Three years in: what has the $42M Atopic Dermatitis Research Network produced?

In July it will be three years since the NIH awarded National Jewish Health in Denver, CO $31 million to create and administer the Atopic Dermatitis Research Network, a consortium of five academic sites across the US. A contractor, Rho Federal Systems of Chapel Hill, NC, won an $11 million contract to operate a center to coordinate statistics and clinical trials for the project.

That makes $42 million—spread over five years—which puts the project on the large end of NIH funding for individual biomedical efforts. The typical NIH research grant ranges from $100 thousand to $2 million, and anything bigger is fodder for university news releases. Which raises the question: what have US taxpayers gotten in return?

I ask this as a patient who is grateful that these scientists are working to understand a disease that affects me, my family, and millions in the US and worldwide.

The answer is not obvious, since the publications page on the ADRN website hasn’t been updated since July 2011.

According to the website:

The Atopic Dermatitis Research Network (ADRN) is a consortium of academic medical centers that will conduct clinical research studies in an attempt to learn more about skin infections associated with atopic dermatitis (AD). The studies will focus on antibiotic-resistant Staphylococcus aureus infections and widespread viral infections of the skin, both of which are more prevalent among AD patients. The ADRN will build on the work of the Atopic Dermatitis and Vaccinia Network (ADVN) which conducted clinical studies focused on making smallpox vaccinations safer for people with AD. 

This research will lead to a greater understanding of the immune system in AD patients and may lead to novel therapeutic strategies to manage or prevent infectious complications associated with this disease. 

The ADRN will conduct a number of clinical studies over the next five years and will be enrolling large numbers of people with AD.

A search on clinicaltrials.gov returns two entries for the ADRN: one (open) to create a database of patients for the study of genetic markers connected to susceptibility to infections, and one (completed) to look into how AD patients respond to a new flu vaccine.

The ADRN’s NIH contract number is HHSN272201000020C. A search in the NIH’s PubMed database returns 12 papers that acknowledge funding by that contract number. Three of those are review papers (which did not involve new research).

So that makes  two clinical trials and nine research papers, three years into a five-year $42 million project.

Should US taxpayers expect more; be satisfied; or be impressed?

The answer is probably that we will have to wait to find out.

In each year, a typical top university research lab operates on about $2-3M a year and publishes somewhere around ten papers. That’s roughly $200k a paper.

Three of the five years in the ADRN contract are up; three-fifths of $42M is around $24M. We might therefore naively estimate that we should have seen upwards of 100 papers produced so far.

Most likely the reasons there are only 12 at the moment are that you don't start publishing papers right at the outset of a project. The research must be done first and then written up; and the process of getting accepted to a journal takes months. And the ADRN appears largely to rely on clinical trials--which take time to set up.

So why do we only see two trials listed on clinicaltrials.gov?

I've never had anything to do with a clinical trial, but when I was a researcher, I conducted animal experiments, and there were formidable administrative hurdles to get over before I could start work. I imagine that trials with human subjects are heavily regulated by the government, and for good reason. So the apparently small output of the ADRN to date is, I'm guessing, because it takes a long time to plan trials, get approval, and conduct them, before you can begin analyzing data and reporting it.

Still, let's keep in mind that the ADRN is an extension of the ADVN. It’s not like the ADRN began from scratch—the scientists had the momentum of existing expertise and administration and research aims.

Looking at the titles of the published papers, I can't immediately judge which are the most important. So I emailed Donald Leung, the principal investigator for the ADRN (he's a professor and head of the Division of Pediatric Allergy and Immunology at National Jewish Health), and asked him whether he could summarize the consortium’s findings so far and highlight key points. I hope to hear back from him soon and perhaps to interview him on the phone.

I’d like to know what ADRN scientists have found that surprises them. What have they learned that is truly new?

And what is going to be truly useful to patients in the end? Publishing papers should not be the be-all and end-all of scientific research. What about patents? I’d like to know whether anyone in the ADRN has thought about controlling intellectual property and commercialization. While it’s true that clinical studies may highlight the ideal dosing amount or schedule for existing therapies, and this does not involve creating a new commercial enterprise, most medical technology must pass through the marketplace before it can benefit the consumer/patient.

