EMBL/EMBO Joint Conference 2002
Peter N. Goodfellow, GlaxoSmithKline Pharmaceuticals R&D, Essex, UK
Peter Goodfellow has worked for many years as a research scientist specialising in human genetics. His first independent position was at the Imperial Cancer Research Fund in London, where he worked for 13 years studying human gene mapping and the genetics of sex determination. In 1992, he was elected to the position of Balfour Professor of Genetics at Cambridge University and he is currently at the pharmaceutical company GlaxoSmithKline Pharmaceuticals R&D. Dr. Goodfellow has consulted widely in the biotechnology industry and was a founder of Hexagen, a genome research company.
The barriers to the production of new antibiotics
The history of drug discovery, in the past two decades, suggests that the invention and development of new antibiotics is difficult. The invention, development and marketing of antibiotics that specifically target antibioticresistant pathogens is going to be even more difficult.
The barriers to invention of new antibiotics include:
- The paucity of potential targets for intervention. For many years, industry focused on known targets, such as cell-wall synthesis, as the starting point for drug discovery. The recent sequencing of the genomes of pathological bacteria has widened the potential targets available but we are yet to see benefits from these sequence-based approaches.
- The need to kill a wide variety of organisms means that any new antibiotic must lack specificity with respect to bacterial targets (i.e. react with the same target from many different species) but must retain specificity against mammals. Although specific, narrow spectrum agents may be more readily identified, the empiric management of patients with infections runs counter to the need for narrow spectrum.
- The very high serum concentrations required for killing bacterial pathogens poses special toxicological problems.
- Bacteria have a variety of mechanisms for avoiding and escaping from toxic molecules found in their environment. New resistance mechanisms can spread between different bacterial genera and species.
The barriers to clinical development of new antibiotics include:
- The size of trials needed and the problems of identifying and recruiting patients suffering from infections with resistant pathogens.
- The need for clinical outcomes as well as microbiological outcomes for trials against resistance pathogens.
- The exclusion criteria for trials e.g. recent use of antibiotics.
- The resultant overall cost. Francis Tally (Cubist Pharmaceuticals) has estimated that clinical studies for resistant pathogens carry a per patient cost of $30,182, with total development cost in excess of $75.5M.
The barriers to sales:
- The market dynamics work against agents targeting resistant pathogens and generally do not support the investment required to invent and develop such an antibiotic.
- Reserving antibiotics for specific groups of patients with specific infections with drug resistant organisms would further reduce the potential return on investment.
It is likely that society will have to adapt the regulatory and economic rules to facilitate the development of antibiotics against resistant bacteria as a matter of public health and security.