We're live at ClinicalTrialsWiki.org!

The title says it all. Check us out at http://www.clinicaltrialswiki.org.

The wiki itself is still in prototype form, but we're working quickly to populate it with objective data from each of over 65,000 federally registered trials. Here's a screenshot:

Yesterday someone asked me how much we're getting paid for doing this. Zip. Yes, you heard it here first -- this is a 100% volunteer-run project.

We're doing it because we're frustrated at the lack of unbiased, comprehensive sources of clinical trial information and analysis. And we're optimistic that a new service like ours could bring together students, researchers, clinicians, and industry to the common cause of improving patient outcomes.

From call centers to... clinical trials

Fascinating post at CenterWatch on the rapid growth of global outsourcing of clinical trials. I highly recommend this post in its entirety.

The study, published in Wednesday’s New England Journal of Medicine (NEJM), reports that the number of countries conducting drug testing has doubled in the past 10 years, and, in November 2007, a total of 13,521 of 24,206 investigative sites being used for studies sponsored by U.S. big pharma were international.

Kevin A. Schulman, the lead author of the NEJM article and a professor of medicine at Duke, was interviewed by NYT. It is surprising just how nascent this field is:

The Duke study has ignited furor from the halls of big pharma. They point to the success of international trials for Gardasil (the quadrivalent HPV vaccine from Merck), and the clinical importance of this vaccine for developing countries. Why, they argue, should we prevent the rest of the world from sharing the cutting-edge therapies that we enjoy here at home? The U.S. enjoys the largest and most innovative pharmaceutical industry in the world, so why not expand our global market share by exporting business worldwide?

Indeed, global outsourcing may provide ancillary benefits ("collateral rescue") to entire resource-poor communities: an executive at Millenium Pharmaceuticals recently told me that his company has invested millions of dollars directly into hospital infrastructure improvements throughout the EMEA region, simply to bring up local quality standards to meet the FDA's trial compliance guidelines.

While there's nothing inherently bad about conducting trials internationally, most criticism stems from concern that good clinical trial practices (things like informed consent, blinded controls, patient compliance and followup) are much harder to enforce abroad. It's also questionable whether data collected in one patient population (e.g., Western Saharans) can be used to justify a claim for efficacy in another (e.g., Southern Californians).

Furthermore, Phase I trials, which primarily involve healthy volunteers, will often use monetary incentives to recruit patients. The ethics of doing this in the developing world is murky at best, particularly when individual incentive structures are sharply skewed by widespread poverty, famine, or conflict. I haven't yet heard any good consensus frameworks for thinking about the ethics of risk v. benefit within the context of international trial design.

CenterWatch offers its own multi-point rebuttal of the Duke study:

• The sample size is almost half of the trials listed at the time, compared to a more comprehensive analysis of clinical trials listed in August of 2007 done by Goldman Sachs.
• The study’s analysis of the 20 largest drugmakers in the U.S. excludes more than 1,900 other companies developing drugs around the world.
• Of the 20 countries outside the U.S. doing the most trials in August of 2007 (from the Goldman study), only four—Poland (13th), Russia (17th), Brazil (19th), and the Czech Republic (20th) could be considered emerging markets.
• The percentage of clinical trials initiated overseas increased from about 13% in 1997 to about 30% in 2005. At the end of 2007, the number was just under 34%. The number of trials being conducted worldwide has gone from around 22,000 in 1997 to about 37,000 in 2007.
• While the number of clinical trials initiated overseas has increased dramatically, the study overstates the share of trials overseas by more than 20 percentage points.

John Lewis of the Association of Clinical Research Organizations (ACRO) posted a lengthy (if boilerplate) comment after the post that's at least worth checking out for its predicability.

Expansion of Clinicaltrials.gov

Another interesting article in the last issue of NEJM on the expansion of clinicaltrials.gov, a topic which is very relevant to the development of ClinicalTrialsWiki.org.

Feb 19, 2009 Volume 360:824-830, NEJM
http://content.nejm.org/cgi/content/full/360/8/824

Effective since September 27, 2008 section 801 of the registration and reporting requirements of the FDA amendments Act has been expanded to include the mandatory reporting of basic results of clinical trials that were ongoing on or after September 27, 2007. As Dr. Allastair Wood suggests, the expansion of the FDA amendment section 801 is an essential step forward for the public availability of clinical trial information. The author also emphasizes that this advance remains to be completed by further broadening the reporting requirements and by providing a source of clear and comprehensible review of clinical trial results.

"Ethical clinical research should contribute to generalizable knowledge and improve human health. The dedication of patients who take the risks to participate in clinical research is dishonored when their data remain secret. Section 801 of the FDA Amendments Act will greatly expand the type and amount of information available on clinical trials. The use of these data and the enhanced public access to the FDA's database on clinical trials proposed in this article will greatly improve the ability of investigators and others to assess the full set of results for a given intervention, whether FDA-approved or not, eventually leading to more accurate systematic reviews, better clinical decision making, improved patient care, and improved research efficiency and safety."

Reading this article, I thought ClinicalTrialWiki.org is emerging just in time to complement the expansion of section 801 by:
1) Providing access to clinical trial information: The "news" tab of ClinicalTrialWiki.org will provide a comprehensive source of publicly available information on ongoing and completed Clinical Trials, easily accessible to health care professionals.
2) Opening the discussion to all caregivers via the "public views" tab.
3) Providing clear and understable analysis of clinical trials: In an effort to disseminate rigorous and unbiased information to the public, a panel of experts analyzes discusses and criticizes each clinical trial in the "expert views" tab.

Sneak preview

Here's a glimpse into the backroom development that's going on while we're migrating servers. The main page has gotten another makeover (this isn't live yet):


I wanted to maintain a simple, clean interface while enhancing the functionality with a search bar that links directly into the wiki. Notice the fancy new "W" logo, which took all of 15 seconds to whip up on Photoshop. ;)

As always, let me know what you think.