Someone has to do the dirty work of developing scientific discovery into therapy, and it’s not academic scientists.

More to come.

Fingernails again/Atopic Dermatitis Research Network update

A nail-cutting night again for Voov. She's been mangling herself again. Not too terribly, but her hands have gotten all red and rough. On nail-cutting nights, at bathtime Hidden B closes the toilet lid and sits on the top with Voov in her lap, and cuts her nails with the clippers. Shmoop's job is to choose a pile of books for me to read to distract Voov. This he is very good at-- he picks the baby books, such as "The Going to Bed Book" or "Moo Baa La La La," rather than the ones he wants me to read when he gets HIS nails cut: National Geographic illustrated titles such as "Eurasia" or "The Mammals" (he likes the exotic animal pictures).

There's one issue with Voov that is somewhat disconcerting to us. Her back is, to put it delicately...um...a little hairy. There's no doubt that she's a mammal. Occasionally we wonder whether the steroids we're putting on her--which are relatively mild, but still known to have hormone-mimicking side effects--are doing something weird. Or that maybe the stronger steroids I put on myself are lingering on my hands and somehow getting into her system.

But the furry bits (we're talking downy, not out-and-out hirsute) bear no relation to where the steroids are going on. We haven't been putting steroids on all over her, which is when systemic effects are supposed to occur. And Hidden B tells me that her sister was always "downy," so maybe it runs in the family.

* * *

I was wondering what was going on with the Atopic Dermatitis Research Network, the $31 million multicampus NIH-funded consortium to investigate why eczema patients are vulnerable to MRSA. The ADRN is the new version of the Atopic Dermatitis and Vaccinia Network, a large study now wrapping up.

So I wrote to Donald Leung, the scientist in charge of the ADRN. (He's at National Jewish Health Center in Denver.) Judy Lairsmith, the ADRN's program manager, responded:

We are still working on setting up the Registry/Genetics protocol for the Atopic Dermatitis Research Network. This is a long process as you can gather. The protocol has to incorporate input from all the participating centers, plus the data coordinating center Rho, Inc., and has to go through several layers of approval at the NIH. Current plans are to start enrolling in February or March. Once the study is approved by NIH it must be approved by the [institutional review boards] at each of the institutions where subjects will be enrolled.

During my Ph.D. I had to get an animal experimentation protocol approved by a national laboratory. I filled out a lot of forms. My brain boggles at extrapolating from my experiment to the Kafkaesque bureaucratic demands of a 10-institution trial in human subjects. Judy must be a machine.

We'll have to wait a couple months yet to see exactly what trials will be done where. Participating institutions are all over the U.S. (list at the bottom of this link) so there's a good chance there's one near you.

I'm taking a break from blogging until January 3rd. Back just in time for New Year's resolutions! I know you'll be making some. Until then, enjoy the holidays.

Eczema sufferers thank you, Dr. Anthrax

Voov and I are in a good stretch-- neither of us has any eczematous patches right now. Of course, that can change overnight. But when eczema isn't bothering you, you tend not to think about it-- you get to pretend everything's normal, and wear clothing that nobody but an eczema patient would find daring-- t-shirts, collarless "shirtly sweaters" (you know, those thin pullovers that were a fad a few years ago). Maybe go swimming.

Not to go on about this Atopic Dermatitis Research Network too much, but I had a thought. Why is this grant so big? One clue, maybe, is the story I mentioned yesterday (NYTimes version) about the 2-year-old son of a US soldier who developed eczema vaccinatum after his father was inoculated with vaccinia virus, the live smallpox vaccine.

The episode must have opened a lot of eyes to the danger this vaccine poses to eczema patients. But the NIH was aware of the problem beforehand. ADRN is the sequel to the ADVN, which was established as early as 2004 and perhaps before. Almost certainly the whole ADVN/ADRN focus on vaccines and eczema is a direct consequence of the 2001 anthrax attacks.

So, eczema sufferers, we can thank Bruce Ivins if, in a few years' time, drugs or other therapies start filtering down the pipeline to protect us against MRSA. Bioterror is big money. I don't know exactly how the NIH receives its funding, but the US civilian biodefense budget for financial year 2011 is about $6.5 billion. $32 million is peanuts. We should angle for more!

