Delivering vaccines in Africa: some unethical obstacles

The attention and money thrown at the H1N1 virus seems to grow by the day, even if the numbers of H1N1 related deaths, relative to other causes of mortality (including plain old seasonal flu), are still very modest. People actually die from H1N1, so it is not nice to make light of it, and because it is contagious, the death toll will rise, though we don't know how high or for how long. Nevertheless, there is no way of getting around the impression that the world's media is drawn to the latest viral threat to the richer developed nations, where the knight in shining armour is played by multinational pharmaceutical companies, whose cutting-edge research thankfully produces the latest vaccine, while the media makes rapid and widespread vaccination seem like the only rational response, and governments and local health agencies stand to be criticized for not getting vaccines into bodies fast enough. The significance of the H1N1 virus as a threat to humanity? Only time will tell. But that a great deal of money is being made: that is already certain.

Elsewhere in the world, other fish are frying. Forget new cutting-edge research for new diseases: in many countries, it is hard enough just to get the old vaccines administered, for the boring old diseases, the ones that people in developed nations hardly get anymore because they are routinely vaccinated against them. Take measles. Two troubling stories about measles vaccination in Africa came in this week.

First, here in South Africa, some media sources managed to revive the discredited measles-autism link, i.e. that the measles vaccine causes autism in children. A little media ethics for journalists working on public health issues could go a long way, and hopefully these incidents will not cause setbacks for measles eradication in South Africa, similar to the problems with polio vaccination in Nigeria some years back. The recent decline in measles mortality in Africa is a success story, but only conserted and sustained efforts (including communication of accurate health information) will keep those numbers going down.

Second, in the Democratic Republic of Congo, measles vaccination efforts face an unusual adversary: government troops. Medecins Sans Frontieres (Doctors without Borders) has accused the Congolese government of using their vaccination sites as bait. Due to a measles epidemic, MSF was vaccinating thousands of children in sites locations that are controlled by the Forces Democratique de Liberation du Rwanda (FDLR) . Knowing that people in the area would gravitate to the opportunity for measles vaccination, Congolese government troops apparently attacked all seven sites with deadly force, scattering populations (including children) into the bush. It remains to be seen if people in the area will trust going back to MSF sites for medical care, and in this troubled part of the world, that is about the only decent medical care around.

Let us compare epidemics

There is always something a bit distasteful about comparing human tragedies, but it is also inevitable. The tsunami in 2004 was terrible, but was it as bad as the ongoing HIV/AIDS epidemic in Africa, which has taken millions of lives over the last decades? Darfur is bad, but has it really reached Rwandan genocidal proportions? We inevitably make these sorts of comparisons in order to get some sort of grip on what people ought to care about, and what nations ought to respond to with their finite resources. And we often lose our way.

The H1N1 virus has captured media attention, as well as substantial funding for task forces, response plans and research, particularly as increasingly more deaths have been linked to it. As has been observed many times, the 'media life' of a virus depends in large part on the extent to which citizens (especially ordinary citizens) of North America and Europe are affected by it, or are likely to be affected by it. When the centers of the world's power is under viral threat, vast resources may be mobilized, even if the numbers in terms of morbidity and mortality are, relatively speaking, small. Worse epidemics, elsewhere, receive much less press and support.

The point was not lost on those aware that today was World Pneumonia Day. Pneumonia is the greater killer of children worldwide. It is responsible for more deaths in children (2 million a year) than HIV/AIDS, measles and malaria combined. The tragedy is that we long ago developed effective vaccines to prevent it, and antibiotics to treat it, but it generally affects children away from the centers of the world's power, particularly in sub-Saharan Africa and South-East Asia. While many lives could be saved in delivering known effective medicines to these populations, there is not much money to be made in the endeavor, so rallying support for pneumonia initiatives tends to be an uphill battle. But it is a matter of fighting the good fight, a matter of trying to regain some sense of proportion, and a matter of not being entirely distracted by the latest virus on the 24-hour news cycle.

