the clinical research industry: an invisible empire…

Posted on Friday 11 March 2011

Back at the end of November, Paul Thacker, now at POGO, wrote a letter to Dr. Francis Collins, Director of the NIH, about ghostwriting. His examples included a textbook by Drs. Charlie Nemeroff and Alan Schatzberg. Nemeroff I knew about from my years at Emory, but I didn’t know much about Schatzberg. I ended up spending some time looking into his drug, RU-486, Mifepristone. I was amazed at the low quality science behind the Clinical Trials involved in trying to get this drug approved. Then somebody sent me a couple of articles by Dr. Madhukar H. Trivedi [A Computerized Clinical Decision Support System as a Means of Implementing Depression Guidelines and Barriers to implementation of a computerized decision support system for depression: an observational report on lessons learned in "real world" clinical settings]. He had developed a computer program to guide clinical decision making in treating Depression, but people didn’t use it. He was perplexed:
    Although state of the art evidence-based clinical guidelines have been available to clinicians for some time, it is now well understood that the implementation or adoption of research information in actual clinical practices lags far behind, with limited potential to change physician behavior. Unfortunately to date, efforts to implement quality improvement (QI) research findings into practice have often proceeded without insistence on the same level of rigor required to establish these QI targets as worthy of implementation. The capacity to base treatment decisions on state-of-the-art knowledge alone appears to be insufficient to motivate behavior change among clinicians.
and he set out to try to understand why doctors were resistant to using his "state-of-the-art" algorithms. I must have had a violent reaction, because I launched into a two week rant about the modern use of the term evidence-based medicine. I thought people didn’t use his alogorhithm because it was simplistic and trivial at best, often off the mark. He was looking at what was wrong with the doctors rather than what was wrong with his algorithm based on Clinical Trials. He wrote as if Clinical Trials held the absolute truth. But back then, all I knew about Clinical Trials was that Industry funded them. Next, I started looking into how Seroquel, a drug I find to be pretty ineffective, got approved – so I looked at the Seroquel Clinical Trials. Pretty lame, at best. Then I got interested in how AstraZeneca got this weak sister of an Atypical Anti-Psychotic to be a major blockbuster on the market – Clinical Trials were a big part of the answer. So finally I ended up where I should have started, wondering about Clinical Trials in general and how they are conducted these days. What I found was a whole Industry, the Clinical Trials Industry, that I didn’t even know existed. And so for the last few weeks, I’ve been reading and writing about it. I was right the first time – simplistic and trivial at best, often way off the mark.

The Ghosts in the Machine

The Clinical Research Organizations are largely invisible. Their main advertised function is to set-up and conduct clinical trials quickly [and successfully]. The graph on the right is from and shows the time from submission to completion of all of Astrazeneca‘s Seroquel clinical trials in Schizophrenia. It demonstrates Parexel‘s success in shortening trial duration [and it shows "globalization" – mostly to Eastern Europe]. I thought it would be worth looking at the web sites of the top CROs to see how they bring off streamlining the process, but they’re written too vaguely to nail down, so I’ll only mention a few notables:

  • Mining Medical Records: When I was looking at the policies promoted by the industry professional organization [ACRO] in the last post, there were a couple I didn’t understand:
      • Ensure ease of access to data necessary to conduct research while considering patient privacy
      • Encourage health information technology policies that include consideration of medical research needs
    They use data-mining of medical records to locate subjects [when they can] and would like to do a lot more of that in their recruiting.
  • Prescreening: Several CROs mention having large databases of pre-screened subjects available to access when the right study comes along.
  • Globalization: They all mention some version of "emerging" or "non-traditional" countries. A quote:
      Different therapeutic indications tend to cluster in different regions of the world. Quintiles staff in non-traditional regions includes physician specialists in key therapeutic areas to help fine tune study design and protocols. Patients in non-traditional regions have a high rate of protocol compliance and low dropout rates, because of the high standards of medical care available through clinical trials. This and our combination of global reach and local knowledge can result in speedy recruitment of specific patient populations.
    Overseas clinical trials are a big deal with each of the large CROs.
  • Communications: Xcellerate® [Covance]; Trial Enrollment Accelerator [Quintilles]; Internet, email, social media, call centers, etc. They have it all. And it’s ongoing, not study specific so they can begin advertising and enrolling for a new clinical trial the day the get the contract. Most of them use sophisticated software to locate high yield sites for a given study.
There are a thousand CROs in the world and many more CRCs [I can’t find a count, maybe like TNTC – too numerous to count], yet this vast empire is largely invisible. If you read a medical article, it may list the investigators at the CRCs, even their locations, but you can only figure out which CRO conducted/managed the study if you know how to do it [see below]. The CROs aren’t listed in either. The over-riding intelligence that organizes these large industry-funded multi-center trials just doesnt show…

