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Journal of Postgraduate Medicine, Vol. 54, No. 4, October-December, 2008, pp. 318-323 Ethics Forum Clinical research in India: Great expectations? Thatte UM, Bavdekar SB Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Mumbai - 400 012 Date of Submission: 16-May-2008 Code Number: jp08107 Abstract India is considered as a preferred site for conducting global clinical trials. Existence of a large treatment-naοve population, availability of English-speaking, skilled doctors, plenty of clinical material, and cost-savings are obvious advantages for carrying out clinical research in India. However, challenges exist at various levels. Lack of formal training in bioethics and research methodology, heavy burden of clinical duties and sub-optimal administrative support restrict investigators. Absence of oversight of functioning of ethics committees (ECs) and lack of mechanisms for ensuring quality of ethics review heighten societal concerns about safety of participants. Conducting research on issues not relevant to local needs and failure to ensure post-trial access further enhance society's cynicism. These issues need to be tackled through capacity building, training of investigators and EC members, strengthening of EC functioning and encouraging greater community participation.Keywords: Clinical trial, research ethics, bioethics The search for new medicines is as old as mankind. As newer disorders are described and novel targets for old diseases get discovered, this pursuit only becomes more intense. Clinical trials involving human participants constitute an essential step in the drug development process and India has attracted its fair share of attention; with both good [1],[2] and bad [3],[4],[5] reports in this regard. All the stakeholders [including sponsors, regulatory agencies, investigators, ethics committees (ECs), research participants and society at large] can potentially benefit from the ethical and scientific conduct of clinical trials in India. Participants could benefit from getting an effective therapy; investigators can upgrade their skills and infrastructure, while the sponsor or Clinical Research Organizations (CROs) would save costs. More importantly, as the safety and efficacy data from the Indian pool becomes a part of the global database on a new drug, future generations of Indian patients can profit from this knowledge. Conducting c linical trials is also a business opportunity for India. It has been projected that over the next few years, up to 65% of FDA-regulated clinical trials will be conducted outside the US [6] and, that India and China would be the most attractive locations for this. [2] It is estimated that the clinical trial market would generate business worth over US $1.5-2 billion. [7] India is an attractive site for clinical trials for various reasons summarized in [Table - 1]. [1],[4],[7],[8],[9],[10],[11],[12] However, a review of available information suggests that India accounts for just 0.1% of the R and D budget of the US pharmaceutical industry. [7] Also, the Indian sites account for only a miniscule proportion of global clinical trials: of the 57811 trials registered at clinicaltrials.gov, only 749 (1.2%) are being conducted in India, compared to 33604 (59%) in the US, 987(1.7%) in Japan and 879 (1.5%) in China. [13] To realize the full potential for clinical trials in India, sites would need to enroll as many as 0.2 million subjects in 4000 trials conducted over 10000 centers! Are we really ready and capable to face this deluge? This communication seeks to identify societal concerns and the challenges that investigators and ECs face and suggest steps that could help address some of these concerns. Investigators The investigator is responsible for ensuring proper and ethical conduct of the clinical trial at the study site. [14] The various challenges that investigators may face include [Table - 2]: Infrastructure and staff: Adequate infrastructure including space, communication and data management equipment, archiving facilities, biological sample or investigator product storage facilities, uninterrupted electricity supply etc. are necessary for appropriate conduct of clinical trials. This is probably the easiest challenge to address as sponsors can set up facilities at newer sites- and identification of new investigators outside of the usual metropolitan sites is an attractive proposition. Another problem that investigators face is the high turnover of junior staff necessitating conduct of repeated training programs for the new recruits. This also has an adverse impact on efficiency. The myth of numbers: Although India is said to have a large number of doctors, it is in fact, facing a shortage of doctors in terms of its huge population. [15],[16] Due to a poor doctor-patient ratio (especially in the public health sector), clinicians need to spend a large proportion of their time in performing clinical duties and providing patient care. In addition, the burden of educational and administrative tasks leaves very little time for clinical research. Hard-pressed clinicians shy away from research, and if they do take it up, paucity of time tends to compromise the quality. The latter manifests itself in terms of frequent protocol violations, non-adherence to ethical standards or less than optimal documentation. On the other hand, there are times when fears are expressed that participating as an investigator could compromise patient care duties, teaching assignments or administrative responsibilities. As the number of trained and experienced investigators with the right attitudes and requisite skills is very limited, the same