Clinical trials are research investigations in which people volunteer to test new treatments, interventions or tests as a means to prevent, detect, treat or manage various diseases or medical conditions.
Some investigations look at how people respond to a new intervention and what side effects might occur. This helps to determine if a new intervention works, if it is safe, and if it is better than the interventions that are already available.
Clinical trials might also compare existing interventions, test new ways to use or combine existing interventions or observe how people respond to other factors that might affect their health
The World Health Organization (WHO) definition for a clinical trial is:
‘any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes’.
Developing countries like India, China and Africa have become an attractive destination for clinical trial activities with India having as high as 30% share of the global market.
Till 1990s, clinical trials were conducted by the government, but with increasing globalisation and a booming pharmaceutical industry, commercial interests have overtaken ethical and medical concerns. India has allowed 100% Foreign Direct Investment in the pharmaceutical industry and as a result, this industry has been booming post-1990s economic reforms.
Most of the patients are referred to these trials in India through their primary physician and doctor patient relationship is such that patient would blindly follow the advice of his doctor especially if it concerns his health. There is a need to examine the wrongs in the clinical trials industry in India and the author has tried to do so in this essay. Part II deals with international guidelines for conducting clinical trials. Part III lays down how the regulation of such trials is done in India while Part IV points out flaws in the regulatory process in India.
Clinical trial interventions include but are not restricted to:
- experimental drugs
- cells and other biological products
- medical devices
- surgical and other medical treatments and procedures
- psychotherapeutic and behavioural therapies
- health service changes
- preventive care strategies and
- educational interventions.
Researchers may also conduct clinical trials to evaluate diagnostic or screening tests and new ways to detect and treat disease.
International Guidelines on Clinical Trials
The first cases to reveal the importance of the establishing guidelines in research ethics were the abuses committed by Nazi researchers and doctors during World War 2. It included forcible administration of salt water and throwing prisoners into icy waters. Hundreds of people died in these experiments and many were forced to live with physical and physiological scars for the rest of their life. This resulted in the creation of the Nuremberg Code in 1947, which clearly stated voluntary consent is an absolute requirement for human trials.
This was followed in 1964, by the World Medical Association’s Declaration of Helenski, which basically deals with the issues of medical research in a lengthier and more systematic fashion. It sets out the basic principles for all forms of medical research and it lays separate part for medical research where medical care is also involved.
The United States FDA approved clinical trials procedure is followed worldwide. Under this, trials are conducted in a number of stages and contribute to immense time, risk and expenditure. First two stages involve the toxicological study of a potential new drug molecule on animals. This is done to ensure that molecule is safe enough to be tested on a living organism. If the drug is too toxic when tried on animals, the trial will not proceed any further, but if acceptable dose ranges can be determined, then the third stage is a three-phase trial in humans.
The Regulation of Trials in the India
Like any research or commercial activity in India, clinical trials are also supposed to go through a very lengthy procedure before they can be conducted. The clinical trials are put under Schedule Y to the Drug and Cosmetics Rules of 1945, which were amended keeping in mind the increasing number of foreign pharmaceutical companies who are using India as their research base. Earlier Phase 2 trials were allowed to be conducted in India only if a Phase 3 study was going on somewhere else.
Phase Apart from this, various professional guidelines has been released. The Indian Council of Medical Research (ICMR) issued the Ethical Guidelines for Biomedical Research on Human Subjects in 2000 and CDSCO released Indian Good Clinical Practice (GCP) guidelines in 2001.
A Clinical Trials can only be initiated after obtaining written permission from institutional ethics committee (IEC) and Drugs Controller General (I). The application utilizes form 44 accompanied by the requirement as per schedule Y, such as documents pertaining chemical, pharmaceutical information, animal pharmacology, toxicology and clinical pharmacology data.
Some other documents are also required to be submitted with the application such as trial protocol, case report form, informed consent sample form and investigator’s undertaking as to the liability. There are additional requirements for conducting trials on vulnerable and special groups such as pregnant women and elderly patients. The protocol must be reviewed and approved by an institutional ethics committee, at a minimum, seven members, including a medical scientist, a clinician, a statistician, a legal expert, a social scientist and a common person from the community.
In the applicant wishes to import the biological samples that have been developed as a result of these trial, he needs a separate license called T-License. This license is valid for multiple shipments for one year and issued simultaneously with that of the clinical trial approval. A separate No Objection Certificate (NOC) through separate application is required for shipping biological samples collected from the trial subjects out of India.
IV- Critical Analysis of Regulation of Clinical Trials in India
Entry of Contract/Clinical Research Organisations-
The increase in CROs or the contract /clinical research organisations can be attributed to changing scenario behind clinical trials. Earlier, the clinical trials were mainly conducted in academic medical institutions, with faculty providing all the necessary resources. However, the growth of the pharmaceutical industry and a large number of molecules being discovered required a large number of patients, who are available at low costs to consent for these trials. Since companies can’t have direct access to patient or doctors, they need an intermediary and CROs function as specialized organisations to fill the void.
A research report has estimated that 40 to 50 % drug applications which are submitted in the EU and US are tested in Latin America, India, China and other developing countries with the help of contract research organisations. Clinical trials are increasingly being outsourced to these CROs in the off shoring countries. About 90 % of all clinical trials in India are conducted by CROs. No audit of individual death is conducted in our countries, although autopsies are conducted, but the personnel conducting don’t have specialised knowledge.
The Supreme Court has also raised concerns over 162 trials were approved in a period of less than two months, even after the court banned all the clinical trials unless there were specifically approved by the health ministry. The court has ordered that health ministry to justify the quick approval of such a large number of trials.
According to the new guidelines, a manufacturer, before requesting an individual to participate in clinical trial of a new drug, must inform the individual all the foreseeable risks or discomforts as well as of the possible benefits. For further regulation, the Department of Health and Family Welfare has appointed an expert committee for setting guidelines for CTs. The committee produced and published its report in July 2013. It suggested various measures to ensure that clinical trials are conducted according to prescribed ethical guidelines. Both the principal investigator of the trial and the ethics committee of the institute should be accredited. Only those trials conducted at such centres should be accepted by the Drugs Controller General of India (DCGI).
An informed consent from each participant is a prerequisite for a clinical trial. In circumstances where informed consent has to be obtained from special groups of people who have limited capacity to protect their interests or give consent for themselves, the consent given by the guardian and should be witnessed by an independent person. The audio‐visual recording of the informed consent process should be undertaken and the documents preserved, adhering to the principles of confidentiality. The audio‐visual recording of the informed consent process and other related documents should be safely preserved after the completion of the study for at least a period of 5 years (Government of India, 2014). If any adverse effect or serious adverse effect occurs during a clinical trial, the sponsor-investigator should be responsible for providing medical treatment and care to the patient at his own cost and also provide proper compensation for disability or death of the participant.
Responsibility of Compensation-
The research subjects in developing are vulnerable due to lack of resources and there is a need to have special mechanism for protection of their rights.
During clinical trial, a patient can die because of several reasons: life threatening diseases like cancer, cardio‐vascular diseases like heart failure/stroke and other serious diseases that the participant may have be suffering from in the past. Death can also occur due to adverse effects of the trials. In UK, it is necessary that all clinical trials include provision for “insurance or indemnity to cover the liability of the investigator and sponsor which may arise in relation to a clinical trial.
The main reasons low cost of drug development are cheap human resources, low recruitment cost and lower rate of compensation for any injury sustained or death during the research process.