Today India has become the world’s preferred hub for clinical trials primarily because of its cost effective advantages and abundance of people with diseases. With more than 15,000 hospitals, 700,000 beds along with about half a million practising doctors, the country holds huge opportunities for the growth of clinical trial industry. There are more than 220 accredited medical colleges besides having a diverse genetic pool who are not exposed to drugs and medicines.
If everything goes smoothly in accordance with regulations and set ethical norms, clinical trials hold enormous potential for benefiting patients, improving therapeutic regimen and ensuring advancement in medical practice that is evidence based.
Thus on the one hand while the overall growth prospects are quite bright for clinical trial industry, on the other, the unethical practices being resorted by some clinical trial organizations violating the rules and ethical norms has become a matter of concern.
Recently a number of cases have come to light regarding irregularities in the conduct of clinical trials in India. Notable among these are dubious consent taking procedures and allegations of drug trials on the poor and the illiterate.
In Andhra Pradesh, in a recent survey report by a group of pharmacologists who dug up the records of CRTI, it is found that the quality of reporting of clinical trials is not satisfactory. More than 500 clinical trials were examined by the team. They noticed that there was no system of post-trial obligations in most cases. Post-trial obligations describe a duty by research sponsors to provide successfully tested drug to research participants, who took part in the clinical trials after the trial has been conducted. The team noted that informed consent was taken in 67.5 per cent clinical trials. Assent taken from children was not mentioned in any clinical trials although 8.6 per cent trials studied related to childhood diseases.
The study team suggested that assent should be taken from children if they are above seven years of age. It also observed that disease to be explored in clinical trials by pharmaceutical companies was not based on healthcare need of that particular region.
Right from the beginning, the issue of ethical practices in pharma companies is a matter of concern. In most of the cases, companies prefer to conduct trial on illiterate and poor patients, which is clearly seen as a sign of exploitation of their poor economic status. “In spite of various legislations and conduct procedures laid by the state and central governments, majority of the firms are not fully compliant with the ethical norms,” reveals a team of pharmacologists in the state.
According to some sources, a majority of pharma companies and hospitals in India fail to observe ethical aspects like assent from minors involved in the clinical and post-trial obligations.
In many cases it has been found that the companies are resorting to “selective reporting” where only the positive results are reported to the Clinical Trials Registry of India, while adverse results are often kept under cover. Rofecoxib’s ignominious withdrawal, use of paroxetine in children despite evidence to the contrary being available with the company are a few examples of dubious practices going on in the name of drug development.
According to a report published in the Bulletin of the World Health Organization, India has less than 40 Ethics Committees that are properly constituted and functioning. It is also a matter of concern that there is no legal requirement for investigators or members of the Ethics Committees to declare a conflict of interest. These issues continue to highlight the importance of transparency, accountability and accessibility of clinical trials and their results.
Unfortunately, the data and reports of various trials are often difficult to find and in some cases it do not even exist as many trials abandoned or are not published due to "negative" or equivocal results. However, this tendency for availability of only selective information from the myriad clinical trials conducted is not commensurate with the practice of "evidence-based medicine".
Today, world over, a need has been felt on the imperative for transparency, accountability and accessibility in order to re-establish public trust in clinical trial data. And this would be feasible only if all clinical trials conducted are registered in a centralized clinical trials registry. Registration of trials will ensure transparency, accountability and accessibility of clinical trials. Keeping this in view and a registry for clinical trials has been initiated in the year 2007 by the ICMR’s National Institute of Medical Statistics (NIMS) and the Clinical Trials Registry – India (CTRI).
What exactly clinical trial constitutes?
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety (or more specifically, information about adverse drug reactions and adverse effects of other treatments) and efficacy data to be collected for health interventions (e.g., drugs, diagnostics, devices, therapy protocols).
These trials can take place only after satisfactory information has been gathered on the quality of the non-clinical safety, and Health Authority/Ethics Committee approval is granted in the country where the trial is taking place. Depending on the type of product and the stage of its development, investigators enrol healthy volunteers and/or patients into small pilot studies initially, followed by larger scale studies in patients that often compare the new product with the currently prescribed treatment. As positive safety and efficacy data are gathered, the number of patients is typically increased. Clinical trials can vary in size from a single centre in one country to multi-centre trials in multiple countries.
Due to the sizeable cost a full series of clinical trials may incur, the burden of paying for all the necessary people and services is usually borne by the sponsor who may be a governmental organization, a pharmaceutical or biotechnology company. Since the diversity of roles may exceed resources of the sponsor, often a clinical trial is managed by an outsourced partner such as a contract research organization or a clinical trials unit in the academic sector.
