Sunday, December 26, 2010

Drug Trials In India: Cheaper and Weak Ethical Controls

Australians don't realise that many of the medications they'll be consuming in the future will have been trialled in India. The reasons drug companies are going there are that it's cheap and ethical controls are weak or non-existent. Indian researchers are sounding warnings. Also, an eminent statistician talks about problems in reporting of medical trials.

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This transcript was typed from a recording of the program. The ABC cannot guarantee its complete accuracy because of the possibility of mishearing and occasional difficulty in identifying speakers.

Norman Swan: Hello, it's Norman Swan here with the Health Report. Today on the program: A major issue that's barely mentioned in Australia. It's the fact that drug companies are carrying out more and more of their medications trials in developing and emerging nations. These are drugs that will be used one day in Australia and one of the leading countries in this is India.

It's a lot cheaper for the pharmaceutical industry and the quality of the research can be high. But a leading Indian ethicist claims that another reason is that it's much easier for drug companies to obtain ethics approval for a trial because, he says, Indian ethics committees are weak, poorly trained and tend to be rubber stamps. The results could be shortcuts, exploitation of participants and perhaps even questionable findings. Ethics committees have to approve a trial to protect the participants.

Dr Amar Jesani is the founder of the Centre for Studies in Ethics and Rights in Mumbai. Possibly the only institute in India devoted to the study of bioethics.

Amar Jesani: There were two major developments that led to the increase in clinical trials. One was the relaxation in the patent act, India had a patent act of 1970 which only provided patent for the process and not for the product.

Norman Swan: So pharmaceutical companies did not want to come to India because they didn't have intellectual rights protection for their drugs?

Amar Jesani: Yes, in 2003 the government carried out a final modification in the laws. The second was in 2005 the government of India made a massive change in the clinical trial law.

Norman Swan: Previously this law had limited the trials permitted in India and the acts liberalisation freed things up and put India more on a par with what's allowed in countries like Australia.

Raju Chacko is a medical oncologist - a cancer specialist - at the Christian Medical College in Vellore, Southern India, one of India's best medical centres. Raju is heavily involved in clinical trials into cancer drugs and there's one big reason why from his point of view.

Raju Chacko: As a medical oncologist I come into contact with many patients with solid tumours and my interest has been developing new drugs for the unmet needs of these patients.

Norman Swan: And when you say solid tumours you're meaning the tumours that turn into lumps rather than say blood cancers like leukaemia or lymphoma that sort of thing.

Raju Chacko: That's correct yes. In a country like India where you have so many patients who need cheap answers to their problems, or you need answers that they can afford, one of the things that I have been trying to do is look at the local pharmaceutical industry and try and support the research that they do. So that the kind of molecules that come out in this country would be answers to problems of this country. Of course I do research for multi-national companies and would sell their drugs out in the international market and it's expensive for India in comparison.

Norman Swan: So give me a picture - you've worked in Adelaide, you've trained in Adelaide so you know what it's like. Give me a sense of what happens to the person in the street in Vellore in Tamil Nadu with cancer compared to a rich country like Australia.

Raju Chacko: This particular person who is on the street in Vellore would have difficulty accessing me because there are so many people who tell them that it would be too expensive to come to me.

Norman Swan: Because there's no public care effectively?

Raju Chacko: Yes, there is some public care but even then what he can access in the public care may not be a standard of care. When he does get to me the main issues would be can he afford the care?

Norman Swan: Cancers are diagnosed late?

Raju Chacko: Most cancers are diagnosed late yes. In this hospital we try and provide therapy to patients who may be potentially cured even if they can't afford it. But that's not the case everywhere and if you come to us for treatment that is going to be palliative we couldn't afford to treat you unless you paid for it.

Norman Swan: So you make a decision up front for people who can't afford it if it's curable you'll treat, if not you make that tough decision?

Raju Chacko: Yes.

Norman Swan: Hard to do.

Raju Chacko: Very.

