Pathological Gambling Caused by Drugs Used to Treat Parkinson’s Disease: Yet Another Closer Look, Part One

In the 2005 study entitled “Pathological Gambling Caused by Drugs Used to Treat Parkinson’s Disease,” the authors mine records of Parkinson’s patients seen at the Mayo Clinic in Rochester, MN (MCR), between 2002 and 2004, and find 11 people who had developed pathological gambling (PG) - they conclude that the PG was caused by Parkinson's drugs. The authors so completely fail to provide evidence compelling enough to support this conclusion that the fact that it was published in a peer-reviewed journal boggles the mind. It is available online for free at the Archives of Neurology, if you are interested. It may actually be necessary to read the study for what I am about to say to make sense – I don’t know.

According to the authors of this study, the 11 people who gambled fit the DSM-IV-TR criteria for PG.* They also say that the PG was temporally associated with the commencement, increase, and/or cessation of dopamine agonist (DA) therapy, a type of drug used to treat Parkinson’s disease (PD), and, for a disproportionate percentage of these people, the culprit was a DA called pramipexole.

Finally, the authors provide the results of their survey of the field of literature, and present in a table six studies in support of their conclusion that Parkinson’s drugs cause – not just “are associated with,” but cause PG.

In Part One, I will address the central assertion, that DAs cause PG, in the context of identifying a causal relationship. In Part Two, I will address the significance of prevalence in that endeavor. And in Part Three, I will address several other questions that come up when one actually reads the study rather than the press coverage it received.

I am probably not telling you anything new when I say that researchers, or responsible ones, at least, can’t just declare that X causes Y, they have to – or are supposed to - prove it, or at least put forth compelling supporting evidence.

Nor can they themselves willy-nilly decide what is compelling and what isn’t – while there is some leeway, there are certain gauges that are accepted as valid, and the degree to which their evidence measures up on those gauges determines its persuasiveness.

One such gauge is Naranjo’s algorithm, which consists of a series of questions to which each possible answer (yes/no/unknown) is assigned a different number of points, thereby weighting the each answer according to its significance. In the end, the total number of points indicates how compelling the evidence is. Below is how this particular study fares using Naranjo’s algorithm:



As you can see, the evidence provided in this study is not compelling enough to indicate even a probable association, never mind definite, or causal, association.

Another set of guidelines can be found on the World Health Organization’s web site – following each bullet point below are my comments on how compellingly the evidence presented in this study fulfills these criteria:

Building on the seminal work on determining causality of the Surgeon General’s Advisory Committee on Smoking and Health (1964),3 the generally established criteria underpinning vaccine [or, in this case, drug] adverse event causality assessment that the GACVS uses may be summarized as follows:

• Consistency. The association of a purported adverse event with the administration of a [drug] should be consistent, i.e. the findings should be replicable in different localities, by different investigators not unduly influencing one another, and by different methods of investigation, all leading to the same conclusion(s).
  
  This study was preceded by a single other study which claimed to have found the same association. Even if that single study had adequately supported its conclusion (which it did not), it would obviously fail to provide what could be called consistency of any sort.
  
  
• Strength of the association. The association should be strong in the magnitude of the association (in an epidemiological sense), and in the dose-response relationship of the [drug] with the adverse effect.
  
  The authors do not provide the information necessary to evaluate the magnitude of the association, i.e. prevalence – see Part Two.
  
  
• Specificity. The association should be distinctive ñ the adverse event should be linked uniquely or specifically with the [drug] concerned, rather than its occurring frequently, spontaneously or commonly in association with other external stimuli or conditions.
  
  PG occurs frequently, spontaneously, and commonly in association with other external stimuli or conditions, like depression and disability.
  
  
• Temporal relation. There should be a clear temporal relationship between the [drug] and the adverse event, in that receipt of the [drug] should precede the earliest manifestation of the event or a clear exacerbation of an ongoing condition. For example, an anaphylactic reaction seconds or minutes following immunization would be strongly suggestive of causality; such a reaction several weeks after vaccination would be less plausible evidence of a causal relation.
  
  The authors neglect to define any parameters for identifying a temporal association, and indeed inclusion of three of the eleven on that basis stretches the bounds of plausibility past the breaking point.
  
  
• Biological plausibility. The association should be coherent; that is, plausible and explicable biologically according to known facts in the natural history and biology of the disease.
  
  There are those who point to the role of dopamine in addiction, but there are serious questions that remain not only unanswered, but unasked. For example, if one’s medication is maintaining an appropriate level of dopamine in the brain, why would one be any more vulnerable to addiction than anyone else?

