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The market, sales and regulatory approval of new human medicines, during the past few years, indicates increasing number and share of new biologics and emergence of new multibillion dollar molecules. The global sale of monoclonal antibodies in 2006 were $20.6 billion. Remicade had annual sales gain of $1 billion during the past 3 years and five brands had similar increase in 2006. Rituxan with 2006 sales of $4.7 billion was the best selling monoclonal antibody and biological product and the 6th among the top selling medicinal brand. It may be the first biologic and monoclonal antibody to reach $10 billion annual sales in the near future. The strong demand from cancer and arthritis patients has surpassed almost all commercial market research reports and sales forecast. Seven monoclonal antibody brands in 2006 had sales exceeding $1 billion. Humanized or fully human monoclonal antibodies with low immunogenicity, enhanced antigen binding and reduced cellular toxicity provide better clinical efficacy. The higher technical and clinical success rate, overcoming of technical hurdles in large scale manufacturing, low cost of market entry and IND filing, use of fully human and humanized monoclonal antibodies has attracted funds and resources towards R&D. Review of industry research pipeline and sales data during the past 3 years indicate a real paradigm shift in industrial R&D from pharmaceutical to biologics and monoclonal antibodies. The antibody bandwagon has been joined by 200 companies with hundreds of new projects and targets and has attracted billions of dollars in R&D investment, acquisitions and licensing deals leading to the current Monoclonal Antibody Gold Rush.

The optimum site and investigator selection process remains a closely guarded confidential matter and an essential part of development expertise of big pharmaceutical companies and CROs. The right and careful selection and evaluation of investigators and site is critical for successful completion of the trial within budget, timelines and generation of high quality data. The criteria for site and investigator selection in India for Good Clinical Practices (GCP) clinical trials are described for a start up company/CRO and can be applied to any country in Asia and Africa. Foreign sponsors doing clinical studies in India should pay close attention to site and investigator selection. The first GCP study in India was done only in 1995. At the dawn of 21st century, India is at the take off stage in clinical trials now. GCP studies can be done in India, as the quality of data is good, costs are lower and patient enrolment is much faster resulting in early completion of studies.

The respiratory syncytial virus (RSV) is a global health problem affecting infants and the elderly and claiming more lives than AIDS in many parts of the world. Only two antibody drugs are approved for its prevention, and ribavarin, a relatively nonspecific antiviral, is used for treatment. In the mid-1990s, a number of pharmaceutical and biotech companies initiated research programs against RSV. Together, the academic and the industrial R&D covered the whole spectrum of antibodies, vaccines, synthetic small molecule antiviral and antisense technology, and at one point, accounted for at least 25 active R&D programs. However, coincident to the marketing of the monoclonal antibody palivizumab (Synagis) in 1998, a sharp decline in such projects ensued. Many companies recently cancelled RSV projects during a prioritisation of their R&D portfolios although the continuing medical need, large market size and sales projections clearly indicate that a safe and effective RSV drug or vaccine is likely to attain blockbuster status. Today RSV receives an insignificant fraction of the R&D budget compared with AIDS, for example. This article reviews the present status of the anti-RSV regimen, covers drugs in the market and in development, and attempts to link basic research to industrial drug development, animal models of RSV, clinical trials, current clinical management, and present and future market projections. It is hoped that the unmet medical need of the victims of RSV will encourage continued involvement of the pharmaceutical and biotechnology industry in developing safe and effective prevention and treatments for RSV., (Copyright 2004 John Wiley & Sons, Ltd.)

Current Indian drug regulations do not allow for toxicology testing and clinical trials in India with compounds or molecules discovered abroad, except for treatments of tropical, cancer and cardiovascular diseases as part of global studies. The number of GCP Phase II/III trials by foreign sponsors has increased dramatically since 1995, attesting to the potential of India for lower cost trials and reduction in drug development costs and time, due to rapid patient recruitment. However, there have been problems with regard to intellectual property protection and adherence to informed consent guidelines. Starting in 2005, a series of regulatory reforms and patent protection will be instituted that are designed to address many of these concerns; the nature of these reforms are presented and discussed. However, sponsors need to pay close attention to informed consent and other ethical issues in Indian trials, which enroll mainly poor and uneducated patients.

