|Year : 2010 | Volume
| Issue : 1 | Page : 15-20
Human subject protection In India - Is it adequate?
Independent Consultant - Clinical Development
|Date of Web Publication||20-Oct-2010|
Independent Consultant - Clinical Development
Source of Support: None, Conflict of Interest: None
| Abstract|| |
India's experience in clinical trials is shorter in time than that of the developed countries but as in everything else in the current globalizing environment, business compulsions characterized by compressed timelines are strong persuaders to catch up. Most global pharmaceutical and biotechnology organizations include India in their strategic plans, Immediate implementation of aspects that attract benefit are an urgent necessity. Technical and ethical issues that remain unresolved constrain India from reaching its deserved potential. To take fullest advantage of the current inflow of clinical trials, India must adopt, without delay, an all-inclusive approach and invest in a widespread and comprehensive GCP-compliance programme taking into account India-related cultural and socioeconomic issues. The initiative should not be allowed to flag. Government, the pharmaceutical and biotechnological research industries, the medical and pharmacy profession including relevant training institutes, the media and the public have a stake in such investment. The programme should involve assessing gaps in current clinical trial compliance measures and possible solutions, set the field for rectification and ensure implementation through mandate and penalty as feasible.
|How to cite this article:|
Mahaluxmivala N. Human subject protection In India - Is it adequate?. Perspect Clin Res 2010;1:15-20
In any field affecting man, research is necessary as it provides data to improve situations for human beings and this laudable objective demands encouragement and motivation at all levels of participation. In the healthcare field, research has added complexities as it calls for experimentation on humans which may expose them to risk. Society permits such experimental research but demands that members of society who participate in such experiments are protected from undue harm. However low the degree of risk, society agrees that it cannot be dismissed or ignored.
In any country, developed or developing, where research involving humans is conducted, the ethical issue of prime importance is how to achieve fullest protection of clinical trial participants.
Ideally, clinical trials should be associated with altruism and trust  - society expects that 1) people will participate in a clinical trial through altruism and 2) that the other stakeholders in the clinical trial will be trustworthy enough to ensure that the agreeing participants are treated with dignity, their well being and rights preserved and safety protected. Good Clinical Practice norms which contribute to these objectives have evolved and guidelines for clinical trial professionals have been issued by countries including India. Regulators in all countries where clinical trials are conducted recognize the importance of these guidelines and their implementation. That such clinical studies should be transparent is now considered important.
In the contemporary globalising environment, clinical trials like other activities, move across country borders to maximize value. Rapid recruitment at relatively favourable cost contributes to accelerated growth in the clinical trial field in India. , Though today's clinical trials have complexities related to enhanced regulatory demands and severe time-ride the desirable objectives of clinical trial activities.
'Adequacy' of an element or quality is not easy to define as it is always contextual - it relates to time, place, cultural behaviour, purpose or socioeconomic and education levels. Unsurprisingly, the understanding of 'adequacy' or otherwise of an element or quality is not uniform across the world. In today's clinical trial environment, where the sponsors of a clinical trial and the subjects and sites are in different geographies which have different cultures, different ways of looking at risk, different standards of care and different economic priorities, it is tempting to assess 'adequacy' or its perceived lack solely in terms of dissimilarity in the way GCP guidelines are interpreted and implemented. This temptation should be resisted and endeavours be made to understand the basic reasons for the dissimilarity.
'Adequacy' indicates sufficiency for a specific purpose for a specific period of time. It does not indicate the ideal, neither is it the minimum that is to be instituted to meet specific norms. When 'adequacy' is considered in the context of human protection, interested individuals will always see opportunities for greater subject safety by lessening the exposure to risk. It is suggested therefore that human protection measures in the context of clinical trials, regardless of geography, cannot ever be considered totally adequate.
It is against this background that this paper takes an overview of human subject protection in India today, discusses some aspects of prime relevance and offers ideas for consideration to enhance and maintain global trust in the Indian clinical trial system.
| Need for a Level Clinical Trial Platform|| |
India's experience with clinical trials is not long covering just about a decade. It should therefore be no surprise that the three pillars which support the clinical trial platform and on which a country is judged in the clinical trial context 1) appropriate infrastructure, 2) technical and ethical understanding and capabilities of research workers and 3) control/governance measures, are unequal in degree of development. Stakeholders of these three verticals have not yet realized the importance of mutual cooperation and coordination, neither is there complete communication with each other in mutually understandable scientific terms. Time and experience will bring about uniformity of growth resulting in a level platform for clinical trials, but till that happens, variations in compliance with GCP norms should not surprise.