Clearly, the evidence presented In this study, as evaluated by two widely respected and utilized measures, is not nearly compelling enough to support the conclusion that there is a causal relationship between DAs and PG. But if that doesn’t convince you, read on to Part Two. ****** * Pathological gambling is defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DMS-IV-TR) as follows, and the study does not describe in which five each patient has engaged: A. Persistent and recurrent maladaptive gambling behavior as indicated by five (or more) of the following:

1. is preoccupied with gambling (e.g., preoccupied with reliving past gambling experiences, handicapping or planning the next venture, or thinking of ways to get money with which to gamble)
   
2. needs to gamble with increasing amounts of money in order to achieve the desired excitement
   
3. has repeated unsuccessful efforts to control, cut back, or stop gambling
   
4. is restless or irritable when attempting to cut down or stop gambling
   
5. gambles as a way of escaping from problems or of relieving a dysphoric mood (e.g., feelings of helplessness, guilt, anxiety, depression)
   
6. after losing money gambling, often returns another day to get even ("chasing" one's losses)
   
7. lies to family members, therapist, or others to conceal the extent of involvement with gambling
   
8. has committed illegal acts such as forgery, fraud, theft, or embezzlement to finance gambling
   
9. has jeopardized or lost a significant relationship, job, or educational or career opportunity because of gambling
   
10. relies on others to provide money to relieve a desperate financial situation caused by gambling
    

B. The gambling behavior is not better accounted for by a manic episode

My Response to Mr. Gratton Regarding the Parkinson's Blog Network

Thank you for your very thoughtful response, Mr. Gratton. Here are my thoughts on your comments. Your main premises are as follows:

1. Incendia is a “health-focused publishing company,” not a marketing company.
2. Incendia’s goal is to provide a helpful service to the online PD community.
3. Ignite Health LLC, the nature of which entity you do not describe, rather than Ignite Health the healthcare advertising agency, owns Incendia Health Studios.
4. The resources required to develop and maintain The Parkinson's Blog Network (PBN) are significant enough to require advertising dollars to keep it up and running.
5. The advertiser took a big risk on PBN.
6. The advertiser took the risk because it was the “right thing to do.”
7. The advertiser has no influence over the content of the site.
8. This particular pharmaceutical company is just the first advertiser – not intended to be the only advertiser going forward.

Premise #1
Incendia is a “health-focused publishing company,” not a marketing company.

The following is the the text that appears between the "title" tags in the HTML code on Incendia’s homepage. The "title" tag is where one puts the desired title of one's site:

Incendia Health: Community healthcare and medical marketing studio

and in the first "meta" tag:

meta name="description" content="Incendia Health Studios provides dynamic health marketing targeted toward educating and reaching the patient community"

and in the second "meta" tag:

meta name="keywords" content="Incendia Health, Healthcare Marketing, Incendia studios, medical cartoons, interactive health, medical videos, health animation, medical animation, patient advocacy, patient education, patient communities, health community, health communities, patient marketing, medical marketing, dtp marketing, dtc marketing, direct to patient marketing" (all emphases added)

For those unfamiliar with "meta" tags:

“Meta elements provide information about a given webpage, most often to help search engines categorize them correctly. They are inserted into the HTML document, but are often not directly visible to a user visiting the site.” Wikipedia

And, as I already quote in my post:

Ignite formed Incendia to “develop and distribute unbranded disease-education programs targeting the millions of people who use the Internet and other digital technologies to seek and share information on chronic diseases."

“Unbranded” simply means not overtly tied to a particular brand. It does not necessarily indicate a goal more noble than marketing, however. The quote below from a May 2006 article in Med Ad News entitled “DTC Takes a Back Seat” provides some context:

Following a year of uncertainty in the direct-to-consumer [DTC] advertising arena, pharmaceutical marketers identify government regulations and consumer and physician backlash as the biggest challenges... A big shift in industry-wide DTC is expected to occur from branded campaign focus to unbranded campaigns and disease education.

And from the same article:

Ms. [Jackie] Herr [CEO of Ignite Health] says companies that develop and support fresh educational unbranded initiatives, rather than focusing exclusively on branded promotion, will help increase patient compliance, improve consumer health, and build brand loyalty, generating long-term rewards that affect their brands.

And from a July 2006 article entitled “Lost in the Blog,”

"Those marketers who come out ahead will place Web initiatives at the forefront of their product’s promotional efforts, delivering sound, relevant, credible content for access when and how their audiences want it," Ms. Herr says. "When this is done well, patients ultimately find their way to the brand."

Premise #2
Incendia’s goal is to provide a helpful service to the online PD community.

Given that Incendia is a for profit marketing company, it is disingenuous to say that its goal with the PBN is to provide a service to the PD community.

In the limited reading I have had the time to do over the last few days, I have learned a lot. I have learned, if Med Ad News is a reliable source, that the pharmaceutical marketing paradigm is shifting. The Vioxx crisis has given rise to a backlash against direct to consumer marketing at the same time that the internet is providing consumers with the ability to communicate directly with one another about their experiences with particular illnesses and/or therapies.

These changes have demanded changes on the part of pharma. I will try to resist my natural inclination to write a treatise on the subject, but suffice it to say that these changes do not appear to be all bad. One major change, however, is the use of the internet - blogs, online communities, commercial sites – as marketing tools.

Again from “Lost in the Blog” a thought provoking tidbit:

"Communicators and marketers are finding it harder to connect with their audiences at the same time as their audiences are finding it easier to connect with like-minded people," Mr. King said at the Healthcare Marketing & Communications Council’s (hmc-council.org) May Industry Forum.

According to Mr. King, online communities are providing an environment where word-of-mouth communication is thriving. Internet users are online looking for advice and recommendations, making like-minded individuals the key influencers. As a result, a mass audience has been replaced by a small but relevant audience as the key to marketing success. (emphasis added)

The PBN doesn’t just list blogs, it ranks them, and Incendia and the PBN have been endorsed by the number 1 ranked blogger on the PBN. According to the above quote, that is likely to have an impact on traffic to the PBN, and therefore on your advertiser's exposure via the PBN.