I pay thy poverty, and not thy will

In Romeo and Juliet, there is the scene where Romeo goes to an Apothecary to obtain a poison. Juliet is presumed dead; Romeo wishes to go to the Capulet's family tomb, take the poison and join her in a deadly embrace. The Apothecary hesitates: distribution of such poisons is against local law. The two have the following exchange:

ROMEO: Art thou so bare and full of wretchedness, and fear'st to die? Famine is in thy cheeks, need and oppression starveth in thine eyes, contempt and beggary hangs upon thy back. The world is not thy friend nor the world's law. The world affords no law to make thee rich; then be not poor, but break it, and take this.

APOTHECARY: My poverty, but not my will, consents.

ROMEO: I pay thy poverty, and not thy will.

I was reminded of this exchange while reading a blog post on the Washington Post website, entitled 'In Praise of Human Organ Sales.' The author, Gary S. Becker (a Nobel prize-winning economist) argues that allowing people to buy and sell their organs would help solve the problem of shortages in organs for transplant, while countering possible objections to this idea. Neither the proposition nor the objection are particularly new; people working in bioethics have made this proposal before and objected to it before. The novelty lies in how quickly and brutally Becker states his case. His response to issues of social justice is succinct:

Another set of critics fears that the organ supply would be likely to come mainly from the poor, who would be induced to sell their organs to the rich. It is hard to see any reasons to complain if organs of poor persons were sold with their permission after they died, and the proceeds went as bequests to their parents or children. The complaints would be louder if, for example, mainly poor persons sold one of their kidneys for live kidney transplants, but why would poor donors be better off if this option were taken away from them?

It is true, the poor who sell their organs, either when they are alive or posthumously, would get their cut -- like the Apothecary. The rich would get their organs, and the middlemen, well, they would get richer. The poor would be mined -- with their agreement, of course -- for organs, without this sacrifice of body parts being likely to improve their lot very much. They would not be in a position, for instance, to buy organs for themselves if they needed them. For their part, the rich would have no (economic) motivation to put up their own organs for sale. Hard to see any reasons to complain here? Depends where you are looking. Romeo was unbalanced, and desperate, but at least he was honest: I pay thy poverty, and not thy will.


Thanks to Steve Levingston at Washington Post, who sent me the link to Becker's piece, and thereby informed me about the Post's excellent Book World blog.

HIV treatment: the good news and the bad

First, the good news: more people worldwide living with HIV/AIDS are receiving treatment than ever before. Over the last 5 years, there seems to have been a 10-fold increase, and now some four million people are taking antiretroviral drugs. Traditionally, UNAIDS 'epidemic updates' on treatment access in Africa made for depressing reading, with only tiny percentages of HIV-positive persons within African countries being treated. For the vast majority of Africans, HIV/AIDS remained what it was in the beginning, a death sentence, even if had obtained the status of a chronic disease in far-off (and better-off) countries. Now there are three million Africans taking AIDS drugs. This impressive achievement has taken more than a decade of advocacy, negotiations with pharmaceutical companies, creation of cheaper generic drugs, lobbying, program development, investments in local capacity ... blood, sweat and tears, in other words.

The bad news. The numbers of persons 'on treatment' cannot be trusted altogether. The statistics are developed by governments in a vested interest in stating the highest possible estimates. To do otherwise might show incompetence in the use of (mainly external) funding. The numbers also tend to reflect the number of those who were placed on treatment, and not those who later stopped treatment for one reason on another.

But even if the numbers were more trustworthy, there are other concerns. AIDS treatment and care is lifelong. To keep these millions of persons on treatment in the future requires a vast and ongoing investment. The World Health Organization is considering revising its treatment guidelines on account of studies that indicate earlier initiation of treatment increases life-expectancy. More HIV-positive persons will fall into the category of those in need of treatment, and meeting this new demand will add to the already soaring costs. In addition, some of those currently on first-line treatment will develop drug resistance and need to switch to (more expensive) second-line drugs. And last but not at all least, millions of persons continue to be infected by HIV, meaning that the 'treatment pool' will grow larger and larger in the coming years.

