Bioethics in China: not wild, but not tame either

Here is a way to turn yourself into a hostage of fortune, in bioethics and elsewhere. It is to vigorously defend something against allegedly unfair accusations, while acknowledging you may not know all the relevant information about what you are defending. That position can, should inconvenient truths come to light, transform you into an advocate of the dubious.

Case in point: back in July of this year, Douglas Sipp and Duanqing Pei wrote a comment in Nature entitled Bioethics in China: No Wild East. In it, they defended Chinese research practices (particularly in regard to genomics research involving human embryos) against accusations of being morally cavalier, loosely regulated, and prey to corruption. According to the commentary, Chinese research has been given bad press about its practices that do not match up with regulatory and laboratory reality. Biomedical research, including highly sensitive studies, is being (or well on the road to being) conducted responsibly there, even to the extent that China has some lessons for the rest of the world in this respect. Probably some truth to it, but you know this will not end well.

Earlier this month, China's State Food and Drug Administration (SFDA) disclosed that after examining a year's worth of clinical trial (n = 1622) data, that up to a whopping 80% of said data was fabricated. According to the report, the fabrication in part took the form of deliberately underreporting harmful side effects and adverse events experienced by trial participants in order to gain the necessary safety approvals. The SFDA surmised that the motivation for the fabrication was financial: trying to get drugs to market faster than their competitors.

You could of course say this is a victory for Chinese regulators who at least looked for, found and reported the research fraud (though what penalties will be levied, if any, is unclear). And certainly every country has its own struggles keeping biotechnological advances on the straight and narrow, particularly in the private sector. But it does complicate attempts to defend the ethical climate of research in China against perceived 'bad press.'

Ebola ethics

Interesting to see the kinds of attention that has been given to the most recent Ebola outbreak in Africa. Part of the reason is that it is a serious epidemic, causing nearly a thousand deaths so far, and it is occurring in West Africa, rather than its usual stomping ground of the Democratic Republic of Congo and thereabouts. Another reason is that some Americans overseas have been infected, and medically evacuated back home, so the story involves not only the familiar 'death exoticism' of faraway anonymous Africans, but has a US domestic component as well.

Perhaps because it involves American citizens, bioethicists have been more active in commenting on the ethics of Ebola control than they were during outbreaks of times past. Two of the infected Americans have been treated with an experimental Ebola drug, the access to treatment being aided and abetted by the National Institutes of Health and the Centers for Disease Control no less. Bioethicists, chronic worriers that we apparently are, worry about this development. If the drug has not been FDA approved, how do we know that it is safe and effective? Even if the conditions of the American patients improve, how do we know whether the drug itself is responsible, if no rigorous clinical trial has been conducted? Why would people continue to join clinical studies if they could gain access to experimental drugs outside the FDA's vetting system?

All fine and good, as worries go. But I wonder what would happen if the Ebola outbreak happened in Louisiana rather than Liberia. Would the American public and leadership -- including its bioethicists -- be so sanguine about waiting years for the results of clinical trials before trying some promising-looking drugs out? Faced with an infectious disease with a very high mortality rate, would we revisit and loosen the rules or hold firmly to the tenets of evidence-based medicine? Is the latter what happened, say, early on during the US HIV epidemic? Or is the ethics a bit different when it is largely somebody else's deadly epidemic? For its part, the World Health Organisation seems more open to the use of not fully tested treatments, for Africans, given that the current alternative for most of those affected is (as the Director of the Wellcome Trust put it) a tepid sponge bath and the promise of a nice burial.

UPDATE: The Scientist issued a short piece on the subject of Ebola and ethics last night, and USA Today has a piece up, with reader comments.

Research protections in India: a case of unethical ethics?