Ghostwriters and the Demigods:

As mentioned, POGO wrote the NIH Director, Francis Collins, about five instances of "ghostwriting." Two of the culprits, Charlie Nemeroff and Alan Schatzberg denied the charge saying they had made edits to the galleys. That’s not ghostwriting, they claimed [enter the lawyers…]. In a way, I agree with them. What they did is an even worse than simple ghoswriting.
    • If I wrote my autobiography and gave it to my wife to edit the grammar, my run-on sentences, and my stilted phraseology, I’d be an Author and she’s be an Editorial Assistant.
    • If I want to write an autobiography but am a lousy writer, so I hire someone who can write well to write my story which I tell him-or-her – that’s a Ghostwriter [my story, his-or-her writing]. I guess in this instance, I’m a sort-of Author.
    • If somebody else writes something and I sign on as a prestigious author, but my only participation is maybe some editing or tweaking along the way, I would be a Demigod – pretending I wrote something that I didn’t write. I suppose that the real writer is still a Ghostwriter, just ghosting for another story-giver [Pharmaceutical Company, CRO], not the actual listed author.
In the case in the Schatzberg and Nemeroff, the real authors were the companies that paid and laid out the story for Sally Laden and Donna Castiglio of Scientific Therapeutic Information [STI], a Medical Writing Company. Schatzberg and Nemeroff were Demigods.

While I doubt the term Demigods will achieve general usage to describe the Physicians who allow the Pharmaceutical Companies to use their names as authors in the medical literature to publish these quaesi-scientific "experimercials," it works for me. Demigods [AKA Titans] comes from the Tibetan Wheel of Life, and describes people who aspire to be Gods, but have only made it part-way. In this incarnation, they pad their resumes with publications, jump on each new break-through treatment, and are vulnerable to engagement on the illusionary stage as key opinion leaders, briefly experiencing the adoration they envy but can’t quite attain on their own. The Pharmaceutical Industry has had a field day capitalizing on their unfullfilled aspirations. Like all personalities driven by envy, they become quite defensive and "prickly" when confronted with their deceit. It appears they actually believe their own mythology and the compliments of their handlers.

The POGO examples are of Demigod/Ghostwiter pairings from Scientific Therapeutic Information, a medical writing company, not specifically a CRO. But in the unsealed documents and articles in the Seroquel story, there are a number of instances that suggest Demigod/Ghostwiter‘s are at work in the Halls of the CROs as well. All of the publications of the Seroquel trials have the same format: a lead academic author, multiple Zeneca/AstraZeneca authors, and somebody who probably did the writing in the acknowledgements. In the early preapproval articles, it was Suzanne Bristow-Marcalus, a pharmacy-type who either worked at or for Zeneca. After 2002 when AstraZeneca signed on Parexel, the probable writers were Parexel employees, Aruna Seth and Max Brady – recall the particularly incriminating episode with Dr. Nassir Ghaemi [selling seroquel VII: indication sprawl…]. Later articles appear to have another medical writing company involved [Extended Release Quetiapine Fumarate Monotherapy for Major Depressive Disorder: Results of a Double-Blind, Randomized, Placebo-Controlled Study]. They acknowledge Jocelyn Woodcock of Complete Medical Communications in that article. It most cases, we have to infer Demigod/Ghostwiter pairings from the acknowledgements. They are difficult to prove because they don’t say Demigod: Dr. Richard Borison, Ghostwriter: Suzanne Bristow-Marcalus for obvious reasons.

