Shivaani Kummar (left) and Sanjay V. Malhotra. 
Seventy per cent of cancer deaths occur in low and middle-income countries.
These statistics are especially of concern for India with its large population, improving life expectancy and the continued use of tobacco. At present there are 8 lakh-9 lakh new cases and 4 lakh deaths per year from cancer in India, and these numbers are expected to keep rising.
Anticancer medicine market
The growing cancer patient population has created the need for anticancer medications. There's a need to make currently available medicines affordable as also increase research in potential novel therapies. This growing market base has raised the interest in further investment in the pharmaceutical sector.
Currently, the pharmaceutical industry presence in the Indian market is dominated by generics. However, recognising the need for innovation and drug development, government agencies such as the Department of Science and Technology (DST) and the pharmaceutical sector on R&D have chipped in.
For instance, in the year 2005-2006, 407 patent applications were filed and 276 were approved in India2 . R&D funding as a per cent of sales has increased from 2% to 10% in recent years. DST's Drug and Pharma Research Programme is mandated to facilitate drug discovery in academia and the pharmaceutical sector. It is currently funding over 110 research projects within major academic and industrial R&D centres3.
CSIR's New Millennium Indian Technology Leadership Initiative (NMITLI) programme is funding 11 R&D projects specifically relating to drug development. The first investigational new drug application (IND) in India for an herbal-based formulation was filed under a collaborative program funded by NMITLI between industry and the National Institute for Pharmaceutical Education & Research.
The drug development chain
Drug development is a complex, long process that requires extensive resources and has a high failure rate. In an analysis of the data from the 10 biggest pharmaceutical companies in the world for the decade of 1990-2000, Kola and Landis reported an overall success rate, as defined by first-in-human to registration, of 11% for all disciplines of medicine.
The reported success rate was even lower for oncology at just 5%. More recent estimates for the proportion of oncologic agents entering clinical trials that receive US Food and Drug Administration approval range from 5% to approximately 25% 4 and less than 60% of oncology drugs evaluated in Phase III trials are approved 5 . This is at an estimated cost of US $800 million to $1 billion from discovery through approval for each drug approved, which includes the cost of all the agents that failed at various stages of development (US Food and Drug Administration 2004).
In order to develop an infrastructure that would promote drug discovery and development, careful attention must be paid to the various stages, the unique resources required for the successful completion of each stage and the team approach required at each step. The preclinical evaluation process of a new molecular entity (NME), once identified as a potential compound of interest, requires extensive in vitro and in vivo evaluation focusing on efficacy, toxicology, pharmacology. This takes 5 to 7 years and has a high attrition rate. Once the NME meets the benchmarks set for its pre-clinical development, it needs to eventually undergo clinical evaluation.
Potential drugs need to be carefully evaluated in human trials conducted in specialised early drug development centres staffed by highly trained professionals. This would entail developing the legislature that allows such early phase trials, regulatory infrastructure to supervise, bioethics training and oversight, health professionals specifically trained in the conduct of early phase trials and institutions with the facilities to conduct such trials including trained personnel to serve on the Institutional Review Boards, Pharmacy management and documentation, and patient support and advocacy.
Data generated from these trials then forms the basis for the decision to proceed with phase II and III trials if certain pre-set milestones are achieved. At present, clinical Phase II and III trials can be conducted in India at the same time as abroad. Previously, companies had to conduct a higher phase trial abroad before a previous phase trial could be conducted in India. This has helped push clinical research forward in India. However, with growing global R&D activity, consideration needs to be given to safely allow human trials in India.
Besides physical resources, the biggest impact to allow this to happen is training of the health care professionals. Such studies should only be conducted by professionals who have been trained in centers that conduct multiple human trials, have experience serving on IRBs and ethics boards and have extensive experience in the nuances of early drug development and patient management. Highly specialised drug development centers need to be created within major academic centers.
India's strengths
India has a rich heritage in natural products with putative health benefits. Several institutes such as IIRL (J&K) are engaged in research in this area. Natural products have formed the basis for a number of currently available active anticancer drugs .
For instance, the first plant derived anticancer agent to be evaluated and eventually approved are the vinca alkaloids, vinblastine and vincristine. Since then multiple newer therapies, some now made synthetically, owe their origins to plant sources such as etoposide, paclitaxel, irinotecan. One of the experimental drugs, flavopiridol, being evaluated for the treatment of leukemia was synthesised based on the structure of a natural product, rohitukine, isolated by chemists at Hoechst India Ltd. in the early 1990s from Dysoxylum binectariferum. The evaluation of this plant is based on its reference in Ayurvedic text as a source of anti-inflammatory and immunomodulatory activity for treatment of rheumatoid arthritis.
Development of herbal remedies could represent a niche area for India's academic and pharmaceutical sector to establish itself in the competitive world of cancer drug development. However, exploitation of natural products for therapeutic application in cancer is challenging.
Traditional texts outlining therapies poorly characterise the underlying disease as defined by modern medicine. The response to these agents is not defined and quantified. Given the complexity of the number of chemicals administered, the dose and effect relationship is not established. Intensive research to identify and isolate active chemical compounds, study of their mechanism of action and drug effect on disease of interest, and the eventual clinical evaluation requires the application of the current state-of-the-science principles.
The recent advances in our understanding of underlying disease processes, the growing need and focus on drug development and the increasing availability of government and private funding for R&D activities is invigorating drug development research in India leading to the identification of new targets and the investigation of novel molecules as potential therapeutics.
However, most of the initiatives focus on developing therapies for infectious diseases. But with the recent projections by the World Health Organization on the rise in the number of cases of cancer in India, the prioritization of investment needs to be re-evaluated and additional funding made available specifically for cancer drug discovery and development and manufacture of cancer medicines. Given the resource intense nature of this endeavor, it will require collaborative commitment from government, industry and academia.
Shivaani Kummar is a staff clinician at the Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland and Sanjay V. Malhotra the Head of the Laboratory of Synthetic Chemistry-SAIC, National Cancer Institute at Frederick, Maryland, USA.
[Disclaimer: The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organisations imply endorsement by the U.S. Government. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.]