This is the story of my quest to jump-start new drug development activities in India at the custom synthesis, animal models, bulk drug production, toxicology and preclinical stages. A snapshot of research and evaluation during the 1995-1999 period is given and compared with the much-improved present situation. Practical experience of managing contract research and avoiding pitfalls are described. Drug discovery and biological development are still in early stages, but are growing. New drugs are being developed for serious and life-threatening diseases, needs are being met and safety and efficacy are improving. However, a project is often started in India solely for licensing-out purposes and develops its own momentum due to weak regulatory oversight and are rarely terminated due to lack of safety or efficacy. Drug discovery is targeted at diseases of the Western world, and not towards the endemic diseases prevalent in India such as malaria, tuberculosis, leishmaniasis, filariasis, leprosy, malnutrition, vitamin deficiencies, blindness, conjunctivitis, and so on. A few licensing deals for new chemical entities from India have been signed; however, some were discontinued and others are ongoing.

The immunosuppressive effect of the novel 4-quinoline carboxylic acid derivative Brequinar sodium on the chronic relapsing experimental allergic encephalomyelitis CREAE model in the Biozzi AB/H mouse was investigated. Although Brequinar sodium actively inhibited peripheral immune responses, it showed a limited potential to control an ongoing disease of the central nervous system (CNS). Doses of 25 mg/kg inhibited in vivo induced proliferative response and prevented EAE when treated from day 9 post-inoculation (p.i.). However, when administered from day 12 p.i. or during the post-acute remission phase-limited effects on the course of disease were observed. By comparison, treatment with a single high dose of cyclophosphamide (200 mg/kg) at these time points was significantly effective in controlling disease. As a possible explanation of the observed results it is suggested that for a compound to be effective in treating an ongoing immune response in the CNS, it must be capable of crossing the blood-brain barrier and act on the disease-inducing cells activated within the CNS. This hypothesis is supported by the finding that intracerebral injections of Brequinar sodium on day 12 p.i. significantly inhibited disease progression. This suggests that strategies aimed at controlling immune-mediated disease of the CNS require therapeutic doses of the compounds to be delivered into the CNS.

The administration of dieldrin (30 mg/kg body weight) caused an increase in the liver weight of rats. The metabolism of aflatoxins B1 and G1 by the microsomes obtained from the liver of dieldrin-treated animals was enhanced significantly as compared to the controls showing that dieldrin increased the activity of mixed function hydroxylases. Dieldrin caused an increase in the activity of liver microsomal NADPH oxidase and a decrease in the lipid peroxidation. Dieldrin brought about an increase in the phosphatidylcholine content of rat liver.

The adenine nucleotide pools were studied in toxigenic (NRRL 3240) and non-toxigenic (NRRL 3537) strains of Aspergillus flavus group in relation to aflatoxin biosynthesis. The levels of ADP and AMP were comparatively low in the non-toxigenic strain throughout the growth period. In the toxigenic strain the levels of ADP and AMP increased significantly during the stationary phase. The ATP content of the toxigencic strain had higher ATP levels during the stationary phase compared to the toxigenic strain. The inorganic phosphate levels of the non-aflatoxigenic strain were higher when compared with the aflatoxigenic strain. High levels of inorganic phosphate have been reported to be inhibitory for secondary biosynthesis including aflatoxins. The energy charge values of the non-toxigenic strain, compared to the toxigenic strain, were lower during exponential phase but higher during stationary phase. The observed changes have been correlated with aflatoxin biosynthesis.

The presence of a functional TCA cycle and its intermediates has been shown in Aspergillus parasiticus and Aspergillus flavus. The role of the TCA cycle in aflatoxin biosynthesis has been studied. In A. parasiticus the TCA cycle was activated on the second day of growth (exponential growth phase) resulting in the onset of aflatoxin biosynthesis. Pyruvate accumulation to toxic levels in A. parasiticus is suggested to shift the growth phase from exponential to stationary with the onset of aflatoxin biosynthesis. In A. flavus, a non-aflatoxigenic strain, no pyruvate accumulation was observed. Moreover, the onset of aflatoxin production in A. parasiticus was followed by a decline in the levels of TCA cycle intermediates indicating their possible utilization in secondary metabolite synthesis. Accumulation of TCA cycle intermediates in A. flavus is suggested to be due to non-diversion to aflatoxin biosynthesis.

A comparative biochemical study of an aflatoxigenic strain Aspergillus parasiticus NRRL 3240 and a nonaflatoxigenic strain A. flavus NRRL 3237 was carried out in order to have a better idea of regulation of aflatoxin biosynthesis. The results obtained revealed continuous primary metabolic activity (protein synthesis) in the nonaflatoxigenic strain while the aflatoxigenic stain showed inhibition of protein and nucleic acid synthesis. The aflatoxigenic strain showed higher levels of oxygen uptake, RNA, NAD, FMN and activities of glycolytic enzymes. Furthermore, it had lower of lipids and reduced activity of glucose-6-phosphate dehydrogenase, which is a source for NADPH. The differences observed have been discussed in relation to aflatoxin biosynthesis and its regulation.