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.

We're moving!

We're moving the webserver for ClinicalTrialsWiki.org from my personal computer to a more permanent residence. To do that, we're taking the site down for a couple of days as we set up shop in our new location (which has 4-5x more storage space), and re-build our wiki there.

Thanks for your patience!

Welcoming a new member of the team (after the toast)

Yesterday morning, I had eight friends over to my apartment for brunch, and we made challah bread french toast (recipe idea courtesy of DW) and chocolate chip pancakes. Delicious. Here's what it looked like:


But today it's back to work, and I'd like to welcome Gaurav Singal as a new member of our team at ClinicalTrialsWiki.org. He's going to take over technology and online operations from now on. You may have noticed his name appear on the sidebar as a new contributor to this blog, and you can read his bio here.

Gaurav is a good friend of mine from medical school who brings us deep knowledge of web design and content management, in addition to having some work experience in the VC world. We're very excited to have him on board!

New main page design

Just finished a major overhaul of the site's main page. It's a cleaner, simpler interface with just a few links -- one takes you to our Mission Statement (see this post), another takes you forward to the wiki, and the third takes you to our blog here at Blogger.

Check it out from either the '.com' or '.org' domains -- both should be live at this point! And let me know if you have any problems.

Here's what you should see:

Next, I'm hoping to add a search bar that links to the wiki search page, and to begin customizing and populating the actual wiki. It'll require learning how to tweak the MediaWiki template.

But all that excitement can wait until Monday -- I'm taking the rest of the weekend off!

Welcome x2

I wanted to add my welcome to Pavan's post. We are very excited to undertake this project. We foresee clinicaltrialswiki.org becoming the go-to website for clear and unbiased analysis of clinical trials, heated discussions over uncontrolled counfounders, and expert views on the latest blockbuster drug.
For now...looking for grant money.

Mission Statement

Last Friday, when we first came up with the idea for ClinicalTrialsWiki.org, we wrote a Mission Statement describing our principles and goals in setting up this site.

You can read the full text of the Mission Statement here.

A few key quotes. The first has to do with why we got this thing started in the first place:

Few sources currently exist for unbiased, data-driven analysis and commentary on the results of clinical trials; neither the pharmaceutical industry nor international regulatory bodies face the appropriate financial incentives or legal imperatives to develop a comprehensive, public source of clinical trial data and expert opinion. We intend to solve this problem by implementing a searchable wiki containing all public-domain information on clinical trials, and inviting expert thought leaders to contribute timely commentary on published trial data.

And concerning our policy regarding receiving compensation from industry:

It is the policy of Clinical Trials Wiki not to receive monetary or significant non-monetary compensation from the pharmaceutical and medical device industries. This includes, but is not limited to, advertising revenue, gifts, speaking fees, and other forms of sponsorship.

Finally, we came up with four principles we'd like to abide by:

1. Transparency: All information placed on the site will be clearly sourced and public-domain. Edits made to any section of the wiki will be cataloged so users can view the state of the wiki at any point in its recent history. A detailed budget listing each source of revenue for Clinical Trials Wiki will be posted on the blog accompanying the site, and an annual report will be made available for download each year. Biographies of each of the site's staff members, expert panelists, and Board of Advisors will be available on the blog.

2. Non-bias: We believe that advertising from pharmaceutical and medical device companies undermines the mission of Clinical Trials Wiki by creating the perception of undue influence and biased reporting. Therefore it is our policy to not allow advertising from these companies on the site. We will consider limited text-based advertising from health providers (hospitals, group practices, etc.) to provide revenues necessary to sustain our operations. We also may apply for grants from charitable foundations and donations from site viewers to sustain our operations.

3. Accessibility: We will attempt to make our site easy to use with a familiar wiki interface. We will attempt to be as platform-neutral as possible in delivering our web content. We will attempt to include clinical trial data from all over the world. We will not charge subscription or login fees for this service. We will not create a "premium" section of the site with enhanced content for paid subscribers.

4. Comprehensiveness: Our goal is to include description, analysis, and commentary for all clinical trials whose information has ever been made public-domain.

We hope to make this a community-centered process, so please let us know what you think.

A little about our idea...

My name is Pavan Cheruvu, and I'm one of the founders of ClinicalTrialsWiki.org. Brice Gaudilliere and I are very excited to be starting this collaborative wiki project.

I'm currently a fourth-year student at Harvard Medical School, and Brice is in his final year of the M.D./Ph.D. program, also at Harvard. You can read our bios on the sidebar of this blog.

A health professional can turn to www.clinicaltrials.gov for a rich database of clinical trial methodology and data, or to one of many online medical journals (e.g., NEJM, JAMA) for editorial opionion on select clinical trials. However, there's no online resource that's a "one-stop shop" for clinical trial information and analysis.

Our idea for ClinicalTrialsWiki.org is to combine a familiar wiki interface for posting information on clinical trials with a forum for discussion of the results.

We will invite users to post their original analysis and commentary and, importantly, for each trial we will convene a panel of distinguished experts (statisticians, pharmacoepidemiologists, clinicians, FDA insiders, etc.) to contribute thier own interpretations and insights.

If you have any innovative ideas, thoughtful suggestions, or staunch criticisms as we launch this collaborative project, we'd love to hear from you in the comment box below, or by email.

Welcome to our blog!

Hello, and welcome to the blog for ClinicalTrialsWiki.org!

ClinicalTrialsWiki.org strives to be world's most comprehensive and unbiased source of expert opinion about clinical trials online.

As you follow our posts over the coming months, we'll describe our progress in getting the website started, and also include links to interesting editorials related to the latest clinical trial news.