India has become a key destination for global clinical trials. Clinical trials are the most significant direct cost -related to drug discovery and development which requires on an average around seven years. Clinical trials in India are about 50 – 60 per cent cheaper compared to the cost involved in developed countries. In addition to the cost advantage, availability of large number of easily available research participants, large pool of trained doctors and other skilled persons, government’s pro-active policy to attract the global clinical trials are the main advantages for the clinical trial industries in India. It is estimated that two million people will be taking part in clinical trials generating € 1.2 billion for the government in 2010.
While it is an advantage for India to get good business coupled with creating plenty of opportunities for employment, there is always a concern for exposing Indians to drug trials. In crudest terms, often it is considered that Indians are being treated as guinea pigs. This may not be in true sense as there are lot of protocols involved both legal and ethical to be
complied while getting approval as well as while conducting a study. Government of India made it mandatory for every study to be conducted in India to comply with Indian Council for Medical Research’s (ICMR) ethical guidelines for biomedical research on humans and the World Medical Association’ Declaration of Helsinki.
Clinical trials are conducted after the safety and efficacy study in animals. The clinical trial is proposed only after the animal study recognises the potential of investigational drug. The clinical trial is basically composed of three stages for obtaining marketing approval (the fourth phase is post marketing surveillance). The phase - I (Human Pharmacology) is done on about 20 to 100 healthy human volunteers under strict hospital control. The phase – II (Therapeutic Exploratory Trial) is a controlled study carried out on around 100 – 500 volunteer patients. The phase – III (Therapeutic Confirmatory Trial) is a more comprehensive study carried out involving around 1000 – 5000 volunteer patients. The phase II and phase III are controlled studies where volunteer patients are randomly divided into two groups - one receiving the investigational drug while the control group receiving the inert drug (product looks similar to investigational drug but contains no active substance). This study protocol is called Randomised Control Trial (RCT). The RCTs have been accepted as gold standard in clinical trials and is usually the basis of evidence- based practice.
The placebos are used in clinical trials as control to rule out the natural variation in disease state as cause of drug effects and to assess comparative safety. This helps to determine whether a particular effect of drug is attributable to drug or not. Placebo has been known to have significant effect especially subjective evaluation conditions like cancer, pain, depression, asthma, blood pressure etc.
The World Medical Association’s Declaration of Helsinki (1964) is a milestone in the development of ethical guidelines. The declaration formulated the general principles on use of human subjects in medical and biomedical research. This has been periodically revised, latest being in 2008. The Declaration of Helsinki has been the guiding force for developing National ethical guidelines for human experimentation for biomedical research. The Declaration of Helsinki (1996) states “in any medical study, every patient including those of a control group should be assured of the best proven diagnostic and therapeutic method. This does not exclude the use of inert placebo in studies where no proven diagnostic or therapeutic method exists.” This emphasized the use of available standard treatment as a control rather than using placebo.
A placebo controlled study reported in maternal – infant transmission of HIV raised concern over Declaration of Helsinki’s provision for use of placebo. While some defended the provision of placebo control while others voiced concern over use of placebo when a proven therapeutic method exists. This provision (of course along with others) was clarified and subsequently revised. The revision (2008) reaffirms its position that care must be taken in making use of placebo controlled trials and in general this methodology should only be used in the absence of existing proven therapy.
However, a placebo controlled study is ethically acceptable, even if proven therapy is available under the following circumstances:
● Where for compelling and sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; and
● Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm.
Though the meaning of ‘compelling and scientifically sound methodology’ is not elucidated further to have clarity, the revised guideline of Declaration of Helsinki clearly sent the signal of not favouring placebo controlled study. The placebo controlled study is preferred by industries for two reasons:
● It is easier to show that a drug is better than placebo than existing therapies. Equivalence studies (which compare old and new drugs) require more patients and consequently more time and money.
● If the new drug doesn’t do as well as the old drug, then doctors will prefer to prescribe the old drug.
The use of placebo groups overseas (outside USA) is justified by arguing that patients in poorer countries would not have access to existing standard treatments outside of the trial. USA Food and Drugs Administration, one of the strongest regulatory bodies, abandons the Declaration of Helsinki’s guidelines on placebo control and insists that international clinical trials can be conducted with placebo as control instead of best standard medical care.
The clinical study now propose to follow ICH’s Good Clinical Practice Guidance (GCP). ICH GCP has much weaker provision regarding the use of placebo control in clinical trials. A double standard of USA FDA regulation: one set of ethics for American citizens and the other set of ethics for citizens of poor countries.
The GCP guidelines of India specifies that the benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo or no treatment in studies where no proven prophylactic, diagnostic or therapeutic method exists. The ICMR guideline, ‘Ethical Guideline for Biomedical Research on Human Participants’ states “Each protocol using placebo requires careful consideration before approval. Denial of the available treatment to control (placebo) group of patients is unethical.” The ICMR guideline is mandatory for India.
Under these circumstances--USA insisting on placebo controlled study and the Indian regulation requiring available treatment controlled study, it is confusing for the stake holders involved in clinical trials. India being a sovereign country, the rules of the country must prevail. But mighty global clinical trial organizations will try to comply with US FDA requirements for registration of the new drugs. This may deny the available treatment to our clinical subject participants. The clarification from the authorities in this regard perhaps would make India’s stand clear.
-Dr. Guru Prasad Mohanta & Dr. Prabal Kumar Manna are professors of pharmacy, Annamalai University and G. Gayathri is lecturer, Karpagam College of Pharmacy, Karpagam University