The R&D based pharmaceutical companies involved in the discovery and development of new drugs have been on the look out for making R&D more productive to enable the marketing of drugs which are more affordable to the vast majority of world's populations. While many new approaches ranging from screening large number of molecules against disease models (both in-vitro and in-vivo), to use of modern techniques of developing combinatorial libraries backed by high throughput screening and use of genomics and proteomics, none of these have so far been able to meet the objectives of reducing costs and time required for developing new drugs. This is at least partly due to the fact that, while some of these can indeed lead to better and more specific candidate therapeutic agents, the daunting, time consuming and expensive task of translation research to convert them into marketable drugs still remains problematic. To reduce these costs and reduce the time period required, a more efficient approach of screening libraries of approved (marketed) and off-patent generic drugs can yield molecules which can bypass much of preclinical work and move into the clinical phase. This approach has been given many names, 'repurposing, repositioning reprofiling old drugs', 'new wine in an old bottle', 'finding new tricks for old drugs' etc. It is useful to look at this approach in greater detail so that some of the major pitfalls of the current drug discovery and development modality can be overcome.
Pitfalls of current models of drug discovery research
The major pitfalls of the current models of drug discovery research are: The very high and unaffordable costs of drug discovery and development; Long gestation for a new drug to reach the market; Most of the new drugs belonging to the "me-too" class have no improved pharmacological or therapeutic profile; Emphasis on meeting market needs rather than medical needs; and Neglect of diseases of the developing countries. An example is the lack of efforts and investments for developing drugs for neglected diseases, which affect one billion people or one sixth of the world population. These diseases receive only $ 1 out of every $ 100,000 spent on biomedical research.
Even though many new modalities are being followed to make drug discovery research more cost-effective, all the new approaches followed by leading R&D based pharma companies as practiced today still pose major challenges of high costs, low specificity with respect to their therapeutic utility, unacceptable adverse effects on the hosts and long gestation period required for completing the total activity from concept to market. The impact of the new science of genetic engineering, the deciphering of the human genome and genome mapping of over 80 other organisms, isolation of disease-causing genes and the proteins they express, the development of molecular targets as screening models for drug discovery are the new approaches which have both supporters as well as detractors. There is no empirical evidence that new approaches have or will off-set the pitfalls faced by the industry in the area of new drug discovery.
What then are possible alternatives?
Three major strategies have been adopted by big pharma in recent times to reduce overall costs and make drug discovery and development more affordable. The first one is the strategy of acquisitions and mergers to make R&D investments more affordable for companies, second strategy is to outsource parts of drug discovery and development activities from third parties at considerably lower costs; third one which has been somewhat successful particularly in the biotechnology area is to license in drug candidates from small R&D based start-up companies, thereby reducing the costs of early and high risk research. The fourth one is related to public private partnerships in selected areas by using Open Source Drug Discovery (OSDD) programmes and patent pooling. Empirical studies show that none of them singly or together have indeed worked and delivered the desired results.
There are yet other approaches which merit consideration. Historically during the drug development process, several useful drug candidates are never developed for purely commercial or patentability reasons. There is a strong case for relooking at those molecules and see whether useful drugs can be salvaged from those. Similarly, searching and identifying new indications for existing drugs would be a very valuable exercise. After all, 20 per cent of drugs currently marketed are for conditions other than those for which they were discovered, developed and registered in the first place.
Advantages of working on new indications for existing molecules
Both drugs in the pipeline of development as well as those which are already marketed would have completed an enormous amount of preclinical and even clinical investigations. So, too the manufacturing process for the active entity (bulk drug) and the formulation would already have been worked out. Over 200 drugs have failed in the market place after they have been launched during the last two decades. They have been withdrawn, banned or replaced by better drugs largely due to issues related to efficacy and safety when used by large populations. In addition, off-label use of drugs is often resorted to by physicians even in the absence of regulatory approvals for other indications largely based on their observations during clinical practice. Regulatory agencies including the US FDA has taken a lenient stand on the issue of off-label use of drugs even though by law a drug cannot be prescribed for a condition for which it has not been approved. Even though there is wide variation in overall costs of discovering and developing a new drug and allocation of resources for the different activities involved, as a rough estimate around 25 per cent of costs of new drug discovery and development are for preclinical tests including toxicology and pharmacokinetic studies while the cost of clinical studies is also around 25 per cent. Process development for manufacture of bulk drug and formulations constitute around 10% and the rest of the total costs is spent on the first and last phases namely the discovery and marketing phases. Developing a new indication for an existing drug can considerably reduce the costs and therefore, it stands to reason that for expediting the drug discovery process, reducing costs and making drugs available to the needy earlier, discovering new indications for existing drugs is a valuable and rewarding option. In spite of such major merits of this approach, efforts by R&D institutions and pharmaceutical companies have been minimal during the last few decades. One of the major reasons for companies' lack of interest in this approach is related to patent laws which generally do not provide strong protection for 'new use' patents. This has a major impact on the economic side of investments in drug research.
(The author is a senior research scientist and industry expert based in Chennai)