The conduct of clinical trials on medicinal products for demonstration of their efficacy and safety has in it a large number of inherent problems due to the diversity in human species caused by genetic and environmental factors. The huge inter-individual differences and gross variations in the occurrence of the same disease in different individuals lead to manifold variability in responses to effects of medicinal products. Hence, evaluation of a disease using a series of parameters, many of which are not quantifiable, such as pain and anxiety, is not an easy task.
Over and above this, assessment of effects of a medicinal product on patients by the clinical investigators, who suffer from their own prejudices, preoccupations, whims and fancies, terribly confounds the whole scenario. The clinical trials organisation offers a stupefying job because of availability of ample room for manipulations in design, conduct, analysis, interpretation, inference and reporting of the results of clinical trials to favour a predetermined hypothesis or concept supporting demonstration of superiority or inferiority of one medicinal product over the other. Therefore, there has been no dearth of fraudulent practices all over the world in the conduct of clinical trials on medicinal products because of commercial interest of the sponsors as well as of the investigators.
Past & present scenario
Indian clinicians, be it from allopathy, ayurveda, homeopathy, unani and siddha, have been practicing a personality based medicine and therefore, not surprisingly, clinical trials have also been conducted in the same style, i.e., in a reasonably unregulated environment. Indeed, there has been a lack of primary interest, seriousness, sincerity and scientific and ethical approach from the part of medical fraternity in conducting clinical trials on medicinal products. Prejudices arising out of commercial interests coupled with lack of scientific approach and personality based medical practice in India have led to publication of erroneous reports resulting in loss of credibility of the same.
So far there have been no uniform guidelines and principles for conducting clinical trials in India. With India being a signatory to the product patent regimen since January 2005 and globalisation of the pharmaceutical industry, the scenario has rapidly changed and now Indian companies are developing new medicinal products (new drug products, drug delivery systems, generic versions of off-patent products and fixed dose combinations) and spreading their wings in the highly regulated international markets, particularly the US and EU. These areas of interest are now driving the clinical research and development in the right direction and good clinical practice (GCP) is being observed to ensure the accuracy and credibility of the observations and reports of trials and protection of the rights, safety and well being of study subjects.
GCP guidelines
Inhumane ways of handling and treating prisoners in the Nazi concentration camps, which included exposure to extreme temperature, performance of mutilating surgery and deliberate infections with a variety of lethal pathogens resulted in the development of Nuremberg Code in 1948, setting forth 10 conditions that must be met to justify research involving human subjects and take care of their health and rights.
In the USA, the Belmont Report on the ethical principles and guidelines for the protection of human subjects was published in 1979 to take care of three fundamental ethical principles like respect for persons, beneficence and justice. The World Health Organisation (WHO) recognised a need for guidelines with broader scope, and thus the Declaration of Helsinki: Recommendations Guiding Medical Doctors in Biomedical Research involving Human Subjects was adopted by the World Medical Society in 1964.
These guidelines have been revised a number of times and are currently in use throughout the world. Based on the principals emanating from the Declaration of Helsinki, the expert working group (Efficacy) of the International Conference on Harmonisation (ICH) for the technical requirements for registration of pharmaceuticals for human use, has developed the guidelines on GCP taking into account the current GCPs of the European Union, Japan, US, Australia, Canada, Nordic countries and WHO to provide a unified standard for the EU, Japan and US to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.
In India, the basic principles of GCP emanating from the Declaration of Helsinki have been included in the GCP guidelines issued by the Central Drugs Standard Control Organisation (CDSCO) and in the ethical guidelines for biomedical research on human subjects provided by the Indian Council of Medical Research, Government of India. The Schedule-Y of the Drugs and Cosmetics Act 1940 has also incorporated the principles of GCP.
Transition in today's perspective
The need of the day is to conduct clinical trials on medicinal products under strict adherence to the protocol observing GCP and respecting applicable regulatory requirements, after obtaining approval of the Institutional Review Board (IRB) or Independent Ethics Committee (IEC). Standard Operating Procedures (SOPs) for clinical examinations, tests, laboratory investigations, data recording and reporting should be followed to ensure accuracy and uniformity of the procedures performed in the trials.
Clinical trial auditing: Unlike in the past, the conduct of clinical trials is not restricted to the clinicians and patients. It is a multidimensional and multidisciplinary activity primarily involving sponsor, investigators and drugs regulators. At the operational level qualified, trained and experienced personnel such as clinical pharmacologists, clinicians, pathologists, biostatisticians, pharmaceutical technologists, bioanalytical technologists, experts in quality assurance and quality control, auditors, monitors, co-ordinators, data managers, medical writers, management experts and financial advisors are involved in the organisation, management, conduct, analysis, interpretation and reporting of clinical trials.
To ensure adherence to protocol, adoption of SOPs, implementation of GCP and applicable regulatory requirements in the conduct of all the trial related activities, a number of quality assurance and quality control measures, monitoring, supervision, co-ordination and site-management are undertaken. Auditing is one such quality assurance measure that is required to be undertaken as a systematic and independent examination of trial related activity and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analysed and accurately reported according to the protocol, sponsor's SOPs, GCP and the applicable regulatory requirement(s).
Auditing is an independent quality assurance activity used by the sponsor and carried out by persons not directly involved in the trial to evaluate the effectiveness of monitoring activities.
Auditing is distinguished from monitoring by the fact that monitoring is carried out while the study is in progress, whereas auditing can occur anytime during or after the study. Sponsors are required to bear the primary responsibility for establishing quality systems and conducting quality assurance audits. Audits are, therefore, carried out to ensure that all the trial related activities are consistent with the protocol, and the study data (interim or final) is verifiable with the source documents.
The audit is also aimed to find out if practices were employed in the development of data that would impair their validity and compliance with the adopted SOPs. Auditors are required to document their observations and should be archived by the sponsors and made available to the regulatory authorities whenever required. It is necessary on the part of the sponsor to promptly initiate action in case any party has failed to comply with GCP, SOPs, protocol and any applicable regulatory requirements. If auditing identifies serious and/or persistent non-compliance, the sponsor should terminate the defaulting party's participation in the study and promptly notify the matter to the regulatory authority.
The sponsor must obtain the audit certificate and audit report for each auditing done during or after the completion of clinical trial. A documentation that allows reconstruction of the course of events in the clinical trial (audit trail) should be generated to ensure consistency and credibility of study.
Clinical trials auditing in India is a pressing need of the day and must be undertaken to ensure that the rights, safety and well-being of human subjects participating in the trial are protected and the reported trial data are accurate and complete. This would give a sufficient guarantee that the report of the clinical trial is credible and worthy of submission to the drug regulatory or licensing authority and publication in a medical journal.
(The author is the executive director of ACEAS Clinical Research, Ahmedabad)