Norman Swan: So let's say you've got a woman who has operable breast cancer and they are positive for this relatively new drug called herceptin, trastuzumab, would they get it in India?

Raju Chacko: They would get it if they could pay for it. They would get it if they got into a clinical trial with me.

Norman Swan: So one reason you do clinical trials is access to drugs?

Raju Chacko: Yes, for example there's a trial which is international being done under the breast international group of which we are a part of. And this enables patients to receive herceptin or another drug which is called lapatinib for patients who've had an operation for breast cancer and they receive this drug in a clinical trial which is arguably the best thing that can happen to them.

Norman Swan: Raju Chacko of the Christian Medical College in Vellore. But the Christian Medical College may be a bit of an exception. As you're about to hear, now that trials are booming in India, there are multiple causes for concern. And the growth is such that in a few years a large proportion of all trials in the world will be done in India.

Amar Jesani of Mumbai's Centre for Studies in Ethics and Rights again.

Amar Jesani: So you find the statistics like saying around 2003 there were about 100 clinical trials taking place in India. By 2009 more than 600 were taking place fuelled by the Drug Regulation Authority and a trial normally covers 5 to 7 institutions, so you may have 3,000 institutions involved in a clinical trial.

Norman Swan: And how many people have been recruited overall do you think?

Amar Jesani: I was looking at the data published in the October issue of Indian General Medicine and this data was up to the end of June 2009 and what I estimate is that something like 80,000 to 200,000 people are participating. But this registry is not reporting the actual number of clinical trials taking place. We also don't have exact estimates of the number of hospitals any more, India doesn't have any law to register hospitals.

Norman Swan: Really. So you just call yourself a hospital and there's no regulation?

Amar Jesani: India has a massive private sector, 80% of the salaries are in the private sector and if you look at financing 80% of health services are paid for by the people directly from their pocket. So only 5% of the people are covered under insurance and government financing is only for 15% of the total expenditure. Government spends 1% of GDP on health while the private expenditure runs up to 5% of GDP. It is a big imbalance and India having 40% of very poor reliant people and almost 80% of the people are near poor. Those people get completely neglected.

There are private hospitals but they are too powerful and they don't want any regulation. Only 8 states out of 30 provinces in India are having some laws related to registration of hospitals. That you just tell us that you are working as a hospital.

Norman Swan: So there's no regulation, it's just registration?

Amar Jesani: There's no regulation because there are no minimum standards set. We have been fighting on this, we were fighting many litigations in the high courts and all and ultimately the government of India introduced a bill for the registration and regulation of private hospitals. Three years back it was introduced in the parliament, it is not moving further because the hospital industry is too strong, it doesn't want any regulation.

Norman Swan: So there could be clinical trials -

Amar Jesani: I can't tell you how many hospitals are there, nearly 15,000 to 20,000, I believe that out them 1000 or 2000 must be involved.

Norman Swan: So this story is both good and worrying. Now people who are doomsayers in the west say oh well, this is the pharmaceutical industry finding cheap, easy ways to do clinical trials where ethics committees are weak and can be bought to be blunt, and the good side is that you get clinical trials done in India which are relevant to Indian populations. What's your analysis of the situation because a lot of it does depend on the ethics committee because they are the group who oversight a trial and guarantee the safety of the person participating?

Amar Jesani: The argument in favour of clinical trials are quite a few. One is that India is a country of contrast we have rich people as well as poor people so we have not got rid of the traditional communicable diseases as the west did.

Norman Swan: You've got cancer and heart disease as well.

Amar Jesani: We have non-communicable as well as communicable diseases present so there is a big scope, again large numbers. Even if a disease is existing in a smaller proportion of the population the absolute number of people that you can get is very high. The third reason is that as I said 80% of the people have to pay from their pocket to get health care and a large number of people are poor so when they fall sick, they are not able to get care and many of them might be dying or going through a lot of hardship so it is easy to recruit. The pharmaceutical companies are finding it difficult to recruit participants in their own countries because people like to go through treatment which is standard treatment, proven treatment, they don't want to get experimented on. When people participate in a clinical trial of this kind isn't the voluntariness compromised? R&D is compromised.