physician is often flooded with clinical trials. This can bring in conflicts of interest and relegation of responsibilities to junior untrained staff again compromising quality. Knowledge, skills and attitude: India can boast of highly trained and experienced physicians in the fields of oncology, cardiology, neurology and gastroenterology where a large part of new drug development activity is focused. Unfortunately, these numbers do not necessarily translate into having a large pool of trained investigators. Apart from being experts in the chosen field, investigators need to have special knowledge about basic principles of clinical research, protocol designing, ethical and regulatory requirements, Good Clinical Practices (GCP) and drug development before they can be considered eligible to conduct clinical trials. Lack of formal training in research methodology and bioethics during graduate and postgraduate courses is a definite handicap for the investigators. In a survey carried out in two Swiss teaching hospitals, a majority of investigators conceded their inability to carry out research-related activities. [17] The situation is unlikely to be better in India. From the point of patient safety, lack of training in pharmacovigilance could compromise the investigators abilities to detect, assess, understand and report adverse events during a clinical trial. Physicians also need to develop skills related to counseling prospective research participants. All this has become even more pertinent since India is being increasingly considered for early drug development studies e.g. Phase-1 (35 trials at clinicaltrials.gov) and Phase-2 (179 at clinicaltrials.gov) trials. [13] Investigators also need to have the right attitude to clinical research that inherently embraces ethical principles underlying clinical research. The characteristics of a "good investigator" are integrity, enthusiasm and experience! Practices: Managing variability in standard of care amongst various Indian sites is a great challenge in itself. The difference between the public and private healthcare facilities in terms of scale of operations, patient characteristics, facilities and infrastructure available, access to medicines and practices followed is vast and this could have a telling effect on the generalizability of results. Poor documentation practices are a bane of many health facilities. Source notes are often not maintained up to the required standard and sometimes there are no source documents at all. Lack of systematically maintained patient databases also tends to slow recruitment rates. Administrative support: Beleaguered as they are by the paucity of human and financial resources, patient care and not research, is a priority for many healthcare institutions. In hospitals attached to medical colleges, medical and para-medical teaching activities take precedence over research and therefore administrative support is not very forthcoming. Thus, institutions hardly ever develop written policies on administrative, medico-legal and financial issues related to clinical trials leading to ad hocism and inconsistency in decision-making. Fewer training opportunities for researchers and lack of establishment of functional institutional ECs further illustrate the inadequacy of administrative support. Many existing ECs have been reported to function below par not adhering to national guidelines. [18] Investigators, meets are organized with a view to train investigators and team members, to discuss center-specific issues and ensure uniformity in the conduct of the trial across centers. However, due to suspicions of an unethical nexus amongst the pharmaceutical industry, CROs and investigators, investigators are often discouraged from attending these meetings, which in fact, could compromise research quality. Private sector: The private sector plays an important role in providing healthcare, especially in the urban setting and private practitioners are showing greater interest in conducting clinical research. Although many large corporate hospitals have adequate administrative backup, including institutional ECs, the smaller players in nursing homes and private clinics typically lack this type of support. The questions related to existence of medico-legal support, awareness of the staff regarding responsibilities of clinical research, availability of facilities and skills to manage serious adverse events and infrastructure for archiving are yet to be answered. Access to appropriate ethical oversight is a major challenge in this scenario. Other issues: Indian investigators are rarely a part of the team consulted for writing a protocol. This further alienates them from the excitement of research and there is no sense of "ownership" of the research conducted. While conducting a clinical trial, an investigator has to assume the dual roles of "investigator" and "healthcare provider". This leads to confusion in the minds of several investigators, which in turn can lead to "therapeutic misconception". Many investigators undertake trials with the aim of providing their patients with free treatment. This runs contrary to the basic tenets of clinical research, as some of the patients are likely to receive a new drug whose efficacy and safety are yet to be proved. Ideally, clinicians should agree to become investigators to "discover something new or validate something that is known", thereby contributing to generalizable knowledge. Financial benefits and peer recognition are also factors that motivate them. As sponsors scramble to meet recruitment targets, they tend to implement the "payment for performance" strategy. This could lead to compromising ethical requirements