The rate of discovery and approval of new medicines is declining despite substantially increased investment. Safety and efficacy failures are caused by:
• Highly novel targets, for which there is limited knowledge of the biology and role in human disease
• Diseases that are poorly understood in terms of pathophysiologic mechanisms, such as chronic obstructive pulmonary disease, osteoarthritis, and Alzheimer's disease
• Limitations in the animal models of human disease
• Limited biomarkers to optimize treatment
The pharmaceutical industry is preeminent in moving compounds from discovery through the development phases. Its scientific and technological expertise is phenomenal - from molecular modeling to protein engineering to metabolic pathways for compounds/biologics - all are industry proficiencies.
With such obvious strength and leadership from industry, why are we in the current crisis? Simply put, despite the huge investment and technological successes, organizational and process weaknesses prevent the effective translation of new therapeutics into medical practice. These weaknesses include: lack of validation of targets with respect to human disease; failure to establish mechanisms of action for new compounds; inadequate experimental approaches for patients' selection to optimize the detection of a therapeutic response; and delays in identifying and utilizing biomarkers to guide efficacy and safety.
The clinical research needed to tease out the activity of innovative compounds is fundamentally different than that needed for regulatory drug approval in terms of goals, approaches, and processes. Indeed, the rigidly controlled bureaucracies for clinical drug development that evolved within the pharmaceutical industry to support regulatory-driven activities actually hinder these types of exploratory approaches - even the FDA believes that pharmaceutical sponsors have not taken full advantage of the flexibility in its regulatory requirements. This is where translational medicine comes in.
Translational medicine relies more on biological readouts and biomarkers than on established measures of clinical outcome. It involves small, short studies, with continuous monitoring of results and adjustment of design to most efficiently reach a conclusion.
The scientific and technical knowledge base and level of clinical experience required is not typically found within industry. Their clinicians are highly skilled in designing clinical protocols, initiating studies, monitoring adverse events, and analyzing data for registration studies. However, they often lack accumulated years of clinical practice and the scientific expertise to conduct highly innovative exploratory research.
Academic medical research centers offer a favorable environment. They unite basic science, advanced technology, and cutting-edge medicine, and have an understanding of disease biology, diagnosis and treatment. There has been an explosive growth in funding of centers for translational medicine, and they are already helping to translate novel discoveries into clinical practice. Wyeth has invested in a partnership with medical schools and the National Health Service in Scotland for the development and implementation of novel biomarkers.
The collaboration of academia and industry, with a focus on early exploratory studies, is our best hope for fast, efficient, innovative studies for making early decisions about a drug candidate. Operationally, this can be achieved in different ways, but separating this function from the existing operation of later-stage clinical trials is essential.
For industry, collaboration with academia provides access to the best minds to solve the problem, and greater objectivity. At the early stage of drug development a negative result is just as important as a positive one, and an independent view will help avoid costly errors in decision-making. For the academic community, a true scientific collaboration based on mutual respect and complementary strengths is a welcome change from the typical contract-based model for clinical trials. It's an opportunity to play an important role in identifying novel medicines - the prize that drives most scientists within the industry.
Lynn Rutkowski and Giora Feuerstein are at the University of Dundee, Scotland, and Wyeth Research, Collegeville, PA.