Yes, ethics committees are also weak and legislations are not in place that means there is more chance of exploitation. I'm not saying that everybody is doing bad things but the general tendency when you see the large number of trials taking place there is a cause for concern.

Norman Swan: So what is the state of ethics committees in Indian institutions?

Amar Jesani: There is a rule that all trials should be reviewed by the ethics committee and that is mandatory using ICM guidelines, Indian Council of Medical guidelines. As a consequence very many trials are taking place, they hope to create an ethics committee at least on paper so if there are clinical trials taking place in 1000, 2000 hospitals I assume that there will be at ethic committees there but nobody knows. They said if those hospitals are not registered, there's no authority to register this ethics committee. And the second part is, do they function, do they really meet and who are the people who are sitting on these ethics committees, what is their competence to actually review this protocol? And whether they are independent to stop the trials it they feel they're being done unethically.

The 2006 guidelines of ICM also say that ethics committees are not only supposed to review trials but they are also supposed to monitor - that is a very tall order.

Norman Swan: A tall order in Australia, much less in India.

Amar Jesani: Anywhere I am telling you. You decentralise the entire staff, you don't use the resources, you don't train people who are going to work there and then close your eyes and say that there will be justice for the people - it doesn't happen. We have decentralised the regulation of the clinical trials in the hands of the institution based ethics committees but we have not done anything to give money for the Secretariat of the ethics committee and train people who are going to be on the ethics committees, give money so that meetings take place and ensure that the appointments which are being made they are not being made in the vested interest of the institution which is having it. Create some kind of selection process. Here there is nothing.

Norman Swan: And in a context where it is predicted that within the next ten years 1 in 3 of all clinical trials will be done in India.

Amar Jesani: That is what they are saying, they are saying that at the moment businesses that have $1 billion 150 CIROs -

Norman Swan: CIROs being clinical research organisations. These are outsourced.

Amar Jesani: Clinical research organisation, they take contracts for doing clinical trials and actually they are a research based commercial organisation.

Norman Swan: And these are trials that will be done for drugs that will be applied worldwide, not just in India?

Amar Jesani: That is not the only thing. In India there are also a number of people who suffer from diabetes and hypertension so we need those drugs. The only thing is if the trial is done in Indian communities, there should be some benefits for the communities but when the drug is actually approved by the regulatory authorities for marketing the prices are so high that only the elite Indians who never participated in the clinical trial, they are the ones who can use those drugs, not the common people who actually participated.

Norman Swan: And the other issue is what happens to participants do they continue on the drug once the trial has finished?

Amar Jesani: Well yeah, there are a number of considerations for trials. When I was looking at the data of June 2009 I found that 30% of the clinical trials taking place in India are still placebo-controlled. So the issue immediately comes is what happens to people who were on placebos?

Norman Swan: So if the drug works do they get converted from a placebo to the real drug?

Amar Jesani: And why are they doing placebo-controlled trials so many in numbers when other treatment is already available?

Norman Swan: You're listening to the Health Report here on ABC Radio National talking about major concerns about the ethics and monitoring of clinical trials in India; trials of drugs which will come onto the Australian market one day.

The issue of trials comparing the drug to a placebo is a hot one among ethics committees in the West. You see, there's a legitimate ethical and scientific argument that it is invalid and unfair in many instances to subject people to placebo when there are accepted, proven treatments available.

What should be done is what's called a head to head study where at the very least the participant receives the best available treatment compared to the new medication.

Amar Jesani.

Amar Jesani: So that is one part. The second part is as you said that if people are having chronic diseases and the trial is done on them they require medication for the rest of their whole life. They may be HIV positive, maybe diabetes or have hypertension. So I've been on the trial for a year, I improve and that proves that your drug is good. And you market it - but after one year I am out.

Norman Swan: Although some pharmaceutical companies say that they do keep people on it, regardless of where they do their trial.