And that is, in my opinion, a much more plausible primary reason for the PBN’s existence. That does not preclude the possibility that it may also be a real and valued resource for PWP, but it is, as I said, disingenuous to say that the PBN’s primary raison d’etre is to provide a service to the community.

Premise #3
Ignite Health LLC, the nature of which entity you do not describe, rather than Ignite Health the healthcare advertising agency, owns Incendia Health Studios.

The following is a quote from an Ignite press release dated September 2006:

Ignite Health, one of the country's top 20 independent healthcare advertising agencies, has formed Incendia Health Studios.

It does not say Ignite Health LLC, and what is described is Ignite Health, the "healthcare advertising" agency.

Premise #4
The resources required to develop and maintain PBN are significant enough to require advertising dollars to keep it up and running.

To put this notion into context, I would point out that Ignite recently created an online game for Bayer that is intended to introduce Aleve to a new audience. This project, which had to be conceived of, written, scripted, cast, shot, architected, coded/built, and maintained, accounted for a mere 1% of Bayer's marketing budget – an amount that was characterized as “miniscule” by the New York Times article I read.

Now – no offense intended, but I could probably build a site like the PBN – it could not have cost a lot to build, and given that aside from the bare essentials (legal disclaimer, advisory board, etc) there is no content to generate, it could not cost a lot to maintain. Seems to me this site is virtually self-maintaining, aside from the basic tech support required by any site.

Premise #5
The advertiser took a big risk on PBN.

In what way? It couldn’t have been the cost, because the only costs I can see are those of creating two electronic ads and whatever they are paying you for the space, which could not cost more than a tiny fraction of what Bayer paid for the creation of the infinitely more costly and complex online game, and, as I pointed out elsewhere, the New York times characterized that cost as “miniscule.”

And unless you are suggesting that you did not do your due diligence and determine that the site was indeed likely to attract customers, the advertiser couldn’t have been taking much of a risk there, either.

So what, exactly, was the risk?

Premise #6
The advertiser took the risk because it was the “right thing to do.”

Are you saying that this pharmaceutical company is spending money - on advertising - on the PBN because supporting the PBN is the “right thing to do?” is that what you think guides companies’ advertising decisions?

Premise #7
The advertiser has no influence over the content of the site.

What content?

Premise #8
This particular pharmaceutical company is just the first advertiser – not intended to be the only advertiser going forward.

That may be.

However, it is interesting at this juncture to look at Incendia’s diabetesblognetwork.com. The same template was used in terms of web design as was used with the PBN (very economical). As with PBN, there are banner advertisements. On the Diabetes Blog Network, they lead www.yourdiabetesgoals.com, an interactive site bearing the image of a doctor, and asking the visitor to the site to indicate which of four diabetes goals offered is his or her diabetes goal.

When the visitor chooses a goal, s/he is offered the opportunity to click another link to find out about a treatment option that would appear to be recommended specifically to help one achieve the exact goal that had been chosen. The link takes the visitor to a site promoting the drug Symlin, a diabetes treatment made by Amylin.

There are two interesting twists to this treasure hunt. First, it doesn’t matter which of the four goals one chooses – they all lead to the same site.

Also interesting is the fact that the domain yourdiabetesgoals.com, which, as you recall, is the place with the reassuring doctor image and the interactive interface, is owned by Ignite Health.

But that shouldn’t be surprising. The domains parkinsonsblognetwork.com, diabetesblognetwork.com, breastcancerblognetwork.com, and bannermoments.com – each of whose sites are owned and operated by Incendia as an entity utterly separate from Ignite - are owned by Ignite Health, not Incendia.

In fact, Ignite owns nearly 40 disease-related ‘blognetwork’ domains. Mr. Gratton is the contact person listed for all of them.

Conclusion
To sum up, as I said, the creation of a blognetwork is not in and of itself a bad thing, and it may even be a useful service to the community. But it is disingenuous to say that providing that service is Incendia’s primary goal. You have simply created a vehicle for marketing, the beauty of which lies in the fact that it really could be useful to its audience - but that doesn't change the fact that the audience is a target market.

That is my opinion, anyway.

Fabio Gratton of Ignite Health and Incendia Responds

Please see Fabio Gratton's response to my most recent post. Mr. Gratton is co-founder and chief innovation officer at Ignite Health, and president and CEO of Incendia Health Studios.

Parkinson's Blog Network is a Giant Advertisement

Just in case there are others out there like me who didn't click into this right away, the Parkinson's Blog Network (PBN) is actually a giant advertisement for Valeant's Parkinson's med.

And I don't just mean that Valeant buys space on the PBN, I mean the PBN itself IS the advertisement.

You may have noticed that the Legal Disclaimer states that a company called Incendia Health Studios maintains the Parkinson's Blog Network "as a service to the internet community."

And if you went so far as to check out Incendia's website, you would have seen this description of the company on their homepage:

Incendia Health Studios is the first and only purpose-driven media company for chronic disease education. We leverage the latest technologies to develop and distribute health-related programming for the millions living with chronic illnesses, and those who care for them. Our purpose: to do good.

