Molecular biomarkers are emerging as key indices for discovery, development, approval, safety, value assessment and individualized medicine. They can and should be employed in all stages of drug development, from pre-clinical through post-marketing. Biomarkers, which are not new to medicine and drug development, are often classified as traditional, preventive, diagnostic, prognostic and predictive. However, as a consequence of scientific, economic and regulatory factors, biomarkers have not yet made the level of progress seen in therapeutics.
In 1998, the US National Institutes of Health set up a task force to standardize the definitions of biomarkers. In the context of disease process, they must exhibit critical features and ideally should:
(1) have a direct consequence of the disease pathology;
(2) be a proximal mediator of one or more components of the clinical syndrome;
(3) be measurable in both clinical and “real world” settings;
(4) be detectable in the pre-clinical state.
More recently, the European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA) have expressed their intention to encourage the integration of biomarkers in drug development and in the clinical practice. They have demonstrated this by organizing workshops and issuing guidances, specifically in the field of toxicology and pharmacogenomics. Moreover, the EMEA and the FDA have recently completed their first combined qualification process for biomarkers of drug-induced renal toxicity in which the pharmaceutical industry has for the first time pooled together data from different companies in order to achieve the critical mass needed for (pre-clinical) qualification of specific biomarkers.
New generation biomarkers, resulting from advances in bio-analytical technology, are enabling researchers to examine single nucleotide polymorphism (SNP), genomic and proteomic profiling, epigenetic profiling and gene expression profiling. The use of validated biomarkers will soon be an integral component in the design of definitive prospective cohort studies. However, a rigorous process for their development and validation, followed by qualification in well-designed studies that demonstrate improved patient outcomes, will be required.
The Human Genome Project opened many new possibilities for improving the understanding of genes and drug responses at an individual level. Genomic biomarkers will play an important role in identifying responders and non-responders, minimizing toxicity and adjusting drug dosage to optimize their efficacy, effectiveness and safety. Genomics provides a more sophisticated version of personalized medicine from findings in genetics and molecular biology. Physicians will be able to assess susceptibility to disease more accurately and prescribe drugs to address any added risk and offer recommendations regarding life style and behavioral changes. Identifying differences in the genetic profile of various diseases is already enabling scientist to develop drugs that target specific disease subtypes, replacing the medical system’s usual trial and error method for finding a more effective treatment. The application of pharmacogenomics will allow physicians to give the right patient the right drug at the correct dose.
The literature is replete with biomarkers for many different applications from diagnostic to pharmacodynamic. However, studies have not taken full advantage of the new technology, neither during drug development nor when the drug reaches the common clinical practice. If clear no-go decisions can be based on biomarkers showing a failed mechanism of action, or exposure-response relationships that are not effective within a predicted safety margin, the design and execution of larger more expensive Phase III trials can be avoided. This would result in lower overall drug development costs.
To date, the number of biomarkers considered clinically useful is very small due to conflicting conclusions generated from clinical trials and methodological limitations. Some of the challenges are related to the design and analysis of studies that incorporate a biomarker as a central component. The planning and design phase of any study must consider how biomarkers may be used as targets and how they may influence methodology to optimize efficiency. Consideration should be given to trials and studies evaluating potential prognostic biomarkers and how the predictive properties of biomarkers can be used to determine which patients might be responders and non-responders.
During this time of increased application of pharmacogenomic and pharmacodynamic biomarkers, there is an opportunity for the industry to take on the promises and challenges facing both the drug development and post-marketing world. This unprecedented opportunity to use state-of-the-art bio-analytical techniques for measuring human physiology in response to pharmacologic intervention requires careful planning, designing and coordinating of all phases of the drug’s life cycle. The drive for ever-more evidence-based clinical end points, higher benefit to risk ratio and product value requires a paradigm shift in our thinking about the business and the science.