I suspect that in practice, the CROs that actually do the Clinical Trials are heavily involved in writing up the Approval Documents for the FDA. Likewise, I expect that the published articles that make it into our literature are often written by the CROs that do the studies in conjunction with the Pharmaceutical Companies. The role of the Demigods is to legitimize the articles to Journal editors and general readers. Of course they don’t advertise such activities on their web-sites. Here are representative pages for what they do say about their Medical Writing departments:

Medical Writing

Quintiles Icon
Pharmaceutical Product Development Kendle
Covance PharmaNet Development Group
Charles River Laboratories PRA International
Parexel INC Research
The secret code word is "manuscripts."

It’s equally frustrating trying to run down who manages the recruitment, scheduling, communications with, and presentations by, the Key Opinion Leaders – the Physicians who ride the circuit giving talks at meetings, dinners, and CME presentations that are essentially stealth drug advertisements. This slide show from Quintiles is an example of the involvement of the CROs with the KOL networks [Improved Commercialization Strategy through Stakeholder Network Mapping]. Here’s another approach from Parexel [Reach KOLs On-Line]. My impression is that the KOLs are connected with the Pharmaceutical Companies, but that the CROs are heavily involved in creating presentations, and maintaining communication networks. I can’t penetrate further [because they don’t want us to know how all this works].

Practical Ghostbusting for Rookies

I guess I have the enthusiasm of a recovering rookie, and would like to go through an article to demonstrate the ghosts. I’ve used this article before because the complete text is on-line. It’s a study using Seroquel XR to treat Major Depressive Disorder:
Results of a Double-Blind, Randomized, Placebo-Controlled Study
by Richard Weisler, J. Mark Joyce, Lora McGill, Arthur Lazarus, Johan Szamosi, and Hans Eriksson
Since most studies are not directly on line, even if you don’t have access to something like OVID through a university affiliation, you still have some research abilities:
    Resource Number 1: PubMed is a database of scientific articles maintained by the NIH. Enter the title and you’ll get an abstract of the article.
Click the + next to Publication Types:
This tells you that it was not a government funded Clinical Trial, and gives you the Clinical Trial ID Number:
    Resource Number 2: This is a database of Clinical Trials maintained by the NIH. Enter the Clinical Trial ID Number and you’ll get the data on the Trial referenced by the article.
    and further down the page:
While there’s lots of information there, it doesn’t name the CRO, but it does tell you that it was funded by AstraZeneca, maker of the tested drug, and that the Investigator was not the listed first author – but probably an AstraZeneca employee. Without the whole article, the only thing further would be to look up the first author to see if he/she is being paid by Pharma:
    Resource Number 3: ProPublica has a database of payments to physicians from eight major Pharmas. Enter the author’s name:
So, with only the name of the article, you can deduce quickly that it is a Clinical Trial funded by the maker of the drug, managed by the drug-maker, and has a first author that is being paid by the drug-maker. That goes a long way towards suggesting unacceptible bias. If you have a copy of the whole article, you can go much further:
    Faculty Affiliations and Disclosures: Dr. Weisler is Adjunct Professor of Psychiatry in the Department of Psychiatry at the University of North Carolina, Chapel Hill, and Adjunct Associate Professor of Psychiatry at Duke University, in Durham, North Carolina. Dr. Joyce is Principal Investigator at CNS Healthcare in Jacksonville, FL. Dr. McGill is Lead Principal Investigator at CNS Healthcare in Memphis, TN. Dr. Lazarus is Senior Director, Clinical Research at AstraZeneca Pharmaceuticals LP in Wilmington, DE. Mr. Szamosi is Principal Statistician at AstraZeneca in Södertälje, Sweden. Dr. Eriksson is Medical Science Director at AstraZeneca in Södertälje, Sweden.
Dr. Lazarus and Mr. Szamosi, two of the authors, are employees of the drug-maker. Two of the authors are Investigators with CNS Healthcare. A simple Google Search of CNS Healthcare shows you it is a CRO-like group of CRCs [who did the study]. Only Dr. Weisler is not part of the drug-makers system, and we already know he is a paid affiliate of the drug-maker [from ProPublica]. Reading further:
    Faculty Disclosures: Dr. Weisler is a consultant to Abbott, the Agency of Toxic Substances and Disease Registry/Centers for Disease Control and Prevention, AstraZeneca, Biovail, Bristol-Myers Squibb, Cephalon, Corcept, Eli Lilly, Forest, GlaxoSmithKline, Johnson & Johnson, Organon, Otsuka America Pharmaceutical, Pfizer, Pharmacia, Sanofi, Sanofi-Synthelabo, Shire, Solvay, Validus, and Wyeth; is on the speaker’s bureau of Abbott, AstraZeneca, Biovail, Bristol-Myers Squibb, Burroughs Wellcome, Cephalon, Ciba Geigy, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Johnson & Johnson, Novartis, Organon, Pfizer, Sanofi, Sanofi-Synthelabo, Shire, Solvay, Validus, and Wyeth; has received grant/research support from Abbott, AstraZeneca, Biovail, Bristol-Myers Squibb, Burroughs Wellcome, Cenerx, Cephalon, Ciba Geigy, CoMentis, Dainippon Sumitomo Pharma America, Eisai, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Johnson & Johnson, Lundbeck , McNeil Pharmaceuticals, Medicinova, Merck, National Institute of Mental Health, Neurochem, New River Pharmaceuticals, Novartis, Organon, Pfizer, Pharmacia, Repligen, Saegis, Sandoz, Sanofi, Sanofi-Synthelabo, Schwabe/Ingenix, Sepracor, Shire, Synaptic, Takeda, TAP, UCB Pharma, Vela, and Wyeth; and owns stock in Bristol-Myers Squibb, Cortex, Merck, and Pfizer.
we find numerous Pharma connections for Dr. Weisler. Finally, we find:
    Acknowledgments: The authors would like to thank Jocelyn Woodcock, MPhil, from Complete Medical Communications, who provided medical writing support funded by AstraZeneca
Googling Complete Medical Communications, we see that it is a Medical Writing Company. So, with the whole article, we can deduce that it is an industry funded and managed study. All five authors are connected to the drug-maker and the first author is a heavily connected to Pharma in general. The study was conducted by a CRO. Finally, the acknowledgment of the Medical Writing Company makes us heavily suspect that it is ghostwritten. Though we can’t prove the last connection conclusively, this certainly looks like one of those Demigod/Ghostwriter pairings all too common these days.

