Alternate approaches to new drug discovery- Use of traditional knowledge
Thursday, February 23, 2006 08:00 IST
In an earlier Article (M.D.Nair, Pharma Biz October 27th 2005) it was argued that the currently practiced Drug discovery and development model is not the one that can be successfully used by Indian Companies entering the portals of new drug discovery research. Some aspects of the use of traditional medicines as sources of modern drugs were also discussed in 2002 (M.D.Nair, Pharmabiz 8th February 2002). The model being discussed here goes beyond these and delineates an approach to new drug discovery based on knowledge of traditional medicines for designing new drugs meeting the standards that modern treatments demand in terms of their efficacy and safety.
For reasons already explained, the models of new drug discovery currently employed have become the most cost-ineffective activity that the R&D based pharmaceutical industry is involved in and it is abundantly obvious that even the largest companies in the world find it unaffordable and difficult to pursue these approaches to drug discovery. The pipe line of new products are drying up and the costs of new drug research are steadily rising with figures quoted as high as $ 1.5 billion for every new drug which reaches the market. The time required for a drug from the time a candidate drug is identified till it reaches the market is still around 8 to 10 years. The approval times for New Drug Applications considering U.S.FDA as the standard, had come down somewhat during the late 90's since the then FDA Commissioner Mark McLellan had done much to accelerate the process for the benefit of patients. However with the recent withdrawal of some of the blockbusters such as Vioxx, due to alleged side effects, the regulatory process is likely to be further tightened in most of the countries. More data would be required from now on, both at the pre-clinical and clinical phases to reduce the risk of severe adverse reactions surfacing in the general population after a drug is marketed.
The largest component of costs in drug research and development is the clinical trials phases I to III, for which according to one study the average total time required for completion of all phases has gone up from 2.4 years in the 60's to 6.8 years in 90's. The costs of this phase in drug development are estimated to be almost 30% of the total costs incurred for drug discovery and development.
Evolution Of Pharmaceutical Research
Historically, the drug discovery process started with a look at natural products and their traditional use for some of the disease indications. The discovery of Aspirin, Digitalis , Quinine, Morphine, various Antibiotics, Steroids etc are excellent examples of the validity of this approach. In fact it is remarkable that these products, some of them even after a century of first use are still part of the therapeutic armamentarium unlike many of the later discoveries which result in drugs becoming obsolete within a few years post-launch.
As the discipline of chemistry developed and after the first real chemotherapeutic revolution heralded by the discovery of Salvarsan by Ehrlich, drug discovery moved to a system of random screening of molecules against available disease models for a variety of diseases such as those of the cardiovascular and central nervous system, diabetes, microbial and fungal infections, inflammatory disorders, respiratory diseases etc. Except for infectious diseases where the leads largely came from in-vitro data , the relevance of animal models as simulating and representing human disease conditions have been always debatable. In spite of such imponderables, the random screening approach, often times supported by serendipity and luck, have been responsible for practically all the drugs discovered between 50's and 70's. This indeed was a number game with the statistical odds of discovery placed in those days at not more than 1 in 10,000 molecules synthesized reaching the market. When the first molecules discovered through this route were per se not active enough or had unacceptable toxicity, they were used as leads for further optimization of their activity through techniques largely based on structure activity correlation studies. The sixty's and early seventies were fertile years for this approach. With better understanding of the biochemical pathways in healthy and disease conditions as well as in vectors responsible for disease transmission and in causative infective organisms, drug discovery moved to the enzyme level with a number of enzyme inhibitors being discovered and developed. Starting with the discovery of sulfonamides, various ACE inhibitors as cardiovascular drugs, HMG Coreductase inhibitors as lipid lowering agents and drugs for various neoplasms belong to this category. The nineties saw the advent of molecular and cellular biology as important disciplines capable of application to new drug research and with the deciphering of the human genome a whole new science of genomics and proteomics became fashionable areas for investments in drug research.
Failure Of The New Approaches To Reduce Costs Of Drug Research
It is a fact that these new areas provided the much needed models for discovering a candidate molecule with specific targeted activities and therefore better efficacy and indeed were improvements over the earlier random screening (hit or miss) approach. The source of molecules moved from synthesis of individual compounds to large combinatorial libraries from common synthons and to a lesser extent from natural products, primarily from extracts of plants. Even though genomic based research and target based assays on large baskets of combinatorial libraries have been extensively used during the last decade, the track record of this approach, however, has not been commensurate with the efforts and investments made by the leading pharmaceutical companies. In any event, even though these approaches are likely to lead to better and more specific drugs, there is no indication to date that the costs of their development or the time required to reach the market phase are any less than in the earlier approaches.