For me, although MRSA or staphylococcus in general is a continual concern, I feel that it would be a shame if a huge expenditure of research dollars removed the danger of eczema infection but left us all itching and scratching without relief. Let's not forget that.

A postscript: I asked a mathematical epidemiologist, Jamie Lloyd-Smith, an assistant professor at  UCLA, what fraction of the US population would have to be vaccinated against smallpox to shut down an epidemic. His answer, which he stresses is a back-of-the envelope calculation (I leave out the math):

"You can prevent an epidemic--or eliminate an endemic disease--by vaccinating a high enough proportion of people that Reff<1. This gives herd immunity...you'd need to vaccinate 70-83% of people to eliminate smallpox."

Since, including children, about 20% of the US population has experienced eczema in some form--and, say, there are three people in the average family, and even if you don't have eczema, you can't expose your child to viral danger-- it is clear that the government cannot vaccinate 70% of the population in the event of a smallpox attack without putting a small fraction at real risk of developing eczema vaccinatum. Given the loud objections of the anti-vaccination fringe to protecting their kids against measles and whooping cough--with vaccines for which the benefit overwhelmingly outweighs any imagined risk--you can imagine the trouble the government would run into if it tried to jab us all with smallpox vaccine.

Say no to smallpox vaccine

In March 2007 a two-year-old boy in Chicago contracted the smallpox virus from his father, a soldier who had recently been vaccinated prior to a tour of duty in Iraq. Only an all-out response from a Who's Who of U.S. infectious disease experts saved the boy, who had become a victim, it appears, because of an immune defect associated with eczema.

Why does this matter to you? Or to me? I read this article in Science (sorry about the paywall) at the time and the story just leaped off the page at me. It's scary. If you have eczema, you basically shouldn't get vaccinated for smallpox because the risk of dying is too high. And the effects aren't pretty.

(You may notice that I never post images of this stuff. That's my policy. I have eczema, and it grosses me out enough on my own body that I don't need to see it on anyone else's. I eat dinner after writing these posts.)

In the year following that nasty discovery, the NIH founded a research group called the Atopic Dermatitis and Vaccinia Network (ADVN) to look into why vaccinia virus can cause such an extreme reaction. Vaccinia is closely related to variola, the agent of smallpox, and used as the vaccine. In most people, it's benign. An ADVN group at the La Jolla Institute for Allergy and Immunology found that levels of "natural killer" cells, a class of white blood cells, are low in a strain of mice used as models for atopic dermatitis, and which develop "eczema vaccinatum," the same condition the Chicago boy nearly died from. In normal people, the theory is,  natural killer cells somehow keep the virus in check.

Science is complicated-- this is one paper, and it's a mouse model, but you can imagine that these results might point the way to studies that could find similar results in humans, and possibly therapies to boost natural killer cells to prevent deadly reactions to vaccine. (The ADVN must have published reams of papers, and right now I have no idea what their most significant findings were. Will have to find out.)

The ADVN has now morphed into the ADRN, the Atopic Dermatitis Research Network, the group that in July received $31.5 million from the NIH to conduct extensive research over five years into why patients with eczema are susceptible to deadly microbial infections. In the NIH's original request for proposals for this funding, they define four research areas; the first two are eczema vaccinatum and staph infections. The second two are vaccine reactions and infections from other organisms. The constraint was that applicants had to pick one of the first two areas, plus one to three of the remaining three. The successful consortium, led by Donald Leung at National Jewish Health in Denver, appears to have picked staph infections as their primary focus, according to their press release.

I wrote to Leung and he informed me that the group has not yet determined a protocol for its experiments, but will have done so by the end of the year. I can't wait to find out the details. It is an undertaking of huge scope-- ten academic centers involved. Staphylococcus, and MRSA, is surely a worthy enemy to vanquish. Imagine bringing up a child with eczema knowing that because of what they discovered on this project, you didn't have to worry about runaway staph infections. Life might not be all smooth sailing, but the fear factor would be a lot lower.

Initially, I called the NIH media department, asking whether they made the details of grant applications public. They do not, and the officer directed me to contact the scientists directly. "I'm an eczema sufferer myself," he told me. "I understand why you want to know."