Clinical trial — a balancing act
Anoop K Agarwal P D, Principal, Institute of Clinical Research talks about the need to strike a balance between regulatory authorities and indigenous research capacities.
‘Pill for every ill’ is an old adage, which is being focused and pursued. It may not be possible to have a disease free world but we can definitely aspire for solutions to relieve misery and make patients’ life comfortable to a great extent. Even though it has been possible to control several fatal diseases during the past 50 years, however, many new ones have come into existence. Thus, there is a great scope to develop novel drugs for treating new diseases and a big concern about improving the therapeutic approach to common ailments. Ultimately, the aim is to ensure good quality of life to patients undergoing treatment. This can only be achieved with quality drugs with maximum therapeutic benefit and minimum side-effects, available at low cost to all communities.
Clinical research helps to achieve this. It includes a whole gamut of activities from drug discovery to pre-clinical studies followed by assessment in human subjects to establish therapeutic efficacy and safety. However, processes and procedures are governed by international guidelines such as ICH-GCP and national regulatory agencies such as FDA (United States), EMEA (European Union), MHRA (Japan), TGA (Australia), DCGI (India), to ensure protection of trial subjects and generate quality data.
During the last decade, the field of clinical research has been expanding at a fast pace due to strong scientific and technological developments. New drug discovery and development has emerged as multidisciplinary and multinational industry with global market estimated at $60-65 billion annually, which constitutes 15 percent of global pharmaceutical turnover. This industry is projected to grow by 10-12 percent annually in the next five years.
Nearly 70 percent of the total time and cost of drug development ($800 million) is spent on clinical studies. Pharmaceutical giants have out-sourced clinical business to the tune of $100 million during 2004-05 to India as the cost of each trial phase is 50-60 percent lower than USA. Moreover, India is one of the most preferred des-tinations for clinical data management due to a vibrant IT industry. Other factors favouring India as a hub for outsourcing contract research are large patient population with a spectrum of diseases, diverse gene pool, specialty hospitals with state-of-the-art facilities, English speaking investigators, IPR environs, new patent law and defined regulatory requirements. The revised Schedule Y (2005) of Drugs and Cosmetic rules (1945) is in line with ICH-GCP requirements empowe-ring to participate in global trials. Moreover, Department of Science and Technology took initiative in setting up a National Board for Accreditation of Testing and Calibration Laboratories involved in clinical studies. The recent allocation of Rs 150 crore to support R&D in the pharma sector is a clear indication of government’s commitment to this cause.
The systematic process of conducting experiments on human subjects with newly discovered molecules, drug formulations or combinations, devices, vaccines and other biological products to establish safety and efficacy is called clinical trial. Clinical trials can be classified as treatment trials, prevention trials, diagnostic trials, screening trials. The quality of life trial depends on the objective of the study. Typically, clinical trials are done in four phases with increasing number of subjects in each phase. This requires co-ordination and contribution from dedicated professionals from different disciplines.
In India, 10,000 patients have been recruited in various trials co-ordinated by 2,300 clinical research professionals. In coming years, the clinical trial market is expected to increase to $300 million by 2010 providing increasing number of job opportunities. The completion of human genome project in 2003 has led to genetic information based drug discovery, which is disease specific ie, ‘molecular targets’ are identified and molecules are designed to influence the target’s activity thereby treating a particular disease. This has attracted many pharma companies to actively involve in biopharma activities (genetic based) for drug discovery with synthetic drug discovery process taking a back seat. As a result, the number of drugs in the world market has significantly increased. In India, DCGI has approved 138 drugs in 2005 as compared to 39 drugs in 2003 (Cygnus Research, CDSCO). New strategies based on engineering proteins, genes and cells as therapeutic agents will not only provide research opportunities but also revolutionise medicine in times to come. Research is being focused on gene therapeutics, tissue enginee-ring, stem cell biology and gene correction technologies.
New drug development process
Any research on humans draws social and legal attention apart from scientific considerations. A clinical trial can only be initiated after permission from the licensing authority and approval obtained from the inde-pendent Ethics Committee. Application for clinical trial is made in Form 44 accompanied by fees and documents pertaining to chemical and pharmaceutical information, animal pharma-cology, toxicology data and clinical pharmacology data. Other trial related documents such as investigator’s brochure, trial protocol, case report form, informed consent form, patient information sheet, investigator’s under-taking also need to be submitted for approval. An independent Ethics Committee comprising of a basic medical scientist, a clinician, a statistician, a legal expert, a social scientist and a common person from the community take into consideration all regulatory guidelines to ensure safety and well being of the trial participants before granting approval. Moreover, it reviews study progress report periodically and records all adverse events occurring during the course of trial for safety assessment.
A clinical research associate monitors the conduct and progress of the trial at various study sites. He ensures that the Standard Operating Procedures (SOPs) are being followed with respect to patient recruitment, informed consent process, completing case report form, drug accountability, ADR/SAE reporting, protocol deviations and documen-tation. This is all the more important in multicentric trials thus providing uniform data, which can be pooled, analysed and reported for drawing conclusions. Clinical data management process will collect and organise enormous trial data using computerised databases that accurately reflect the findings and events of the study. Finally, a trial report is prepared and presented in a scientific format by experts in medical writing which is suitable for publication and submission to the regulatory authorities for approval.
According to a study by Ernst and Young, the total market for clinical research activities in India is expected to touch $1.5-2 billion by 2010 which has led to setting-up of private contract research in the recent past requiring 50,000 trained professionals in the next five years. These big figures have also raised questions concerning regulation and ethics:
- Will lax laws, poverty and profit margins reduce patients to the status of guinea pigs?
- Does big attraction of fame, funds and foreign jaunts influence investigators to overrule safety of poor patients?
The apprehensions have been substantiated by certain unlawfully conducted trials with anti-cancer drug Letrozole prescribed to 430 young women and new molecule M4N and G4N tested on 26 oral cancer patients at regional cancer centre in Thiruvananthapuaram.
Thus, Central Drugs Standard Control Organisation (CDSCO) is attempting national registry of trials. Last year, 175 trials were undertaken in various Indian hospitals, which are expected to increase significantly in the next two years.
This is because 30 percent of global clinical trials are likely to take place outside US and Europe with major companies outsourcing clinical research to CROs mainly Phase III and IV, which involves large number of patients.
The new patent law, under Trade Related Intellectual Property Rights (TRIPS) agreement related to patentability criteria, validity period of 20 years, provision of grant of compulsory licenses under specified conditions have made many Indian companies to start consolidating their R&D activities. In 2003-2004, the top 10 Indian pharma companies spent about $400 million on R&D.
In a nutshell, outsourcing of clinical trials to India has great potential for economic benefit providing economic returns to the country and the multinational companies with tangible benefits to public health. However, these are not mutually exclusive and great insight need to be exercised to strike balance between regulatory authorities and indigenous research capacities.