At such a stage in the country's clinical trial development, the responsibilities on the sponsor/CRO are indeed high to ensure that the gaps in development of the three pillars supporting the clinical trial platform do not jeopardize the safety and well being of the subject participant. It is essential that interested parties in the clinical trial arena conduct a gap analysis for each clinical trial and for each site. Constant improvement of standards through motivation, encouragement, mandate and penalty is the need of the hour, as also vigilance that cost-effectiveness in India remains a perceived advantage.
It must be reminded that excellent investigators and investigator sites are already available in India. Naturally, they are overloaded with studies and the less experienced sites require time to reach the same degree of excellence. Technical and ethical knowledge development and site infrastructure development have already begun and governance measures are being put in place. Yet reports that a proportion of Indian clinical trial professionals do not always give priority to ethical considerations,  are matters of concern and cannot be ignored. The expected high inflow of clinical studies into India demands, on an urgent basis, more rapid and more extensive technical, process and attitudinal enhancement in clinical research workers than is seen now.
| GCP-Compliance - Priorities|| |
The time has come for India to urgently consider a comprehensive and widespread GCP- compliance programme to defined norms. Though excellence in the clinical trial process already exists the Indian clinical trial arena, it is not uniform to a defined standard across all relevant activities. It will be agreed that global trust in the Indian clinical trial process will only ensue if all India-based stakeholders cooperate to lessen risk. A clinical trial environment that does not tolerate non-compliance is conducive to this happening. It is suggested that a time-bound programme, simultaneously involving at least the following four groups be taken up for consideration by the Government, Indian Council of Medical Research ( ICMR) and industry bodies.
- Ethics Committees: 1) capacity building - personnel and scope of activity, 2) clearer understanding of the Informed Consent process and its implementation 3) audits and accreditation and 4) continued oversight of the clinical trial
- Public: relationship building with the Public - communication methodologies
- Clinical Trial Stakeholders: appropriately delivered training on an ongoing basis to different categories
- Regulators: 1) resource building 2) continual updating of knowledge in regard to contemporary clinical trial design and conduct, 3) create with the help of industry and other bodies a comprehensive auditing mechanism and 4) lead the multiple-pronged national clinical trial compliance endeavour.
- This paper will expand on the first two aspects.
| The Ethics Committee|| |
Through its initial review and opinion as well as subsequent oversight of the study, the Ethics Committee's role is key in ensuring that the research that ensues is in compliance with accepted ethical norms and thereby, subject protection is assured. Ethical review of a contemporary protocol is not easy, inherent complexities often taxing the understanding of even experienced Committee members. There is potential for diverse conflicts of interest to emerge. It does not need emphasis that the degree and extent of subject protection associated with a country is directly proportional to the level of competence of the Ethics Committees operating in that country and also to the degree of independence that the Committee exercises in adherence to ethical norms.
It is realized, even globally, that Ethics Committees with knowledgeable and caring members and which meet all required standards, do operate in India. Admittedly, there are variations in composition and systems of operation in other Ethics Committees, placing greater responsibility on the sponsor or the CRO in site/investigator selection and study conduct. Sites in which the respective Ethics Committees are non-compliant with CDSCO, ICMR or ICH/ GCP guidelines for composition and functioning, should be shunned. It is noteworthy that generally, Ethics Committees are actively revising their systems and procedures to bring about compliance. The outcomes of such revision can only be positive.
Registration of Ethics Committees in India is on the way to becoming a reality. The activity is expected to be within the scope of the proposed Biomedical Research Authority, the Central Ethics Committee of the ICMR being the national advisory body. Accreditation of Ethics Committees is yet to be widely accepted though a beginning has been made through workshops conducted by FERCAP (Federation of Ethics Review Committees of Asia Pacific). Till date just a few Ethics Committees have been audited and have received accreditation with validity of a year from SIDCER (WHO - Strategic Initiative for Developing Capacity in Ethical Review). It is already accepted by Government and the private sector that accreditation will allow only those ethics committees that comply with a defined level of expertise to operate in the country, but the current initiatives need encouragement to reach a wider audience.