while undertaking hasty recruitment of subjects and could result in poor quality research. Ethical Oversight Oversight of a clinical trial by an appropriate Independent Review Board or EC is mandatory for clinical research. [9],[10] These committees are responsible for safeguarding the rights and wellbeing of research participants by reviewing and approving the study protocol, performing periodic review of safety data and progress of the study and also monitoring the conduct of the study. However, ECs face daunting challenges such as, reluctance of individuals to serve on these committees, infrequent meetings, heavy workload, inadequate space and lack of administrative support. These constraints not only lead to delays in approvals but also force most of the ECs to restrict their activities to initial appraisal and approval of study protocol and documents, review of reported serious adverse events and examination of the periodic and final report submitted by the investigators. Hardly ever does any EC undertake in-depth monitoring of studies or scrutinizes the process of obtaining consent. In the absence of any formal training in bioethics, most members undertake mere scientific review of research proposals. They are not well informed about issues related to reduced autonomy, increased vulnerability, distributive justice, use of placebo, obtaining and documenting consent, management of and compensation for study-related injury. [19],[20] This compromises the quality of ethical review of proposal. Lack of active participation by the non-medical members in the discussions at the meetings, common practice of appointment of institutional head as the Chairman compromising its independence, absence of written standard operating procedures (SOPs) and poor archiving and record keeping are some of the other areas of concern related to the functioning of the ECs. Schedule Y has understandably specified that the legal expert and lay person have to be present to fulfill the quorum. This makes arrangements of meetings a daunting task with these members achieving "prima donna" status [Table - 3]! Societal Concerns Relevance: When individuals participate in clinical trials, they do so in the hope that they would benefit from the treatment but also expect that their participation would result in improving healthcare in general. Implicit in this hope is the expectation that the community or the society that they come from would also derive some benefit. Analysis of trials registered at clinicaltrials.gov that are being conducted at Indian sites indicate that studies related to diabetes (113), psychiatric disorders (77), cardiology (91) and oncology (48) far outnumber those in other fields. [13] This list is obviously not in tune with the country′s list of major health problems such as tuberculosis, malaria, kala azar, diarrheal and acute respiratory diseases. Use of Indian participants for finding solutions to problems of the western world could be labeled as "neo-colonization" and exploitation. [3] Post-trial access: Many drugs are developed using research participants from developing countries including India. However, if the drug is marketed (and it may never be), it is often not within the reach of most Indians. This approach, where the risks are borne by individuals without benefits for the society, amounts to exploitation. This issue of post-trial access is not only the responsibility of the sponsor but also of the government. Medicines that are being evaluated in the Indian population must be made available to the population at an affordable price. [21] Loss of voluntariness and autonomy: When patients from the economically challenged sections of society are invited to participate in trials, the question of whether they have any real choice in consenting often arises. It is known that 75% of the total out-of-pocket health expenditure is spent on drugs in India, and therefore it is not surprising an individual may be forced to participate in a trial overlooking the risks involved and ignoring the fact that he/she may be receiving an ineffective treatment which is under trial (or even a placebo). [22] Such examples are the "rule rather than exception" and are examples of "reduced voluntariness" or "loss of autonomy". Other issues: Another issue that impacts society is the lack of translation of research activity to tangible human benefit. High costs, slow results, lack of funding, regulatory burdens, fragmented infrastructure, incompatible databases, and a shortage of qualified investigators and willing participants are the major road-blocks identified that impair translation of research into useful medicines for society. [23] It is pertinent to ask whether the Indian community is prepared for clinical trials. [19] This is particularly highlighted in vulnerable populations like women with human immunodeficiency virus (HIV) infection. Creating awareness among potential participants about the disease and the possible therapies being offered is a challenge that needs to be addressed to improve recruitment. Further, individual participation can be maximized when the community understands the need of specific research studies. [19] Possible Answers and Solutions What is the way forward if India has to remain the preferred location for conducting clinical trials and at the same time ensure that the research done conforms to the highest standards of quality and ethics? These are summarized in [Table - 4]. Capacity building : This is one of the most important strategies for overcoming many of the challenges enumerated above. EC members, investigators and regulators need to undergo training in bioethics, research methodology and regulatory