The Clinical Trial – A Ghost of its Former Self

I criticized this article earlier as an example of a CRO-Chart article that may [or may not] have achieved significance, but was irrelevant, based on the reported data [selling seroquel III: the data factories…]. Here, I am suggesting more – that this article in the medical literature is little more than a stealth ad, a way to advertise Seroquel XR [extended release and patent extending] as an off-label first-line treatment for Major Depressive Disorder. The article reeks of bias and deliberate obfuscation of the primary data.  AstraZeneca did not get Seroquel XR approved as monotherapy in MDD, but not because of the likely bias and inadequacy of this study. They were turned down because the FDA saw the side effects as too dangerous to approve it for this indication as a primary treatment.

The privatization of Clinical Research has created a lucrative Invisible Empire of CRCs and CROs, employed by the Pharmaceutical Industry that often uses Physicians [KOLs] as Demigod Authors for the largely ghostwritten articles that have populated our Psychiatric literature. The articles don’t belong there. These jury-rigged Clinical Trials don’t belong in FDA applications. One shouldn’t have to vet an article for signs of ghosts. The Clinical Trial is the last step before a drug is approved for actual use by sick patients and deserves to be conducted under pristine scientific conditions – should be an example of evidence-based medicine at its best. This is not anything at its best. It’s something we ought to be ashamed of. It’s something to change…

UPDATE: Just in [hat tip to Nancy]:
Texas and 37 States Reach $68.5 Million Settlement With AstraZeneca
Attorney General of Texas

 Settlement comes after three-year investigation into marketing of Seroquel
March 11, 2011

