"I’m a kind of paranoiac in reverse. I suspect people of plotting to make me happy."
Raise High the Roof Beam, Carpenters , J. D. Salinger
The last five years of writing about the misadventures of the pharmaceutical industry and the contingency of cooperating KOLs in academic psychiatry and elsewhere have taken something away from my world view. I’ve more or less lived my life walking on the sunny side of the middle of the street, but the steady diet of jury-rigged, ghost written clinical trials and beyond questionable marketing practices abetted by a subset of physicians who should be my mentors and colleagues has taken its toll. It wouldn’t be fair to say I’m diagnosable as fully paranoid, but the skepticism nuclei on my MRI are bilaterally enlarged and my trust circuits have some early atrophic changes. Thankfully, I’m still capable of hope, and last night, I got a much needed reminder of what that feels like.
Last Friday, I read the news report
that Johnson & Johnson had contracted with the Yale University Open Data Access [YODA] Project
to officiate access to the raw data on their clinical trials, past and present, and flagged it for further study [a placemarker…
]. It was enthusiastically announced as a game-changer on the AllTrials web site
as well. Then on Sunday, there was a New York Times Op-Ed piece [Give the Data to the People
] by Yale’s Dr. Harlan Krumholz of the YODA Project. It was all happy talk, but there was a piece that bothered me. And I’ll admit up front that after sitting through the J&J TMAP Trial in Texas in January 2012 and reading all the trial exhibits, J&J had a big place in my skepticism scanner. The part that bothered me is in my post about it [reassure us…
The pharmaceutical companies have insisted on talking about what I call Data Transparency as if it is a synonym for Data Sharing. It’s not. Data Sharing is a magnanimous act on the part of the company to allow other researchers access to the data from their clinical trials for further research for the good of mankind. I’m all in favor of the good of mankind, but that’s not what I’m interested in here. I want us [some us] to be able to check their work independently starting from the same place they do – the instant the blind on a clinical trial is broken – the raw data itself. And the reason I want to do that is the outrageous record they have for cheating in the way they handle that raw data…
I wanted reassurance that keeping them honest would be considered a research project. In going over countless clinical trials, the funny business hasn’t been in the trial itself, it has been in what happens once the blind was broken and the raw data was available. The creative license in presenting the data in published articles has been beyond impressive. So I said:
We need some recognition that our goal is considered a research topic – namely, "Are they telling the truth in the published paper or are they presenting the data in a way that misleads the reader [like so many have done before]? Are they withholding data to make their drug look more efficacious or safer than it really is [like so many have done before]?" Putting the "re" in research!
And I sent my blog post to Dr. Krumholz. The first encouragement was that he answered at all. I’m not used to that. He asked that I clarify my question. So I did ["Would your program consider checking the authors' analysis based on their submitted protocol an acceptable research question?"]. And he answered promptly:
They have relinquished control over the data release to us, by contract. So it is up to us to put in place the right process. If you have many questions then you can submit many proposals. I don’t see us rejecting requests that might be about replicating results. JNJ knows that – it was part of our discussion with them – and they still signed the contract. I cannot speak for past actions – but they signed over this authority to us. I think that given this action, JNJ deserves the benefit of the doubt.
I couldn’t have hoped for a more direct answer than that. The data itself is to be in the hands of YODA, and they would see replicating results as an acceptable research question. That is Data Transparency
. They reserve the right to insist on a qualified team that agrees to stick to the submitted question. Those are expectable hoops and within their right to request.
The great fear in the pharmaceutical companies’ offers to come around and relinquish their claim of proprietary ownership of clinical trial data is a Trojan Horse scenario. And that was my fear here. The Trojan Horse was something that looked like a gift, or a concession, but turned out to be a trick. In this case, it would be turning down access because the "research question" wasn’t some new research project, but just to "replicate" results, or in the case of an unpublished study, find out what the results were in the first place. The title of my post was "reassure us," and he did. Of course, the real test will come when the system is in place and someone asks for access to vet a study. All we can do is wait for that day and see what happens. But for the moment, I’m well pleased with Dr. Krumholz’s response. Like Salinger’s Seymour in my opening quote, the universe is plotting to make me happy [or at least, hopeful].
And Dr. Krumholz has credentials that add credibility to his response:
by Harlan M Krumholz, Joseph S Ross, Amos H Presler, and David S Egilman.
British Medical Journal. 2007 334:120.