The old questions keep coming back: is this magnitude of spending on HIV/AIDS treatment ethically justified? Is it justified when there are other diseases and conditions, causing greater numbers of deaths, but which do not attract nearly the same level of political and financial support? Why not devote greater attention to HIV prevention research or prevention strategies that may help reduce the rate of new infections?

This is becoming a dramatic example of 'hell being paved by good intentions.' Back a few years ago, we had the unacceptable situation of Africans routinely dying of untreated AIDS, while North Americans and Europeans accessed antiretrovirals and went on with their lives. It was a striking case of global health inequality, and no one with any sense of solidarity could fail to be moved by it. But in the process of trying to improve the situation, something else, vaguely Frankensteinian, has emerged. Billions of dollars will need to be spent to keep the (growing) millions of HIV-infected on treatment. This might not be sustainable, and all the spending might not be proportional or fair, but it would also be unwise to stop financing global AIDS treatment programs now that they have been started. Halting treatment would not only spell death for those living with HIV/AIDS, it could also mean creation of new drug-resistant strains of HIV, making prevention efforts more difficult than ever.

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.

The regulation of desperation

We think sometimes that, when we are terribly sick, medical science must have progressed to a point where there is an effective treatment. That belief (or faith) sometimes turns to be true, and sometimes not. In the latter case, there is a terrible feeling of fear and powerlessness on the part of the patient, family members and friends. Science turns out not offer salvation. So if there is a chance that some new experimental treatment, being tested or offered somewhere, could provide some benefit, this can be a wildly attractive prospect. And the idea that access to a 'last chance therapy' could be prohibited by regulations can seem like unjustified paternalism. It is a bit like the scene in Monty Python's Life of Brian, where a man is about to be stoned to death for saying the holy name 'Jehovah'. As he is lined up to be stoned, he yells 'Jehovah! Jehovah! Jehovah!', and the priest presiding over the stoning exclaims: "You are only making it worse for yourself!" And the condemned man understandably replies: "But how can I make it worse for myself?" Those seeking last chance therapies might ask the same thing: even if the therapy is risky, even if it may not help, how can I make it worse for myself?

A couple of years ago, some of the people working at the National Institutes of Health clinical bioethics program wrote about different periods and paradigms in clinical research and research ethics. According to Emanuel et. al. (2007), there have been four periods and paradigms: researcher paternalism (1940's to early 1970's), regulatory protectionism (early 1970's to mid-1980's), participant access (mid-1980's to mid-1990's) and community partnership (mid-1990's onward). The AIDS crisis in the United States drove the paradigm of participant access, with patient rights groups increasingly demanding that people with terminal illnesses (and not just AIDS) should have the choice to join experimental trials. As Emanuel et. al. write, the desperate search for treatment tends to blur the distinction between experiment and therapy. A clinic offering a new intervention may be part of a clinical trial or it may be simply be offering 'experimental treatment'. Either might help the patient, either might push our medical knowledge further: but both could be dead-ends in any particular case.

Those trying to regulate this new paradigm have their work cut out for them. Not unrelated to the fact that much clinical research is being outsourced around the world, and the rise of medical tourism, people (who can pay for it) are seeking potential therapeutic benefits from cutting edge stem-cell research or clinical practice taking place in countries like China. This research may well not be taking place in the home country of the beneficiary, due to cost or regulatory/legal prohibitions. There is the possibility that such trials or practices may not be in the best ethical shape, for instance involving unnecessary risks and promising to desperate patients more than they can keep. The underlying ethical principle behind the patient access paradigm -- patient autonomy -- is unlikely to capture all of the ethical concerns associated with globalizing experimental therapy.