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Increasing cultural awareness is key to helping the country meet recruitment challenges.
Global pharmaceutical and biotech sponsors spend an average of 6% of their clinical trial budgets on advertising and marketing to facilitate subject recruitment.1 In spite of this level of investment, 86% of these trials do not meet the enrollment expectations.1 Globally, more than 80% of trials fail to enroll on time, and the failure to recruit patients on time leads to loss of 85%–95% of days in a clinical trial.2 Hence, internationally, subject recruitment remains one of the main challenges for sponsors. As such, sponsors are seeking innovative solutions and to experiment with newer global territories such as India, which is perceived to meet the expectation of fast recruitment.
The sheer presence of a huge potential clinical trial population makes India an attractive destination that has the potential for fast subject recruitment for western countries even without any overt advertisement and recruitment campaigns. This article attempts to analyze the geographic, socio-economic, cultural, and other India-specific market related environmental factors that may impact on subject recruitment and retention.
Despite improvements, the health care system in India is still considered relatively unadvanced, and it is not supported by health insurance. Private medical support is very costly and is beyond the financial reach of the majority of the population. Thus, the majority of the population still remain largely dependent on government-run subsidized health care facilities (see Figure 1), even if these facilities are dispersed in diverse geographical locations. Hence, there tend to be many referral hospitals run by the Indian Government and trusts in major cities and towns that are specialized in certain therapeutic areas.
These hospitals have gained popularity because of their subsidized nature, high quality, and advanced treatment options. Some of the names are well-known nationally in India, such as CMC (Christian Medical College, Vellore), Tata (Tata Memorial Hospital, Mumbai), and AIIMS (All India Institute of Medical Science, Delhi). Although these hospitals are located rather far away from major Indian cities, they attract a large pool of patients presenting with several diseases.
Figure 1. Total expenditure on health as percent of gross domestic product (2002 estimate).
The public trust and medical college hospitals have found favor with clinical research organizations and pharmaceutical sponsors, as the investigators attached to these institutions are held in high regard for their experience and enthusiasm for clinical research. Furthermore, they have a large database of patients who are of a heterogeneous nature and profile. The institutions are also well-organized and have the appropriate infrastructure, facilities, and defined ethics committees to conduct trials that meet international standards.3
By and large, these referral centers attract populations from diverse communities, with many of the subjects originating from geographically distant locations. Although these centers have the potential for very fast recruitment, because of large patient in-flows subject retention is an issue of concern. As the majority of clinical trial designs require continuous and long-term follow-up at different time intervals, there could be myriad tasks for the investigators and study coordinators to carry out to ensure compliance and follow-up and to reduce the chances of subjects being lost during follow-up. Considering that the subjects are drawn from distant locations for treatments, sponsors may have to agree on social admissions (e.g., planned hospitalization) and provide logistics, stays, and other support for those patients who are participating in a clinical trial.
In their 1979 Belmont Report,4 USFDA's National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research highlighted the ethical principles and guidelines for the protection of human research subjects. In the context of this report, three basic principles (i.e., the principles of respect for persons, beneficence, and justice), among those generally accepted in Indian cultural tradition, are particularly relevant to the ethics of research involving human subjects. In contrast, it has been a taboo subject, and much discussion has focused on the idea that impoverishment, illiteracy, and social ills in Indian society may have an impact on the ethical conduct of a clinical trial.
There has been a widely acknowledged belief that people with less education who are classed as impoverished cannot decide of their own free will and may, through socioeconomic compulsion, end up participating in a trial. But several observers argue against this belief, pointing out the danger of generalizations. The potential subject may be poor and illiterate, but this must not be mistaken for a lack of common sense or intelligence; they should be capable of making decisions on their own. They may not comprehend the complicated statistical design of a clinical trial, but if the investigator engages them through proper coaching and guidance, adequate information will be provided to the subjects. In this manner, potential subjects can understand, read, and comprehend in order to decide for themselves whether or not to participate in a trial. If they are not convinced, they will not participate. It must be remembered that these potential subjects have an equally strong commitment to their life and loved ones as the rich and more literate. Although it isn't very easy to convince them, it is also equally difficult to take them for granted just because they are on the lower social strata. If one reflects on this scenario, it is as equally or even more difficult to make a literate and rich subject participate in a trial.
