By Karen Politis Virk
As demands for reducing drug development costs and achieving higher patient recruitment rates increase, India is projected to become a dominant clinical trial location. By 2011, it is expected that India will conduct more than 15% of the total number of global clinical trials. Several factors are responsible for this predicted growth. India’s large, genetically diverse, treatment-naïve patient population (over one billion) which greatly facilitates patient recruitment and the significantly reduced cost of conducting clinical research (60% less than in the West) are major contributing factors. The emergence of common Western diseases in the Indian population is another factor, as is the high rate of English proficiency among clinical investigators.
Despite the presence of many leading biopharmaceutical companies in India, there are several challenges that foreign companies continue to face. These include language and cultural barriers, socio-economic factors, and the effects of genetic diversity on drug testing. In addition, because of the continued surge of clinical trial activity in the country the lack of staff adequately trained in ICH-GCP practices has raised well-founded concern. Finally, despite an improved regulatory environment, sponsors must still overcome hurdles in the regulatory approval process.
Language and Cultural Barriers
Although English is considered a second language, the majority of Indians with adequate English proficiency are those who have had the benefit of higher education. Hindi, only one of the official languages, is spoken by 30% of the population. There are 14 other official languages and several other dominant languages, such as Hindustani, a combination of Hindi and Urdu. As a result, informed consent forms and patient information materials need to be translated into many local languages, frequently into a minimum of eight to ten regional languages. Because India is such a multilingual country, it is required that patients be given a verbal explanation in their own language prior to signing written informed consent forms. Since the majority of investigators are multilingual, they can overcome these language barriers. However, the translation of regulatory documents for clinical trial approval, especially informed consent, is best provided by local translation experts who are fluent in the local language(s) and culture, have a background in clinical research, and are experienced in dealing with the local regulatory authorities.
Because of India’s vast cultural and regional diversity, cultural differences among patients are an important consideration. This is especially crucial in the preparation of the written informed consent form. General differences in culture between India and the West that affect clinical research must also be taken into account for their potential effects on informed consent procedures. For example, because physicians in India are highly respected, they play an important role in a patient’s decision to enroll in clinical trials. In addition, cultural attitudes in India may sometimes interfere with a physician’s full disclosure of a patient’s diagnosis as well as the risks related to clinical trial participation. Another important factor is the role of family in healthcare decision making, as most informed consent discussions usually include family members.
India is one of the most genetically diverse regions in the world. Although genetic diversity is considered a positive asset in patient recruitment, it poses new challenges in drug testing and development. According to one recent study, a drug for treating asthma and other respiratory diseases was reported to be potentially less effective on the native population of Rajasthan than on the population of Tamil Nadu (http://www.livemint.com/2008/04/26000244/Indian-gene-map-links-ethnic-g.html) . This may make developing a drug for the Indian market particularly difficult. Moreover, while each region has its own language(s) and culture, because of migration, a mix of people from more than one group exists in different parts of the country. For example, the people of northern Punjab differ significantly from the people of southern Tamil Nadu, and individuals from each may be enrolled in the same clinical trial in an institution or hospital in Delhi. Mixing between different groups is minimal, which means that these genetic differences are significantly maintained even after migration.
Poverty and Illiteracy
According to the CIA World Factbook March 2007, India’s literacy rate is estimated at 61% of the total adult population. However, there is a great amount of variability throughout different regions and among different socio -economic levels. In order to help protect illiterate patients and assure that informed consent is obtained in an appropriate manner, Indian regulatory procedure mandates that illiterate subjects be accompanied by a literate relative who serves as a witness during the informed consent process. Furthermore, informed consent procedures require the signatures of the patient’s witness, an independent witness, and the site staff.
More than a third of the Indian population is reportedly too poor to afford an adequate diet (CIA World Factbook 2000). Beyond the medical problems associated with poor nutrition, the nutritional status of a patient can also affect clinical research data. Furthermore, because many patients otherwise cannot afford medical care or have inadequate access to treatment, this has a significant impact on subject recruitment. Although participation in clinical trials may be beneficial because it provides access to modern medicine and, in some cases, is the only available treatment, sponsors must ensure that patient rights are protected. It should be noted, however, that although many poor patients are still enrolled in clinical trials, over the past decade India’s patient population has changed significantly due to a growing middle class. Furthermore, as most clinical trials are not conducted at healthcare centers where the abjectly poor access healthcare, India’s poorest patient populations are generally not enrolled in clinical trials.
The Indian government has reported that a chronic shortage of trained clinical research personnel and staff qualified to serve on ethics committees and data safety management boards is a major problem affecting ethical practices in clinical research. Because of the current and projected growth in clinical trial activity in India this is of even greater concern. Sponsors must therefore ensure that investigators understand and respect ICH–GCP guidelines (including the documentation of patient informed consent) and should establish adequate training for associated personnel. Although the situation is improving gradually due to efforts by the Indian government, India’s NGOs (nongovernmental organizations) and free press have played a significant role in providing an open environment to help ensure that ethical standards are maintained.
Currently, all clinical trial applications are submitted to the Drugs Controller General of India (DCGI) for approval, and are regulated under Schedule Y, which was updated in 2005. The regulatory approval process in India was streamlined in 2006, such that regulatory approvals for clinical trials that have been previously approved in certain countries including the United States, Europe, and Japan usually take about three months. Clinical trials that have not been previously approved may take considerably longer, and timelines are often
unpredictable due to bureaucracy and additional regulatory requirements. Depending on whether the drug undergoing testing is categorized as a biologic or a genetically engineered product, additional approval from other agencies such as the Indian Council of Medical Research (ICMR), the Genetic Engineering Approval Committee (GEAC), and the Department of Biotechnology (DBT) is necessary and can take up to six months. Submission to Ethics Committees can be done simultaneously.
Although the regulatory approval process in India has evolved considerably, many issues remain. In large part, this is because India’s Ethical Guidelines for Biomedical Research on Human Subjects were established relatively recently as were the Indian GCP guidelines, 2000 and 2001, respectively. However, sponsors should be aware of differences in the Indian GCP version of ICH-GCP, including the Indian specifications for the composition of the Ethics Committee, informed consent procedures, and patient compensation for participation. In addition, sponsors should be familiar with the Indian GCP specifications concerning the role and responsibility of foreign sponsors conducting clinical trials in India.
Regulatory reforms and the adoption of ICH-GCP guidelines are good indicators that the Indian government is seriously committed to improving the regulatory environment. Recent efforts by the government to improve ethical practices will also play a critical role in positioning India as a leader in global clinical trials. In addition, FDA plans to establish an FDA equivalent in India by opening two offices this year, one in Delhi and one in Mumbai, will inevitably improve regulatory approval processes and increase the quality of clinical research outsourced to India.
The clinical trial industry in India holds great promise. Improved regulatory approval processes, successful patient recruitment, reduced costs, highly skilled investigators, English-speaking hospital personnel, and large patient populations with diseases common in the West are all contributing factors. Despite the known advantages of conducting clinical trials in India, however, many challenges remain. In order to successfully outsource clinical trials to India, these barriers must be taken into account. Translation and localization expertise must be employed to help overcome any linguistic or cultural barriers. Ethical practices must be improved such that international standards are maintained. Genetic diversity among patient populations must be taken into account for drugs developed for the Indian market. Finally, an awareness of the regulatory requirements necessary to initiate clinical trials in India can ensure greater success.