Yesterday, in the post below, I mentioned a controversy regarding a substantial withdrawal of research activities by the National Institutes of Health (NIH) in India. The controversy is gradually getting more media coverage, but little in the way of official explanation from the NIH. Here is one possible conjecture, however: the Indian regulations protecting human participants in research are problematic enough to necessitate halting NIH-funded biomedical research there, but the NIH is reluctant to pass official judgment on the regulations of another country with which it has collaborated fruitfully in the past. It is politically sensitive. This hunch can be supported to some extent by an editorial that came out yesterday in the BMJ, which states that the Indian regulations have three main problems, and that these problems are causally responsible for the recent decline in research activity in India overall, and not just by the NIH.

According to the authors, the three main problems are: (1) the regulations do not state how injuries suffered by research participants, and to be compensated by research institutions, are to be determined as 'research-related'; (2) the regulations have an overly broad interpretation of what counts as a research related harm, including (for example) use of placebo in a placebo controlled trial; (3) the regulations state that ethics review committees and licensing authorities have to help determine whether and to what extent compensation for harm is warranted, but it is unclear they have the relevant skills and resources to do so.

On this reading, it looks like a case of 'unethical ethics.' Unethical ethics occurs when, even with the best intentions, actions or policies meant to promote certain values end up doing serious damage to other important values. In this case, the drive to promote the welfare of research participants has apparently been taken to a point where it becomes difficult to conduct health research at all, including research focusing on important public health problems in India. The BMJ authors end on an optimistic note: the Indian government has the power to restore balance between the interests of research participants and research institutions by reforming the regulations. Time will tell.

NIH pulls clinical trials research out of India: but why?

Last month, the National Institutes of Health (NIH) postponed, delayed or scraped nearly 40 clinical trials in India, and it is still not completely clear why. What is clear that it has something to do with the local, Indian regulations governing the conduct of clinical trials, what is called the Drugs and Cosmetics Act. But what about the Act is making the NIH withdraw or suspend its activities is not receiving a clear answer, and creating a vacuum for speculation to enter. Industry experts are talking about an 'unstable regulatory environment' in India, which could mean anything: contradictory policies, bureaucratic cul-de-sacs, or just obstacles to (potential lucrative) drug development. Maybe the Act requires a regulatory structure that the Indian government is not prepared to adequately bankroll: it is always easier to create shiny new regulations than to establish institutions capable of effectively implementing them. Ethics committee chaos can grind research to a halt. Or maybe it has to do with provisions in the Act regarding compensation for research-related harm, that could drive up research costs, precisely in a country that has attracted biomedical research due to its low overhead, ease of recruitment, drug-naive populations, and so on.

India has been a hotbed of concern about global health research ethics for some time. Typically the concerns are about conducting responsible research there among the vulnerable, impoverished sick. But this time it is about the ethics of pulling up stakes and halting research in such circumstances, including (one supposes) research with current or potential benefits for patients. To tap down adverse speculation, you need transparency. Without that, there is nothing to do but watch the rumors freely breed and spread.

Video recording consent processes in India

As mentioned before on this blog, India has become a magnet for global clinical trials as well as for research ethics controversies. The potential in India for fast, cheap biomedical research with drug-naive populations is great, and since India is a fast-growing economy, you can throw the attractions of local expertise and decent clinical infrastructure into the mix. However, many participants in the trials may be illiterate, unfamiliar with scientific concepts, unhealthy and poor. This situation puts a great deal of pressure on regulatory bodies and research ethics committees: it is up to them to keep studies from being exploitative and harm-causing. They must ensure the responsible conduct of research between powerful pharmaceutical companies on the one hand, and the destitute sick on the other. If the last few years is any indication, they are struggling to meet this formidable challenge.

This is the background for a new regulatory safeguard being proposed by India's Drug Technical Advisory Board (DTAB) for clinical trials: video recording of the consent process. The proposed change to the regulations would have language like: "An audio/video recording to the informed consent process of the individual subject including the procedure of providing information to the subject and his understood consent shall be maintained by the investigator for the record." Some Indian observers, concerned about the ethical problems with local trials, support this proposal. But there are some reasons to be skeptical.