Well, I think that is just a teensy bit misleading, because if you look up the domain www.parkinsonsblognetwork.com (.com is usually a tip off for all sorts of interesting things), you find it is owned by a company called Ignite Health. The following is a quote from a February 2007 press release that is posted on their site:

Based in Irvine, Calif, Ignite Health specializes in medical advertising and interactive communications targeting patients, caregivers and healthcare professionals. One of the top 20 independent healthcare agencies, Ignite has won more than 100 industry awards since its founding in 2001. Key clients include Amylin Pharmaceuticals, Bausch & Lomb, Cephalon, Eli Lilly and Co., Genomic Health, Gilead Sciences, Merck Publishing, Novacea and Valeant Pharmaceuticals.

Note the use of the word "targeting" in the above quote - interesting that they don't use that word in the Legal Disclaimer - instead, they are providing a "service," and on Incendia's website, their purpose is to "do good."

Also note that Valeant is a client. You may also have noticed the Valeant product plastered all over the site.

Ignite Health formed Incendia in 2006 - again, from a press release on Ignite's site:

Irvine, California, Sept. 28, 2006 — Ignite Health, one of the country's top 20 independent healthcare advertising agencies, has formed Incendia Health Studios to develop and distribute unbranded disease-education programs targeting the millions of people who use the Internet and other digital technologies to seek and share information on chronic diseases. ..

Incendia Health Studios turns the traditional medical marketing and advertising model on its head," [Fabio] Gratton [president of Incendia] says. "By leveraging the power of new and emerging technology, Incendia will provide an unprecedented number of people with engaging health information tailored to their specific needs and interests. Our main objective is to serve patients and caregivers affected by chronic diseases — they, in essence, are our 'clients.' This makes Incendia Health Studios the first and only 'purpose-driven' media company in the field of chronic disease education.

Now, I am not saying that creating a Parkinson's blog network is, in and of itself, a bad thing. I just think people should know what the true goals and priorities of the entity creating it are. So, now you know.

Just for the record, I don't know who registered me there - just know it wasn't me.

Depression and PD - Where's the Beef II

I can't tell you how tired I am of hearing folks who are part of the Parkinson's disease (PD) research machine (who, almost by definition, do not have PD) skip, tra la, right by the need for a symptomatic therapy that works, and I am talking about the cardinal, or defining, symptoms, i.e., motor symptoms, for anywhere near as long as the average life of the disease.

Instead, they are out there funding studies of depression in PD - well, I have asked an authority on that subject, Paul Wicks, resident researcher for PatientsLikeMe, based at King's College Hospital/Institute of Psychiatry in London, to point me in the direction of any study that provides evidence that depression is a symptom of PD and guess what? There is no hard evidence, or even middling evidence, and yet $2 million in his lab alone has been committed to studying this totally unsubstantiated phenomenon. I would link to his response but one must be a member of PatientsLikeMe to access the site, so I am pasting it in below, instead:

In terms of the evidence most of the studies so far have been observational studies of the symptoms of people with PD as compared to say other older people with a diagnsosis of depression.

He did not provide any references.

The dollars available to fund PD research are far exceeded by the quantity of possible research to be funded, and that means there is an additional cost to funding any given study, and that is the opportunity cost of not funding some of the gazillion other possible projects.

That $2 million could have been spent on looking for treatments that would allow us to move freely again, to be pain free, to smile, to play the piano, to work, for pete's sake - treatments for phenomena that are so clearly symptoms of the disease that two or more of them must be present for a diagnosis of PD.

To pour $2 million into the study of a completely unsubstantiated phenomenon could hardly be categorized as the best use of that precious money or time, with "best" defined as the most likely to bring new improvements to the quality of life of PWP, the most quickly.

That, of course, is from the perspective of someone with PD, a perspective that, to my knowledge, is not represented at all, certainly not in any formal capacity, anywhere, in the making of funding decisions.

Letter to the FDA regarding research misconduct

If you have read my September 2006 post, "Gambling and Dopamine Agonists: Where's the Beef?" you are already familiar with my criticism of the FDA-sponsored "study" that mined the FDA's Adverse [Drug] Event Reporting System (AERS) database and found what it claimed was an exorbitantly high reporting ratio for pramipexole (a dopamine agonist) and gambling. What they failed to reveal was the profoundly stimulating effect that publicity clearly had on the reporting ratio, i.e., 38 out of the 39 reports they attribute to this reporting ratio were registered after the publicizing of the first study that claimed to have found an association.

Here is the letter.

My complaint concerns the research letter to the editor entitled “Association Between Pathologic Gambling and Parkinsonian Therapy as Detected in the Food and Drug Administration Adverse Event Database” by Ana Szarfman, MD, PhD, P. Murali Doraiswamy, MD, Joseph M. Tonning, MD, MPH, and Jonathan G. Levine, PhD published in the Archives of Neurology in February of 2006.

In their letter, Szarfman et al say they found 39 reports linking Mirapex to gambling in the FDA's AERS database. They then go on to apply the Multi-item Gamma Poisson Shrinker (MGPS) statistical algorithm to the reporting rates of certain drugs in conjunction with gambling, and come up with an exorbitantly high adjusted reporting ratio for Mirapex and gambling.

