Jay O. Boyle, MD
Anna J. Duffield-Lillico, PhD
M. Abraham Kuriakose, MD
Jay O. Boyle, MD
Department of Surgery, Head and Neck Surgery
Associate Attending Surgeon
Memorial Sloan-Kettering Cancer Center
New York, New York
Anna J. Duffield-Lillico, PhD
Assistant Attending Epidemiologist
Epidemiology Service
Department of Epidemiology and Biostatistics
Memorial Sloan-Kettering Cancer Center
New York, New York
M. Abraham Kuriakose, MD
Chairman, Head and Neck Institute
Amrita Institute of Medical Sciences
Kerala, India
It is estimated that by 2020 the annual number of worldwide cancer deaths will reach 10 million, which represents almost a 100% increase from the 6 million deaths recorded in 2000. The majority of this increase will occur in developing countries where there is extensive population growth, a high prevalence of risk factors such as tobacco and alcohol consumption, obesity, poor nutrition and sanitation, and inadequate access to quality health-care, screening, and treatment.
Cancer prevention strategies, such as chemoprevention for high-risk individuals, have the potential to decrease the morbidity and mortality associated with the worldwide cancer burden. It is appropriate to test cancer prevention strategies in the same countries that are likely to benefit most from effective intervention. The planning and conduct of chemoprevention trials in developing nations, with high prevalence rates of a specific malignancy, is rewarding, can be done ethically, and may yield faster accrual to important trials, leading to more rapid progress in the field of cancer prevention, not only for that particular nation but for the rest of the world as well.
Oral cancer is a good example of this strategy. Although relatively uncommon in the US--about 15,000 cases annually--this malignancy is encountered very frequently in India, where use of the betel nut, alcohol, and tobacco (risk factors for this malignancy) is common. Oral leukoplakia, a precancerous white patch in the mouth, is a good target for cancer prevention trials because it is easily detected on examination, biopsied, and measured. However, due to the low incidence of oral leukoplakia in the US, it can take several years to complete even a relatively small study. It is apparent that there would be major accrual advantages to the conduct of oral cancer prevention studies in India due to the high prevalence of the disease. Accrual would be faster and study results would be obtained more quickly, leading to more efficient implementation of chemoprevention strategies both in India and worldwide.
The design of such international prevention trials presents some unique ethical and logistical challenges, however. It is critically important that both US and host country standards of informed consent and human subject protection, and data and safety monitoring (DSM) apply to patients accrued in the US and in the host nation. Collaboration with local investigators and institutions to help develop infrastructure and research capacity in developing nations is integral to enhancing accrual success. International trials require tremendous planning in order to overcome differences in language, culture, resources, and physical location. Teamwork between physicians, research scientists, academic institutions, and governments is necessary for success.
One such study is now underway. To evaluate whether clinical trials on oral leukoplakia could be safely conducted in New York and India, a multicenter, randomized, double-blind, placebo-controlled chemoprevention trial of the agent sulindac and its effects on oral leukoplakia was developed with the aid of two National Institutes of Health (NIH) grants; one for planning the trial and one for the trial itself.
For this study, a clinician-scientist and a research study coordinator from India were trained in clinical research at Memorial Sloan-Kettering Cancer Center in New York in order to facilitate communication and education regarding the ethical and regulatory aspects of clinical research. Negotiating Indian government approval for the trial was challenging and required an excellent DSM plan, and substantial effort from the local investigators to prepare applications and attend interviews with various regulatory and bureaucratic authorities in India. Sulindac, with its excellent safety profile, was a promising agent to study, as its generic form is widely available in India. Surrogate endpoint biomarkers were planned that could be analyzed in India with US oversight and validation, again to build capacity and experience. In addition, a detailed manual of procedures containing all standard operating procedures for the trial was developed to ensure consistency of study procedures at both accrual sites.
This trial represents an intriguing strategy of taking the clinical trial to a developing country where there is a significant population at risk rather than limiting the trial to the US where, in contrast, the proposed study population would be smaller leading to longer accrual. Conducting the trial mainly in the developing country, it is hoped, would maximize accrual, benefit those at high-risk for cancer, and yield results that could be applied worldwide. It is hoped that this trial will provide evidence that cancer prevention trials can be run internationally with the same rigorous standards of ethics and DSM as trials conducted in the US.
Another excellent example of taking the clinical trial to the population at risk is the story of esophageal cancer prevention trials in the Linxian province of China where esophageal cancer is common. In 1993, results from two large vitamin/mineral intervention trials conducted in the general population or in individuals at high risk for esophageal cancer were reported. Most recently, results from a randomized, placebo-controlled chemoprevention trial of selenomethionine and celecoxib also were reported. These individual agents or placebo were given to patients with squamous dysplasia, a precursor of esophageal squamous cell carcinoma. Among subjects with mild esophageal squamous dysplasia at baseline, selenomethionine had a protective effect. It is likely that further trials of esophageal cancer prevention in the US will be influenced by these findings. Significant progress in the identification of cancer risk factors, diagnosis, treatment and prevention has been facilitated by these international trials.
There are clearly some trials that should not be performed internationally. Interventions or drugs should not be studied internationally if they are not available or are too expensive for the study population to gain any potential benefit from the study findings. Studies should not be done in developing nations if they are not feasible in the US due to ethical considerations, need for informed consent, Institutional Review Board (IRB) approval, or risk of adverse events. It is unethical to conduct international research in countries without medical research oversight; or within institutions without an established Institutional Ethics Committee or IRB.
International chemoprevention trials in general have various pros and cons. First, as mentioned, pros include faster accrual rates and targeting at-risk populations most likely to receive benefit from the intervention. Additional pros include the relative cost-effectiveness of conducting clinical trials in developing countries compared with the cost in the US; indeed, personnel costs for qualified investigators and research coordinators in developing countries are substantially less than those in the US. Pros also include the large pool of potentially eligible individuals, not only due to the high prevalence of the disease, but due to the treatment-naïve status of the population and lack of competing trials. On the other hand, cons include the extensive planning to overcome difficulties in the operations of the trial. Examples include the logistics in establishing double-blind randomization procedures, labeling and shipment of the drug/placebo, sharing electronic data including photomicrographs in real-time, and ensuring the viability of biological specimens during collection and transportation. However, it should be recognized that these cons are inherent within any clinical trial, whether conducted at single or multiple institutions within the US, or internationally.
Trials in developing nations should be designed to include accrual in the US whenever possible. Developing nations are justifiably concerned about potential exploitation of their population by unscrupulous investigators. Trials that are open for accrual in the US demonstrate that the trial meets all good clinical practice requirements. The development of international collaborations and research capacity building in developing nations should always be underlying themes in international chemoprevention studies.
