Wednesday, February 16, 2011

Gold Standard Clinical Trials - Science or Marketing?: Part III

The story so far ...

At the 12th International Congress on Schizophrenia Research in April 2009, J&J debuted a “randomized, double blind, placebo-controlled” study which found its antipsychotic Invega produced a better result on a population of schizoaffective patients than did the placebo.

Researchers point to studies of this type as representing the gold standard of clinical research, but there is a major fallacy in their reasoning, and this study in particular represents a splendid example: Although the methodology of the study was flawless - even dazzling - the result showed us nothing. We already knew antipsychotics, including Invega, worked (with obvious limitations) for conditions involving psychosis. Psychiatrists already prescribe antipsychotics to patients with schizoaffective.

The result was meaningful to one party, and one party only: J&J (which owns Janssen, which manufactures Invega). Thanks to the success of this trial (and to the decidedly less convincing success of an earlier one), J&J had a bullet-proof brief to take to the FDA. In July, the company announced in a press release:

“The U.S. Food and Drug Administration (FDA) today approved the first and only [my emphasis] antipsychotic for the acute treatment of schizoaffective disorder.”

J&J had received clearance to market its Invega as a treatment for schizoaffective - which, since it was the only player in the field, translated to a golden opportunity to market an illness rather than simply a product. Thus, in its press release:

Among people who frequently use mental health services, schizoaffective disorder may account for approximately 24 percent of cases.

And again:

“Schizoaffective disorder can be challenging to diagnose because of the broad range of symptoms patients experience," said Nina Schooler PhD, SUNY Downstate Medical Center.

And again:

"Schizoaffective disorder is a chronic, disabling condition," said Husseini Manji MD, FRCPC, Global Therapeutic Area Head, Neuroscience, Johnson & Johnson Pharmaceutical Research & Development. "This new indication for Invega further demonstrates Janssen's commitment to helping people with serious mental illnesses."

In the article of the second study, published in the Oct, 2010 Journal of Clinical Psychiatry, we are told that schizoaffective was first identified in 1933, and the first study article in the April JCP we are informed that:

Although schizoaffective disorder occurs less commonly than schizophrenia, it may account for up to one-quarter of admissions to inpatient mental health facilities.

Back in the glory days of Pharma, J&J would have sponsored at least two dinner (or luncheon or breakfast) symposia at the American Psychiatric Association’s annual meeting. Anywhere from five hundred to a thousand psychiatrists would have crowded into a hotel ballroom to hear a panel of experts expound on “Schizoaffective Disorder, the Forgotten Illness” or “Treatment Modalities for Schizoaffective Disorder” or something similar. The psychiatrists (and other clinicians) would have received CME credits for their attendance.

From 2002 to 2009, I must have attended more than 60 symposia of this nature at APAs. Some of them were blatant advertorials, but most were highly educational and a large number of them were outstanding. I actually recall congratulating some Wyeth people for sponsoring a luncheon symposium the year before that had nothing to do with depression or Effexor. They looked at me funny, as if to say, “How did we screw that up?”

But in the eight consecutive APAs I attended, never once did I see in the program an industry-sponsored symposium devoted to schizoaffective disorder. If I had, I’m sure I would have penciled it in.

The APA has done away with industry-sponsored symposia at its annual meetings, but J&J would have had ample opportunity to get out the word in the exhibit hall. I did not attend last year’s APA, but I guarantee any clinician approaching their exhibit could have watched a multimedia display on schizoaffective, helped themselves to the literature, put their names on a contact list, and had their questions answered by a phalanx of J&J eager beavers. If the clinician expressed an interest in knowing more, one of the eager beavers would have escorted him or her to a back area to talk one-on-one with a J&J big cheese. 

Meanwhile, J&J would have been getting out the word in the poster area of the annual meeting. Perhaps attendees there would have viewed the same poster I did at the Schizophrenia Congress. In all likelihood they would have been exposed to many many more, of little significance, something like “Paliperidone ER Taken with Bottled Water vs Tap Water in a Nursing Home Mongolian Population with Schizoaffective Disorder.”

The multiple poster effect would have been wall-to-wall, marketing dressed up as research, with illness and product occupying an attendee’s entire field of vision. Working the posters would be an academic superstar with his or her minions, eager (okay, perhaps not eager) to answer questions.

In the meantime, away from the APA, J&J would be staging its own events with expert speakers, as well as launching its drug reps on special missions of search and sell. Moreover, they would be placing articles in publications. In a recent piece on his Carlat Psychiatry Blog, Daniel Carlat, author of “Unhinged,” had this to say about a feature in Current Psychiatry, which goes out free to psychiatrists:

Another promotional CME Supplement was published in October 2010, and is entitled  "Differential Diagnosis and Therapeutic Management of Schizoaffective Disorder." It is supported by Janssen, the maker of Invega, which was recently the first medication FDA approved for - you guessed it - schizoaffective disorder. I haven't read it yet, but this is a de facto advertisement simply by virtue of the choice of topic. Janssen makes the only approved product for schizoaffective disorder, and in order to advertise it, they paid off Current Psychiatry to write a huge article about the disorder. It doesn't need to be "biased;" it just needs to be focused on a topic that is of inherent commercial benefit to the supporter.