What is the rationale for recording? When it comes to the use of recording as a form of data collection, researchers are routinely asked for justifications. The reason is that recording (especially the visual part) involves collection of a major identifier, i.e. the participant's face. Since recording adds a piece of identifying information which then has to be covered by confidentiality protections, researchers are advised only to record what is essential to conduct the research. So why record consent? One answer could be to document the process for reasons of quality control. With a recording, you could see/hear how the research study was presented to the prospective participant. The obvious limitation is that the recording might not capture what the participant actually understood, and (unless we are talking about the self-protection of research institutions) that is the ethical point. Another possibility is that the requirement to record has a deterrent effect: if the researchers know they are on camera, then they will be on their best behavior. This sounds intuitively plausible, though to my knowledge there have been no studies to support the claim of a deterrent effect, and the researchers (due to inadequate training) might not know what best behavior would be anyway, and fail to be deterred. Another drawback of the regulation is the burden of work it would add to research ethics committees, to the extent that they are charged with reviewing/monitoring the recorded consent processes. Another consideration is that the regulation seems to unduly privilege the informed consent process: if we are concerned about the ethics of such trials, and recording is supposed to help, why not record the recruitment process, the study visits, and other procedures that could compromise the well-being of the participant?

If this proposal is taken up, it will constitute a kind of regulatory experiment, interesting to observe from afar.

Hat tip: Louise Winstanly, IntraHealth

Ethics and the global registry of clinical trials

We do not really know how many clinical trials are taking place in Africa. In fact, we don't know -- and have not known ever -- how many clinical trials are taking place around the globe. And, a fortiori, we don't have much of a grip on what kinds of research questions are being tackled in such trials, and when such trials are concluded, there is often (at best) only piecemeal and partial reporting of their outcomes. The spread of clinical trials around the world has not made information about them much more available.

Why does this information matter? Knowing about what trials are already ongoing would prevent duplication and waste, and would let patients and doctors know what is in the pipeline. It would help Ministries of Health and scientific institutions define research priorities, and would assist in focusing the efforts of regulators, including those charged with the protection of human participants in trials. Those thinking of participating in trials would also be better informed about 'what is out there'. It would also allow us to learn about negative results, which tend to be underreported or selectively reported. And it would be interesting to know how much (or how little) of the global research endeavor is devoted to diseases and conditions that disproportionally affect developing countries. However, the pharmaceutical industry for their part has traditionally been reluctant to share information about their activities, not necessarily because they have skeletons in their closets (though they might), but because they feel that greater transparency might reveal too much to their competitors, and result in the sacrifice of their competitive edge.

The World Health Organization, back in 2004, launched an initiative to create a global database of clinical trials, called the International Clinical Trials Registry Platform, ICTRP. The moral philosophy behind the initiative is that information generated by clinical trials conducted worldwide constitutes a 'public good' that must be shared to improve health. But if the carrot of 'doing good' is not enough to motivate agencies to register their trials, there is always the stick: the International Committee of Medical Journal Editors (ICMJE) has a policy that if there is an intention to publish trial results in any of its 11 member journals, the trial (including Phase 1 trials) must be registered with the ICTRP. And these are real journals like the Lancet or the New England Journal of Medicine, the kind that get you tenure or help you market your drug.

This week the global registry grew an African wing. The Pan-African Clinical Trials Registry (or PACTR) has been accepted as the first World Health Organization (WHO) endorsed trials registry in Africa. This registry will channel data into the ICTRP, and therefore we will come to know more about Africa-based clinical trial activities. It will be interesting to see what's cooking once the lid is taken off and we are allowed to peer in.

