Sunday, February 13, 2011

Gold Standard Clinical Trials - Science or Marketing?

This is the second in a new series on analyzing information. Credit Robert Whitaker’s “Anatomy of an Epidemic” for getting the ball rolling, as there is no way of critiquing his book without evaluating the evidence he relied upon. Only then can we ask ourselves if his conclusions are justifiable.

This is a different proposition entirely than whether Whitaker is right or wrong. You can decide that for yourself.

In my previous piece, I commented on some findings at the very bottom of the evidence food chain (a series of wholly unscientific reader polls I had conducted here), but that actually told us something. In this piece, I will flip it. I will talk about a study at the very top of the food chain, but that tells us nothing. Let’s get started ...

Two years ago, in my capacity as a journalist, I was at the 12th International Congress on Schizophrenia Research in San Diego, just down the hill from where I live. The top brain scientists in the world were presenting and in attendance, including 2000 Nobel Laureate Arvid Carlsson. I recall going to a table with my morning coffee and greeting the researchers there with, “Hi, I’m the only C student at this table.”

Part of the Congress involved poster sessions, where scientists stand in front of blow-ups of their latest findings. This affords an invaluable opportunity for the researchers at the conference to engage their fellow researchers in one-on-one discussion. It also affords a golden opportunity for people like me to walk up to some future Nobel Laureate and ask, “What’s a neuron?”

The first three or four days of posters involved cutting edge brain research. I was like a kid in a candy store ... a wrestler in a chair factory, a hippie in a drum circle. (Did you see that Super Bowl commercial?) The last day of the conference featured posters on treatment. Instantly, I felt I had been sucked back in time a half century.

Some very enthusiastic Johnson&Johnson people informed me of a new study of theirs that shed some very important new light on schizoaffective disorder.

Really? I thought. Schizoaffective is probably the most confusing diagnostic classification in the entire DSM. Everyone agrees that it has something to do with that undelineated middle ground where bipolar and schizophrenia bleed into one another, but what is it exactly? Schizophrenia lite? Bipolar heavy? Some kind of schizophrenia-bipolar mix? Or a stand-alone illness in its own right?

Naturally, I was interested. I looked at the poster. "A Randomized, Double Blind, Placebo-Controlled Study of Flexible Dose Paliperidone ER in the Treatment of Patients with Schizoaffective Disorder," I read.

I smiled politely, engaged in very short chit-chat, then made my way to other posters. In one glance, I knew, the study told me nothing. Here’s the deal:

Randomized, double blind, placebo-controlled studies are the gold standard of treatment research. Perhaps the most celebrated example of a clinical trial is James Lind’s 1747 experiment involving 12 scurvy-infected sailors. He divided his patients into six pairs. Five of the pairs showed no improvement. Of the pair receiving oranges and lemons, one had fully recovered after five days, the other had almost recovered. (Then they ran out of fruit.)

A more refined study would have pitted a much larger group of orange-and-lemon people against a proportionally large group taking a look-alike, taste-alike placebo (say a citrus pill vs a sugar pill). To keep the study honest, one would have made sure the clinicians handing out the pills had no way of knowing which pill was which (the double-blind).

I knew at a glance the J&J people had all their “i”s dotted and “t”s crossed. Studies of this nature are immensely expensive - my best guess is the $20 million-range - designed by some of the smartest people in the world overseeing an immense and highly complex undertaking where an infinity of things can go wrong (and often do).

The catch? Even though the study was conducted scientifically, to rigorous standards, it was not a scientific study. It was a marketing exercise.

Paliperidone is the generic name for J&J’s recently-approved Invega, which is Son of Risperdal. Risperdal represents the first of the new-generation atypical antipsychotics (discounting Clozaril) introduced in the early 1990s and hyped as superior to old-generation antipsychotics.

We already know that as problematic as antipsychotics may be, they are very effective in knocking out psychosis. The first studies involving Thorazine proved that six decades ago. Since then, antipsychotics have been the treatment of choice for schizophrenia and any condition involving psychosis, including bipolar and schizoaffective, accounting for some $20 billion annually in sales.

So what’s new? Nothing much, really, except that no drug company had ever undertaken a trial on a schizoaffective population. What was the point?

Keep in mind that when James Lind was investigating scurvy, the British Royal Navy was not issuing citrus fruit to its sailors. His findings would give them cause to change their practice, though it would take them another fifty years to get around to it.

Contrast this with the Invega study. Is a clinician, reading this study, really going to change his or her practice by putting all his schizoaffective patients on an antipsychotic? He already has them on an antipsychotic.