To reach the end objective of ethics committee accreditation, a focus on development of capabilities and of personality is required. The need of the hour is the promotion of a knowledge base of local and international regulations in culturally-attuned individuals who will provide time and objectivity to review study protocols, who understand potential risks, who operate to defined procedures and have the courage and are granted the independence to take a stand on what they believe is right. Such an accredited EC will be able to withstand the conflicts of interest that may arise and will oversee the clinical trial through its duration, ensuring that methodologies which guard subject protection are observed at all times.
Imparting of relevant technical knowledge is an aspect that has already begun but is not the sole criterion to be considered. It is re- emphasized that knowledge development without personality development or in persons who do not have a flexible mindset and who are incapable of taking a broad perspective will not fulfill the true objectives of accreditation. That people of stature are desirable to take responsibility for the ethical assessment of a protocol, was recognized by Justice M N Venkatachalliah in the year 2000. In the foreword he wrote to the 'Ethical Guidelines for Biomedical Research of the Indian Council for Medical Research ( ICMR)'  he reminded that
"Biomedical Research has acquired dimensions which are at once exciting and awesome. It raises some delicate and difficult issues of ethics which need to be dealt with sensitivity to human values and great circumspection".
The accreditation process of an ethics committee is incomplete without systems that ensure that quality parameters are maintained at the required level. Audits are required and the setting up of knowledgeable audit committees should receive top priority. Government has made a beginning with a few 'site' audits. This paper emphasizes that audits of ethics committees are the need of the hour and it would be desirable if, with industry and international help, Government takes the lead to institute them without delay, in order to justify adoption of required practices and attitude and to validate the same at regular intervals. It is convenient to restrict auditing of an Ethics Committee to committee composition and to procedures adopted. Such restrictive auditing saves time but is not ideal. Comprehensive Ethics Committee audits should also consider the impact of the decision of the Ethics Committee on the conduct of the clinical study  in terms of subject protection measures, including the process of obtaining subject consent, the number and type of adverse events and reporting thereof and analysis of subject drop-out rates. To repeat, the audit committee should ideally examine for accreditation, two different aspects 1) the composition of and procedures followed by the Ethics Committee and 2) the outcomes of the Ethics Committee's decisions on the reviewed clinical study.
To re-emphasise, high priority must be assigned to ensuring that only GCP-compliant Ethics Committees are allowed to review clinical trials. Policy -making towards achieving this objective will be by Government, but clinical trial stakeholders cannot absolve themselves of responsibility. If sponsors and CROs decline to associate with medical institutions which permit non-compliant Ethics Committees to function on their premises, it will serve as a major deterrent. Unfortunately, business compulsions to accept studies and to avoid time delays in site initiations along with the absence of penalties allow Review Committees without total compliance with GCP to operate with relative impunity.
| Informed Consent Oversight by Ethics Committees|| |
Though intellectually aware that the process of obtaining consent from the subject is distinct from entering information on the consent form itself, clinical trial professionals often forget this important fact in practice.  Unless specific training repeatedly stresses this fact and Ethics Committees exercise continual overview, busy clinical research personnel will not realize the value that lies in this differentiation. Commonly used guidelines refer to a 'written' informed consent form as an essential requirement  and Ethics Committees appear to agree. It is seldom recognized even by specifically trained Ethics Committees that the 'written' informed form is for purposes of documentation and that in actual fact, the signed informed consent form only reflects the 'verbal' permission that the participant gives AFTER relevant information is appropriately imparted and discussed. For 'verbal' consent to be valid, two requirements must be fulfilled 1) full understanding by the participant of the disclosed information which should be comprehensive and should contain all information that is material for the participant to take a decision, followed by 2) verbal statement by the participant that he/she is willing to participate.  The verbal statement is then documented on the consent form.
