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Research: From the Superb to the Questionable

 

F Edward Yazbak MD

It is safe to say that in the last few years, researchers who dared question a vaccination policy or only mention vaccination and autism in the same sentence were certain to get a public and unrelenting flagellation.

I was therefore overjoyed when the accomplishment of a distinguished researcher in that venue was recognized. It was certainly wonderful to hear that the Briloff Committee at Baruch College very recently awarded The Briloff Prize for 2012 to Dr. Gayle DeLong for her magnificent exposé titled Conflicts of Interest in Vaccine Safety Research”. In the citation, the Committee described Dr. DeLong’s publication as “an excellent exposition of ethical issues and biases in the examination of conflicts of interests related to vaccine safety research. The main thrust of this paper is the questioning of the ethics of industry sponsorship of vaccine use“

The abstract of Dr. DeLong’s article[1] on PubMed summarizes the extensive document quite clearly:

Conflicts of interest (COIs) cloud vaccine safety research. Sponsors of research have competing interests that may impede the objective study of vaccine side effects. Vaccine manufacturers, health officials, and medical journals may have financial and bureaucratic reasons for not wanting to acknowledge the risks of vaccines. Conversely, some advocacy groups may have legislative and financial reasons to sponsor research that finds risks in vaccines. Using the vaccine-autism debate as an illustration, this article details the conflicts of interest each of these groups faces, outlines the current state of vaccine safety research, and suggests remedies to address COIs. Minimizing COIs in vaccine safety research could reduce research bias and restore greater trust in the vaccine program.”     

Dr. Delong's previous publication (2011) titled "A positive association found between autism prevalence and childhood vaccination uptake across the U.S. population [2] was, I thought, just as remarkable. Its PubMed abstract was also an informative and clear summary of the author's extensive research:

 “The reason for the rapid rise of autism in the United States that began in the 1990s is a mystery. Although individuals probably have a genetic predisposition to develop autism, researchers suspect that one or more environmental triggers are also needed. One of those triggers might be the battery of vaccinations that young children receive. Using regression analysis and controlling for family income and ethnicity, the relationship between the proportion of children who received the recommended vaccines by age 2 years and the prevalence of autism (AUT) or speech or language impairment (SLI) in each U.S. state from 2001 and 2007 was determined. A positive and statistically significant relationship was found: The higher the proportion of children receiving recommended vaccinations, the higher was the prevalence of AUT or SLI. A 1% increase in vaccination was associated with an additional 680 children having AUT or SLI. Neither parental behavior nor access to care affected the results, since vaccination proportions were not significantly related (statistically) to any other disability or to the number of pediatricians in a U.S. state. The results suggest that although mercury has been removed from many vaccines, other culprits may link vaccines to autism. Further study into the relationship between vaccines and autism is warranted.”

***

The devil made me do it

Sure!

Except that the devil in this case is usually rectangular, flat and green and carries the portrait of a US President. The amount of money recently going from drug and vaccine companies mostly to helpful doctors but also to several research institutions can only be described as obscene.

A nice resource on the subject is well worth a visit.[3]

The just updated site opens with the statement: “ProPublica’s Dollars for Docs database contains more than $2 billion in payments to doctors, other medical providers and health care institutions that have been disclosed by 15 pharmaceutical companies since 2009.” 

The sales of the fifteen disclosing companies reportedly represented 41% of the US Market in 2011.

On another screen,[4] one can easily search for the names of the lucky and fortunate recipients of Big Pharma’s largesse.

On a third screen,[5] the states are listed in alphabetical order together with the corresponding number of dollars spent as payments to physicians and institutions in 2011. The four states with the largest payments to physicians or grants to institutions were California: $241,788,042, Florida: $168,661,914, Texas: $161,199,659 and New York: $142,114,783.

The disclosing drug and vaccine companies are listed on the right of the screen together with the disbursed amounts and the periods of time during which those dollars were distributed. The most generous companies in alphabetical order were Astra Zeneca: 236.1M from 1/2010 to 9/2012, Eli Lilly: 490.6M from1/2009 to 6/2012, GSK: 238.6M from 4/2009 to 9/2012, Merck: 224.3M from 7/2009 to 9/2012 and last but not least, Pfizer: 538.2M from 7/2009 to 9/2012.

***

The initial investment

A while ago, a few people in high places at the CDC decided that Danish Autism Research was amazing because as I was told, Denmark had “a wonderful recording and tabulating system“, even though Danish autism figures were relatively small and the population of Denmark was about equal to that of the State of Maryland.  