Clinical trials often involve patients with specific health conditions who then benefit from receiving otherwise unavailable treatments. In early phases, participants are healthy volunteers who receive financial incentives for their inconvenience. During dosing periods, study subjects typically remain on site at the unit for durations of anything from 1 to 30 nights, occasionally longer, although this is not always required.
In planning a clinical trial, the sponsor or investigator first identifies the medication or device to be tested. Usually, one or more pilot experiments are conducted to gain insights for design of the clinical trial to follow. In medical jargon, effectiveness is how well a treatment works in practice and efficacy is how well it works in a clinical trial. In the US, the elderly comprise only 14 per cent of the population but they consume over one-third of drugs. Despite this, they are often excluded from trials because their more frequent health issues and drug use produce unreliable data. Women, children and people with unrelated medical conditions are also frequently excluded.
In co-ordination with a panel of expert investigators usually physicians well known for their publications and clinical experience the sponsor decides what to compare the new agent with one or more existing treatments or a placebo, and what kind of patients might benefit from the medication or device. If the sponsor cannot obtain enough patients with this specific disease or condition at one location, then investigators at other locations who can obtain the same kind of patients to receive the treatment would be recruited into the study.
During the clinical trial, the investigators recruit patients with the predetermined characteristics, administer the treatment and collect data on the patients' health for a defined time period. These patients are volunteers and they are not paid for participating in clinical trials. These data include measurements like vital signs, concentration of the study drug in the blood and whether the patient's health improves or not. The researchers send the data to the trial sponsor who then analyzes the pooled data using statistical tests.
Payment of compensation
There has been lot of debates happening on payment of compensation to trial subjects. Payment to research subjects for their participation is a pervasive yet uneven practice. Although there is nothing inherently unethical about paying clinical research subjects, knowing more about its effect on recruitment and its use in different research circumstances is critical. Investigators might offer money to research subjects as incentive to participate, as fair compensation for their contribution or as a way to reduce any related financial sacrifice. Worries about undue inducement can be reduced by careful assessment of risks as well as attention to eligibility criteria and to the informed and voluntary consent of research subjects.
Although it is unclear exactly how common this practice is, according to available data it suggest that a sizeable subset of research studies at most organizations or institutions that conduct clinical research pay subjects for participation. In addition, studies that offer payment to subjects cover a wide spectrum of types of research, from short-term physiological studies offering no benefit to subjects to longer, phase 3 clinical trials that may offer the prospect of direct therapeutic benefit to subjects.
Interestingly, there appears to be some variation according to disease or medical subspecialty in the frequency with which payment is offered to research subjects. For example, it is more common in the US to offer payment in asthma, HIV, diabetes, or dermatological research trials than in oncology or cardiovascular trials. There are currently no data to explain why this variation exists. Although decisions about offering payment could be influenced by disease severity, socio demographic characteristics or the availability of treatment alternatives, some of the variation probably reflects the culture of the sub speciality.
Some commentators believe that the act of paying research subjects is wrong, maybe even coercive, while others find it an acceptable and perhaps necessary part of recruitment for clinical investigation; others see payment of at least healthy subjects as fair and appropriate.
In addition, only minimal guidance exists to help investigators determine whether or how much to pay participants in a particular study.
Ethical concerns
Several ethical concerns have been raised regarding the payment of research participants. The most commonly expressed concern is that payment could be coercive or serve as undue inducement to research participants. However, money for research participation is an offer or an opportunity and not a threat and therefore cannot be perceived as coercion.
Models of payment
Assuming that paying research subjects is ethically acceptable, there still remain questions regarding how to pay subjects. Several possible models of payment capture the various ways that payment could be conceptualized and the amount of payment determined: a market model, a wage-payment model, a reimbursement model, and an appreciation model.
In a market model, payment is designed to be a straightforward incentive. The amount of payment is determined by the market; that is, the value necessary to recruit the number and type of subjects needed in a given time frame. Consequently, studies that need to recruit individuals with rare conditions or characteristics may offer more money, while studies for which there are many willing participants may offer no money.
According to the market concept, the amount of money could be increased to overcome aversion to risk or inconvenience. Completion bonuses and escalating incentives would be commonly employed as incentives for subjects to meet data points or complete a study. In contrast, in a wage-payment model, subjects are offered payment as compensation for the time and contribution they make to the research. Money offered to subjects is calculated by a standardized hourly “wage” offered to compensate for their hours of participation, with reasonable additions made for added inconvenience.
In a reimbursement model, payment is offered to research participants to reimburse them for actual expenses, such as travel, meals, and parking. One version of a reimbursement model would also offer reimbursement for lost wages. If the latter were adopted, subjects in the same study might be reimbursed at radically different rates, depending on their occupation and normal salary.