Getting to the heart of the matter at Columbia?

A recent story from the Huffington Post, as reported by Jeanne Lenzer and Shannon Brownlee, highlights a story about a cardiac surgery trial at Columbia that began in ~ 1999.

The story reports that the Office of Human Research Protections (OHRP) in the US has requested that Columbia University notify participants enrolled in the trial entitled "Effect of different intravenous fluids on thromboelastography during cardiac surgery” that they may “have suffered harms that were a function of the design and procedures of [a] study” (quote from OHRP as reported in HuffPo) conducted a decade ago. According to the story, some of the patients in the trial had severe adverse reactions to a blood-expanding fluid used in surgery. The main goal of the trial was, in fact, to test different kinds and doses of blood-expanding fluids in surgery (used to replace lost blood volume). In high doses, some of these fluids had previously been shown to cause serious bleeding. According to the story, a number of participants received excessively high doses (higher than recommended safe maximum amounts) of the fluids. Two patients in the trial died and many more required transfusions as a result of serious bleeding.

Here is the story as reported in the Huffington Post: Government Orders Columbia to Tell Patients 'True Nature' of Drug Study

The main criticisms of the trial include the claim that participants were not fully informed of the goals of the study and potential risks of trial participation, including the potential risk of serious bleeding. Additionally, the authors claim that there may have been some misconduct in the recruitment of patients who were Spanish-speaking only, socio-economically disadvantaged or considered to be more vulnerable.

This story has been reported all over the Internet by sources such as The Indiana University Center for Bioethics (IUCB),the Google group on progressive activism, The Alliance for Human Research Protection, Cardiobrief, and finally, the law firm of Weitz & Luxenberg who are asking that patients of the trial contact them as part of a "lawsuit review".

Here's what worries me. This seems, at first glance, to be an extremely serious potential breach of research ethics. It also is a pretty monumental medical story — a clinical trial resulting in deaths and serious morbidity. Yet I haven't been able to find any sources, other than HuffPo, that have corroborated this story. The blogs and newsgroups I note above each cite the HuffPo story only. The story has not been picked up by mainstream media. Documents supporting the story, such as the letter to Columbia from OHRP, are not publicly available. The Huffington Post has had its share of criticism over their coverage of science, medicine and health-related reporting. It may not be the most reliable source for science and medicine stories. And yet it's still the only one for "this" story.

Why are there no corroborating sources? Why, when you search for more information on what appears to be a "breaking news" clinical trial story, do you simply end up back at the original Huffington Post report? With a story as potentially serious as this, with lives lost, with people hurt and with even more lives and careers at stake, I'd feel much better about this story if someone else were asking these questions. And getting some answers from more than one place.

HIV vaccine trial: a "shot in the arm"?

Last month, it was announced that an HIV vaccine trial carried out in Thailand showed hope for further progress towards use of a vaccine for HIV. This was not a small trial — it was carried out on more than 16000 Thai volunteers, costing $105 million USD. The initial press release which was heralded, blogged, tweeted and retweeted reported that the data from the trial showed a decrease in the risk of HIV infection by 31% compared to a placebo. Characterized as a veritable "shot in the arm" for those engaged in HIV vaccine research (so called by the Principal Investigator of the study, Dr. Scott Hammer) this trial seemed to be the most positive and hopeful news in this area to date.

But is it?

New reports shows that the initial data (demonstrating the "moderate" 31% decrease in infection rates) included a subgroup of participants who did not follow the trial protocol. According to the Scientist's most recent report, if that subgroup is excluded, the data, when analyzed, still shows a moderate decrease in infection rates but the result is no longer statistically significant.

Here's the most recent update, from The Scientist: Hubbub brews for HIV vax data

Although both sets of data were available to the researchers at the time of the original announcement, they chose not to report them alongside the initial analysis, Jerome Kim, a US Army scientist who was involved in the study, told the Wall Street Journal. "We thought very hard about how to provide the clearest, most honest message," Kim said. "We stand by the fact that this is a vaccine with a modest protective effect." But some AIDS researchers (who preferred to remain anonymous) have suggested that the study leaders were dishonest and put a positive spin on a study with, at best, inconclusive results.

For those of you who haven't been in a stats class recently, statistical significance is not a trivial matter. It's the measure by which you can state that a particular finding isn't simply due to chance, that it can be reproduced, that it is a reliable finding. In this case, it's the justification that would have allowed researchers to claim that the decrease in infection rates was really due to the vaccine, and not something else. If in fact a number of participants did not follow the protocol, it's very difficult to say that confounding factors (things other than the vaccine that might well be responsible for some of the decrease in rates of infection) were adequately controlled.

We've talked about the responsibility of researchers and the media in reporting research stories to the public ( here, here, and here) and this story serves to remind us, yet again, of the responsibility when presenting data to the public in a non-scientific, easy-to-understand way (at the time of the update, the data had not been presented at a scientific meeting or in a publication). While it's important to be clear and honest — and the researchers have said repeatedly that they were aiming to be as clear and honest as possible — researchers also have an ethical obligation to ensure that the data, disseminated in any context, are not misleading, are scientifically sound, and are presented in a complete way. Especially with an issue like this one, an issue in which many are actively looking for a glimmer of hope.

It may well be that the data support a conclusion that does provide hope — a decrease in infection rates that is really due to the vaccine. But with this current confusion and doubt, the burden of proof rests now with the researchers to present all the data to both the public (again) and the scientific community, in ways that everyone can clearly understand.

Trust in Pharma?

Should we trust Big Pharma? Plenty of people don't, and for good reasons familiar to readers of this blog.