Amar Jesani: They do but again normally there is a lot of negotiation that requires a very active ethics committee to do the negotiations with them. How many years will they continue giving them?

Norman Swan: So these are issues which are common to Britain, Australia, to the United States, how do you train ethics committees, how do you maintain them, how do you resource them to monitor trials. It's hard enough for a country with 20 odd million people like Australia, it's just mind boggling to think how you would change the situation in one of the most populous countries.

Amar Jesani: 1 billion people.

Norman Swan: So what's afoot, because the world shares in this issue, we all should have an interest in this issue because we are all going to be taking medications which might have been trialled in this country?

Amar Jesani: What I believe is and I also have been interacting with European regulators in Brussels. My argument is that people in the developed countries should be concerned simply because I would not feel very comfortable using a drug which is tried out, which has been developed with the violation of human rights of other people. And how would you like to use a drug that was developed in a Nazi concentration camp? So I think the regulators in the developed countries should also pressure, the politicians and the public opinion should also pressure the developing countries as well as their own pharmaceutical industry because the centre of power of the pharmaceutical industry is in the developed countries, to bring about some control over them or regulation over them so that they carry out clinical trials in India using the same standard of ethics that they are using there.

Norman Swan: But it's still up to the institution, the hospital, the university to create the ethics committee and they've got to be independent of the pharmaceutical industry - how is it going to work, how should it work?

Amar Jesani: These countries will also have to share the responsibility to our resources, because developing countries can't invest in creating the regulatory structure. But if trials are to be continued then somehow or other I think developed countries have that responsibility. That doesn't mean that my country doesn't have responsibility I'm not only fighting with my government I am fighting with the institutions but I believe that those ultimate users of this drug should be concerned that this drug was produced with human rights violation of poor people somewhere.

Maybe in India, maybe in Eastern Europe, maybe Brazil - it doesn't matter, I'm not saying that it is because my people that's why you should be concerned, it's anywhere. Weren't we concerned when minorities were used in some of the developed countries, or prisoners were used in some of the developed countries to get these drugs out and there was a hue and cry?

Norman Swan: What is happening internally in India to improve the situation?

Amar Jesani: The economic forces are very powerful, Indian democracy is very weak. When the political process is highly controlled or coloured by the influence of corporations then it becomes very, very difficult. I mean you tell me why should Indian parliamentarians sit on a simple legislation that says all hospitals, all clinical establishments should be registered and then a multi-state committee should work out minimum standards for them where they all should come from. It looks very simple, logical, common sensical and yet for three years it's not that they are inefficient, you'll find that every day they are passing laws, whenever they meet in the parliament, even when they're shouting and there's a ding and half the people are walking out, certain laws are going through straight away without even debates.

But this law is not going through simply because they have interests which are blocking it. Because most of these parliamentarians are under the influence of various interests of this kind. The same thing is happening in clinical trials, because the pharmaceutical industry is very strong it has an economic influence and political influence because the corporate hospital sector is very strong. And the medical profession itself which is profiting from clinical trials because they are getting large amounts of money. If you look at clinical trials in the private hospital sector the principle investigator at the hospital is directly paid for every recruitment he carries out he may be paid $10,000 or $20,000 just like that. Out of that a very miniscule amount goes into someone else's pocket. So these are the people who are blocking this thing, it's quite a strong organisation in which he works.

I must tell you because we run this journal the Indian Journal of Medical Ethics for the last 17 years. When we started we thought we won't last, we survived - we survived simply because they found that there is a good committed section of doctors who are ethical and doing good jobs and they can continue to support.

Norman Swan: So there is a core to build upon?

Amar Jesani: There is a lot we can build upon but there is support coming internationally and if they join hands together it would be easier, otherwise it will take years and by that time I don't know how many clinical trials will take place in India without any kind of ethical oversight.

Norman Swan: Dr Amar Jesani is the founder of the Centre for Studies in Ethics and Rights in Mumbai.

