The high and unaffordable costs of drug research with estimates of over 1 billion dollars for every new drug discovered and developed, the very low success rates, the high degree of obsolescence due to undesirable adverse drug reactions, the decline in the pipeline of new drugs and patent expiries leading to generic competition have all significantly contributed to the problems of this lifeline industry. The strategy adopted by the large R&D based Corporations to get bigger and bigger through mergers and acquisitions to improve cost-effectiveness and productivity of R&D has so far not worked effectively. Evidence to date do not establish that these strategies have worked in reducing costs and improving the output in any meaningful manner. Estimates show that the two largest components in costs are related to the early discovery phase and the late clinical trials phases. The latter as an average could constitute 25-28% of total costs and together with regulatory clearances a time frame of 6 to 10 years to complete. Reducing these costs and time frames and discovering and developing more precise drugs with better efficacy and fewer side effects are the primary goals of pharma companies. The high impact of costs of drugs on healthcare itself has compelled pharmaceutical companies to look for cheaper and effective alternate approaches to discover and develop new drugs. Networking of programmes between various partners, pooling skills and resources, utilising and sharing proprietary and public domain information sources are all part of this new paradigm.
In 2008, India initiated an open source drug discovery (OSDD) programme under the aegis of the director general of the Council of Scientific and Industrial Research (CSIR) Dr. Samir Bramachari. It would be interesting to evaluate the potential for this programme to develop drugs particularly for diseases of the developing world at affordable costs and within reasonable time frames.
Open source drug discovery (OSDD)
OSDD is basically a system of pooling global information sources, expertise, facilities and management systems for drug discovery where individuals, groups and organisations pitch in as a combined effort, to develop new drugs by offering their resources and networking to produce an integrated model with multiple skills through an open format. Free access to all required information and their use in an integrated manner by designated groups will accelerate the process of drug discovery. Such an approach has been successfully deployed in the case of the Linux operating system in the IT area and the Human Genome project in the biological space. So too in the automotive industry. The primary and seminal objective is to speed up the drug discovery process. Under Merck's programme called the 'External Basic Research', company scientists can collaborate with outside agencies, for example, to utilize available targets for drug discovery or identify new ones. Further, one of Merck's former scientists Dr. Stephen Friend started a no-profit open access information platform called 'SageBionetworks'. The rationale behind such a strategy is to ensure that total available information from any source can be gainfully accessed and used by all those who have the will, skills and material resources in the biosciences field.
Of the over 10,000 targets implicated in health and disease, only around 500 have been so far explored. Of these, 45% were related to receptor sites and 28% to enzymes. And almost all of them are in areas of diseases of the west. It is however to be realized that distinction in disease patterns between the developed and developing world is fast disappearing with the new world diseases growing at a faster rate in the latter. In fact, the incidence of life style diseases such as cardiovascular diseases, diabetes, cancer, and mental disorders have become major scourges even in the poorest countries. While in sheer numbers these constitute only around 10% of all disease cases, 90% of R&D global investments are made on them emphasising the skewed priorities of the market driven pharmaceutical companies. Commercial considerations preclude R&D efforts for neglected diseases. That is where efforts at the development of OSDD comes in. Realising the lacunae in the current drug discovery model, MIT in USA initiated a pharmaceutical innovation programme, termed New Drug Discovery Paradigm, wherein the team has gathered a consortium of highly skilled and inter parties from other companies as well as Federal agencies, Universities etc. Apart from exchanging and sharing of all available information, they also provide data on candidates which failed during pre-clinical testing. The recent requirement of registering and providing information on clinical trials on the net has more or less made clinical test data available in the public domain. However as per the present norms, proprietary pre-clinical or clinical information cannot be used for commercial development (ANDA submission) by a third party for a limited period since that is protected through the data exclusivity/data protection systems approved by most countries (not India as of now). In any case the new developments augur towards a system of OSDD which wishfully will make competing and collaborating at the same time possible.
Public private partnerships (PPPs)
Such an open source approach also brings in possibilities of effective public-private partnerships (PPPs). The best examples of successful PPPs providing the base for new drug discovery and development is collaboration of NIH, Bethesda with many global healthcare organisations both in the public and private sectors. Much of the basic research on diseases and drugs by NIH, the largest public funded health research organisation in the world with annual budgets exceeding $ 25 billion have been used very successfully by private institutes in the drug discovery area, even though NIH itself is not in the drug discovery space. One of the best examples of PPP in recent past has been the discovery and development of the anti-ovarian properties of Paclitaxel (Taxol). But for this partnership between NIH and Bristol Myers Squibb, Taxol would never have become a drug of choice for saving or improving the lives of hundreds of thousands of people. The main advantages of PPP in drug research are: Abundance of basic knowledge accumulated over years of dedicated work by the public institutions; Providing a platform for lowering overall costs; Availability of multidisciplinary skills; Focused approach; and Access to adequate resources.
