Friday, October 26, 2007

African Vaccine Trials Ethics Problems Continue


A few weeks ago much propagated microbicide trials designed to test the efficacy of a microbicide aimed at reducing or preventing HIV transmission during sexual intercourse ended in failure. It turned out that the microbicide actually increased the risk of HIV infection. All sorts of ethical questions arose, of course, including whether an infection acquired during the course of the trial should count as a trial related injury that ought to be subject to compensation.

Well, much better resourced preventive HIV vaccine trials also crashed in a spectacular way today. Again, it turned out that the trials left those who were injected with the vaccine candidate more susceptible to HIV infection than those who were in the placebo arm. In all fairness to those who undertook this trial, the plug was pulled quickly when these results came to light. Equally, how would one ever find out whether a vaccine candidate works other than by means of undertaking such trials. So, the problem with both the microbicide trials, and the preventive vaccine trials isn't that they took place at all. The problem is to do with the question of what is owed to those who became already infected during the course of the prevention trial, and to those who are now at greater risk of catching an infection. There were also clear failings in the informed consent process.

I think these quotes from two of the participants are revealing in important ways. I found them in an article in the Washington Post:

"It's quite shocking," said Nelly Nonoise, 26, who had received three injections of the vaccine in her left shoulder. She added, "I probably wouldn't have joined the study knowing there's a risk." Another participant, Nonhlanhla Nqakala, 22, said she thought the text message urging her to visit the vaccine test site meant she had tested positive for HIV. Her brother and a close friend had the disease and died, she said. Nqakala said she was relieved when a doctor explained that she was not infected, but the news of a possible problem with the vaccine -- she had received three doses, not placebos -- left her distressed. "I thought the trial would help us find a cure for HIV," she said."

Now, here is a problem obviously! Two people are being interviewed by the journalist, and both indicate that they didn't understand properly the nature of the trial. This does not reflect well on the investigators' professed best practice standards in their informed consent process. It seems obvious that they happily accepted participants into their trial who did not actually comprehend the nature of the trial.

Again, the question is what is owed to the trial participants by the trial sponsors and / or the investigators. Surely if you accept people into your trial that end up being worse off when the trial is stopped, you have some responsibility for these folks, particularly so when obviously you took participants into the trial that didn't understand what was going on in the first place.

And yes, this smug ethicist can claim without embarrassment that 'I told you so' prior to the start of the trial. I argued that trial participants' competence and level of information / comprehension needed to be tested in order to rule out that people would end up in the trial that do not understand its nature. This was rejected at the time with arguments such as 'we would never be able to recruit enough participants then'. So the public health and research imperative was prioritised over individual participants' well being.

Lessons to be learned: Well, to be frank, the warnings were there prior to the trial and they were ignored. That one should not do this isn't exactly a new lesson, so, if anything we should probably consider erring on the side of caution on the odd occasion in future.

The Washington Post cites the Principal Investigator with these remarks:

"This is my worst nightmare," said Glenda Gray, the lead South Africa investigator for the vaccine study. "I haven't slept for days. I have a headache. I'm ready to resign from trials for the rest of my life."

Of course, while I have no doubt about Glenda Gray's integrity as a researcher, and while I have no doubt that her current qualms are genuine, much of this could have been avoided if sensible procedures in terms of the informed consent process had been put in place, including knowledge and comprehension evaluation of the prospective participants. The failure to do so puts the moral responsibility for this trial's failure squarely on the shoulders of the trial sponsors and investigators. It's not about resigning from clinical trials, it's about avoiding ethical short cuts (for instance in the informed consent process).

9 comments:

  1. Udo, I apologize in advance for asking what is probably a profoundly stupid question: what is it exactly that is required of the participants in an Aids vaccine trial? Are they expected to have unprotected sex in order to ascertain if the vaccine is effective?

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  2. well, they're expected to live their lives ideally just as before. they're all told that it's a vaccine candidate and that nobody knows whether it works, and also that there's a placebo control. some people in such trials take higher risks as a result of trial participation because they've a therapeutic misconception meaning they think they're protected or better protected etc.

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  3. There are a number of inaccuracies in this posting and there are a number of excellent sources for information on how trials are conducted and what the data actually say about the vaccine and microbicide trials referenced herein. One source: www.avac.org They dont conduct trials and dont have a vested interest in products.

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  4. it's tempting to delete the above posting obviously. 'anonymous' claims that there are (unknown) 'inaccuracies' in a posting that references a Washington Post article as its main source of information, and then goes on to praise a website where people can find information etc. anyway, let the buyer beware.

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  5. hmm, actually... the independent source states as one of its objectives, 'AVAC is dedicated to accelerating the ethical development and global delivery of vaccines for AIDS.' While they might not have a vested interest in particular products, it's probably beyond doubt that they're keen on the continuation of vaccine trials.

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  6. Thanks for answering my question. Frankly, this Aids vaccine business is dead in the water, and they might as well pack it in, right now. I mean, we're not talking measles vaccination here; more like Russian Roulette.

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  7. Just a point of clarification--the Washington Post article and the press releases from the trial sponsors noted that vaccine recipients might be at increased risk. The posting above states, "It turned out that the trials left those who were injected with the vaccine candidate more susceptible to HIV infection than those who were in the placebo arm" which at this time is not an accurate statement.

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  8. I find this HIV vaccine research business problemmatic for many reasons - one of which of course relates to the fact that such research typically takes place in areas where large numbers of people are poor, illiterate and lack formal education. Coupled with this is the fact that more often than not it is NOT the researcher who obtains consent from subjects, but lay people (who may or may not be) from the community who have been put on some training run by researchers themselves, after which they're exepected to go into the community to recruit, interview and retain subjects. Many of these researchers are either incapable of conversing with potential subjects or fear entering these communities. I suspect only a minority of researchers actually go into these communities to recruit and collect data... otherwise tey sit in their safe havens waiting for subjects to visit them. My experience of working in HIV prevention research programmes has certainly been this, so my sense is that informed consent is not seen as a process by many researchers and that some crucial and material information may sometimes be left out when discussing research with potential subjects... so telling me what some website says tells me nothing about what actually happens on the ground. Being a researcher should surely mean that you do some things yourself (rather than delegate it to often poorly trained fieldworkers). It is not enough to sit in an office and wait for data to be handed over to you for analysis... perhaps if researchers were actually out in the field, and didn't just rely on textbook knowledge of what's happening in a community or how it functions, many of these problems could have been avoided as they could've been picked up earlier.
    But alas, as you mentioned, public health takes precedence, and certainly it seems that researchers do not do enough to ensure that subjects are competent and that they do in fact understand and comprehend the risks involved in this kind of research and now they are paying the price. I wait with abated breath for their next move!

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  9. One of the grounds for objection to this trial in South Africa was that the administrators of the trial were less than enthusiastic about providing details of the arrangements for providing informed consent: see

    http://www.biosafetyafrica.net/portal/DOCS/GM_HIV_vaccine_trial.pdf

    Objections were also raised on the grounds that the trial made no provision for monitoring the health of the participants after the end of the trial.

    And then there's the whole modified adenovirus bag of worms.

    All of which may explain why the administrators in South Africa felt they had to unblind the trial once the bad news started coming in. I don't suppose the BCG/HIV debacle helped either.

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