^{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.}

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 www.clinicaltrials.gov 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.

Ghostwriters and the Demigods:

• 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.

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:

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

Extended Release Quetiapine Fumarate Monotherapy for 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

Resource Number 1: pubmed.gov. PubMed is a database of scientific articles maintained by the NIH. Enter the title and you’ll get an abstract of the article.

Resource Number 2: clinicaltrials.gov. 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:

 

Resource Number 3: probublica.org. ProPublica has a database of payments to physicians from eight major Pharmas. Enter the author’s name:

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.

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.

Acknowledgments: The authors would like to thank Jocelyn Woodcock, MPhil, from Complete Medical Communications, who provided medical writing support funded by AstraZeneca…

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.

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.