Clinical Trials in India: Key Issues

Clinical Trials refers to a set of practices and procedures performed on living organisms to test the safety and adverse effects of new drugs. India has been the favoured destination due to large number of diverse participant’s available, skilled human resource, talented scientists, low cost of trials and most importantly its compliance with TRIPS etc. But the number of clinical trials being conducted saw a drop since 2013. Only 19 trials were approved as compared to 260 in 2012 and 500 in 2010. This was due to Supreme Court intervention which noticed as many as 2,262 people died in India in the clinical trials during the past five years. Consequently court ordered to regulate the clinical trials stringently and ensure safety of the patients. Following the SC order, amendments to clinical trial regulations under the Drugs and Cosmetics Rules (Third Amendment) were also introduced in February 2013.

Why clinical trials are needed

• To check if a new drug or device is safe and effective.
• To compare existing treatments and determine which is better.
• To study different ways to use already existing treatments to make them more effective and easier to use, and/or to decrease side effects.
• To learn how best to use a treatment in a different population, such as patients in whom the treatment was not tested previously.

Various Phases of Clinical Trials

There are six phases in clinical trials as follows:

• Phase-0:This refers to exploratory study involving very limited human exposure to the drug, with no therapeutic or diagnostic goals. For example, screening studies, microdose studies.
• Phase-1:This refers to studies that are usually conducted with healthy volunteers and that emphasise safety. The goal is to find out what the drug’s most frequent and serious adverse events are and, often, how the drug is metabolised and excreted.
• Phase-2:This refers to studies that gather preliminary data on effectiveness [whether the drug works in people who have a certain disease or condition]. For example, participants receiving the drug may be compared with similar participants receiving a different treatment, usually an inactive substance called a placebo) or a different drug. Safety continues to be evaluated, and short-term adverse events are studied.
• Phase-3:This refers to studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.
• Phase-4:This refers to studies occurring after the drug regulator has approved a drug for marketing. These include post-market requirement and commitment studies that are required of or agreed to by the sponsor. These studies gather additional information about a drugs safety, efficacy, or optimal use.

Need of Clinical Trials in India

Out of the total population in India, 70 million suffer from rare disorders like cystic fibrosis, Wilson disease, etc. many of which still does not have any cure. Moreover, the cost of treatment of many of such disorders is very high. Apart from this the research in India is more skewed towards non-communicable diseases like cancer etc. Less focus is done on communicable diseases like TB, malaria etc. So, clinical trials in this arena brings a balance in overall research.

Although most of the trials in India are Phase III trials that involve testing of already ‘well tested’ drugs, therefore, done to test the therapeutic dose of the drug on large population. Hence, not only is the risk minimal, but also participants gain access to new treatments before they are widely available.

Regulatory mechanism of clinical trials in India

There are some laws governing clinical trials-Drugs and Cosmetics Act, 1940, Medical Council of India Act, 1956, Central Council for Indian Medicine Act, 1970.

There is also a three tier review process before final approval. First, the applications are reviewed by the Subject Expert Committees (SECs).In second stage they are monitored by Technical committee and finally by the Apex Committee. Once this mechanism is completed then final approval is given by Drugs Controller General of India (DCGI) whose approval is mandatory. Indian Council of Medical Research, the apex regulatory body for clinical trials, was set up to promote research culture in India and develop infrastructure for clinical trials.

What are the issues with respect to conducting clinical trials?

The key issues are as follows:

No informed consent

One of the most important problems is that the consent of the participants in the clinical trials is not taken. It is due to a large proportion of participants in India is illiterate and lured into trials by offers of free healthcare but they are not informed of the difference between treatment and research. For instance-In 2004,bhopal gas leak survivors getting treated at Bhopal Memorial Hospital and Research Centre (BMHRC), were recruited for clinical trials without their knowledge and 14 of them died while conducting the trials.

Problem with ethics committee

Ethical committees are constituted to monitor the ongoing drug trials. However, it is often found that in most cases ethics committee is not constituted. Further people on such committees are not well trained nor these committees work independently.

Non registry of trials

Clinical Trials Registry of India calls for registration of all clinical trials conducted in India. However since its launch less than 70 trials have been registered. Registration is mostly done for positive trial cases. Consequently, there is lack of transparency regarding current trial practices. Moreover, it also undermines the stronger regulation which can be achieved if some database on the trials is available.

Unethical practices of CROs

The companies outside India get there clinical trials conducted through clinical research organisations (CROs)—independent companies hired by sponsors to undertake clinical trials. They are chosen primarily because of their ability to form partnerships with local research organizations, recruit large numbers of participants and quickly conduct trials. However they are found to be conducting trials in most irresponsible and unethical manner. In 2011, CDSCO even suspended the licence of Hyderabad-based CRO Axis Clinically Ltd for recruiting illiterate women for a trial without obtaining proper consent.

Slack international standards

There is lack of international standards governing clinical trials. For instance, the Declaration of Helsinki, of which India is a signatory voluntary in nature and lack regulatory teeth.

Delay in approvals

Three tier approval mechanisms has led to considerable delays in approval. This is attributed to the unpredictability in the SEC and Technical and Apex Committee meetings. Consequently, India became less competitive in comparison with other emerging markets for the conduct of clinical trials.

Ambiguous language

Non clarity of the language of the amended 2013 rules also deters companies to come to India. For eg-Rules says the consent of the participant will be recorded in audio-visual recording. It is mandatory only for cases where vulnerable population is involved but it does not clarify the definition of  “vulnerable”.

Ranjit Roy Chowdhary committee on Clinical trials

With the objective of making more innovative medicines available to the patients with critical illnesses like hepatitis, tuberculosis and HIV the Health Ministry had planned to do away with clinical trials with respect to some drugs that have been approved by the developed markets like the US, Japan, European Union, Canada and Australia. The conclusions have been drawn from the recommendations of the Ranjit Roy Chowdhary Committee on Clinical Trials. Some of the major recommendations of this committee are as follows:

• Clinical trials must be carried out only in the accredited centres.
• The accreditation must be both of the principal investigator of trial and the ethics committee of the institute.
• A Central Accreditation Council must be set up which will look into the selection of assessors for accreditation and the experts who will review the new drug applications through a random procedure.
• There should not be any violation of the approved process which highly emphasizes on the informed consent of the participant. If found violating, the Principal Investigator shall be blacklisted for a period of minimum of 5 years. Audiovisual recording of this informed consent must be facilitated which shall be preserved while maintaining confidentiality.
• The 12 drug advisory committees must be replace by a single broad expertise based Technical Review Committee for quick clearance without any compromise on the rules and regulations.
• The responsibility for compensation in case of adverse or serious adverse effects during trial lies with the sponsor investigator. This must be given irrespective of whether the patient is in control group, placebo group, standard drug treatment group or test drug administered group.
• The drugs that have been in the market of well-regulated countries with a post-marketing surveillance of atleast four years.
• A special expert committee other than the Drug Technical Advisory Board must be set up which will review all the drug formulations in the market and identify potentially hazardous drugs.

While the health ministry had accepted the recommendations, the final implementation has not been possible owing to the objections raised by the Drug Technical Advisory Board. The fear is that the drugs which have been accepted in other countries may not be suited to the genetic structure of Indians. This point is being considered on a case to case basis with a view to ensure the efficacy and safety of the drug along with increasing quick availability of the drug.