Clinical trials: Cart before horse?

The Nation, 25/12/2011,

By Panduka Karunanayake The government has stated that it will bring three new bills relating to health, by early next year. One relates to the national medicinal drugs policy, which I discussed recently (The Nation, November 13, 2011). Another relates to clinical trials. According to a news report, this bill “…would be introduced to attract researchers in the field of medicine and pharmaceuticals to the country to conduct medical research along with local consultants” (The Sunday Times, December 11, 2011). Clinical trials: What it is The type of “medical research” that the bill proposes to encourage is called clinical trials. In simple terms, a clinical trial is a human experiment that seeks to scientifically establish the efficacy of a new drug (medication) in a certain disease (see Boxes 1 and 2). This is necessary for registering the drug with regulatory authorities, such as the US Food and Drug Administration (FDA), which is a pre-requisite for marketing drugs in Western medicine. Naturally, a clinical trial subjects the human beings in the experiment (who are called ‘participants’) to potential risk. Its usefulness lies in the results of the experiment, and this is, in essence, beneficial for future patients, not for the participants. Importantly, there are examples of trials that have caused death or permanent complications. In other words, a clinical trial is a situation where we, as a society, ask our altruistic companions to subject themselves to an experiment, at personal risk to themselves, for the sake of humanity’s shared future. Almost all of the highly effective Western medicines that we benefit from today have gone through clinical trials. Just as importantly, such trials have also weeded out many useless or dangerous substances, keeping the general public safe. Clinical trials are a legitimate, worthwhile and valuable exercise in scientific experimentation, since they further our collective knowledge of diseases and their treatments. What it is not But a clinical trial is not a strategy to give the participants ‘better care’ or care that they would otherwise not receive – for which society needs to develop or strengthen other suitable strategies. Although participants might indeed receive such care, this comes at the personal expense of exposure to additional potential risk – the former should not be an inducement for accepting the latter. Furthermore, the participants must take part in a trial out of altruism – not ignorance, helplessness, respect for the doctor, fear of reprisals if they refused to participate (such as denial of usual treatment), inducement by material gain, etc. A trial must have enough justification to subject participants to the risk involved (see Box 3). To ensure this, it must receive prior approval – and if possible, monitoring – from a recognised research ethics committee, which should be well constituted, effective and independent. \ Underdeveloped countries: Benefits Clinical trials were conducted mainly in developed countries, but in the last two decades, they have increasingly shifted to underdeveloped countries (see Box 4). This is achieved by having foreign collaborators in those countries, usually medical consultants, who can recruit the necessary participants from those countries. The collaborators may be rewarded professionally (e.g., career advancement) or materially (e.g., equipment, gifts, overseas trips, money, etc). Over the years, clinical trials have become more common, complex and costly. As a result, a new type of service industry, called ‘contract research organisations’ (CROs), has arisen to conduct them on behalf of the biopharmaceutical industry. It is important that underdeveloped countries are able to conduct clinical trials for their own public health problems, so that local scientists can find contextually valid solution to them. For instance, Sri Lankan researchers have conducted several excellent clinical trials on the treatment of snake-bitten patients – without these our patients would have suffered more, because few other countries are interested in this problem. It is also important for us to conduct clinical trials with foreign collaboration, because (like in other branches of technology) this enables transfer of know-how and technology and elevates local standards. Underdeveloped countries: Risks But the shifting of clinical trials to underdeveloped countries also has a global context that we must consider. CROs are attracted to underdeveloped countries for several reasons, such as cheaper cost, less legal obstacles, and less likelihood of having to pay compensation for any injury caused, especially in phase 1 and 2 trials. But the most worrying reason is that underdeveloped countries may be a permissive setting for trials that would not be permitted in developed countries, such as RCTs with active control groups. Developed countries have strict, evolving criteria on research ethics. Trials that are considered unethical there (but would provide the data for pharmaceutical companies to obtain registration for marketing) might then be conducted in the more permissible underdeveloped countries. Here, ethics issues might be considered less strictly, the public may be less aware of the implications of being participants, and research ethics committees might not be as robust or independent as in developed countries.  Underdeveloped countries may have professionals or academics that would willingly collaborate in clinical trials in return for career advancement or material gain. The patients themselves may be relatively less informed of their rights and the risks involved, and they may be economically and culturally too disadvantaged to question, negotiate or argue with their doctors. The cost of the trial may be less, and compensation to participants for any harm caused by the experiment may be cheaper or even entirely avoidable. Not surprisingly then, there has been a tendency for clinical trials to be moved to underdeveloped countries, including phase 1 or 2 trials and trials with ethically questionable study designs. Local and global We must remember that in Sri Lanka, the ordinary patient attending the state hospital is not usually in a position to properly understand the implications of being a trial participant, not usually capable of exercising autonomy in decision-making, and perhaps may not even be informed about the nature of the drugs given to him or her. The ordinary patient here is far more vulnerable than his or her Western counterpart. Although ethics approval must be obtained before starting clinical trials, research ethics committees in Sri Lanka at present may not have the expertise to appreciate the nuances of international biomedical research, the capacity to monitor the conduct of trials, or the logistics to detect non-adherence to protocols and take corrective action. In fact, it is possible that some committees even lack independence and are vulnerable to pressure from powerful groups. To ensure that clinical trials are conducted appropriately, at least two requirements must be fulfilled outside the medical profession and the scientific community. First, there must be a robust, independent and effective system for monitoring research ethics. Each trial must receive clearance from a recognised research ethics committee and be monitored on adherence to the protocol throughout its conduct. Importantly, the issue of the consent of the participants must be treated with the greatest possible care and circumspection, because it is around here that much of the vulnerability of the participants from underdeveloped countries hinges. Secondly, awareness about clinical trials and their implications must be developed amongst the general public, civil society groups (including patient rights groups), lawyers, social scientists, etc. Caution In this context, legislation that merely seeks to “…attract researchers…to the country to conduct medical research along with local consultants” may be a steppingstone for the abuse of innocent, ignorant and helpless patients in our state hospitals, while research ethics committees lacking independence or capacity helplessly look on. Indeed, such trials in other underdeveloped countries are seen as a new form of colonialism, and we must tread this path with the greatest possible caution. Above all, the policy elite (including legal draftsmen and state economists) must not think of clinical trials as a revenue earner – that would be both a recipe for disaster (because financial considerations can take precedence over research ethics, especially with the existence of poor, ignorant and helpless patients in plenty) and a cause for disappointment (because any appreciable revenue actually comes to collaborators, not to institutions or the national treasury). We must first create the appropriate background for conducting trials ethically, which especially includes strengthening the capacity of local research ethics committees and educating the public. International biomedical research is indeed a useful, legitimate and justifiable project, and legislation that seeks to regularise it is indeed a good move – but only if the appropriate background is created first. People who push for legislation (and who have the ‘powerful connections’ to do so) for the sake of promoting foreign collaboration must not think that their social responsibility stops short of creating this background. Otherwise, the harnessing of ‘power’ in this ‘asymmetrical’ way – and putting the cart before the horse – can lead to the exploitation of the ignorant, poor and helpless ‘biomass’ and, on the long term, their loss of faith and trust in the state healthcare system and the medical profession. The writer teaches medicine at the University of Colombo.

