Download (direct link):
Walsh, C. (2002). Combinatorial biosynthesis of antibiotics, challenges and opportunities. Chembiochem. 3(2-3), 125-134.
Chapter 2 The drug development process
In this chapter, the life history of a successful drug will be outlined (summarized in Figure 2.1). A number of different strategies are adopted by the pharmaceutical industry in their efforts to identify new drug products. These approaches range from random screening of a wide range of biological materials to knowledge-based drug identification. Once a potential new drug has been identified, it is then subjected to a range of tests (both in vitro and in animals) in order to characterize it in terms of its likely safety and effectiveness in treating its target disease.
After completing such pre-clinical trials, the developing company apply to the appropriate government-appointed agency (e.g. the FDA in the USA) for approval to commence clinical trials (i.e. to test the drug in humans). Clinical trials are required to prove that the drug is safe and effective when administered to human patients, and these trials may take 5 years or more to complete. Once the drug has been characterized, and perhaps early clinical work is under way, the drug is normally patented by the developing company, in order to ensure that it receives maximal commercial benefit from the discovery.
Upon completion of clinical trials, the developing company collates all the pre-clinical and clinical data they have generated, as well as additional pertinent information, e.g. details of the exact production process used to make the drug. They submit this information as a dossier (a multi-volume work) to the regulatory authorities. Regulatory scientific officers then assess the information provided and decide (largely on criteria of drug safety and efficacy) whether the drug should be approved for general medical use.
If marketing approval is granted, the company can sell the product from then on. As the drug has been patented, they will have no competition for a number of years at least. However, in order to sell the product, a manufacturing facility is required, and the company will also have to gain manufacturing approval from the regulatory authorities. In order to gain a manufacturing licence, a regulatory inspector will review the proposed manufacturing facility. The regulatory authority will only grant the company a manufacturing licence if they are satisfied that every aspect of the manufacturing process is conducive to consistently producing a safe and effective product.
Regulatory involvement does not end even at this point. Post-marketing surveillance is generally undertaken, with the company being obliged to report any subsequent drug-induced side effects/adverse reactions. The regulatory authority will also inspect the manufacturing facility from time to time in order to ensure that satisfactory manufacturing standards are maintained.
Biopharmaceuticals: Biochemistry and Biotechnology, Second Edition by Gary Walsh John Wiley & Sons Ltd: ISBN 0 470 84326 8 (ppc), ISBN 0 470 84327 6 (pbk)
Drug discovery ²
^_____ I ______________________
Regulatory approval sought to commence trials in humans
Clinical trials (phases I, II & III)
Submission of marketing/manufacturing authorization applications to regulatory authorities
Regulatory authorities review information and grant (or refuse) marketing/manufacturing licences
Product goes on sale
Figure 2.1. An overview of the life history of a successful drug. Patenting of the product is usually also undertaken, often during the initial stages of clinical trial work
The discovery of virtually all the biopharmaceuticals discussed in this text was a knowledge-based one. Continuing advances in the molecular sciences have deepened our understanding of the molecular mechanisms which underline health and disease. An understanding at the molecular level of how the body functions in health, and the deviations that characterize the development of a disease, often renders obvious potential strategies likely to cure/control that disease. Simple examples illustrating this include the use of insulin to treat diabetes, or the use of growth hormone to treat certain forms of dwarfism (Chapter 8). The underlining causes of these types of disease are relatively straightforward, in that they are essentially promoted by the deficiency/absence of a single regulatory molecule. Other diseases, however, may be multifactorial and, hence, more complex. Examples here include cancer and inflammation. Nevertheless, cytokines such as