In spite of the tremendous hype and hope which modern Biotechnology drugs, the products of recombinant technology, have created, the market today for the over 2 dozen recombinant therapeutic proteins and over a hundred monoclonal antibody-based diagnostics and therapeutics are still only 5-8% of the global pharmaceutical turn-over. It is expected that by 2010 this will increase to 10-12% and by 2025 to 40% in value terms.
Thus, looking at the overall prevailing scenario, it is obvious that none of the above approaches are likely to solve the problems of new drug research at least in foreseeable future, namely declining pipelines, unaffordable costs, continuing unmet medical needs , emergence of drug resistance and perennial problems of sometimes very severe and unacceptable adverse drug reactions.
The nature of medical needs is also undergoing a radical shift in view of the increase in the ageing population in society and the shift to very high incidence of chronic ailments of a degenerative nature and the ageing process. Further, apart from the fact that the most impressive advances of modern medicines have been in the fields of infectious diseases, the overall morbidity and mortality from them have not declined. This has been not only due to the continuing emergence of resistance of infective organisms to the existing drugs , but also the incidence of new bacterial and viral infections during the last three decades for which existing prophylactics or therapeutics are not useful and new ones can never be developed in time to beat the menace.
Apart from the low productivity and declining returns from modern research for the discovery of much needed drugs, there has been increasing concern about the long term safety of many classes of drugs, particularly those used for treatment of life-long chronic disease conditions. For many drugs which are currently in use particularly for cancers, the adverse reactions they produce are truly unacceptable to the patients and very often the remedy is worse than the disease itself.
Taking all these into account it is clear that there is an urgent need to design and practice new approaches to drug discovery so that the momentum of progress in this field is not slowed down and drugs will continue to be discovered for the still unmet medical needs of the world. Since the current approaches have been shown to be unsatisfactory and far too expensive, new and alternate approaches need to be explored. And one of the ways of meeting that need is likely to be by resorting to an alternate approach, namely use of the knowledge on natural products primarily medicinal plants, to discover new drugs. It is interesting that the new emphasis on this approach makes the cycle nearly complete with drug discovery going back to where it all began in early part of the 20th Century when all the medicines discovered came from plant sources.
Alternate Approach : Development Of Drugs From Traditional Medicines
Thus , while many alternate approaches to new drugs discovery may be considered to face the current crisis , use of the knowledge and concepts embodied in Traditional Medicines is the one which deserves immediate attention and application. Use of Traditional Medicines to treat practically all ailments known to mankind have been in vogue for several millennia and surprisingly even after the advent of modern science and modern medicine during the last century, they continue to be the backbone of healthcare among a vast majority of the World's population. These medicines have evolved through the ingenuity of living beings to correlate cause and effect , when confronted with health problems and the remedies for the afflictions were more often than not found in nature and its bounty. In fact it is said that the instinct to look for natural remedies was not only present in humans, but also animals which resort to use of selected plants for alleviating the symptoms of certain diseases from which they suffer from time to time.
One of the earliest documentation of a traditional system of medicine is often ascribed to the ancient Vedas, the Rig, Sama, Yajur and Atharva and have been reportedly mentioned in the 10572 slokas (hymns) in Rigveda. Documentary evidence in the form of some of the ancient texts , such as Charaka Samhita, Sushruta Samhita, Ashtangahridaya date back to the late pre-Christ era. The principles of positive health according to Ayurveda are related not only to physical well-being but also to mental, social and spiritual welfare. It is interesting that WHO at the Health Summit at Alma Ata in 1977 defined health along the same terms as defined in Ayurvedic texts over three thousand years back.
Use Of The Knowledge On Ayurveda To Discover New Drugs?
The thesis propounded here is not to find ways and means of validating Ayurvedic drugs as effective remedies for treating diseases for which modern medicines are not effective and if effective are not safe. The proposal is indeed to use the information available from the long term use of these drugs not only as indicative of their safety but also of their efficacy, while looking for new drugs as per modern standards and requirements.
Traditional drugs by and large are based on plants as their main components, even though a small percentage of products use minerals including many metals, metalloids and in a few cases even products from animal tissues of various types, most notably as Bhasmas. Most preparations use in a single product a number of plants processed separately and then physically mixed in specified ratios to get the desired results.
The approach which can be gainfully employed for drug discovery from the traditional knowledge base, consists of the following discrete steps.