CABG vs. stenting

There's an excellent roundtable discussion on outcomes of coronary artery bypass graft (CABG) surgery vs percutaneous coronary intervention (PCI) in this week's New England Journal of Medicine. On the panel are Elizabeth Nabel, David Hillis, and Tom Lee. I had a chance to spend some time with the Nabel family last year -- she's a terrific cardiologist and currently Director of the National Heart, Lung, and Blood Institute.

Link to video after the jump.

In the international SYNTAX trial (ClinicalTrials.gov number, NCT00114972), funded by Boston Scientific (manufacturers of the TAXUS drug-eluting stent), 1800 patients with three-vessel or left main disease were randomly assigned to either revascularization with CABG or PCI involving drug-eluting stents. The paper published in NEJM (Serruys P et al. N Engl J Med 2009) shows us these dramatic Kaplan-Meir curves by treatment group:


The need for repeat revascularization was significantly lower with CABG, but the risk of stroke was significantly higher in the surgery group.

As Dr. Mohammadzadeh of CA has pointed out,

Many of the commentators have cited the difference in stroke rates in the two study groups as a justification for choosing pci over cabg. I do not see how their argument holds when there was such a vast difference between the post-procedural medical therapy that the two groups received. It seems to make good intuitive sense that if the surgical group had received as aggressive medical therapy, that not only the stroke rates may have been comparable, but the other end points such as mace would have crystallize more strikingly in favor of the surgical group. There is no question that there are patients that are better served by pci even in the setting of LM stenosis or 3-V CAD, but the bottom line should be that the patients should be given a fair and balanced explanation of their options before making a decision that is best suited for them.

Exactly. The risk vs. benefit analysis has long favored CABG in three vessel or LM disease, and this study should not really change clinical practice in these circumstances. However, it is striking that CABG patients often receive subpar antiplatelet therapy on the surgical floor. Establishing clinical directives for aggressive medical therapy in CABG patients might produce a welcome drop in stroke risk and rates of repeat revascularization.

And let's not forget that, despite the heated rhetoric surrounding this trial, we're really not considering one treatment strategy versus another. PCI has a secure and well-established place in the treatment of stable angina due to CAD.

The truth about comparative effectiveness

It's all the rage now: Peter Orzag of OMB at the White House seems to think comparative effectiveness research is worth appropriations valued at $1.1 billion. Will it be worth the money?

I wasn't sure what "comparative effectiveness" actually meant, so I looked up the term at Consumer Reports:

What does it mean? Comparative effectiveness quite simply means comparing two or more treatments for a given condition. Studies may compare similar treatments, such as two drugs, or it may analyze very different approaches, such as surgery and drug therapy. Comparative effectiveness evaluations may focus only on the relative medical benefits and risks of each option, or they may also weigh both the costs and the benefits of those options. In some cases, a given treatment may prove to be more effective clinically or more cost-effective for a broad range of patients, but frequently a key issue is determining which specific types of patients would benefit most from it.

Transparent, unbiased, comparative research conducted without industry support? I'm all for it, so long as Congress doesn't bypass the clinical judgment of individual physicians -- or attempt to meter out care. Reminds me a bit of the Clinton-era attempt to develop standardized clinical recommendations for wide range of conditions, from chronic back pain to diabetes.

Here's a few independent takes at the NYT health blog, THCB, and The Gray Sheet (subscription required).

Crowdsourcing

Interesting post today by Matthew Holt over at THCB. He interviewed Alexandra Carmichael, CEO of CureTogether.com, who claims to be at the cutting edge of something called Open Source Health Research.

Her company is trying to leverage the collective knowledge of disease communities to discover new connections between symptom patterns and underlying diagnoses. For example, after the jump you can see a graph generated by CureTogether.com's user surveys that illustrates the most frequent co-morbidities reported with vulvodynia.

Could information like this one day be useful in clinical decision-making? Perhaps, though it would be terribly difficult to interpret. How's a doctor supposed to tease apart co-morbidities that are spuriously linked from those that represent real clues as to common etiology? Is it ethical to make clinical decisions on the basis of uncorroborated Internet surveys?

It's my hope that generic user surveys like this get tied to more robust analysis, including an attempt to tease out confounders (it sounds like CureTogether.com is trying to do this). Currently the population sizes in question are probably far too small to drive any significant outcomes analysis, but expect to see more sites like this spring up in the coming years...

The real value may be in the sense of 'working towards a cure' that it gives to patients. Here's a money passage:

Me: Which kinds of takes us back to your prior life in genomics and ideas about GeneTwist. Care to speculate about the actual ways that CureTogether's data and community will actually lead to cures, together?

Alexandra: Yes, the grander vision for down the road is to integrate all kinds of data - genome scans, biomarker tests, streaming data from wifi health tracking gadgets. Collaboration with the larger research community as well, integrating our data with traditional clinical trial data. We already have researchers knocking on our doors wanting to start analyzing the data.

Me: So now "all" you have to do is get more people and more data into the site. How are you going to do that?

Alexandra: That's a good question! By talking to people like you, for a start. Health and condition-specific bloggers seem happy to help spread the word. Disease foundations have also approached us, eager to help out. And media have all been coming to us so far. I just started the process of seriously getting out there in the past couple of weeks - I'm even on Twitter @accarmichael. It's still mostly a grass-roots effort though. If and when we get funding, that could change. But it's very rewarding work. At the end of the day, I know I've spent my time helping people and working to make a difference.

Reading her comments, it strikes me that we face a similar challenge at ClinicalTrialsWiki.org in trying to develop a core community of users who are motivated to populate our site with discussion and commentary.