However, what Szarfman et al failed to reveal, never mind take into account when interpreting the reporting rates, was that *all but one* of the reports in question regarding Mirapex were registered *after* a study purporting an association between it and gambling was publicized heavily by the American Academy of Neurologists in August of 2003 (Stacy, Driver-Dunckley. Neurology, August 2003).

Just to put this in context, in the six years Mirapex was on the market prior to the publicizing of Stacy’s 2003 study, there was one report concerning it and gambling (there were three such reports for levodopa-carbidopa, the “’gold standard” of Parkinson’s therapies, during the same time period), and in the year and a half after the publicizing of Stacy’s study and before the end point of Szarfman et al’s presented data, there were 38 reports for gambling and Mirapex - that is a 149-fold increase annually.

Research misconduct consisting of omission is classified as falsification and is defined in CFR 42 93.103(b) as follows:

“Falsification is [intentionally]... omitting data or results such that the research is not accurately represented in the research record.”

Given that without the reports generated by the publicity of the first study, there are virtually no reports involving Mirapex and gambling, and therefore no exorbitant reporting ratio, this omission clearly results in the inaccurate representation of the research in the research record.

That leaves the question of intent.

In the absence of some sort of admission on the part of an author, the determination of intent in the context of omission can only be inferred from the answers to the following questions:

1. was the author aware of the relevance of the omitted data (precludes ignorance);
2. was the author in possession of or did the author have access to the omitted data (precludes lacking access to the data); and
3. did the omission of the data require that the research record be written differently than it would have been had the omitted data been included (precludes oversight)

The answer to the first question is yes, as is evidenced by the following recommendation made by Dr. Szarfman and her co-authors in their 2005 paper entitled “Perspectives on the Use of Data Mining in Pharmacovigilance”:

"Publicity resulting from advertising, litigation or regulatory actions (e.g. "Dear healthcare provider" letters and product withdrawals) may result in increased reporting and can generate higher-than-expected relative RRs.[reporting ratios] Relative RRs should be examined over time in hopes of detecting these influences, although there are no definitive criteria for using data-mining techniques to reliably identify such effects."

The answer to the second question is yes, as well, as not only is every entry into the AERS database dated, but Dr. Szarfman herself responded to my inquiry regarding the dates of the reports by saying “this information is publicly available through NTIS,” which is true.

Finally, the answer to the third question is obviously also yes - if the data in question had been included, a completely different letter would have been required.

And while the authors do make mention of some level of stimulated reporting, they fail to reveal the extent to which the stimulated reporting contributed to the reporting ratio in question. Given the skyrocketing in reporting activity (from 0.17 reports per year to 25 reports per year) after the first study received such publicity, it would be impossible not to acknowledge that the stimulated reporting *was* the MGPS score, and that in fact without it, there would be no MGPS score for Mirapex at all – unless one omitted that information, of course.

So - the lead author on the study was aware of the relevance of the omitted data; and, just in case the fact that every AERS record is dated weren’t evidence enough that she was in possession of the omitted data, her response to me proves that she both knew where to find the data and that it was accessible to her. Finally, including the omitted data would have necessitated the reporting of a failure to find a reporting ratio of any note rather than the success that was reported – in other words, the omission could not have been an oversight, since it necessitated (or facilitated) the writing of a completely different letter.

Therefore, there is a preponderance of evidence that the omission was intentional.

As an aside, oddly, they also attribute the stimulated reporting to the reporting to the AERS of the cases outlined in Stacy’s 2003 study, which is clearly nonsensical, since such reports are not publicized.

I would provide you with some background as to why this misinformation is damaging to people with Parkinson’s, but I get the sense that it is really not relevant to the evaluation of an allegation of scientific misconduct.

I have attached a bar chart illustrating the sudden influx of reports related to Mirapex (pramipexole) upon the publicizing of the 2003 study by Stacy, et al (it also shows the reports related to Sinemet (levodopa-carbidopa) for a little context.)



On another note, the only one of the authors who makes any disclosure is Dr Doraiswamy, who merely states that he has received research grants and consulting or speaking honoraria from “several pharmaceutical companies.”

Clearly, the fact that Dr. Doraiswamy has had a long standing relationship with Novartis (including serving on an advisory board and their speaking bureau) is relevant, given that Novartis owns 33% of Roche, which makes the European version of Sinemet (levodopa and a decarboxylase inhibitor); and given that Novartis’ generic arm, Sandoz, makes levodopa/carbidopa; and Novartis/Orion market/make the newest iteration of levodopa, Stalevo, all of which are competitors of Mirapex. Also omitted are his past relationships with Merck/Bristol Myers Squibb, maker/marketer of Sinemet and Sinemet CR, which are also levodopa products and therefore Mirapex’s major competitors.

I will be happy to provide my sources for the above – and anything else in this letter, including the information I obtained from the AERS under the FOI act – please let me know if I should.

I would appreciate it if you would tell me exactly what I should expect going forward in terms of transparency and sharing of information (for example, if an inquiry is initiated, how updated will I be kept regarding what is going on, or should I expect no information until the matter is resolved? And will I be told who else, if anyone, will review my complaint?)

Thank you for your time.

Pathological gambling associated with dopamine agonist therapy in Parkinson’s disease1 - A Closer Look

The above study was published in Neurology in August of 2003, in conjunction with its unveiling at the 55th Annual Meeting of the American Academy of Neurology (AAN). This unveiling came complete with press conferences with lead author, Dr. Mark Stacy, and a press release issued by the AAN and picked up by Reuters.