- Select preparations from the traditional system for evaluation based on the nature of the disease and their claimed utility.
- Narrow down the choice to products that contain the least number of plants, preferably single plants , but in any case not more than 5 plants.
- Study the plant extraction process and the formulation as is used in the traditional system.
- Evaluate the available data on their reported activity against special human disease conditions. If clinical evidence is ambiguous and not established, carry out additional clinical evaluation with well defined protocols which will provide unambiguous evidence of their clinical utility.
- If clinical evidence is convincing, do a detailed analysis of the plants and / or extracts and develop standardised preparations. Carry out finger printing of the product (the extract or the whole plant) and identify suitable chemical markers which can be used for checking the quality of the plant material used and of the preparations developed from them.
- Carry out reverse pharmacology to correlate clinical evidence with pharmacological evidence through use of in-vitro (where appropriate) and in-vivo models.
- Confirm the findings through the use of molecular targets, cell lines etc for further confirmation of efficacy and safety of the preparation.
- Develop and finalise the process of preparation of the selected bulk material as well as the formulation selected.
- Conduct limited but focused toxicity evaluation ( Acute, Sub-Acute & where indicated Chronic toxicity studies in two species , one rodent and one non-rodent).
- Convert the formulation to modern, more acceptable and palatable forms without changing the composition.
- Carry out additional open , comparative or even double blind studies (where warranted) to establish the product superiority over existing therapy.
Merits Of The New Approach
The approach is based on established use of the plants or their standardized extracts to develop new drugs validated by modern methods of drug discovery. Since the plant has been presumably in use in humans for a long time, it is permissible to carry out clinical studies and confirm clinical activity before extensive pre-clinical evaluation is carried out. Assuming that uniformity and homogeneity in the final product with no batch to batch variations can be assured, there is no reason to isolate the active molecule from the extract and evaluate it as a New Chemical Entity (NCE). In fact, if the active principle is isolated, the plant is being used only as a source of a new chemical and the new chemical entity has to be developed through the conventional process of drug development. If adequate data on long term use is available, that by itself is indication of the product's acceptable safety and only minimal toxicity studies would be required. Overall costs of drug development will be as low as one tenth or less of the costs of modern drug discovery when this approach is pursued.
Problems Of The New Approach
The primary negatives of this approach are related to the difficulties in the selection of the appropriate plants and correlating their reported use with modern concepts of diseases, symptoms and treatment modalities. Plant based medicines are rather restricted in their use to chronic conditions and not for acute disorders. The areas where they are most likely to be useful are as immunomodulators, adaptogens, antioxidants, anti-ageing products etc, most of which are primarily helpful as preventive rather than curative agents. The disease conditions they are likely to be effective are metabolic disorders such as Diabetes, Respiratory Diseases (Allergy), Musculoskeletal diseases (Arthritis), Skin Disorders, Gastro-intestinal Diseases , and certain selected CNS Disorders and some specific Cancers. Sustainable availability and accessibility of the plants are problems which need to be addressed through appropriate strategies to cultivate them, so that the natural sources are not depleted and the plant is nor endangered. The galenic forms which can be developed from such extracts or whole plants are limited to solid and a few liquid dosage forms; parenterals being strictly ruled out. Pharmacokinetic studies to determine the levels of active moiety in tissues and gathering of information on metabolism of the preparation in-vivo are difficult since there is little knowledge of the active constituent itself.
From the commercial point of view the greatest deterrent is the fact the patent system as of today is unsuitable to protect these products from being copied by others. If innovative formulations or specific plant combinations with unique and synergistic features can be developed, patenting strategies could be evolved.
Notwithstanding some of the negatives mentioned here, the overall balance is in favour of very seriously utilising this alternate approach to new drugs discovery to offset some of the major problems faced by the R&D based pharmaceutical Companies and the Healthcare system in general. Not only costs, but also the total time required for drug discovery and development will be considerably reduced through this approach. The chances are that in view of established use of traditional medicines on which the new drugs are based, it is more than likely that the outcome of these efforts would be safer and better drugs for indications for which they are suitable. For all this to happen, there has to be a paradigm shift in mindsets of not only the discovery groups, but also the regulatory agencies responsible for approving these drugs, to ensure that the new approach succeeds.
- (The references here to Ayurveda are equally applicable to any other system of medicine based mainly on medicinal plants.)
- (The author is a leading pharma consultant based in Chennai, India. He can be reached through: firstname.lastname@example.org)