requirements. [24] It is heartening to note that Central Drug Standard Control Organization (CDSCO) has recognized this need and has organized workshops for training in GCP. [25] The Indian Council of Medical Research (ICMR) has also held workshops for training EC members as well as undergraduate and postgraduate medical and science students. [26] These efforts should be continued to improve the skill sets amongst researchers and EC members till a critical mass of trained personnel is created in various institutions across the country. The Forum for Ethics Review Committees of India (FERCI) has been established with promotion of capacity building of EC members as one of its primary mandates. It can make its valuable contribution by complementing the efforts of CDSCO and ICMR in this regard. Expanding investigator site base is the key to be able to meet the real demand. A search of the clinicaltrials.gov website revealed that metropolitan cities like Mumbai, Delhi, Bangalore, Chennai and Hyderabad account for the majority of sites conducting trials in India. [13] Other cities like Ahmedabad, Lucknow, Jaipur and Ludhiana appear to be used but their full potential is yet to be tapped. Mysore, Cochin, Manipal, Nagpur and Kolkata are examples of cities with good medical infrastructure and patient population. These sites must be strengthened to be able to take advantage of the demand that has been created for more clinical trial centers. Accreditation of investigator sites: Another possible step to improve the quality of investigator sites would be to have a system for accreditation of investigator sites- where training, infrastructure, human resources and ethical conduct could form part of the accreditation process. This would also be an incentive for the investigator sites in the more remote areas of the country to participate in the clinical trial process. Mandatory training : Investigators wishing to participate in a clinical trial could be mandated to undergo GCP training by regulatory authorities and institutional ECs. The GCP training could be imparted through an online course, which would be easy to administer and would be less expensive. Private sector : Private healthcare sector plays an important role in the delivery of healthcare to Indian masses. If properly informed and trained, there is no reason why private practitioners cannot make their contribution to research. Improvement in functioning of ECs: Mandatory training of EC members, formulation and functioning according to SOPs, improved documentation and archival practices are some of the recommended changes to the working of ECs. A mechanism needs to be developed that would enable ECs to share their views on controversial issues related to clinical trials. This would aid in capacity building, learning through dialogue and communication, and would discourage "EC shopping". The FERCI could play an important role in developing this mechanism. For many smaller institutions that take up clinical trials infrequently, it is neither feasible nor cost-effective to set up institutional ECs. They get their protocols approved by independent ECs. These independent ECs are autonomous and there is no organization that supervises or oversees their functioning. There is a need to have a mechanism which would assure sponsors and society at large regarding adherence to guidelines, quality of ethical review and monitoring of clinical trials. ICMR and FERCI could provide such an assurance through a process of registration, accreditation and periodic inspections of ECs. Other measures: Adherence to national and international guidelines is of utmost importance and this needs to be enforced through regulatory inspection of sites, CROs and sponsors as well as ECs. Implementation of the law with greater clarity about liability and punishments would also protect participants in a better way. National Guidelines should be amended to provide greater clarity on issues such as compensation for study-related injury, risk-benefit analysis while reviewing research protocols, role of ECs in serious adverse events review process and role of the Data Safety Monitoring Board. Building confidence in the community is an important aspect to be addressed and for this media have to be also educated. The involvement of non-governmental organizations (NGOs) in research from the outset can help the researchers gain confidence of the community. A useful and effective approach to increasing community participation is to set up a Community Advisory Board (CAB) which is an independent panel of representatives of stakeholders in community-based research. For example, if the research involves intervention in HIV, it has been suggested that members of the CAB could be drawn from women′s organizations, sex workers, truckers, people living with HIV, NGO representatives, grass-root level workers, lawyers, etc ., all of whom are likely to be interested in the development of the intervention. [19] Conclusions For obvious advantages, global players view India as a favored destination for conducting clinical trials. The activity, in the long run, has the potential to help our citizens, professionals and society. However, our infrastructure and systems are not yet in the optimal state to meet this challenge. Indian policy makers, administrators and professionals should initiate positive steps to ensure that this opportunity is exploited to its maximum potential. References
Copyright 2008 - Journal of Postgraduate Medicine The following images related to this document are available:Photo images[jp08107t2.jpg] [jp08107t1.jpg] [jp08107t3.jpg] [jp08107t4.jpg] |
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