THE ASSERTION
The authors report that in a retrospective database review of all patients seen at the Muhammad Ali Parkinson Research Center (MAPRC) between May 1999 and April 2000, they found “nine patients with pathologic gambling associated with chronic high dose dopamine agonist (DA) therapy.”

THE PROBLEMS WITH THE ASSERTION
The component parts of the study's central assertion are as follows:

1) timeframe for data collection
2) nine patients
3) pathologic gambling
4) an association
5) chronic high dose dopamine agonist (DA) therapy

And I have found that a closer look at each of these component parts raises quite a few questions. For example, what is the reason for shift in the data collection time period between the first presentation of this data in abstract form in 2000 and its published form in 2003? Likewise, why was there one more patient in 2003 than there had been in 2000, and even more confounding, which patient was it that had been added? Then we encounter the fundamental questions - by what measure(s) are the authors identifying pathologic gambling and the presence of an association? And finally, how can they possibly characterize the drug regimens in question as chronic high dose DA therapy, given the data provided?

BACKGROUND
When this study was published in 2003, the authors presented nine patients - seven men and two women – in support of their assertion. However, this was not this data’s first exposure. Two of the final three authors submitted the same findings in abstract form to the 6th International Congress on Parkinson’s Disease and Movement Disorders in June of 2000. The conclusion presented was largely the same, but there was one immediately obvious difference in the data presented - there were only eight patients in 2000 - seven men and one woman. Seven of the eight patients in 2000 and eight of the nine patients in 2003 were taking pramipexole.

I have been told by a clinician/researcher that there can be legitimate reasons for such an addition – indeed, he said that oftentimes data changes between time of submission of an abstract to a conference and the time the data is actually presented at the conference, and that it could change again between the conference presentation and the publication of the completed study.

1) TIMEFRAMES FOR DATA COLLECTION ~ DISCREPANCY
Nonetheless, it appears there are discrepancies. As I will say again later, if any of the authors would like to educate me on the validity of their claim, I am all ears. I have tried going to the mountain, i.e., I have emailed the lead author asking for clarification. He chose not to respond. I have invited each of the authors of this study to read this post and asked for their feedback, input, and corrections – maybe the mountain will come to me.

The complexities of the shifting timeframes put forth as those in which the data was collected for these publications raise many questions for me. In the abstract that would have had to have been submitted by Feb 8, 2000 to meet the deadline for submission, the authors made reference to data that had been collected over a 12 month period – which, presumably, could not have ended later than the date of submission of the abstract, i.e., February 8, 2000 and therefore could not have begun later than February 9, 1999.

However, when the paper was finally published in 2003, the timeframe in which the data was collected had shifted forward almost three months – beginning May 1, 1999 and ending April 30, 2000, That would have to mean that at a minimum, data collected for the abstract between February 9, 1999 and May 1, 1999 had been discarded.



Should we conclude that the time that was included in the 2000 abstract but excluded from the 2003 study, February to May 1999, never yielded any gamblers to begin with? If not, wouldn’t it have made sense in the abstract to specify the actual timeframe in which gamblers became known, i.e. May 1999 to February 8, 2000, rather than tacking on several pre-May months to the timeframe?

I don’t know the answers to those questions.

2) NINE PATIENTS ~ WHICH IS THE NINTH?
Given the above, perhaps it was pointless for me to try and figure out which of the nine cases presented in 2003 had not been part of the 2000 dataset, since the only way to go about making such a determination would be to assume that the addition of the ninth patient was the only change to the data – everything else would have had to stay exactly the same in 2003 as it had been in 2000. But I figured there couldn’t have been that much change; there might be one or two averages that would be off, but the majority of the changes should indicate the addition of the same case.

So I started with the two incontrovertible pieces of information about the ninth patient – it was a female, and she was taking pramipexole.

At first blush it looked pretty straightforward – there were two women in 2003, Cases 1 and 9, so since the number of women had gone up by one with the addition of the ninth patient, it had to be one of them. They were both taking pramipexole, so that was no help. However, in the 2000 abstract, one person is listed as being on an antidepressant at the time of discovery of the gambling behavior. In the 2003 study, two people are listed as being on antidepressants at the time the behavior was discovered – Cases 8 and 9. Since Case 8 is male, and we have already determined that the ninth patient was female, Case 8 must have been the one on an antidepressant in the 2000 abstract, which would make Case 9 the ninth patient.

Except for one thing – the number of people whose treatment was to switch to another DA did not change from 2000 to 2003 – both the abstract and the published paper cite six patients whose behavior resolved with a switch – and Case 9 is one of the six in the 2003 paper, which would seem to indicate that she was also one of the six in the 2000 abstract, which would knock her out of the running as the ninth patient.

So, I considered the possibility that Case 1, the only other woman, was the ninth patient. After all, perhaps the discovery that one of the original eight was taking an antidepressant had come after the abstract had been submitted to the conference. The theory that she was the ninth got off to a good start with her being female and taking pramipexole, but came to a screeching halt at her treatment. In 2000, two patients were listed as having received counseling as part of their treatment for gambling. The same number of patients is listed in 2003, and Case 1 is one of them, which would seem to indicate that Case 1 was not the ninth patient either.