The article doesn’t tell us what we don’t already know about about schizoaffective, but it does hit on all the talking points in the J&J press release and related literature, including the fact that:

Only 2 randomized, double-blind, placebo-controlled studies of an atypical antipsychotic (paliperidone extended-release, now FDA-approved for the treatment of SAD), have been conducted in a well-defined SAD patient population.

Even a squeaky-clean expert in a forum uncorrupted by Pharma would be obliged to mention something to this effect. There is no way of avoiding it, and that is the beauty of J&J’s strategy.

But when all it said and done, psychiatrists will not be changing the way they treat patients with psychotic features, whether you call it schizoaffective or something else. They will still use an antipsychotic, just as they have been doing for the last fifty years. It’s just that a few more of them will be doing it with Invega.


Smitty said...

Interesting installment, John. It was disheartening to see the caveat at the end, that only 2 randomized studies on Invega's effectiveness have been done with the new SAD-affected target group.

I noticed at the end that the formulation of Invega is sustained release. Does that complicate the story?

Also, regarding my medication concerns earlier this week: When I voiced my complaints/concerns (weight gain, excessive sleep, impacted speech centers with Seroquel XR) I was switched to Saphris, which has supposedly less side weight gain effects.

However, its side effects can include insomnia and chills, of which, by night three, I have both. We are discontinuing and switching me back to the XR Seroquel, which is also a medication new to me this past few months. God willing the sleep issues will resolve tonight.

I wonder what, if any reputable studies you may know about, regarding seroquel-XR or Saphris? I'd like to understand what happened to me this past few nights. Interestingly, I see this morning that the side effects of seroquel withdrawal can be insomnia and headache, just like I had last night. And I wasn't even anxious, just concerned about how odd I felt, and naturally... why I was not sleeping!

John McManamy said...

Hey Smitty, two successful studies are all the FDA requires. I don't think the extended release complicates things.

The timeline sounds suspicious on your meds switch. Standard practice is to slowly taper off one med while slowly tapering on to the other. It sounds like your doc did an abrupt switch.

Also, I'm constantly amazed why docs consider a switch - tapered or not as a first option - when a patient complains. It sounds like the first med was working fine except for the weight gain. So maybe the same med on a lower dose would have been a better risk than switching to a complete unknown. Also, combine this with a weight-management strategy.

I'm not an MD. I don't have clinical experience on this. But it does seem docs have an unreasonable phobia concerning lower doses.

Clinical trials are only done to get an FDA indication. There is no way from a clinical trial to predict how a med will perform for your particular situation (or mine or someone else's). We know what certain classes of meds (such as antipsychotics) do in general, then it's all pill roulette from there.

Hope this helps ...

Smitty said...

Thanks for your careful reading of my comment. I realized I did not say explicitly that my doctor took me completely off the 300 mg of Seroquel XR and was offering me the Saphris in a 5mg dosage as replacement. I admit to having concerns about this switch as 5mg from what I've read is not the usual starting dosage. This shows, I think, his willingness to work with me, so I took the chance. I think I was afraid to ask him follow-up questions as my fifteen minutes was about up, and I had the strong hunch there were no other alternatives.

The result is that I am happy to go back on my medications; darn sure tooting I hope that was not my doctor's ulterior motive. But from my experience last night, now I know the Seroquel XR can pin me to the mattress almost 14 hours after I've taken it.

Thanks again for your careful and considered reply. I'm going to investigate proven medication weaning programs to share with my doctor at our next appointment in two weeks.

Seattle-Jeff said...

Have you looked into the transcranial magnetic stimulation tms?

bipolarbatesy said...

Hi John,

Oh! Placebo Placebo, where art thou Placebo.

My own experience with med's was always an initial period of positive 'affect,' followed by the negating problem of side effects, chronic constipation gets me every time with almost any med.

Its an issue that I'm slowly learning to manage through sensation awareness and how I have habitually braced my muscles in distress, from years of fending of Asthma attacks.

Did I condition my autonomic nervous system in this way leading to future 'affective' states, affect is an important word in the new awareness of the emotional sense of self, yet its hard to find succinct explanations of what exactly 'affect' implies.

My current ability to do the Bipolar gig med’s free started with a chance introduction to ‘affect’ when I stumbled across a copy of “Affect Dysregulation & Disorders of the Self” by Allan Schore, although four years on I’m still not certain what it means, apart from the vague notion that I can’t think it.

Years of reading the newer understandings from neurobiology have had there ‘affect’ but I will probably never be able to say why, mind you its great material to read when your hypomanic, like Russian literature it’s a magical cure for insomnia, like reading three pages of “War & Peace” you go out like a light.

What is the ‘affect’ in ’affective disorders,’ who knows?

Take care,