It is not known exactly when the love fest between the CDC and the Danes began. What is known from documents obtained through the Freedom of Information Act is that one afternoon the head of the Developmental Disabilities Section at CDC was worried about missing the opportunity to undertake and fund a new Autism and MMR study in Denmark because of lack of funds. She saved the day and “the study” by e-mailing the Director of the National Immunization Program at CDC, who was never short of funds, and asking for $ 25,000.  The e-mail carried a sense of urgency because someone called “Poul” was leaving very shortly for Denmark and could get things rolling. Possibly thinking about his own MMR vaccination program, the NIP Director promptly obliged.

The DD Director had already secured a commitment for another $ 25,000 from a supportive Autism Association.[6] On its web site, the association explained that in 2000, it “received a $25,000 donation from Merck“… but “To be clear, our unrestricted donation of $25,000 from Merck in 2000 was not used to fund the Danish study – or any other vaccine-related studies.”

The investment seemed to have paid off and the definitively helpful “Big Danish MMR and Autism Study” by Madsen & Co was created and published[7] in the New England Journal of Medicine on November 7, 2002  with great fanfare.

A CDC epidemiologist who had participated in the study was listed as a co-author.

The following was disclosed with the article:

Supported by grants from the Danish National Research Foundation; the National Vaccine Program Office and National Immunization Program, Centers for Disease Control and Prevention; and the National Alliance for Autism Research.


Source Information

From the Danish Epidemiology Science Center, Department of Epidemiology and Social Medicine, Århus, Denmark (K.M.M., M.V., P.T., J.O.); the Danish Epidemiology Science Center, Department of Epidemiology Research, Statens Serum Institute, Copenhagen, Denmark (A.H., J.W., M.M.); and the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta (D.S.).

A McGill University Epidemiologist who carefully reviewed the publication promptly disagreed with the authors’ calculations and conclusions in a Letter to the Editor of the Journal… that was never published.

Another world-renowned Canadian Epidemiologist also weighed in about the quality of the study, the CDC connection and the moral and ethical implications of the situation. In sworn testimony at the December 10, 2002 Hearing of the Government Reform Committee, Professor Walter O. Spitzer M.D., M.P.H., F.R.C.P.C, Emeritus Professor of Epidemiology at McGill University and Emeritus Editor, Journal of Clinical Epidemiology stated:  

 “Only 40 cases (13%) were reviewed. That is very inadequate especially if done for validity purposes only. To fail to examine all records among the 787 children in the numerators of the cohort (738 in Table 2), with a clinical multidisciplinary approach leaves the project wide open to errors and misclassification.

Professor Spitzer then went on to criticize in detail other epidemiological findings of the study before turning to what he perceived were the ethical questions about potential conflicts of interest:

"The concerns are about the process of funding, the interaction of sponsors with protocol formulation and approval, compliance with protocol, the role of investigators vis-a-vis sponsors in the actual conduct of research and the input of CDC epidemiologists in the preparation of the report with its conclusions:

a) Was there a protocol?

b) Who approved it?

c) Were there changes as the study progressed?

d) Who approved the changes?

e) Who monitored work-in-progress?

f) Who approved the final report?

g) Was there a Scientific Advisory Board?

h) What exactly was the role of the CDC and its professionals?"

For "Total Transparency" Dr. Spitzer advocated:

1. That the main protocol should be published in advance of the fieldwork, notably including the analysis plan with attendant definitions declared in advance.

2. A Scientific Advisory Board be created to monitor all phases especially protocol changes in progress and proposed publications.

3. A Community Advisory Board to look at conflicts of interest in finances.

 ***

 Having many lingering questions about the study results, I tried to get the sacred “official autism figures” from Denmark through regular channels and was unable to. Thankfully, a Danish Mom of a child with autism came to my assistance and was able to send them to me.

I thought there were several problems with the design and the figures and asked a good friend, a wonderful statistician, to review them with me. We then carefully wrote a response to the “Big Danish Study”, rebutting it point by point. Our paper was rejected by the Associate Editor of the NEJM but was ultimately considered, carefully peer-reviewed and published in October 2004.[8]

***

The gift that keeps on giving

As months went on, it became apparent that the CDC’s 25,000 dollars were only a down payment.  