AUSTIN – Texas Attorney General Greg Abbott and 37 other state attorneys general today reached a record-breaking agreement with AstraZeneca, which the states investigated for improper marketing practices. The states’ $68.5 million settlement resolves a three-year investigation into AstraZeneca Pharmaceutical’s efforts to market the antipsychotic drug Seroquel. Under today’s settlement, the State of Texas will receive $3.8 million. Today’s multistate agreement stems from a complaint in federal court charging AstraZeneca with unlawfully marketing Seroquel for unapproved – or off-label – uses. The states also charged AstraZeneca with failing to disclose Seroquel’s harmful side effects and concealing scientific data that revealed safety concerns…

Under the settlement, AstraZeneca agreed to comply with state and federal laws governing its marketing – including legal requirements that prohibit manufacturers from promoting their products for off-label uses not approved by the U.S. Food and Drug Administration [FDA]… The states’ legal action explained that AstraZeneca targeted Alzheimer’s patients at nursing homes, as well as patients who suffered anxiety, depression, sleep disorders and post traumatic stress syndrome. The settlement also imposes injunctive provisions that require AstraZeneca to:
    • Publish any payments it makes to physicians on the Internet;
    • Implement policies that ensure its marketing and sales personnel are not financially compensated for marketing off-label uses;
    • Establish polices to ensure that its sales personnel will refrain from marketing Seroquel to health care providers who are unlikely to prescribe it for an FDA-approved use; and
    • Cite Seroquell’s FDA-approved indicators when referencing selected symptoms.
Atypical antipsychotics, including Seroquel, can produce dangerous side effects, including weight gain, hyperglycemia, diabetes, cardiovascular complications, an increased risk of mortality in elderly patients with dementia and other severe conditions.
    March 12, 2011 | 10:43 AM

    You should have been on the FDA approval panel discussion committee, clearly they did not have anyone with such common sense and ability to see plain sight reason not to (keep) approve Seroquel, again and again —imagine why FDA approved use for this drug in kids age 10!??

    Same day as the multi-state litigation settlement for AZ came through the news, my anonymous source received a letter from attorney stating the diabetes (off-label use) settlement packet will arrive in approx 3 weeks. My source, and victim of THE CRIME OF ILLEGAL MARKETING OF A DRUG BY ASTRAZENECA, has diabetes, sued AstraZeneca and will (rumor and Bloomberg says) has it that the victims will only receive $10-12K and that is BEFORE taxes and attorney fee reduction. For a lifetime body damage of an organ that now shortened the victims lives by 5-6 years, all because they were offered Seroquel and most off-label for insomnia not approved for that use and promoted to doctors via reps by AstraZeneca!!

    AstraZeneca’s mouthpiece Tony Jewell states AstraZeneca “denies allegations”.

    Look at the documents in this series on this blog and then sit back and wonder who has been duped and innocent people continue to be injured/killed by this antipsychotic being promoted now as an antidepressant!

    March 12, 2011 | 11:34 AM

    The irony increases when you see that Richard “Smoke and Mirriors” Lawrence now works for a medical writing company!

    March 12, 2011 | 2:07 PM

    Richard Weisler is currently pocketing income from:

    in ProPublica Dollars for Docs database


    for “Speaking and consulting”

    March 12, 2011 | 2:09 PM

    oh oops, did not see it in the post! sorry for double exposure of the doctor in dollars for docs!

    March 12, 2011 | 10:05 PM

    Yeah. Weisler has cut quite a swath as a KOL. One wonders what he does for UNC and Duke that justifies his using his adjunct affiliations as credentials.

    March 13, 2011 | 8:08 PM

    Hey Mickey, have you seen the movie “Inside Job” (Academy Award winner for Best Documentary 2010)?

    Saw it last night, and couldn’t help but think about this series of articles. In fact, I think someone should take the script of that movie, take out “CDOs” and “credit default swaps” and replace them with “atypical antipsychotics” and “SSRIs”; replace the banking execs with KOLs; and replace Lehman Brothers and Goldman Sachs with Emory and Stanford, and you’d have a fairly accurate story.

    March 13, 2011 | 8:18 PM

    That analogy hits me at times too – it even fits temporally. Something happened that infected the land in multiple places. I’ll put Inside Job on the must-see list…

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