|Year : 2009 | Volume
| Issue : 2 | Page : 69-70
Phase 1 trials in oncology in India: The clear case for innovation
Huntsman Cancer Institute, University of Utah, Salt Lake City (UT), USA
|Date of Web Publication||16-Jun-2009|
Huntsman Cancer Institute, University of Utah, Salt Lake City (UT)
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Sharma S. Phase 1 trials in oncology in India: The clear case for innovation. J Can Res Ther 2009;5:69-70
According to the latest studies based on the Indian Council of Medical Research (ICMR) cancer atlas, cancer is the second commonest noncommunicable disease in India after ischemic heart disease; almost 8.7 million disease-adjusted life years are lost due to cancers in India.  An estimated 70% of the 800,000 cancers diagnosed annually in India are at an advanced stage when detected.  With the improvements in technology and reporting, an ever-increasing number of cancers are being diagnosed in major metropolitan areas in India.  Although infectious diseases like malaria are a major problem in India, the total mortality figure from malaria pale in comparison to that of cancer.  Several cancers, e.g., gall bladder cancer, breast cancers, head and neck cancers, lung cancers, and upper aerodigestive cancers are common in special pockets in India. 
Phase 1 trials refer to initial exploration in humans of promising cancer drugs. Drug development is a complex process but is clearly required in oncology. Expensive treatment modalities such as chemotherapy and radiation therapy can cure only a minority of the patients diagnosed with advanced cancers. New therapies are desperately needed but, in India and other developing countries, research on new therapies for cancer has low priority since resources are reserved for other diseases. Most novel cancer therapies are discovered in the west and transferred to India under unequal terms.
Several Indian companies are engaged in drug discovery and development of novel cancer therapeutics but the numbers are small compared to the situation abroad. India has a large cadre of trained investigators that have the expertise for conducting early phase clinical trials of compounds developed in India and elsewhere. However, there are still regulatory restrictions on the conduct of initial (first-in-man) trials of new therapeutics in India although later phase and repeat phase 1 trials are allowed. The Drug Controller General of India cites several reasons for this; for example, there are ethical considerations (the need to ensure that Indian patients do not become 'guinea pigs' for foreign drug companies), there is a perceived lack of expertise in India for conducting such trials, and cancer is not a major focus area in India at present, etc.
The ethical considerations in phase I trials have been closely scrutinized in Western countries. In a letter published in the Journal of Clinical Oncology, I have pointed out several salient facts.  For example, the overall rate of severe toxicity to patients is very low in phase I trials. There were two large retrospective reviews published recently that have examined the toxicity and efficacy of drugs undergoing phase 1 trials. One article,  examined 213 studies (involving 6,474 cancer patients) published in peer-reviewed journals and found that the overall toxic death rate was 0.54%, while the overall objective response rate was 3.8%. Toxic death rates decreased over the study period, from 1.1% over the first 4 years of the study (1991-1994) to 0.06% over the last 4-year period (1999-2002); this decrease was statistically significant ( P = 0.01). It is not clear what caused this reduction in toxic death rates, but it could be related to better monitoring of patients, better patient selection, and the advent of targeted therapy. Response rates also decreased but by proportionally much less. The article excluded patients with hematological malignancies who were on phase I trials and were likely to have higher response rates. In the other study,  the authors analyzed 460 trials involving 11,935 participants, all of whom were assessed for toxicity and 10,402 of whom were assessed for a response to therapy. The overall response rate (i.e., both complete and partial responses) was 10.6%, while the overall rate of death due to toxic events was 0.49%.
If one compares these rates of toxicity and efficacy with that of a standard approved agent, e.g., docetaxel for treatment of second-line lung cancer, the results can be surprising: Docetaxel is associated with a 2.8% risk of treatment-related deaths. Thus, overall, the drugs used in phase 1 trials compare favorably with standard drugs as far as risk/benefit for patients with advanced cancers is concerned. Therefore, no special ethical consideration is required when conducting such trials beyond ensuring that patients clearly understand the risk-benefit equation before giving consent for participation in the trial.
Expertise is now developing in India to conduct high-quality studies. Several centers in India have accumulated expertise in this area including Nizam's Institute of Medical Sciences (Hyderabad), Tata Memorial Hospital (Mumbai), Jaslok Hospital (Mumbai), All India Institute of Medical Sciences (New Delhi), etc. Phase 1 trials involve small numbers of select investigators around the world working to develop novel, promising agents. These trials often require a clear understanding of the scientific principles surrounding drug development and a good knowledge of oncology and the biology of disease. Participation in early phase studies like these will allow Indian investigators to publish original work on promising agents and potentially steer the development of therapies for uniquely Indian cancers.
There are potential benefits to Indian patients in these trials. Through phase 1 studies there is an opportunity for patients to get access to novel medications free of cost. These medications are likely to have very little toxicity and a reasonable chance of efficacy (as pointed out above). In addition, with full informed consent being obtained, there is no exploitation of patients.
Nothing in life is free. India stands at the crossroads of innovation. The service sectors in various fields must innovate if India is to lead. Clinical research is no exception. The time has come for a constructive dialogue on phase I trials, especially first-in-man studies. I feel that the regulatory authorities in India should allow experienced Indian oncology researchers to participate in these trials. This is important because the burden due to advanced cancer continues to increase and Indian investigators need to find novel therapies that are suited for our local circumstances. This is not going to happen unless India is regarded as being at the forefront of innovation in oncology.
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