Impoverishment is considered by many to be another compelling factor for potential subjects in India to become involved in clinical trials. But if one looks into the existing health care system, the majority of the impoverished population, in any case, depend on free or subsidized treatment from government-run hospitals and dispensaries, since "health insurance for all" does not exist in India. So, participating in a clinical trial may be seen by these subjects as a means to ease some of their additional economic burdens in terms of medication and treatments. In a few studies, the trial design demands additional visits for tests and procedures; hence, the sponsor provides compensation toward the conveyance, stay, and loss of wages for the subject and other earning members of their family, as well as incidental expenses, which acts as a motivation and improves subject compliance and retention. Similarly, if the investigational product is temperature sensitive sometimes the sponsor may provide pool-refrigerators for use by the patients, either through a facility attached to the investigator's site or through their local physicians. These represent genuine compensation and logistical economic support for trial subjects, and would not be construed as an inducement or compulsion for enrollment.
At first glance, some of these India-specific costs appear to be additional burdens to the sponsor considering India. However, these costs rarely represent a major expense and should be viewed with respect to the fast recruitment potential and the increased subject retention. It is a fact that poor and illiterate subjects are more compliant, as they are very sincere and follow protocol tests, instructed procedures, and advice from the physician. Hence, the so-called taboo of potential exploitation in developing countries because of illiteracy and poverty can be entirely ruled out with a positive shift in approach and orientation, and pharmaceutical sponsors should give equal justice and respect without any accusations of exploitation. Therefore, it is in every sponsor's interest to ensure that high ethical standards for clinical trials are maintained so there can be no accusations of subject exploitation.
India is a country with diverse culture across the geographic territory. If one travels from north to south and east to west, several local dialects, subdialects, and life styles will be found. Not surprisingly, communication is achieved through more than one major language (see Table 1).
Table 1. Languages in India
Although the official language of India is Hindi as per the constitution and most people understand Hindi (barring a few states in the southern region), the English language continues to be used for all official purposes. The medium of education in India in higher studies (i.e., bachelors, masters, and doctoral programs) in science, medicine, pharmacy, nursing, and alternate medicines is in English. Hence, although culturally India is a Hindi-speaking community, because of the educational systems, the physicians, nurses, monitors, and most literate subjects speak, write, and understand English. Even India's judicial and governing institutions, health ministry, regulatory bodies, and ethics committee use English as the medium for day-to-day communication and management.5
But it is a fact that many subjects are illiterate or limited, only able to read, write, and speak in their local language. Hence, looking at the multilingual culture, the sponsors and other clinical research stakeholders should make every effort to design information sheets in lucid local languages so that they are easily understood by the subjects and their relatives. What is important and essential in an Indian context is proper counselling and thorough guidance by the investigators, which may indirectly call for a lot of time spent mentoring the subjects—thus ensuring recruitment and retention.
There are many other cultural factors that have major effects on patient recruitment and retention. Indians celebrate many festivals and cultural programs, and each community has their own set of cultural functions. Similarly, with poorer labor-class subjects, harvesting season is an important period during which time the family members jointly work together to earn a livelihood for the entire year. During festive and harvesting seasons, patient inflow to hospitals tends to be less, thereby leading to slower subject recruitment. Cultural programs sometimes even compel subjects to miss scheduled follow-up visits if the event falls during those days. Hence, knowledgeable investigators sometimes change the visit schedules, window periods, and drug-dispensing patterns depending on the cultural calendar of the subjects. Investigators also arrange for necessary staff, translators, study nurses, and other personnel who can understand subjects' cultural differences and languages in a trial context.
There are other cultural values in the Indian family. For example, if a female subject participates in a trial, she gives her consent only after consultation with the male member of her family, who may be the father or husband. In this society, the male member takes charge of all decision-making processes. Another important sociocultural issue concerning unmarried female subjects is that they feel offended if they are asked to perform pregnancy tests, which is a common requirement in almost all protocols. Therefore, it is all the more important for the investigator to understand the cultural value of the society and educate both the subject and other leading member in their family for proper compliance.
Another cultural factor in India is that subjects have deep respect for the study physicians. They listen to the study physicians and follow their instructions without any lapses. These cultural values help the study in terms of fast recruitment and better retention. However, this cultural factor also bestows a lot of responsibilities and demands on the physicians to behave appropriately without neglecting patient care and/or misusing patients' trust.
In India, there are more than 30 strong networks/associations of physicians in different therapeutic areas. These associations are active and meet at frequent intervals at regional and national levels (see Table 2). Most of these associations have a Web site and publish their research articles in their association journals. The membership of each of these associations is in the range of 300–500 physicians. Hence, all the investigators associated in a clinical trial program interact to facilitate investigator and subject participation in a trial.
Table 2. Potential Investigator, India
However, physicians in referral and general hospitals who have an interest in clinical research have the dual responsibility of routine hospital care and clinical trial duties. The huge patient inflows in a typical hospital in India put considerable time pressure on physicians to see 200–300 patients during an average out-patient department (OPD) care period. Besides these OPD assignments, investigators attend other referral clinics inside the hospitals, which can be very fertile ground for screening for trial recruitment.