On the negative side, apart from ambiguity on common interests, lack of involvement and leadership, issues of transparency in exchange of information, bureaucratic hurdles, establishment of accountability and hierarchical organizational structure, lack of adequate manpower and resources, sharing of IPR and sharing of commercial returns are some of the important impediments for successful outcomes from OSDD programmes. It is estimated that total funds available globally for the public private partnership model for drug discovery and development are to the tune of $ 5 billion of which $ 1.5 billion has already been disbursed. Real efforts have been ongoing in the area of Malaria and Tuberculosis, wherein global alliances have been actively involved in the development of vaccines and therapeutics. The financial resources are today relatively meager for such activities when one considers that global expenditure on new drug discovery and development are of the order of $ 65 billion. Pfizer alone annually spends over $ 7 billion for this activity.
Given such an overall scenario, OSDD, whether they are public-private, public-public and private-private partnerships for new drug discovery and development, is a sustainable model over time and the benefits would considerably alter some of the lacunae currently facing the healthcare scene namely the high costs of research and the neglect of research on drugs which have low market potential. Who indeed will be the champions for such an approach? What will be the main motivating factors which will enable entry into this area? With limited resources, how do we establish new priorities for such efforts? How do we share the rewards if any, arising out of these efforts? What about the rights over the intellectual property generated through joint efforts?
OSDD in India
The concept of OSDD, even though known and tried out before has been mooted in India for new drug discovery by the new director general of CSIR, Dr. Samir Brahmachari in 2008. The success of the Human Genome project where a consortium approach was followed was perhaps one of the reasons for initiating such a project. The efforts in the HUGO project had many dimensions dovetailed as per the specific needs of the project and the ultimate results were made available in the public domain for all to benefit.
India unfortunately opted out of that major coordinated effort. It is therefore gratifying that India as a country is taking some leadership in trying out this modality for drug discovery. Whether such a model is applicable to new drug discovery and development is a moot point, since the data on the human genome was always conceived as and is indeed a valuable service tool rather than a commercial product. On the other hand a new drug until it reaches the patient has to undergo several steps including development of screening models in-vitro and/or in-vivo, preclinical testing including toxicology tests and pharmacokinetic studies, clinical evaluation in three phases I to III and continued post-marketing surveillance. The objective of the CSIR is to develop a strong OSDD system which will enable supply of more affordable drugs for neglected diseases. The idea is to network and attract the best talents and infrastructure to pool all their resources in a common and transparent developmental programme with the focused objective of meeting the demand of one major disease areas at a time. The programme will provide an online platform for exchange of ideas, data, and computational resources. Already under the aegis of some UN agencies three such organizations are functioning in the area of Malaria, TB, and HIV/AIDS, three very visible targets for global attention.
The Indian efforts are planned to concentrate on TB as a starting point and with good reasons. The genome of the organism, Mycobacterium tuberculosis as well as that of the human being are known and there is a fair volume of knowledge available in the public domain as well as with leading research groups in the world. Combining that knowledge base and using it for drug discovery would be the scope of the project. A reasonable funding of Rs 150 crore ($33 million) has been allocated for the project which hopefully will cover a few more disease areas in the coming years. Already large R&D based companies such as GlaxoSmithKline, Bristol Myers Squibb, Pfizer and others have pledged their support.
There are, however issues to be handled. Since most participants enter the project voluntarily, the question comes up 'how does one entice them to do so'? What are the incentives which will make it attractive for them to be part of the project? Social benefits objective is just one. Are the available and accessible data on the disease and the concerned vector meaningful and adequate? While in recent times, tools for the analysis and interpretation of biological data particularly in the genomic area, are better developed due to the emergence of bioinformatics, the same is not true of chemical data. It is only with the advent of ' Pub Chem' that a certain degree of interrelationships between chemical structure and biological activity and even clinical utility is available.
Yet another very important issue is that OSDD is largely limited to the discovery phase. The arduous task of development of a candidate drug to the marketing stage constituting 75% of total efforts largely fall under the realm of those skilled in that process, primarily the pharmaceutical industry. Whether they would be willing to take up that component of the work in the absence of proper reward systems generally offered through the patent system is a moot point. Certainly very few OSDD teams will be skilled and equipped to carry out that activity and take the candidate drug to the market.
To succeed OSDD programme, you not only need a champion team and a knowledgeable leader but also collaboration arrangements to take a lead preparation through the entire cascade of the drug development process including regulatory submissions for every stage (IND, NDA etc), product profiling, positioning and management and marketing skills and expertise. The question is whether these important components can be carried out outside the ambit of industry activities or in case, industry involvement is imperative, how it could be attracted to take up even on professional basis this activity with assured returns for their investments in time and resources. At the moment it appears that companies with their own priorities to develop their own products will have inadequate capacity to provide such third party service. Of course ultimately the success of the OSDD programme will depend upon all these factors. The outcome of current attempts in the area of Malaria, TB, HIV/AIDS etc will determine the future of this approach.
Considering India's leadership as a generic drugs producer, emerging core strengths in R&D, acute medical needs and availability of skilled human resources and infrastructure, the country through any of the organised agencies such as the CSIR with around a dozen institutions working in the biology space could well take leadership in the development and implementation of OSDD programmes for diseases primarily affecting the developing world.
(The author is a senior research scientist and industry expert based in Chennai)