But Western countries can't be complacent about the trials they conduct. Just before Christmas last year a scandal was exposed about the trials conducted into Tamiflu, the influenza drug widely stockpiled at major cost.

It turns out there's no reliable evidence that Tamiflu prevents the complications of influenza and the manufacturer has been reluctant to release the raw data from Tamiflu trials. Then there's the way researchers write up their trials and an eminent statistician claims there are worrying gaps.

He's Professor Doug Altman who directs the University of Oxford's Centre for Statistics in Medicine.

Doug Altman: Yes, the essence of publication of a result of a trial is to describe in detail what the idea was, what the methods were, what was done and what was found. It's not too difficult. What did you do, what did you find, what does it mean?

Norman Swan: And you've analysed the extent to which that is actually done in scientific papers which is what we all rely upon?

Doug Altman: Well indeed, there are some well recognised criteria for what aspects of a study ought to be included in the research report and when one looks at samples of papers published in journals, even the most eminent journals, there are major deficiencies. Many papers omit key information which would reassure the reader about the reliability of what they found. Indeed also the findings are often reported in a less than ideal manner.

Norman Swan: So just describe the sort of things that you are looking for in a paper and the extent to which they are actually reported when you do a survey?

Doug Altman: Well if we're thinking of randomised clinical trials in particular evaluating new treatments in terms of methodology the most crucial aspect of a randomised trial is the way in which it's decided which patient receives which treatment and that should be done using a random process. So one would look for reassurance in the journal article that this was done in an accepted method. But often we find in a ridiculous proportion, maybe three quarters of publications they just don't say how they did it. They say oh, we randomised but there's no detail, we're being asked to take it on trust that these people did what they say they did. And I'd like to do that but we know when we look at some publications where they've used the term randomised we know sometimes the detail shows that they didn't actually do it properly. In terms of the results what we're hoping to see is that the researchers had pre-specified what they were most interested in looking at and that they had then analysed that and reported that.

Norman Swan: So we're looking at say the prevention of heart attacks they've defined that up front, that's what we're trying to do here is to prevent a heart attack or somebody dying of a heart attack, that's what we're going to do and here's how we measured it so that they didn't change the story halfway through.

Doug Altman: Well that's right but sometimes you find that when a paper is published describing the study the focus is switched to maybe how often patients were hospitalised, or how many medications they took because that gives them a more exciting story. But it's not valid to change courses in midstream like that.

Norman Swan: And what's the extent to which that simple thing which is what you call defining the end point of your study clearly, how well is that adhered to in reporting?

Doug Altman: Studies comparing trial protocols with trial publications for the same study have shown between 40% and 60% of the journal articles have primary outcomes that don't exactly correspond to what was in the protocol.

Norman Swan: I mean that's amongst the most basic of things, what are you actually trying to study and the majority, up to 60% don't fulfil that basic criterium?

Doug Altman: That's correct, it's a little more complicated because studies tend to have more than one primary outcome and they may report one accurately and another one less accurately. Or they may switch one and keep one but yes, in essence, these most fundamental aspects of a study are often either not reported properly or distorted in a sense that what is reported is not what was stated as the intention in the study that was planned.

Norman Swan: Another area of controversy is where they say look, if you look at it overall the average person didn't respond but you know if you had blue eyes and green hair you responded strongly - it's what they call sub -group analysis and people go to war over this.

Doug Altman: Yes, sub-group analysis can be done in a reasonably professional way but it can also be done in a very exploratory way. The real danger with sub-groups is that people just play around with the data on the computer, find something that looks interesting and publish it and perhaps put it forward as if they'd intended to do that, a similar issue to the outcomes, you know moving away from what was intended. When we've compared trial protocols with the subsequent publications we find that most of the pre-specified sub-group analyses are not actually reported and nearly all of the reported sub-group analyses were not actually in the protocol. So there's clear evidence that people are exploring the data and presenting something which really is of very little reliability as if it's fact and then they believe it.

