| Dr Prem Pais |
On January 30 this year, the Government of India issued a gazette notification modifying the regulations for conducting clinical trials in India. The purpose of these new regulations was to protect the rights and safety of Indian subjects participating in clinical trials. This is a laudable and required objective. Changes and tightening of oversight into how clinical trials are being conducted was needed. While many of the regulations are unexceptional such as the need to register ethics committees and the need to compensate trial subjects who suffer harm due to their participation in the trial, some are unscientific and seem to have been put together in haste without adequate thought. The result is that the regulations threaten to kill the conduct of clinical trials in the country. This would be a great pity and would be detrimental to the health of our people.
What are clinical trials?
A prospective drug has to go through a long process before becoming available for the doctor to prescribe to his or her patients. Many fall by the way side. The molecule is first born in a biochemistry laboratory where biochemists synthesise a large number of molecules tailored to fit into receptors in human cells normal or abnormal or cells of disease causing germs to promote their function, decrease their function or destroy them. Molecules that seem promising are then tested in animal models to see if they behave as expected and to study how a living body handles the molecule, its side effects at various doses and to estimate what doses would be likely to be useful in humans. The few molecules which pass this phase enter the phase of human clinical trials. Initial human trials are in a few normal volunteers to test human handling of the molecule at various doses and any side effects. After this phase a series of trials are done in patients with the disease in question to test whether the drug is safe and effective. The most important phase is the so called phase three trial which replicate more or less usual practice situations. These trials are required by drug regulatory agencies, including India’s before a new medication can be approved for general use. The usual requirement is for a double blind placebo controlled trial. What do these terms mean? Controlled means that there will be at least two groups – one which receives the new treatment and the other a comparison control group. Randomisation ensures that a trial subject enters the experimental or control arm randomly to ensure the arms are truly comparable. A double blind trial is one in which neither the subject nor the doctor knows which treatment the participant is getting using identical appearing tablets or injections. Finally a placebo is a tablet/injection which looks like the trial medicine but is inactive and inert.
Death and complications in clinical trials
It is obvious that just as patients with serious conditions like cancer, heart attack or infections like cerebral malaria will die or have serious complications as part of usual clinical practice, those participating in trials are also going to have such unfortunate events. Media headlines that many patients died in clinical trials can be misleading. The important question is how many of these died because of being in a trial. These could be called trial related death (or complication) and be considered for compensation. A clear example of a complication not arising from a trial is if a trial participant is involved in a car accident. Conversely if such a participant develops liver damage from the trial medicine that would be a trial related “adverse event”.
Regulation of clinical trials
Clinical trials are regulated. As a first step every clinical trial has to be approved by a research ethics committee. An ethics committee is a group of people from different backgrounds – physicians, scientists, lawyers, sociologist and lay members of society – who review any research project in which human will be subjects. Their main duty is to protect the rights and safety of the research participant while at the same time permitting relevant and ethical research. The approval of this committee is essential. Even if the DCGI (Drugs Controller General of India) gives approval for a study, the local ethics committee has the final word. The committee has also to review any untoward events that may happen in projects that it has permitted and report them to the DCGI with its opinion on possible causality. At a national level permission for a trial and its oversight is the responsibility of the DCGI. The permission of both the DCGI and the institution’s ethics committee is a prerequisite for starting the trial in any site in the country. Both these bodies are supposed to periodically monitor if the trial is being conducted appropriately. The prime responsibility for this lies with the local ethics committee. This has been a problem area because of shortage of trained manpower.
Problems with the new regulations
The new regulations (Drugs and Cosmetics (First Amendment) Rules, 2013) for clinical trials have some problematical clauses. One clause states that for an injury/illness occurring to a clinical trial subject, he or she shall be given free medical management as long as required. Notice that this does not specify what type or cause of injury. Thus a trial participant may be involved in a traffic accident or assaulted by someone. Under this clause the trial sponsor has to cover all costs in an open ended fashion. This clause is unreasonable. Moreover the clause is unethical as it is an inducement for people to participate in a trial even if it is risky merely to get what amounts to free health insurance. Another clause calls for financial compensation to be paid over and above costs of any medical management in the case of an event occurring that is considered trial related. This is certainly justified. However the key question is what constitutes a trial related injury. These are defined in subsequent clauses most of which are unexceptional. There are however some which are confused. One such is “failure of investigational product to provide intended therapeutic effect”. This is counterintuitive. Regulatory authorities require a trial to be carried out to prove that the medication works. Earlier phases of clinical trials give a fairly good idea of the medication being likely to be effective but it is the large phase three trial that has to prove this. Some medications may not meet the required standard. Again, even if a medication works it may not work 100 per cent of the time. A person whose cancer was not stopped from progressing may claim compensation under this clause even though in the trial as a whole the treatment was effective.
A second definition of a trial related injury in the regulations is use of placebo in a placebo-controlled trial. A placebo controlled trial is usually a requirement by regulatory agencies to ensure lack of bias in a trial being done to prove effectiveness of a new medication. It should be made clear that in any condition in which treatment already exists, all subjects in the trial should get this treatment. The new treatment or placebo is given in addition as an add – on. Thus no group should be denied best available treatment especially in a potentially serious condition. The use of a placebo cannot be considered as equivalent to a trial related injury unless it is shown that the subject was denied existing standard treatment. A third confusing clause calls for compensation for an “adverse effects due to concomitant medication excluding standard care, necessitated as part of approved protocol”. This clause seems to imply that if the patient has a reaction or complication not due to the trial medication but to one of the other medicines that he/she is taking or advised to take, the trial sponsor is responsible not only to pay for any treatment but also to pay compensation in addition. How can the trial sponsor take responsibility for drugs that the patient has been taking all of which have been approved for marketing and are in common use? Often trial protocols advise investigators to make sure that trial participants are taking the best available treatment for their illness apart from the trial medication. These are all approved marketed medication. This clause may discourage such steps to ensure best treatment for study participants.
Does it matter if clinical trials stop in India?
Since the notification, clinical trials in India have almost come to a halt. Scientific agencies such as the National Institute of Health of the US have stopped trials in India. For the academic community in India it will now be near impossible to carry out trials of important low cost treatments that may have great impact in a poor country like ours which may not of interest to industry. There is no way such an investigator can take the risk of the kind of liability these regulations put him or her at.
The pharmaceutical industry has become hesitant. A number of multinational trials by such companies have now excluded India from their list of participating sites. They can find willing sites in other countries in the region. Halting of clinical trials in India will result in quite a few people losing their jobs and the country losing foreign investment. Apart from this relatively less important consequence does it matter if clinical trials are no longer done in India? It does. The great advances in medicine that have occurred over the last 60 years have largely been the result of clinical trials. Trials have not only identified new and effective treatments but have also identified harmful treatments that have saved many lives. As an example, 60 years ago 30 per cent of people who suffered a heart attack died in the first month. Today about 8 per cent do. In the absence of clinical trials new treatments will not be available for our people unless the DCGI accepts only evidence collected from other countries. This means that either we will stop getting new medication to use of we will have to use them without definite evidence of how they work in our people and whether Indians will react differently to the medication compared to others.
It is important for the Ministry of Health to have a re-look at its notified revised regulations and consult people with the knowledge and experience in the ethics as well as the science of clinical trials both from India and abroad. It is most important that the rights of trial participants be protected while at the same time ensuring that the greater good of our people is not harmed by killing off clinical trials. Other countries have found the right balance. There is no reason we should not be able to do the same.