Biochemical Markers as Tools to Increase Efficiency in Drug Development
The current cost of bringing a new medicine to market is estimated to be as high as US$0.8–1.7 billion.1 Product development programmes are often abandoned after extensive investment of time and resources. This high failure rate increases costs. Even the path to market for successful candidates is long, costly and inefficient, due in large part to the current reliance on cumbersome assessment methods. During the last decade, the number of new drug and biological applications subimitted to the US Food and Drug Administration (FDA) has declined significantly.
As the costs and challenges of medical product development continue to surge, innovation may continue to stagnate or decline; as a result, a long list of health needs will remain unmet. This emphasises the absolute need to improve the predictability and efficiency of drug development, thereby providing optimal conditions for projects with the highest probability of success. There is a need for novel methodologies, a drug development toolkit containing powerful scientific and technical methods such as in vitro tests, animal predictive models, biomarkers for safety and efficacy and new clinical evaluation techniques.
In pre-clinical development it is important to have the necessary tools to predict human response from disease models. Product efficacy and safety methods are needed to build a brige between disease models and human experience. However, the combination of better animal models and tissue-specific biomarkers is important to predict the clinical outcome of drugs that are intended for use in any given disease. During the later stages of development in clinical trials there is a demand for innovative and efficient trial designs with improved clinical end-points.
A range of important statements have recently been put forward independently. These may be crucial in the development of a new and improved drug development toolkit. Although not exhaustive, this list of important events focuses on two major topics: the ‘Critical Path Initiative’ and the use of biochemical markers in pre-clinical and clinical science.
The FDA has articulated a Critical Path Initiative1 that is a vision statement to improve the efficiency of product development industry-wide and to identify and prioritise the most pressing development problems for new drugs and therapeutic agents. In particular, the FDA Critical Path Initiative attempts to draw attention to new scientific research tools that may revolutionise the regulatory and scientific process for new product approvals. The FDA stipulates that: “There is a demand to create new tools to get fundamentally better answers about how the safety and effectiveness of new products can be demonstrated, in faster time frames, with more certainty and at lower costs”.1
Recently, a novel classification of biomarkers was proposed, referred to as the BIPED classification: Burden of disease, Investigative, Prognostic, Efficacy of Intervention and Diagnostic. This was proposed by by the National Institutes of Health (NIH)-founded Osteoarthritis (OA) Biomarker Network and has further highlighted the need for understanding and use of biomarkers in pre-clinical and clinical science. Importantly, an emerging class of biochemical markers that are more pathology-specific have been identified. The use of novel techniques in which specific protein degradation fragments are investigated has proved valuable for slow-progression diseases such as osteoporosis (OP) and OA. Specific lessons may be learned from these approaches that can be implemented in other diseases. In this article we will describe two successes in the fields of bone and cartilage, and describe how some biochemical markers may be unique methods of assessment in translational science (from basic research to clinical trials) and therefore could be used as efficacy and safety makers.
We ask the question of whether we can implement what is learned from diseases such as OP and OA in an optimal drug development toolkit that may assist in the safety and efficacy evaluations undertaken between animal and clinical studies. OP is particularly suited to this process, as during the last decade the field has evolved from having an absence of assessment techniques and drugs to having a selection of validated surrogate markers of efficacy and prognosis and a range of potential treatment options. We speculate that this new product development toolkit and methods of application may be closer than they appear if the lessons learned from the success of assessing protease-generated fragments are further harvested and applied to other diseases.
Bone and Cartilage – The Challenge of Slow Progression
OP and degenerative joint diseases (DJDs) such as OA and rheumatoid arthritis (RA) remain major and growing epidemiological problems worldwide. Due to upward trends of longevity in the elderly populations of industrialised countries, the number of patients requiring medical attention and treatment is continuously increasing. 3 OP has an estimated prevalence of 40% in Caucasian women >80 years of age, whereas OA and RA affect 12 and 1% of the population, respectively, in the US. 4,5
OP and OA are characterised by slow progression. Slow-progression diseases pose a range of drug development challenges, in particular in phase II dose-finding studies. As disease pathogenesis is slow, measurable progression is timely and costly. Although the basic and clinical research of the past decade has been instrumental in clarifying some of the major mechanisms underlying the pathogenesis of these diseases, much remains to be achieved before we can provide curative treatments to patients.