But could the study possibly be persuasive in getting a clinician to change her practice from prescribing say Geodon or Zyprexa to Invega? Ah, a marketing question.

More to come ...  

5 comments:

Smitty said...

John, I came across a post of yours where you spoke of your need to reduce medications, before your doctor was ready to do so. I see my doctor tomorrow and realized I might want to ask you how you would try to approach your doctor if you thought he or she would listen to you. I am on the seroquel XR right now and it is quite a doozy at leaving me hungover in the mornings. I am getting some 10 hours of sleep a night and am gaining weight at the rate of 8 pounds a month.
I'm symptom-free at this point. How would you recommend I approach my doctor? I really would like my phD husband to come with me and advocate the negatives in his gentle low key way. I am afraid I am going to act a wee bit bitchy (out of fear) tomorrow. I really want off the XR because it is more expensive than the regular seroquel, I don't agree with these drugs anyways, and there seems to be something damned sinister and mistrusting about putting a patient on an XR formulation to me. I need coaching on the most diplomatic way to request change... especially when it comes to reducing dosages.

Thanks for whatever time you are able to take in addressing my concerns.

bipolarbatesy said...

Hi John,

Love this post, especially;

"I knew at a glance the J&J people had all their “i”s dotted and “t”s crossed. Studies of this nature are immensely expensive - my best guess is the $20 million-range - designed by some of the smartest people in the world overseeing an immense and highly complex undertaking where an infinity of things can go wrong (and often do)."

Sounds a bit like the brain with all those neurons, and I for one would love to known what the "affective" part of schizoaffective disorder actually means in processes of neurons & their networks within the brain and how they affect the nervous system through which much of our "symptoms" are expressed.

I am one of those who has needed to do the bipolar gig largely unmedicated through a low tolerance to side effects, a thirty one year journey that I have begun to blog about at; http://bipolarbatesy.blogspot.com

The last five years in particular have seen a thirst for knowledge about what goes on inside me when the energies of mania and depression overwhelm me, so neurology became a must read.

Although I expected to be led into more awareness of my brain and how it works, I find myself becoming more aware of my body, its sensations and the feedback loops to the brain that maintain the 'state' when I become euphoric and perhaps how I drive that state into mania.

Five months ago I had a classic mania episode that used to result in a classic dip into depression, which has not happened this time around, perhaps the digestion of new knowledge has seen a shift, a firing of neuronal networks that is a bit different than before, who knows?

One significant difference is the absence of the feeling of shame this time around, an emotion some suggest bipolar thrives on?

Take care,

Batesy.

John McManamy said...

Hey, Smitty. I can't make specific meds recommendations, but you are entitled to request your doc come up with a specific treatment plan with no weight gain or hang-over effects in your future.

Since reducing the dosage is your idea, I would not hesitate putting this to your doctor. If you can spot bad things happening before they happen, then you can always bump your dose back up.

You can present this to your doc as a trust issue. Do you trust me or don't you?

Keep in mind, he or she is the doc, but you are the boss. Don't be afraid to hold your ground. Let me know how it goes ...

John McManamy said...

Hey, Batesy. I'm glad you appreciate where I was coming from. Here I was, absorbing all this mind-boggling brain science where highly dedicated researchers are trying to figure out all the neuron stuff. Then I walk into the J&J study.

I go with your digestion of knowledge/brain shift theory. Robert Cloninger is onto this. Basically, a realization can bring quantum shift change. Change is very difficult, but when it happens it can be very dramatic.

Willa Goodfellow said...

Can I suggest a second approach to Smitty's doc? -- Treat the med change as an experiment. For example:

I have been on xxx mg for xx months. When I went on it, I was experiencing thus and so. This is what has improved. This is what my current mental state is. And these are my side effects... I am concerned about the side effects, about the health risks of this extra weight, and want to find out if I can maintain the improvement while decreasing the side effects. So I would like to find out what would happen at a lower dose

How do I go about it? What should I look for/what should my husband look for as warning signs that it isn't going well? What protocol should we follow if we notice these warning signs?

You can also throw in any self care strategies/support groups/learning about how to manage your illness at this point, to demonstrate that your context has changed.

I think the idea of husband's company is great. He can provide the outside observation of improvements and side effects. I don't know whether trust is an issue for your doc. But your husband's presence can assure the doc that this experiment is not in the hands of a crazy person.

I take my spouse with me when scared about these med change chats. I find even her presence in the room shifts the balance and decreases my fears.

Best of luck!