|Year : 2013 | Volume
| Issue : 1 | Page : 1-3
Ethics at crossroads: Global guidelines vs. local laws
President, Clininvent Research Pvt. Ltd, A-103, Everest Chambers, Marol Naka, Andheri-Kurla Road, Andheri (E), Mumbai, Maharashtra, India
|Date of Web Publication||23-Jan-2013|
President, Clininvent Research Pvt. Ltd, Mumbai
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Bhatt A. Ethics at crossroads: Global guidelines vs. local laws. Perspect Clin Res 2013;4:1-3
"There is but one law for all; namely the law which governs all law - the law of our creator, the law of humanity, justice, equity; the law of nature and of nations."
Over the last decade, India has become part of globalization of clinical trials. The regulatory changes of 2005 promoted the growth of clinical trials industry. Growing globalization of clinical trials to India and other developing countries has raised ethical concerns. , The ethical issues reflect the diverse demands of adherence to global ethical guidelines and local practice of compliance to regulations governing clinical trials. The global guidelines - Nuremberg Code, Declaration of Helsinki, Belmont Report, Council for International Organizations of Medical Sciences' and World Health Organization's International Ethical Guidelines for Biomedical Research Involving Human Subjects, and International Conference on Harmonisation's Good Clinical Practice (GCP) - provide the basis for fundamental ethical principles for conduct of clinical research.  Based on these guidelines, Emanuel et al., proposed essential requirements, which are vital for ethical conduct of research globally and in developing countries. , These requirements are:
The basic premise of these principles is that they provide an ethical framework which should minimize the possibilities of exploitation of research subjects in developing countries.  We need to reflect on how these principles have been practiced in Indian setting.
- Value: Research should have social or scientific or clinical value.
- Scientific validity: The methodologically for research must be rigorous, based on accepted scientific principles and methods
- Fair subject selection: The selection of subjects should be based on scientific goals, considering potential distribution of risks and benefits amongst the target population, and protection of vulnerable population.
- Favorable risk-benefit ratio: The potential risks to research participant should be minimized, and the potential benefits enhanced, and the potential benefits to individual subjects and society are proportionate to or outweigh the risks.
- Independent review: The research study should undergo a review by individuals who are not affiliated to the research.
- Informed consent: Individuals should be informed about all aspects of the research study - purpose, procedures, potential risks, benefits, and alternatives, - and provide their voluntary consent
- Respect for enrolled subjects: The research participant's privacy should be guarded. They should have the option to withdraw, and their well-being should be monitored.
The evaluation of social value of any new intervention is under government/regulatory purview. The current controversy about the need for cervical vaccine in India  raises questions about how the process is carried out and who is responsible for this evaluation.
The assessment of scientific validity and favorable risk-benefit ratio is done by the regulatory authorities and ethics committees (EC). The Indian regulatory authorities require phase III data in at least 100 patients for a drug already approved in other countries, and on at least 500 patients for a new drug substance discovered in India.  These numbers are not as per current international regulatory expectations and do not appear to be scientifically or statistically acceptable. Since last year, the new drug advisory committees (NDAC) advise the regulatory authorities in approval of clinical trial. The NDAC are supposed to conduct an in-depth evaluation of non-clinical and clinical data on the investigational product, a review of risk: benefit to the patient, and assessment of unmet medical need in India and innovation vis-ΰ-vis existing therapy.  As majority of NDAC members are clinicians lacking expertise in drug development, and as there is no guidance on how the review/decisions are made, there is a likelihood of subjectivity in decision making process. The EC, whose focus is on ethical aspects, usually accepts the scientific validity and risk: benefit assessment for a clinical trial, if it is approved by regulatory authorities.
One of the biggest challenges for India is how to ensure fair subject selection and protection of vulnerable population. Indian GCP stresses on the need to protect vulnerable population e.g., poor or unemployed and recommends
These recommendations do not provide specific suggestions as to what action an EC should take to protect vulnerable population. There is also no additional or specific guidance in Indian Council of Medical Research (ICMR) ethical guidelines.  The ICMR guideline for preparing Standard Operating Procedures (SOP) does not describe any SOP for protection of vulnerable population. 
- Effort may be made to ensure that individuals or communities invited for research be selected in such a way that the burdens and benefits of the research are equally distributed.
- The observations and suggestions of EC should be given in writing in unambiguous terms in such instances.
- For vulnerable population, mode of consent should be carefully considered and approved by the EC.
The independent review by EC suffers because of deficiencies in EC functioning. A recent survey of EC approval letters revealed deficiencies in composition, quorum, and review of insurance, and clinical trial agreement.  Indian GCP discusses conflict of interest issue for a member, whose proposal is under discussion by EC. However, it does not describe conflict of interest in selection of EC members. This issue has become paramount in formation of "independent" ECs, most of which are formed by the investigator, with membership consisting of friends/relatives. As per US FDA checklist for Institutional Review Boards (IRB), policy on conflict of interest, the investigator cannot select IRB members.  Unless there are clear regulatory guidelines about how EC should function and make decisions, there will be deficiencies in the independent review process.
The informed consent process and respect for enrolled subjects are primarily responsibilities of the investigator. There is a difference between the understanding, training and practice of these principles between medical practice and clinical research. Additionally, the issues of patient's poverty, illiteracy and vulnerability make the consent process quite demanding.
The fundamental question is: How can the ethical quality of EC review and the consent process be ensured, if compliance to other principles of ethical conduct is not assured?
Indian clinical research is at a critical juncture as the implementation of local regulations and global guidelines does not seem to be in harmony. We need urgent steps to improve ethical quality of clinical research and harmonize local regulations with global guidelines. These steps would include:
These actions are essential for creation of a robust ethical framework for clinical research, which could boost public confidence and provide assurance that the rights, safety and well-being of trial subjects are protected, in compliance with the global principles.
- Creation of a central ethics and scientific review body to review and conclude whether the clinical trial meets the benchmarks of social value, scientific validity, fair subject selection and favorable benefit: risk ratio
- Development of clear regulatory guidance on institutional EC responsibilities, composition, quorum, functions and operations, with specific focus on protection of vulnerable subjects, and EC responsibility for oversight of conduct of clinical research by the investigator.
- Development of clear regulatory guidance on informed consent process, and documentation, with special emphasis on autonomy, capacity, and literacy.
- Mandatory education and training of EC members in science, ethics and regulation of clinical research.
- Mandatory education and training of investigator and site staff members in science, ethics and regulation of clinical research.
- Accreditation of ethics committees and investigator sites.
- Regulatory inspections of investigator sites, ECs and sponsors.
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