Research data from developing countries as 'the new gold'

The ethical complexities involved in outsourcing of clinical trials in developing countries have been discussed over the last few years, and by the looks of things, this discussion will continue. For different reasons. First, and probably foremost, because the practice itself is lucrative: there are millions of dollars to be saved by holding your trial in Mumbai rather than Miami, and success in a clinical trial, especially when translated into a well-marketed pharmaceutical drug, can reap billions of dollars in profit. Second, no one to my knowledge has ever said that the practice was morally impermissible or that it should be prohibited. It has always been a matter of how to ethically conduct such studies in impoverished communities whose members may have little to no understanding of the nature of the research and will probably not benefit much directly from their involvement. Making research ethical in such contexts has always been a matter of adding protections and safeguards. Perhaps being ethical in a deeper sense would involve chipping away at the gaping inequalities in power and wealth between the researchers and the researched, but almost no one wants to touch that one: not researchers, not their funders, and (sadly) not governments.

The Guardian in the United Kingdom has a short piece on this issue. Frankly, the article itself adds little to the debate, but some of the comments on the article are worth looking at. Some depict outsourced trials in terms of exploitation, others as opportunity; and opportunity for local communities and trial participants, not just those trying to make a profit. For example, in poor countries, getting into a drug trial might be synonymous with gaining entry to a higher standard of medical care than one would otherwise get, and prohibiting this opportunity in the name of ethics, to some observers, sounds perverse. Communities might also gain some ancillary benefits in terms of facilities or training. And yet the possibilities for exploitation are still there, and these benefits (sometimes real, sometimes not) do not silence the concerns. So outsourced trials come across as a kind of mixed blessing, a partly dirty business, but not all bad.

A detailed and nuanced understanding of global drug research and outsourcing can be found in a new book by Adriana Petryna, When Experiments Travel: Clinical Trials and the Global Search for Human Subjects. The book makes clear that reliable data in support of new investigational drug applications to the FDA is a rare and highly lucrative commodity, like gold or diamonds. But to get the data, you need humans. And not just any humans: you need humans with this or that disease or condition, preferably who have not taken many other drugs before (drug interactions may influence the data), and many other specific inclusion criteria besides. And you want the study to run in places where you can get more for your dollar (or Euro), and where the regulatory climate is still immature. Contract research organizations (CROs) are paid by pharmaceutical companies to find the right humans in the right places, recruit them, run the study, deliver the data. Petryna's book shines a light on an obscure global industry, peopled with not so much with heros and villains, but with ordinary actors engaged in a partly dirty business across national boundaries.

Exploitation in drug safety trials

The New England Journal of Medicine, amazingly, has published a piece on research ethics that you can access online for free. And it is a worthwhile article too: in Exploiting a Research Underclass in Phase 1 Clinical Trials, Carl Elliot and Roberto Abadie describe the basic conditions of those who sign up for safety trials on new drugs, and the analogies with sweatshop labor is never far away. Elliot and Abadie argue that participants in such trials are exploited for three reasons: they are unlikely to gain access to the drugs that are being tested on them, there is little effective regulatory oversight of the clinical drug trial industry, and there is little to no compensation for research-related injuries. In short, it is a bad job, disproportionately done by the poor. Yes, like the positions on offer at the meat-packing plant, you do get money for it. Yes, it is a step up from unemployment and/or living in cardboard box. Yes, you could always argue that this is not exploitation, but merely a fair exchange: the research participant offers his or her body to test drug effects, and gets cash in return. There is no shortage of complex arguments in bioethics that end up defending the status quo in this area. But Elliot and Abadie will have none of it: if participants in phase 1 clinical trials are 'drug tasters' for the more affluent, exposed to the prospect of uncompensated injury and buried far beneath the radar of regulators, that is not a 'negotiating position' for a fair trade of services -- it is a rotten place to be.

The article is a reminder that there are populations in affluent industrial nations analogous to those in the developing world, and equally vulnerable to the corporate model of clinical trial research. It is not that we can do without drug safety trials involving human beings: we can't. But as long as phase 1 clinical trials round up the usual suspects as participants -- low income, without health insurance, immigrants (documented or not) -- the accusations of exploitation will not, and should not, go away.