervention. Co-development of biomarkers during the development cycle of drug candidates is a synergistic way to leverage knowledge of biological mechanisms. Early clinical trials of drug candidates provide a good environment to simultaneously evaluate candidate biomarkers. Timely biomarker data provide more accurate information regarding drug performance and lead to better drug development decisions, particularly early in clinical development.

The interest of diagnostic companies in marketing rights to a specific biomarker will be influenced by factors such as market share and company profile. There are few, if any, pharmaceutical or biopharmaceutical companies that have the depth and breadth of expertise and resources to develop, support and market diagnostic kits. Consequently, partnering between pharmaceutical and diagnostic companies is becoming a common practice. This trend will increase in the future with the evolving concept of ‘personalized medicine’.

Contract research organizations (CROs) have also recognized the business opportunities linked with the new biomarker technologies, and are partnering with specialized providers or developing capabilities internally. There is an increased understanding that CROs play a significant role in the successful implementation of biomarker-driven drug development programs. Biomarker assays, developed early on at the preclinical stage, can be the glue integrating a program from preclinical to early clinical studies to proof-of-concept studies in patients and beyond. Experienced scientists within CROs will have had exposure to a wide variety of applications of biomarker assays, and the data generated from these studies. CRO scientists who have had broad exposure to specific biomarker tests are best positioned to advise sponsors on the biomarkers selection and assay technology limitations.

Summary

The impact of biomarker technology and biomarker strategies in pharmaceutical development is still in its infancy, but the impact is already proving to be significant. Biomarker strategy forms the basis for Translational Medicine and the industry/regulatory focus for improving the success rate and reducing the high attrition rate often encountered in Phase II clinical research. The depth and breadth of knowledge required to successfully implement biomarkers into drug development are generating company collaborations and inclusion of professionals that traditionally have not been part of drug product development.