Sometimes more eligible patients (availability) and less spare time (time-pressure) to complete the trial-related documentations, tests, and procedure formalities compel the investigators to recruit fewer subjects in a trial. In cases where there is a rare disease and inclusion and exclusion criteria are very stringent, the network and association of investigators can help identify the right subjects for a trial. With due respect to confidentiality, if the investigator discusses the trial synopsis with network members it improves the trial participation.6
A frequent observation is that some Indian investigators do not consider subject recruitment a barrier at all and overlook the inclusion and exclusion criteria during the feasibility to predict an unattainable recruitment potential. But in practical terms, these investigators essentially fail to fulfill the commitment of recruitment. Hence, extra care should be taken to properly assess the recruitment potential during any feasibility studies.
In today's scenario, India may not have more than 20 investigators in a major therapeutic area who are trained and experienced to conduct a key clinical trial. Lack of sufficient numbers of trained investigators and study staff may sometimes act as a strong barrier to recruitment in a clinical trial program, particularly if these investigators are occupied with competing trials. India's popularity as a location for clinical trials means that the chances of competing trials taking place are increasing. Hence, it is a must for industry sponsors and clinical research organizations to train investigators and include an additional number of sites and investigators in their clinical trial programs. This may necessitate the sponsors to provide financial and technical support to equip the site with trained investigators and adequate infrastructure and facilities.
Over the years, Indian investigators, who have had the experience of participating in global trials, have realized the importance of their contribution in meeting the sponsors' recruitment needs. There has been an increase in expectations over the years in terms of fees, and some investigators have started expressing a desire to receive almost the same fees as investigators in western countries.
Although clinical practice in India is more or less driven by western education, because of the heavy patient load, routine patients usually receive less attention and time from senior physicians compared with clinical trial subjects. In big referral hospitals, sometimes routine patients have to wait longer for treatment than their counterpart who elects to participate in a trial. Although the routine patients are given proper treatment, subjects are given special personalized care by the participating investigator and study staff. This acts as an indirect motivation for the subjects' recruitment and retention.
As most of the clinical trial protocols are designed considering the criteria suitable for normal western populations, a consideration of ethnic factors for working in India is important. Similarly, there is a perceptible difference in stage and severity of disease at presentation in India from western counterparts, which makes it difficult to recruit patients with disease in early stages or with a mild to moderate severity. For example, most cancer patients on presentations are at advanced stage III/IV. So merely looking at the total number of patients with a particular disease would not provide accurate information when determining the recruitment potential.
Many effective evidence-based treatments and practices are not performed in large numbers of Indian patients because of several socioeconomic factors. For example, the inclusion of a breast cancer patient who had previously failed on Herceptin (trastuzumab) therapy may be difficult because a large number of patients may not have received this treatment due to cost considerations, even though it may be considered to be an effective treatment.
Another area of concern in recruitment and retention is the availability and wide spread practice of alternate medicines in India, such as homeopathy, ayurvedic, and unani.7,8 Many subjects may have taken these forms of treatment and would not have sufficient documentation of their treatment history. Thus, those patients may not be considered for recruitment in a clinical trial. In addition, if the clinical trial procedure in a subject's opinion is painful, time consuming, and yields no result, it is conceivable that few clinical trial subjects may migrate to these less costly alternate methods of treatment.
Another issue of common concern is the nonavailability of sufficient hospital records and treatment histories for most of the subjects taking treatment in hospital OPDs. In the absence of a proper clinical history, it becomes difficult to identify potential subjects suitable for the trial. But looking at the current trends, many investigators have started creating databases of potential subjects with chronic diseases, and over time this trend will facilitate the recruitment process.
The Indian regulatory system allows recruitment of patients only after obtaining an approval for conduct of clinical trial and a test license for import of drugs from the Drugs Controller General of India. The process is fairly streamlined, and it takes almost 8–12 weeks to obtain the necessary regulatory approvals3 (see Figure 2). Unlike procedures followed in USFDA, a sponsor can start trial enrollment a month after sending in the application.
Figure 2. An overview of the Indian regulatory approval process for clinical trials.
In India, it is not possible to import a drug unless a test license is obtained. Therefore, subjects cannot be recruited unless written approval from the Drugs Controller General of India is obtained for the conduct of a clinical trial. Other procedures such as EC approvals from the individual institutional ethics committee and the finalization of financial contracts with the investigators do not take a long time and can be completed within that 8–12-week time period.3
In the United States, it is not uncommon for patients to become interested in enrolling in a clinical trial without being briefed by their doctor. This is essentially because of the massive awareness created through recruitment campaigns and advertisements on Web sites and in other media. In India today, almost 100% of the subjects become enrolled through their doctors. Therefore, the most practical marketing efforts to expedite recruitment should include:
It must be remembered that marketing efforts such as advertisements through Web sites and other media may not reach the masses, even though such efforts are not inconceivable in the current scenario. If these advertisements proved essential, then the appropriate media would likely be television and/or radio. However, in such a scenario, careful examination of the existing legal situation would be required. It is possible that a provision in the Indian Drugs & Cosmetics Act or Drugs & Magic Remedies Act would first be required.