Over at the Business Ethics Blog, I just posted a longish item about reasons for, and against, trusting Big Pharma — or rather, trusting particular companies on particular issues on particular days.

The "against" side is easy: pursuit of profits has clearly driven a pattern of disreputable behaviour within the industry.

The "for" side is more complex. I'll just list 5 factors briefly (see my other blog entry for greater detail) and then make an additional comment about Research Ethics & the role of Ethics Boards.

1) Individual Ethics — Pharma, despite being a troubled industry, is full of normal people with normal ethics. Most of them are likely to be honest most of the time.

2) Regulations — The industry is highly regulated. Enforcement isn't always great, but generally there are serious penalties for clear wrongs.

3) Peer Review — The basis for all pharma product claims is open to public, and especially expert, scrutiny. A good but imperfect system.

4) Scientific Overlap — Pharma may have too much influence in some parts of Medicine, but not all physicians are on the payroll, and nor are most of the biologists, chemists, statisticians, etc., who also get to see and critique published medical research.

5) Competition — Pharma is intensely competitive, as are medical researchers. Collusion and conspiracy are the exception, not the rule.

In the list above, I left out the role of Ethics Boards and scholars in research ethics. Ethics Boards are, in a sense, the public's first line of defence, making sure that the clinical trials that get conducted are conducted ethically — and as it happens, good ethics in research overlaps very considerably with good science. On the scholarship side, you've got people like Charles Weijer, working to make sure that the principles according to which biomedical research gets done are the best ones. (Charles has argued, for example, that for ethical and scientific reasons, in almost all cases new drugs ought to be tested against the best drugs currently available, rather than against placebos.) To the extent that good scholarship influences policy, it helps ensure that drugs that make it to market really do deserve to be there.

The pharmaceutical industry has, alas, seemingly worked very hard at gaining its own lousy reputation. Trust Big Pharma, full stop? Clearly not. But we should be careful not to throw the baby out with the bathwater. We need instead to think clearly about the social and institutional mechanisms that help keep Pharma in line, and about how we can make those mechanisms better.

Being Excited About Research: Is it Still Possible?

This isn't a research ethics story per se - but a fascinating story about some exciting research that highlights a few important things that researchers, research ethics board members and the public often forget.

Here's the story, from the New York Times: A Race in Cardiology

A race is on to develop the potentially next big thing in heart surgery: a replacement valve that can be implanted through thin tubes known as catheters rather than by traditional open-heart surgery.

The contest pits two major companies, Edwards Lifesciences and Medtronic. Analysts estimate a market for the product that could exceed $1.5 billion within six years. But if the valves catch on, their benefits for the nation’s aging population could be substantial — even if the impact on the nation’s health care bill may be hard to calculate.

The new valves — which make it possible to repair the heart without the rigors of chest-opening surgery — have been available in Europe for about 18 months, with sales of about $100 million split about evenly last year between the two companies. While doctors say that the early results have been promising, they add that it is too early to gauge the technology’s long-term benefits.

In the United States, the devices are currently being tested in older, critically ill patients in clinical trials. Many medical experts and financial analysts predict that if the devices live up to their makers’ claims, they could revolutionize valve replacement, a common heart operation, and extend the lives of thousands of frail patients who are not now considered candidates for surgery.

In addition to my own fascination with cardiac medicine and surgery from my previous career as a cardiac surgery nurse, I found that this story reminded me, as I said above, about a few things we tend to forget about.

First, industry isn't all bad. It's awfully trendy to, in a knee-jerk way, resent big corporations. Yet here is an example (and there are many) of multi-billion dollar corporations who are the only ones who can and will fund research like this. Of course, I'm not naïve — I do realize that there are huge potential future profits for whichever company perfects the valve that allows for minimally invasive cardiac valve replacement. But it's important to realize that while corporations must aim for profit, they can and sometimes do so through support of technologies like this one, that offers hope to many and helps to revolutionize health care. Without collaborative relationships between corporations, research ethics boards, clinicians and researchers, this kind of research simply wouldn't be possible.

Second, it's necessary to respond to changing technology in health care and the only way to do so is through research — sound, ethical research. It's up to us, as research ethics boards, to recognize potential benefits and the possible fecundity of those benefits. It's also up to researchers to clearly articulate potential benefits alongside risks. As research ethics board members, we tend to focus on risks. We do (and must) attend to potential benefits, but often not on their own. We need to always view benefits as they are weighed against potential risks. However, when reading a story like this, it does make one pause for a moment. Making minimally invasive cardiac valve replacement surgery an option really does mean that the procedure could be available for many patients who would otherwise be deemed inoperable. It would open the doors for more and more minimally invasive procedures (coronary bypass surgeries and angioplasties can be done in a minimally invasive manner) that reduce risks of surgery and allow surgery to be carried out on more potential patients than ever before. Don't get me wrong — I'm certainly not saying here that research like this shouldn't be very carefully reviewed and monitored with a thorough risk-benefit analysis but it's also okay to sometimes say, "Wow, wouldn't this be great if it really did live up to its potential!" Having read probably thousands of research ethics protocols by now, I'd like to think I could still get excited about possibilities like this — despite all the skeptics waving red flags at me about big corporations and profit and ompetition and risk.

As research ethics board members, we tend to be inundated with negative stories that are often fraught with problems, wrongdoing and concerns. Realistically, it is our job to look at research with a critical eye. Nevertheless, this story reminds me of the excitement, the possibility, and promise of research, and why it's so satisfying to be a collaborative and integral part of the facilitation of research.