Ethical Research? “Prove it works, then work out how to do it”

The fun’s over for the moment, so its back to a more medical theme for this blog. I’m going to start with a story of a 13 year-old girl I met on the ward today. She came in with the worst headache she had ever had. She lay on the bed as her mother held her head and she cried. She had recently completed treatment for TB and her and her mother both said her HIV status was negative, however a test today found that she was positive. Given all of these pieces of her history the Ugandan team admitting her astutely felt the most likely cause was Cryptococcal meningitis.

She was clearly very unwell: Cryptococcal meningitis in high resource settings has a mortality of approximately 25%. In the best study settings in low resource countries this is around 40%. A team from the Infectious Disease Institute (IDI) running an ongoing trial into Crytpococcal meningitis management came to see her and agreed with the diagnosis. Unfortunately, being under the age of 18, she did not fit their study criteria and therefore could not receive the “best available treatment”; a CT head, serial lumbar punctures (LPs) from pre-prepared packs, a full follow-up from the study team using a treatment protocol, all at no cost to her.

Instead, and despite being in the best equipped national hospital in the country, she would be looked after by an overstretched team of Ugandan Doctors and Nurses without easy availability of equipment (even one LP would cost her and her family, then the equipment was not easy to find), medications (Amphoterecin B was available at a cost, Fluconazole is free) and no available CT as it was broken (although if it were available it would be at a cost). The contrast is care is obvious and goes along way to explaining the sadness of her situation. It’s also probably why the IDI team offered an LP pack to her family. She duly received her LP, and her cerebrospinal fluid hit the wall as the needle went in. Within a few minutes her headache was better. Her prognosis from now is likely guarded. She will need a full course of antifungal treatment, serial LP’s and careful follow up to start antiretrovirals (ART), but for the moment she was much more comfortable.

To me this case highlights the deep chasm that separates clinical trials from standard practice in developing countries. I think this raises some ethical issues to do with equity of care for patients, and for the implementation of research after the trials have been performed. Perhaps at its most extreme on could argue that the last few years have given rise to a heavily funded research fetish that is open mainly to the western researcher and deals with ideas that are far beyond the scope of system and resource availability they are set in. On the other hand, perhaps trials like these are the only way to create high quality evidence to guide national and international policy.

Ethical Guidance

In 1964, TheDeclaration of Helsinki was created to guide medical research worldwide. Today it is the cornerstone of medical ethics worldwide but sadly lacks any legal capacity. From this document, point 17 of 34 states:

“Medical research involving a disadvantaged or vulnerable population or community is only justified if the research is responsive to the health needs and priorities of this population or community and if there is a reasonable likelihood that this population or community stands to benefit from the results of the research.”

The interpretation of this can of course be debated. What is the timeframe of the “benefit”? Does the statement create a relationship between the investigators and the person, or community, in the trial that means they should continue to receive treatment after the trial? To me it underpins the fact that if you are doing research somewhere the primary benefactors of that research should be the population or community that is being used. For example, on the basis of a trial performed in Kenya HIV positive individuals it shouldn’t be the case that American or British HIV positive individuals receive those benefits years before their Kenyan counterparts.

The Research Buzz

In the HIV/AIDS arena several trials have created a “buzz” amongst researchers and to some extent their clinicians; people think that for the first time controlling the HIV virus is a real possibility. Male circumcision reduces the risk of contracting the virus for men by 54%. Tenofovir gel reduces the risk of infection for women and gay men by 39%.  Pre-exposure prophylaxis reduces the risk of infection by between 62-73% in concordant couples, with relatively few side effects. There is also emerging evidence for vaccine efficacy; a recombinant vaccine in Thailand recently showed a 31% reduction in new HIV infections, although the length of protection is still unclear. Finally, and perhaps most interesting at the moment, is the idea of treatment as a method of prevention; HIV discordant couples (on HIV positive the other not) showed a 96% decrease in infection rates, with the same virus, when the positive partner was started on ARTs.

(Interestingly, researchers in the treatment as prevention study got around the problem of what to do with these HIV discordant couples who they had started on ARTs early, at CD4’s of 550, that they felt they couldn’t ethically discontinue ART in by continuing to treat them in a “demonstration project’.)

Given all this evidence it can be argued that the future is bright. But what about the current reality? The two most important factors in this are resources and the epidemic.

Resources

In Sub-Saharan Africa, most of the funding for ARTs and the systems that provide them comes from the Bill and Melinda Gates Foundation and PEPFAR, the Presidents Emergency Plan for AIDS Relief. Between 2003-8 PEPFAR committed $15 billion, which was expanded to $48 billion to 2013. In Tanzanian terms this amounted to a budget of around $350 million (similar in Uganda), in other words approximately a third of the national health budget. The Gates fund is more difficult to estimate however as far as I can see it is probably worth in the region of $30 billion to be spent over the coming 60 years. For both PEPFAR and Gates funding, especially given the current state of the financial market, the sustainability of funding is definitely not clear. Local resource input is clearly important, however as I have argued previously a country like Tanzania has very little available to spend on health relative to the costs needed.

Epidemic

As I am currently based in Uganda I will use it as an example to show the current deficits in basic provision of ART:

Number of people on ARTs	200,000
Estimated number of people needing ARTs (WHO definition CD4 350)	520,000
Approx number of people to treat for prevention (CD4 550)	? 750,000*

 (*estimate via personal communication)

Add into this the dynamism of the epidemic; more and more people are infected and diagnosed on a daily basis. In Uganda the HIV positive, untreated population is still growing as more people are diagnosed with HIV daily than start on ARTs. Despite the boom in funding we still cannot keep up with demand for HIV treatment at the most basic level of ART provision.

“Prove it works then work out how to do it”

The obvious argument for doing these trials is that we badly need evidence to show what does and doesn’t work in HIV, for individual patients and policy. And, although most countries that face the brunt of the HIV/AIDS epidemic have weak health systems that are not capable of implementing many of the interventions, if researchers can show that these interventions work, then the funding will come as the allure of slowing and possibly stopping the epidemic becomes too tempting. People say “look at what happened with ARTs; 10 years ago people said that you couldn’t put people ART and now look what’s happened” – PEPFAR has reduced AIDS deaths by an estimated 10% by starting them on ART. Maybe this is true but at the least it’s a gamble.

Personally, I can’t help but feel sad and angry about the care that this 13 year-old girl will receive. I’m sad and angry because I know down the corridor from her is someone who, by virtue of being 5 years older, is being looked after by a foreign research doctor (getting paid a western salary) to provide international quality care for their trial patient. Care that can, in the words of one researcher, "we only do in a research setting". Underpinning this is the fact that her health system can’t provide (for a myriad of reasons) a similar standard of care and, unless we see a paradigm shift in how HIV care and health systems are going to be funded and interventions rolled out, is most likely not going to provide that standard of care in the near future. This funding could be donor driven but in the current climate this is unlikely, which leaves resource limited countries the option of reprioritizing their own scant resources, the alternative is that they perform an economic miracle of growing their economies in an equitable way at a vastly increased speed. For research there is a growing move towards “operational research” focusing on how to scale up interventions by cost-effective means. Perhaps this will prove to a more equitable and just method for improving access to care, we will have to wait and see.

P.s. To add to the western focused research fetish; why do trials publish in NJEM when there is f*^k all chance that a clinical officer or medical student, who is arguably the most important reader of these trials, is able to access them?