Many busy study teams view disclosure of information as a chore that has to be gone through. Efforts are seldom made to make this process one which endeavours to reduce the natural apprehension in the subject while at the same time, imparts to the subject the information that is material to a decision to participate or not. Carefully chosen words in short sentences allow better understanding - as does repetition.  It is rarely remembered that repetition of any information is necessary for its retention. Consequently, single reading of the information or just one explanation of the information is not adequate. Yet, this is often resorted to in practice. It is important that the investigator through discussions repeated over a period of time, allows the subject to arrive at a decision which is in the subject's best interest. This is not possible unless the investigator has empathy with the subject and spends time on the consent process.
To repeat, the Ethics Committee should view the signed informed consent form not as a binding document to enter the study but as evidence that 1) the meaning of the study has been made clear to the subject, 2) that a comprehensive discussion has taken place and that 3) verbal consent has been obtained. This is a major responsibility of the ethics committee as it is agreed that the quality of information, the manner in which it is communicated and the subjects' understanding of it are important determinants of the protection of the interests and safety of the study participants.  Therefore, enquiring of site personnel how the study information is imparted, whether there is repetition of key material, whether time is allowed for the decision, and whether questions from the subject are answered fully to his/her satisfaction, is within the scope of the Ethics Committee. The methodology is not difficult, but sadly, it is often considered by Ethics Committees to be timeconsuming. Ethics Committees should realize that the advantage of contributing in a major way to subject protection far outweighs the time spent.
| Relationship-building with the Public|| |
In India, the public has little contact with clinical research understanding of this important activity. Media pronouncements are rarely balanced and create an 'exploitive' or unethical impression of research workers. Though bringing wrongdoings into the open is necessary, the absence of mention of the advantages of research does a disservice to the public and to the research industry. Such selective reporting dramatizes and draws readership, but causes lowering of public trust which is not conducive to development of clinical research in the country.
It is believed that public understanding of research could contribute to earning public trust in the research enterprise  and in the observance of human protection measures in clinical research. In the USA, the Council of Public Representatives (COPR) reports to and assists the National Institutes of Health in this context. It is believed that subject protection in clinical research can be brought about not just by imparting appropriate technical and ethical knowledge to the researchers, but also by increasing public awareness of relevant issues. Though it is agreed that a certain educational level in members of the public will allow rational understanding, it is becoming increasingly clear that members of the public in countries which host clinical studies, want their concerns to be heard. It is time that appropriate communication channels between the research body and the public are established. Innovative educational and information outreach methodologies need to be given consideration. Suggestions would include educational pamphlets and brochures or newsletters in local languages, with simply worded and pictorial information on specific aspects of a clinical trial related to subject protection. The following would be pertinent in this context:
- information on the consent discussion between the participant and the investigator,
- the facts on maintenance of confidentiality and also the privacy of the participant,
- how the subject's rights and well being are protected,
- that clinical trials will not be conducted without ethical review and approval,
- information on insurance.
It is suggested that such information be made available in doctors' waiting rooms, at research sites, near registration windows in a hospital, and at patient-aid societies. These materials necessarily need to be directed towards increasing awareness of GCP and to educate and inform about the subject-safeguards that GCP makes available. Naturally no mention of a specific study is made.
Another manner which is believed to lead to lessening public mistrust of the research activity is by making available to interested parties, information on all clinical studies undertaken in the country. The International Committee of Medical Journal Editors (ICMJE) believes that this is an effective way of avoiding 'selective awareness' of trial outcomes and the ICMJE member journals now follow a 'trials-registration' policy  . India agrees and as of June 15, 2009, all approved clinical studies are to be entered into a public registry maintained by the Indian Council of Medical Research (ICMR).
The availability of clinical trial information on a registry accessible to the public is laudable. It is intellectually plausible that knowledge about clinical trials and access to clinical trial information may allow the non-scientific public to decide what is acceptable to them or not. At the same time, it is suggested in this paper, that this fact needs to be considered with great caution. Clinical trials have complexities on which even the experts cannot always agree. If experts differ on interpretation, it is difficult to believe that the non-expert public will have the capabilities to use such knowledge in a rational manner. Unnecessary alarm may be created which will not be conducive to promoting reassurance to the public on the clinical trial activity. It is not advocated that registration of clinical trials should cease, nor that information on clinical trials should be inaccessible except to a select few, but the issue requires careful handling through discussion and debate. In the Indian situation where differing levels of education create differences in understanding, where culture and traditions often override rationality, where group autonomy is favoured over individual autonomy in some cases, care needs to be exercised that alarm or concern do not ensue. Media, which has the capacity to reach a wide audience, has a responsibility in this context that it cannot abrogate. If media develops innovative ways of reaching different levels of the public to inform and educate, it will contribute immensely to public understanding of clinical research.