The table below shows the data that was presented in each publication – 2000 data in the first column and 2003 data in the second column. The addition of the ninth patient changed all of the averages, of course, but since only the averages were provided in the 2000 abstract, as opposed to each individual’s data as was provided in the 2003 study, it is necessary to extrapolate the data profile of the ninth patient based on the differences between the averages presented in 2000 vs 2003. In doing that, as I said earlier, I made the assumption that the only change to the data was the addition of the ninth patient.



None of the nine cases detailed in 2003 comes anywhere near fitting the data profile I have extrapolated for the ninth patient.

It is interesting to note that, according to the data, the ninth patient was taking more than twice the 2000 average dose of pramipexole, i.e., 8mg/day, which bumped the average dose of pramipexole up from 3.6mg/day in 2000 to 4.3mg/day in 2003, thereby bringing the average DA dose more in line with the assertion that “chronic high dose dopamine agonist (DA) therapy” was the culprit, since 4.5mg/day is the maximum recommended dosage of pramipexole.

Also according to the data, the ninth patient was taking less than half the average dose of levodopa, i.e., 400.2mg/day, which bumped the average dose of levodopa down from 943.8mg/day in 2000 to 883.4mg/day in 2003. Levodopa misuse and addiction have been implicated in PG in several studies^{2, 3, 4, 5} but the fact that every one of the eight cases in 2000 and nine cases in 2003 was also taking levodopa was dismissed as inconsequential.

3) PATHOLOGIC GAMBLING ~ BY WHAT MEASURE?
The closest the authors come to defining what they term “pathologic gambling” is to characterize the gambling in question as “behavior severe enough to cause financial hardship,” which, as it happens, is not a criterion for pathological gambling as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (see Wikipedia Pathological Gambling), a definition that is widely accepted and used as a basis for research and clinical practice.

4) AN ASSOCIATION ~ BY WHAT MEASURE?
Regarding the presence of an association, while the authors clearly assert that an association exists, they fail completely to delineate what standard or standards of measure they are using to evaluate the presence of an association.

Statistical Significance Implied but Actually Nonexistent
One universally used standard of measure in the research world is statistical significance –a calculation that assesses whether the difference between, for example, the incidences of behavior X among those exposed to and those not exposed to a particular drug is large enough that it is unlikely to be due to chance.

Among the people taking dopamine agonists in this study, the authors find an incidence of pathological gambling among those taking specifically pramipexole of 1.5% (eight out of 529) and of 0.3% among those taking pergolide (one out of 331). By comparing that incidence to the incidence of PG in the general population, which they cite as being 0.3%-1.3%, when they have already asserted in the title of the paper that an association exists, they effectively create the impression that those numbers indicate the presence of an association, i.e., that an incidence of 1.5% represents a significant elevation from that of the general population – otherwise, why include them, right?

They have not actually said this, however, and if one looks more closely, one might discover why.

The first problem with these numbers is that the authors provide no source for their incidence rate range in the general population. I have looked around quite a bit and the lowest incidence rate I have found is 0.93%⁶ and that was reported in 1999. There is universal agreement pathological gambling is on the rise, so more current numbers would most likely be even higher.

So, where did the authors find an incidence rate as low as 0.3%? They do not say.

Second, out of curiosity, I used a chi square to calculate the significance of the degree of difference between 1.5% among those taking pramipexole and 0.3-1.3% among the general population. I also had my calculations checked and confirmed by a statistician.

Now, while I cannot explain the mechanics behind chi square, I can tell you that if you plug in two incidences, it derives a number representing the probability that the difference between the two incidences is due to chance. A frequently-used benchmark is 0.05, or 5%, so if the number derived is smaller than 5%, the difference between the two incidences is considered statistically significant. So in this case, the difference between the very bottom of the range for the general population and the incidence found in the pramipexole group, i.e., 0.3-0.4% and 1.5%, the difference is statistically significant; but from 0.41-1.3%, the difference is not statistically significant. As I said, the lowest incidence rate I can find is 0.93%, more than twice 0.4%. Without a source for the range provided by the authors, there is no way to evaluate the validity of those numbers.

As I understand it, if the difference is not statistically significant, one has actually failed to find an association.

A third problem with these numbers is that the sample size of 529 people in total taking pramipexole is probably too small for an incidence rate of 1.5% to be meaningful. From what I understand, and I cannot provide a source because in spite of extensive searching I have not found a resource that defines “large” and “small” sample sizes as they relate to the level of meaning that can be read into the incidence rates found in them, 529 is not a large enough sample size for 1.5% to be suitable as a basis for drawing any conclusions whatsoever.

And finally, it is interesting to note that the incidence of PG among those taking pramipexole in 2000, i.e., seven out of 529, is exactly 1.3%, which is the upper end of the range provided for the general population three years later. The addition of the ninth patient, who, as it happened, was taking pramipexole, brought that incidence up to 1.5% (eight out of 529).

So the question remains – if valid, definitive conclusions cannot be drawn based on the numbers they provide, then by what standard of measure do the authors conclude that an association exists?