1: Clinical trials A new drug must successfully negotiate three sequential phases of clinical trials, before it is registered for marketing: • Phase 1: The drug is given to a small number of human beings (usually healthy volunteers) to determine initial safety. • Phase 2: A small number of patients suffering from the disease in question are given the drug, to obtain preliminary data (such as the correct dose). • Phase 3: This consists of a controlled experiment (usually a randomised controlled trial, or RCT: see Box 2) involving hundreds, thousands or even tens of thousands of patients with the relevant disease. (There is also a phase 4, but this is not important to the current discussion.) Naturally, phases 1 and 2 are riskier to the individual volunteer or patient (called ‘participant’), because of the unknown element of any new drug.

4: The shift to underdeveloped countries• According to the US Department of Health and Human Services (DHHS), the number of clinical trials for drugs that were intended for use in the US which were conducted in foreign countries has increased from 271 in 1990 to 6,485 by 2008 – an increase of over 2,000%. By 2008, 80% of applications for the registration of new drugs submitted to the US FDA were based on data from clinical trials conducted in foreign countries. • The triennial number of new foreign collaborators in the FDA’s database grew from 988 in 1990-2 to 5,380 in 1996-8.  • Some ‘foreign hot spots’ for such trials were Brazil, China, India, Poland, Romania, Russia and Uganda. Sources: Kamalakar Duvvuru (Dissident Voice, 2011.09.15) and DHHS.

3: When is a clinical trial justified?• It must have the capacity to yield valid conclusions: scientific value. • These conclusions should be useful to the community from which the participants are selected (social value). For this, the disease in question should be a public health problem in the community, and the community must benefit from its participation (for instance, if the drug is proven to be efficacious, the community should be able to afford it). • The risk that the participants are exposed to must be kept to a minimum, and it must be commensurate with the usefulness of these conclusions (favourable risk-benefit ratio). • The participants should be selected from the community in a fair manner (fair selection). For instance, it is not fair to select participants from the poor to test a drug for a disease that mainly affects the rich. • The rights of participants, including their autonomy, respect and dignity, and rightful compensation must be safeguarded. • The results of the experiment should be made available widely amongst researchers (dissemination of results), whether or not this is profitable to the manufacturer of the drug in question, so that the wider scientific community can share the lessons learnt and more participants elsewhere need not be exposed to the same risk to learn the same lesson.