Clinical trials have been facing some adverse reactions and scrutiny for a while with the matter now before the Supreme Court. One of the big question that is being asked is should the Supreme Court or the judiciary have intervened in an issue, which could have well been addressed by the drug regulator or a regulator as the case may be.

There is a little bit of a history to this: there have been questions about lapses, questions about unethical practices and questions about some deaths that occurred during clinical trials between 2005 and 2012. Perhaps, there are also questions about what this really means for the drug industry.

Govindraj Ethiraj, Editor, IndiaSpend, spoke to Kiran Majumdaar Shaw, chairperson and managing director of Biocon, about specific problems of clinical trials that have been held in abeyance by the courts and what the trials mean for the industry. Here are the edited excerpts:

Kiran Shaw: Clinical trials are a very intrinsic part of drug development. It goes through a pathway that is very well regulated. To begin with, you have to look at any new drug development process by starting to evaluate the drug in what we call non-clinical or pre-clinical model such as animal models where you basically establish safety and toxicity of the particular drug before you even plan human trials. When you enter human clinical trials, it’s done in a step-wise manner. You start with, you know, healthy volunteers who are then administered small doses of the drug based on the data you have derived from your animal trials. You have what are called dose escalation studies to see how the medicines perform at different dose levels to evaluate the safety of the drug. Then you conduct phase-2 trials on a larger number of diseased patients. Once you establish safety, you get into efficacy, which you first establish in a small cohort of patients. Once you establish both safety and efficacy in that small batch of patients, you move on to larger phase-3 clinical trials that evaluates the safety and efficacy in a larger diseased population. This allows the drug to be evaluated and approved in terms of the data you derived from the phase -3 clinical trials. Finally, you have post-marketing trials called phase-4 trials, which are the real use testing setting. This is where you actually have the meta analysis of patients who are actually using these drugs and you basically compile data over a certain period of time that allows you to see how safe and efficacious the drug is in patients.

Govind: Right, so the first question: how many of these trials or to what extend do these trials impact the creation or the development of drugs that are aimed at Indian consumers or Indian patients?

Shaw: Well, you know, if I may say so Govind, most of these trials that are being conducted in India are actually phase-IV studies. So, a number of these reports that you are actually talking about - both in the media and by the NGOs who are raising these alarm bells- are actually pertaining to meta analysis of drugs that are being used in patients in India. In fact, many of the deaths that have been reported are in trials that pertain to hypertensive drug or certain other kinds of drugs. Say, even cancer drugs and things like that. If you actually look at the kind of deaths that are being reported, these are about people at high risk. So, the data that you are generating, is showing that the standard of care arm had so many deaths and the new drug arm had so many deaths. And actually, it’s interesting to know that if you actually went by the evidence, you will see that the standard of cared drug actually… arm had many more deaths then the new drug arm. So, actually you are showing that the new drug is benefitting patients. But the way it has been put across is as if to say clinical trials are being conducted in India and you getting a large number of deaths.

Govind: Would you agree with the figure that’s been widely disseminated, almost 2,800?

Shaw: Yeah! Those figures are there but they are not being portrayed in the right manner. I mean today if you are going to take people who are high risk cardiac patients, you know that these are high risk patients, and if you see that the standard of care, for instance I’ll give you an example, if you take say aspirin, which is a normally used drug by any heart patient today. And then you compare it to a new drug, okay, arm, you will see that the Aspirin arm probably has I am just giving an example say a hundred deaths in that arm.

Govind: Right…

Shaw: And you are seeing in that, new drug arm there are 70 deaths.

Govind: Right….

Shaw: Now, does that mean you have to stop using Aspirin? No! this is a meta analysis. The way the deaths are reported is, Oh! there was a hypertensive drug trail and there were 70 deaths in the trial. That’s the way the data is being generated and that’s the way NGOs are portraying this data and that’s the way the media is, you know, slicing and dicing this data and even analyzing the data .

Govind: Can I ask you for a comparison? I mean, for instance, similar trails are being conducted, let us say in Africa, Latin America or for that matter even North America. What is the kind of fatalities they would produce if one could draw these comparisons?

Shaw: The same, I mean these are just meta analysis. This is not that you are doing it for the first time in India. These are approved drugs which are being used the world over and all that you are doing is that in every population setting, they want to just measure the number of deaths that are taking place and they just want to collate the information. It is required by law, it is required by regulation. That’s what we are doing.

Govind: Let me come back to the Supreme Court and the case in a moment… but can you give us a live example of what is going wrong or what is being curtailed or restrained because a certain clinical trial is not happening in the context of a drug that’s needed for the Indian market?

Shaw: If you don’t allow clinical trials to be conducted in India, then drugs that are being developed for the Indian market will not reach the patient.

Govind: Any examples?

Shaw: For instance… say a company like ours. We are trying to develop a large number of drugs, some of them are bio-similar, some of them are novel drugs. Now, if trials are not being allowed, these drugs will never make it to the market. So, what happens is that companies like Biocon will say O.K, if we can’t develop drugs in this country, we will take these drugs out of the country and develop them elsewhere? Even if those drugs are approved elsewhere, they will not be made available to Indian patients. I think there is a huge problem in this kind of an attitude.

I would now also like to say, Govind, that I am not saying that there has been no lapses on the part of clinical trial organisations, Yes, there have been certain CROs that may not have gone according to norms, there might have been certain violations amongst a few CROs that have conducted clinical trials in the country. You cannot tarnish the whole sector because of a few errant companies. Regulators have to deal with the errant companies and take action against those companies but you don’t just stop, you can’t crucify the whole industry.

Govind: Does this mean that there are no clinical trials happening in India?