Several other “Danish” studies somehow helped by the CDC and in return, invariably supportive were created and published with great pride and jubilation. I reviewed most of them in June 2005 in “The CDC finances, writes and helps publish Danish Research”[9]

Like many, I had no idea how much the Danish Love Affair had cost the US taxpayers until Wednesday April 13, 2011 when I saw a press release[10] from the office of “The United States Attorney’s Office, Northern District of Georgia” titled:

AUTISM RESEARCHER INDICTED FOR STEALING GRANT MONEY

“Thorsen Allegedly Absconded With Over $1 Million”
 
After mentioning that Dr. Poul Thorsen had “been indicted by a federal grand jury on charges of wire fraud and money laundering based on a scheme to steal grant money the CDC had awarded to governmental agencies in Denmark for autism research” the press release went on to quote three US officials involved with the case:

“United States Attorney Sally Quillian Yates said of the case, “Grant money for disease research is a precious commodity.  When grant funds are stolen, we lose not only the money, but also the opportunity to better understand and cure debilitating diseases.  This defendant is alleged to have orchestrated a scheme to steal over $1 million in CDC grant money earmarked for autism research.  We will now seek the defendant’s extradition for him to face federal charges in the United States.”

“Stealing research grant money to line his pockets, as Poul Thorsen stands accused of here today, cheats U.S. taxpayers and will simply not be tolerated,” said Derrick L. Jackson, Special Agent in Charge of the Atlanta Region for the Office of Inspector General of the Department of Health & Human Services.  “HHS/OIG will continue to work closely with our law enforcement partners to bring these criminals to justice.”

Reginael D. McDaniel, Special Agent in Charge of the Atlanta Region for Internal Revenue Service Criminal Investigation said, “Today’s global economy demands a high-level coordinated approach by multiple agencies and authorities in the investigation of financial crimes.  While schemes often become more sophisticated over time, fortunately so do our investigative techniques.  IRS Criminal Investigation is proud to have shared its hallmark expertise in following the money trail in the scheme alleged in this indictment.”

According to US Attorney Yates, the sordid saga went like this: “In the 1990s, THORSEN worked as a visiting scientist at the U.S. Centers for Disease Control and Prevention (CDC), Division of Birth Defects and Developmental Disabilities, when the CDC was soliciting grant applications for research related to infant disabilities.  THORSEN successfully promoted the idea of awarding the grant to Denmark and provided input and guidance for the research to be conducted.  From 2000 to 2009, the CDC awarded over $11 million to two governmental agencies in Denmark to study the relationship between autism and exposure to vaccines, between cerebral palsy and infection during pregnancy, and between childhood development and fetal alcohol exposure.  In 2002, THORSEN moved to Denmark and became the principal investigator for the grant, responsible for administering the research money awarded by the CDC.

Eleven million dollars constituted I thought, an impressive small fortune for a few studies, regardless of where they originated.  

US Attorney Yates ended by reminding everyone that “the indictment contains only allegations.  A defendant is presumed innocent of the charges and it will be the government's burden to prove a defendant's guilt beyond a reasonable doubt at trial.”

Weeks later, the story with a photograph of the doctor was featured on the web site of the Office of the Inspector General of HHS.[11] To this day, the closing sentence still is “Thorsen is currently in Denmark and is awaiting extradition to the United States.

The first paragraph of the document also remains as upsetting:  

From approximately February 2004 until February 2010, Poul Thorsen executed a scheme to steal grant money awarded by the Centers for Disease Control and Prevention (CDC). CDC had awarded grant money to Denmark for research involving infant disabilities, autism, genetic disorders, and fetal alcohol syndrome. CDC awarded the grant to fund studies of the relationship between autism and the exposure to vaccines, the relationship between cerebral palsy and infection during pregnancy, and the relationship between developmental outcomes and fetal alcohol exposure.

I have personally never seen CDC-sponsored Danish studies on infant disabilities, genetic disorders and fetal alcohol syndrome. If they exist, they surely did not get the publicity they deserved.  

On the other hand, several studies from Denmark on “the relationship between autism and the exposure to vaccines” that supported the CDC’s position have certainly been published with great fanfare.

***

Two questions need to be asked: 

What was expected from the researchers for 11 million dollars? 

Did that in any way constitute a Conflict of Interest?
 

F Edward Yazbak MD, Falmouth, Massachusetts


[1] DeLong G. Conflicts of interest in vaccine safety research, Account Res. 2012;19(2):65-88. doi: 10.1080/08989621.2012.660073. PMID: 22375842

[2] Delong G. A positive association found between autism prevalence and childhood vaccination uptake across the U.S. population. J Toxicol Environ Health A. 2011;74(14):903-16. doi: 10.1080/15287394.2011.573736. PMID: 21623535

[7] Madsen KM, Hviid A, Vestergaard M, Schendel D, Wohlfahrt J, Thorsen P, Olsen J, Melbye M., A population-based study of measles, mumps, and rubella vaccination and autism. N Engl J Med. 2002 Nov 7;347(19):1477-82.

[11] https://oig.hhs.gov/fraud/fugitives/profiles.asp (Accessed 3/22/13)

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