| National GCP Compliance Programme|| |
It is clear that there is urgent necessity to deal systematically and simultaneously with ALL factors that could increase the risk potential to the subject. These factors include but are not limited to:
- Lack of uniformity in 'understanding' GCP and the importance of implementation - as opposed to 'awareness' of GCP
- Absence of a widespread and accepted system for accreditation of Ethics Review Committees
- Absence of a comprehensive Ethics Committee auditing policy
- Resource constraints at regulatory level and relative inexperience with contemporary clinical trial methodologies
- Poor understanding by the public of research - unbalanced media pronouncements
- Uneven site and investigator training
- Inadequate systems to deal with fraud and scientific misconduct
It will be apparent that GCP compliance involves a number of different elements in multiple stakeholders. It is mentioned again that much has been achieved in this context through the efforts of individual stakeholders and stakeholder groups, but 'piecemeal' improvements, though praiseworthy, will not allow the country to reach the compliance-level it deserves in the eyes of the clinical trial world as rapidly as it should. Efforts towards GCPcompliance must be comprehensive, multipronged, concerted and united, continued over defined timelines and then audited at regular intervals for effect to be noticed. Committed leadership is called for and it is strongly suggested that Government through the regulatory body and/ or the Department of Pharmaceuticals, takes the initiative and leads this effort. The clinical trial and pharmaceutical and biotechnological industry are willing helpers and the expertise of their local and international members is available.
Though it is suggested that leadership of this initiative should lie with Government, it is realized that systems involving Government bodies are slow to change particularly in relation to legally enforceable mandates. Having said this, there is justifiable impatience among clinical trial stakeholders in India. With the increasing inflow of trials into India, time is a commodity in short supply.
Clinical trials are essential for new medicines and each international clinical trial is a learning experience for clinical trial professionals in India. Critics of international clinical trials being conducted in India tend to overlook this important aspect. Such critics are vocal within India and in other countries. They raise valid points. All will agree that these points need attention and rectification. Often however, the critics view and report issues in terms of black or white forgetting that ethical considerations exist in several shades of grey.  They also overlook the fact that the contextual nature of ethics requires background information for completeness of understanding. No rational person will deny that procedures need to be put in place to prevent repetition of reported incidents. The solution of these problems however, lies not in raising alarm signals that the Indian clinical trial system has irreconcilable ethical concerns nor in preventing international trials from coming to India, but to extend, expand and build upon the material, knowledge and policy infrastructure that already exists. Leadership by Government of a comprehensive GCPcompliance initiative will lend credibility, though its own systems may take time to be instituted. If Government leads the GCP-compliance initiative, setting methodologies and time lines, if industry bodies support it and if Institutions in which clinical trials are conducted take responsibility for GCP-compliance for studies in their respective institutions through competent ethics committee oversight, if implementation and auditing of GCP policies and processes at all levels but specifically at ethics committee/ site/investigator/monitor levels are committed to by research professionals, an environment will be created in India which will enable and facilitate adherence to GCO. Such environment will, at the same time, encourage research workers to look askance at non-compliers bringing about a healthy respect for reputation and image. Thus compliance with the tenets of the Declaration of Helsinki will be enhanced and protection of subjects of clinical trials will be effectively contributed to.
| Conclusions|| |
India offers advantages not available in many other countries. These are already recognized and do not need repetition. This paper emphasizes that India's already existing infrastructure, knowledge base and control measures be consciously enhanced through a widespread and concerted programme of technical and ethical education, the introduction of supporting systems and procedures and of checks and disincentives. An overall clinical trial environment with poor tolerance to non-compliance with GCP norms will then be created. It is suggested that this programme be led by Government, aided by experts in the pharmaceutical, biotechnology and CRO industry, using international advisors wherever necessary. It is through such a globally visible programme that India's current human protection measures and efforts to enhance them will create and maintain global trust in the Indian clinical trial system.
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