Shaw: No, it doesn’t mean that, it just means that the process has slowed down considerably.

Govind: Okay.

Shaw: An expert committee, the Ranjit Roy Chaudhury Committee, has been mandated to evaluate all the CROs, audit CROs and come up with the findings of clinical trials that have supposedly resulted in a number of deaths. There was another issue in the clinical trial regime that has also created a lot of controversy, which is about compensation norms.

Govind: Yes!

Shaw: That issue has also been addressed by the Ranjit Roy Chaudhury Committee. I am pleased to say that there has been some rational decision-making in that sense. There was a view by the NGOs that anybody participating in a clinical trial, if there is any adverse event, whether its connected with the drug or not, should be compensated. This, the industry felt, was completely unrealistic and unfair because adverse events can even be a motorcycle accident. I mean, if you are a volunteer in a clinical trial and if you have a motorcycle accident, that’s also considered to be an adverse event even though it’s not drug-related and you are supposed to compensate such patients. We all know that cancer drugs are being evaluated to see if they can save patients. In many cases, we know that these are seriously ill, terminally ill patients. Even if those patients were, to say you know, succumb to cancer, again the compensation requirements from the companies were exorbitant.

I think now there has been a realisation that yes we do need to look at compensation in a fair manner. I think the Ranjit Roy Chaudhury Committee has said that compensation should be linked to the drug arm. And I think they have come up with a very different viewpoint from what it was originally.

Govind: Right! Let me come back to, I mean, let me kind of switch back to the larger issue in some ways, which is the fact that it’s actually landed up in the Supreme Court and is not being able to or has not being resolved by the drug administrator in this case. Is that something that needs to be addressed at a larger level or is this really a specific problem that will get resolved once this whole process is gone through?

Shaw: It should not have become an issue for Supreme Court had to intervene in. I personally believe that if you have a strong regulatory system in place, it is up to the regulators to address these kinds of issues like it is done all over the world, I don’t think the US FDA would turn to the Supreme Court and say O.K now you decide how clinical trials should be conducted. There are standard norms; there is what is called GCP and ICH norms, which are practiced the world over. The norms are no different in India. We are all confirming to ICH, GCP guidelines. I think that is not the issue. The issue is that the regulators did not have probably the wherewithal and the bandwidth to address many of these issues, and I think they have basically abdicated the responsibility to the courts.

Govind: I know this is a very large question but how can it be fixed to ensure that this does not happen again in the context of regulation of the Indian pharmaceutical sector?

Shaw: Well, I think, first and foremost, you have to put a very strong regulatory regime in place. I think the regulators must carry out their responsibility of regulating this particular sector. I think a number of issues have been raised and we are spending a lot of time trying to correct them. I think once the Ranjit Roy Chaudhury Committee and others who have helped come up with a rational policy for conducting clinical trials is finalized, these norms have to be the way forward. And its then up to the regulators to make sure that they enforce these norms and they are very vigilant about how clinical trials are conducted in the country.

Govind: If I want to start summarizing, there are two or three things we are looking at. I think, one is, let’s say the patient who comes in for the clinical trial or volunteers for the clinical trials has declared all his or her prior diseases.

Shaw: Consent.

Govind: Yeah, consent and the nature of prior diseases. Number two, whether or not the CRO is being adequately monitored or is someone who is, let’s say a fly-by-night operator , which is a possibility. The third is the ability of the FDA to take its own decisions and to ensure that it does not, as you say, abdicates its responsibility. So, if we were to be in an environment where all these three things are taken care of and there is an agreed upon structure for compensation of the patient, then we are looking at a situation which is, I am assuming, reasonably good for all players, including companies like yours. Would that be correct?

Shaw: Yeah! I think there are already well prescribed norms even today, Govind. So, I really don’t think that, you know, we are doing things in a haphazard manner.

I think companies conducting clinical trials as per GCP, ICH guidelines are meeting all internationally prescribed norms. I don’t think, you know, the system today is lacking in anyway. I mean, before you start any trial, there are enough checks and balances. You have ethics committees, you know, at various investigational sites. You have various, you know, clearances to go through, various approvals to go through, you know, before you can even start a trail. So, I don’t think people should think clinical trials are being done in a very haphazard manner. I think, today, every organisation is conforming to international norms for doing clinical trials.

Secondly, I think you should also ask a large number of patients who have benefited from the trials. I think we go on focusing on reports of people who have succumbed or who have had adverse events in clinical trials but I think you should also ask patients who have vastly benefited from clinical trials. If you ask all the patients who participated in our trials recently, they are absolutely delighted that they were able to participate in these trials and benefit from these trials.

Govind: Right! The last question – why does India need clinical trials or a safe and sound regime for clinical trials?

Shaw:I think India as a country has a huge disease burden. There are many unmet medical needs. We need new drugs. We need to evaluate new drugs. You cannot just be developing generic drugs and assume that it’s the same as the originator drug. That also needs to go through clinical evaluation through BEBA studies, that’s also a clinical trial. So, please understand, that if we want to be the pharmacy of the world, if we want to develop novel drugs and talk about innovation, let’s understand that we do need a very strong and robust clinical evaluation system. That’s why we need to conduct clinical trials. Otherwise, let’s not do any research, let’s shut shop, let’s not make any drugs. Let’s import all the drugs from everywhere in the world, and let’s not complaint that you know, it hasn’t been tried on Indian population so we don’t know what this drug is going to be like. If we want to use the drug, if we want to benefit from the drug, we have to be part of the clinical evaluation community.

Govind: That’s a compelling case for clinical trials and the growth of the Indian healthcare and pharmaceutical industry. Thank you very much for speaking to us.