But there are a lot of cases where people have come up with sub-group effects from a single study which later studies have disproved quite clearly. So there's a real risk of being mislead by these types of analyses.

Norman Swan: And I should have clarified earlier, when you say trial protocol this is the trial plan so when people submit their trials, say for ethics approval or something like that, saying this is what they're going to do, this is how they're going to do it, these are the people they are going to recruit, and these are their intentions of the trial.

Doug Altman: That's correct, the trial protocol is a very detailed plan, it's a blueprint for how the study will be done, it would include not just scientific aspects but operational aspects, who's going to measure what, when.

Norman Swan: And the other thing about clinical trials is that you're blinded so if you're involved in the trial you don't know whether somebody is getting the treatment or the placebo. To what extent is that blinding process reported adequately, in other words how they kept the information about what somebody was on away from the person involved in the trial or doing the analysis?

Doug Altman: Unfortunately, like all the other aspects we've discussed and others too it's not reported particularly well. Sometimes it will simply say this trial was a double blind trial meaning that the patients didn't know what treatment they had, nor did the doctor treating them. But one would really want to know how was that achieved, by what mechanism? Again it's not that I automatically distrust everyone if they don't tell me something but I know from research that's been done that at least some of the time when people don't give details, they didn't do what on the surface it's claimed that they did do.

Norman Swan: What are general editors doing publishing papers where these things are inadequately reported? They must know and you send it out for review to experts who look at these things. You're looking at published papers where there's only a minority which fulfil all the criteria that you'd want to know for a reliable trial for treatments that are going to go into the clinic and be used on you and me. Why aren't journal editors and peer reviewers making sure about this?

Doug Altman: That's a matter of some speculation. Clearly one would hope that they are alert to the risks associated with bad reporting and they try to spot deficiencies when they see them. But so many papers are published with so much information missing it's clear that they're not really doing their job. We do have guidelines now which should help peer reviewers in terms of looking for key bits of information in a journal article. I think that the main responsibility still has to rest with the authors for not writing an adequate report but peer reviewers are clearly letting through, and editors are letting into print a lot of stuff which is not going to be helpful to clinicians because it doesn't contain the information that can allow them to assess the reliability of those studies.

Norman Swan: Now people listening to us talking have not got a degree in clinical epidemiology or bio-statistics yet they've understood perfectly what you're talking about. You don't know whether they are properly blinded, you don't know whether people are properly randomly allocated, you're not sure the results have been well reported, this is basic stuff. When you talk to journal editors what's their excuse?

Doug Altman: Well I do talk to journal editors and they will be very supportive of what I'm saying that things need to be better, they will point to the difficulty of getting people to peer review, it's a thankless task peer reviewing other people's papers, it's often done for no money in the late hours of the day and it's clearly done to a standard that isn't high enough. I believe that part of the problem is that the authors and the peer reviewers are the same sorts of people so they have a similar sort of knowledge and it's not that surprising therefore that those people who write poor papers are being judged by people who can't spot the problems.

I think there should be more training for peer reviewers, maybe online training to allow international participation but at the moment I really don't think there's any training for peer reviewers. People need to know how to do these things, they don't know innately,

Norman Swan: This is all an enormous waste of public money, these people are taking money in Britain from the Medical Research Council, in Australia from the National Health and Medical Research Council doing these randomised trials, promising the earth and delivering an inadequate product.

Doug Altman: The truth is that a recently high percentage of funded trials and indeed other funded research never sees the light of day in terms of publication. I think yes, you could say that's a waste of money, I think there are moral and ethical issues also in terms of getting patients to participate in studies that produce no useful outcome. And indeed it could be harmful because if you publish a study which is missing information that would allow the reader to know was not done very well you could be misrepresenting a bad study as a good study. At the moment I think oversight from funders, ethics committees, is negligible.

Norman Swan: Doug Altman is Professor of Statistics in Medicine at the University of Oxford. And he and like-minded colleagues have set up the Equator Network which provides training and guidelines resources to help fix these problems.
Their URL is

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