Rofecoxib [Vioxx] was introduced by Merck in 1999 as an effective, safer alternative to non-steroidal anti-inflammatory drugs for the treatment of pain associated with osteoarthritis. It was subsequently found to increase the risk of cardiovascular disease and withdrawn from the worldwide market. Merck now faces legal claims from nearly 30 000 people who had cardiovascular events while taking the drug. The company has stated that it will fight each case, denying liability. Our recent participation in litigation at the request of plaintiffs provided a unique opportunity to thoroughly examine and reflect on much of the accumulated court documents, research, and other evidence. This story offers important lessons about how best to promote constructive collaboration between academic medicine and industry…
Merck faces legal claims from nearly 30 000 people who had an adverse cardiovascular event while taking rofecoxib [Merck denies liability]
Published studies of the drug obscured the risk
Merck had influence over all aspects, including data analysis, safety monitoring, and reporting
Academic medicine, industry, medical journals, and government agencies need to define a set of principles to restore trust in collaborations on drug development
He was an expert witness for the plaintiff’s in the Vioxx® case. And then there’s the recent story of Medtronic’s INFUSE®:
by Harlan M. Krumholz, MD, SM; Joseph S. Ross, MD, MHS; Cary P. Gross, MD; Ezekiel J. Emanuel, MD, PhD; Beth Hodshon, JD, MPH, RN; Jessica D. Ritchie, MPH; Jeffrey B. Low, AB; and Richard Lehman, MD
Annals of Internal Medicine. 2013 158:910-911.
This issue of Annals heralds a historic moment in the emerging era of open science. It features 2 systematic reviews on recombinant human bone morphogenetic protein-2 [rhBMP-2], an orthobiologic agent used in certain surgeries to promote bone growth that once achieved close to $1 billion in annual sales for Medtronic. The reviews are based on patient-level data from all clinical trials conducted by Medtronic, which were shared through the Yale University Open Data Access [YODA] Project. With the publication of these reviews and the public release of its comprehensive reports, all of the clinical trial data for this product will now be made available by the YODA Project to other investigators for further analysis and examination.
The YODA Project seeks to address the problem of unpublished and selectively published clinical evidence. Nearly half of clinical trials are never published, and many that are have long delays in publication. Among those published, the information is often incomplete. Evidence suggests that some data are not missing at random and that the sharing of data, particularly patient-level data, often provides new insights that are consequential to patients.
Currently, even the most conscientious physicians — those committed to knowing the latest literature — cannot fully understand the true risks and benefits of many treatments. Patients, therefore, are hampered in their ability to make truly informed decisions. In addition, missing data undermine evidence-based medicine, as recommendations based on the published literature, whether in systematic reviews, guidelines, book chapters, or online resources, are not based on the totality of the evidence. To improve the care of patients, clinical trial data, protocols, and results need to be made more widely available and shared for public benefit…
As many of you know, in the independent reviews commissioned by Dr. Krumholtz’s YODA Project, Medtronic’s INFUSE® didn’t come out looking very good – probably less effective than the alternatives and potentially harmful. I knew about that part of the story only too well because INFUSE® was used in my own rather extensive back surgery five years ago. That kind of thing grabs one’s attention like no other. But I didn’t know about Dr. Krumholz’s involvement in the Vioxx® debacle. I find the Vioxx® episode the most encouraging because, like my experience with the TMAP discovery documents, that’s the place where one’s skepticism nuclei really start lighting up and growing. If Dr. Krumholtz’s YODA can pull this off with J&J like he did with Medtronic, I’ll become a downright YODA groupie.
I think the tone of my post and my questioning the RWJF connection offended Dr. Krumholz [reassure us…
], just as my looking into the Wellcome Foundation offended Ben Goldacre last week [an irony of pharma past…
, a snowy evening…
]. I apologized to both and repeat those apologies here. There are precious few good guys around and they don’t deserve grief for the sins of others. But I don’t apologize for looking under every rock in the stream. Unfortunately, benevolent intent doesn’t go very far in this particular area [as I've learned writing this blog]. This is the age of evidence based medicine
which is also unfortunately sometimes guilty until proved innocent
. But my daughter didn’t name this blog, 1crotchetyoldman
– she mercifully called it 1boringoldman
. So I’ll take the recent feedback into advisement and follow my own advice
, "It’s ready, aim, fire
not fire, ready aim