Temporal Association Implied but Not Supported
The authors suggest that the presence of an association can be read into the temporal coincidence between the onset of the behavior and an increase in DA dosage – they make a point of saying that seven out of nine of those who gambled started within a month of undergoing an increase in their DA dosage, which gives the impression that they are using time from dosage increase to onset of behavior as a criterion by which the presence of an association can be detected. It even gives the impression that they have quantified the length of time necessary (a month or less) to indicate an association.

However, if there are seven that gambled within one month, then there are two that did not gamble within one month – on what basis are they included? The authors don’t say.

But if one removes two people from the DA/PG data pool of nine total, and if one assumes that one of the two being removed was taking pramipexole and the other pergolide, the incidence rate among those taking pramipexole goes down to 1.3% (eight out of 529); if they were both taking pramipexole, the incidence rate goes down to 1.1% (seven out of 529). We don’t know which it is because the authors don’t provide this information, but either way, removing those two people from the equation blows even the appearance of an increased risk of PG on DAs.

5) CHRONIC HIGH DOSE DOPAMINE AGONIST THERAPY ~ REALLY?
Even the characterization of the allegedly responsible drug regimen is inaccurate. The authors report “nine patients with pathologic gambling associated with chronic high dose dopamine agonist (DA) therapy,” but, as I have already pointed out, they also say that “In seven cases the initiation of gambling occurred within 1 month of increasing the DA dose.”

Well, given that in spite of the recent dosage increases only one out of the nine exceeds the maximum recommended dosage for either DA; four have just been upped to the maximum recommended dosage of pramipexole from an unspecified lower dose; three are still nowhere near the maximum; and the one person on pergolide has just been upped to what might be termed a high dose, the use of the term “high dose” is questionable. It becomes even more questionable when it is paired with ‘chronic,’ given that seven of the nine had only been taking the dose in question for a month at the time that they started gambling.

“GIVEN THE COMPLEX WORLD OF THE PATIENT WITH PD — dopaminergic therapy, chronic illness, and casino availability…”

And so we come to the 2003 study’s conclusion, from which the above headline is a direct quote, believe it or not.

Less comical but equally disturbing is the authors’ closing statement, in which they say that in most of the cases described in the study, excessive gambling appeared to resolve with a dosage reduction. Of the nine cases detailed in the article, however, only one is listed as having resolved with a reduction in dose. Six switched to another DA, an inconsistency that is compounded when one considers that the entire thrust of the study appears to hold DAs in general responsible for the PG.

The assertion that encapsulates the meaninglessness of this study as a whole, however, is this one: "...these subjects illustrate that excessive gambling may occur in advancing PD," a statement that sounds like it is saying something relevant, but actually says nothing at all, given that excessive gambling "may occur" at any time, under any circumstance, and it could happen to anyone.

I could go on, but I probably don’t need to.

Suffice it to say that if each of the component parts of the authors’ central assertion is examined more closely than the average journal reviewer apparently would, and certainly more closely than any of the journalists who swallowed this story hook, line and sinker ever would, the whole premise falls apart. First, there are enough inconsistencies in the transition from eight patients in 2000 to nine patients in 2003 to raise questions about the legitimacy of that change. Second, it is abundantly clear that the authors fail to identify key criteria, namely how they are defining pathological gambling and what standard or standards of measure they are using to identify the presence of an association – it couldn’t be statistical significance because a) there is none, and b) the sample size is most likely too small from which to draw any conclusions; it can’t be temporal coincidence because a) they do not define what length of time qualifies as temporally significant, and b) they include two people for whom they provide zero temporal information, thereby pretty much knocking that out as a potential measure of association. Finally, even their characterization of the drug regimen they say is responsible is inaccurate.

It seems clear to me that the authors fail to support their assertion that they have found an association between DAs and PG. If any of the authors disagree, I would welcome their feedback – I am not interested in thinking I am right when I am not. I am interested in the truth, and in accountability on the parts of researchers, institutions and journals to the people whose lives are going to be affected by what they publish and what they publicize.

¹ Driver-Dunckley E, Samanta J, Stacy M. Pathological gambling associated with dopamine agonist therapy in Parkinson's disease. Neurology. 2003 Aug 12;61(3):422-3.
² Molina JA, Sainz-Artiga MJ, Fraile A, Jimenez-Jimenez FJ, Villanueva C, Orti-Pareja M, Bermejo F. Pathologic gambling in Parkinson's disease: a behavioral manifestation of pharmacologic treatment? Mov Disord. 2000 Sep;15(5):869-72.
³ Gschwandtner U, Aston J, Renaud S, Fuhr P. Pathologic gambling in patients with Parkinson's disease. Clin Neuropharmacol. 2001 May-Jun;24(3):170-2.
⁴ Serrano-Duenas, M. Chronic Dopamimetic Drug Addiction and Pathologic Gambling in Patients with Parkinson’s Disease Presentation of Four Cases. German J Psychiatry 2002;5:62-66.
⁵ Avanzi M, Uber E, Bonfa F. Pathological gambling in two patients on dopamine replacement therapy for Parkinson's disease. Pathological gambling in two patients on dopamine replacement therapy for Parkinson's disease. Neurol Sci. 2004 Jun;25(2):98-101.
⁶ National Opinion Research Center at the University of Chicago. Gambling Impact and Behavior Study: A report submitted to the National Gambling Impact Study Commission. April 1, 1999.