Globally, site management organizations (SMOs) play a major role in increasing recruitment rates and in improving subject retention. At this point in time, there are few SMOs in India (just two or three) that are fully operational, and they do not have the reach or capability to provide services at all the potential sites. Investigators in India are therefore focusing on study coordinators who are trained and educated to perform the role of clinical research coordinator (CRC) for the SMO. Since these CRCs remain in direct contact with study subjects, they play a vital role in the recruitment, patient compliance, and retention process. It is possible that an increase in the number of SMOs would strengthen the recruitment and retention process in India.
As an increasing number of clinical trials are being initiated by global sponsors (pharmaceutical, biotech, and CROs) in India, the country will face challenges concerning patient recruitment and retention. Increased public awareness through campaigns would eliminate the recruitment and retention barriers created by geographic, socioeconomic, and cultural factors. The stakeholders (i.e., regulators, investigators, and sponsors and/or CROs) will have to play a major role when designing their programs to take into account "India-specific factors" that will facilitate recruitment and retention.
This places huge responsibility on the shoulders of the investigators. These individuals must be extra careful when dealing with the majority of subjects, who are illiterate, poor, and have a deep respect for and perhaps a blind faith in the physicians treating them. A slight aberration in consent procedure or improper behavior on the part of any of the stakeholders may dampen the clinical research environment in India, which, prima facie, looks rather straightforward, smooth, and attainable on the recruitment and retention front. The public at large also have an important responsibility, especially the literate population, to come forward and raise awareness through community education and consultation.
Each stakeholder involved in the clinical trial process should make efforts to increase the awareness concerning the protection of the rights of potential participants during recruitment. Only in this way can understanding of clinical research be promoted and public participation be furthered.
Umakanta Sahoo, MBA, PhD, is general manager with Chiltern International Private Ltd., B Wing, 4th Floor, Navkar Chambers, Andheri Kurla Road, Marol, Andheri (E), Mumbai - 400 059, India, email: email@example.com. Vimal Sanghavi, MD (Radiotherapy), is manager, medical and regulatory affairs with Chiltern International Private Ltd., B Wing, 4th Floor, Navkar Chambers, Andheri Kurla Road, Marol, Andheri (E), Mumbai - 400 059, India. email: firstname.lastname@example.org. Faiz Kermani,* PhD, is European marketing manager with Chiltern International Ltd., Slough, Berkshire, UK, email: email@example.com
*To whom all correspondence should be sent.
1. B. Hirschhorn, Understanding the Development of the Clinical Study Budget While Avoiding Bumps and Pitfalls. Presentation at The Office of Clinical Trials Workshop. 15 January 2004. http://www.research.temple.edu/oct/
2. V. Sanghavi, U. Sahoo, A. Bhatt, "Challenge of Patient Recruitment and Retention: Critical Role of Clinical Research Coordinator," Pharmabiz.com (8 July 2004). http://www.pharmabiz.com/article/detnews.asp?articleid=22867§ionid=50
3. U. Sahoo, "Global Perspective: India—The Future Clinical-trials Destination," PharmaVOICE, 38–39 (July 2005). http://www.pharmavoice.com
4. The Belmont Report, Ethical Principles and Guidelines for the Protection of Human Subjects of Research, The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, Appendix F. 18 April 1979. http://www.fda.gov/oc/ohrt/irbs/belmont.html
5. M. Stober, "Multinational Clinical Trials: Breaking Language and Cultural Barriers," Applied Clinical Trials, 13 (9) (September 2003). http://www.actmagazine.com/appliedclinicaltrials/article/articleDetail.jsp?id=79882
6. J. Sullivan, "Subject Recruitment and Retention: Barriers to Success," Applied Clinical Trials, 14 (4) (April 2004). http://www.actmagazine.com/appliedclinicaltrials/article/articleDetail.jsp?id=89608
7. C.R. Choudhury, "Alternative Medicine Must Get Scientific Validation for Rational Use," Bulletin of the World Health Organization, 82: 635636. http://www.who.int/bulletin/bulletin_board/82/who news08041/en/
8. Whole Medical Systems: An Overview. National Center for Complementary and Alternative Medicine. NCCAM Publication No. D236. http://nccam.nih.gov/health/backgrounds/wholemed.htm (2004).