to obey the scout law…

Posted on Wednesday 30 September 2015

A 2002 article by Stanford Biostatistician Helena Chmura Kraemer et al summarizes the "characteristics of a well-performed RCT" [referencing the 1986 classic, Clinical Trials: Design, Conduct, and Analysis, by Curtis Meinert]:
Considerable progress has been made in the development and evaluation of treatments, both pharmacologic and psychological, for a variety of different psychiatric disorders. This research has emphasized the use of the randomized clinical trial [RCT], which is widely regarded as the gold standard of evaluation of efficacy and effectiveness in medicine. The characteristics of a well-performed RCT are well established. They include the following features:
  1. A well-defined and justified population, with a representative sample of sufficient size, to yield power to detect clinically significant differences between treatments and to provide accurate estimates of the effect sizes in that population on which to base considerations of clinical or policy significance.
  2. One or more control or comparison groups, with protocols for treatment in each group specified well enough to permit replication in the clinic or another research project.
  3. Randomization to treatment and control or comparison groups to avoid confusing selection effects with treatment effects.
  4. A few a priori, well-chosen, and justified outcome measures, selected in advance of the trial, obtained either blinded to treatment group or otherwise with measurement bias controlled to avoid confusing the opinions or expectations of patients or researchers with treatment effects.
  5. Analysis performed by intention to treat [ie, all randomized subjects are included in the analysis of outcome]. Only those subgroups specified and justified in the a priori hypotheses [eg, baseline severity] or in the design [eg, sites in a multisite study] are addressed in the primary analysis.
  6. A valid test for statistical significance and estimates of effect sizes informative enough to guide consideration of clinical and policy significance.
The knowledge derived from such RCTs is of direct relevance to health care system reform and the growing demands for accountability…
There’s nothing particularly new about doing Randomized Clinical Trials [RTCs]. Each point is clear – the rationale intuitively obvious. One has the sense that the analyses of trial efficacy data could be programmed from an a priori protocol before commencing the trial. The problems haven’t come from the algorithms used to crunch the numbers. They’ve come from the two legged critters that use them.

In psychiatry, we’re primarily focused on the problems from two classes of drugs – the "SSRI Antidepressants" and the "Atypical Antipsychotics" – both variations on older themes. We thought of their predecessors as dangerous and self limiting, used in dire situations. Their toxicity was on the front page – too many everyday adverse effects to expect people to take them long term even when recommended. One way to frame the modern problems doesn’t have to do with the Clinical Trials that got them on the market but rather with the dramatically broadened indications. With the "SSRI Antidepressants," the DSM-III had handed indications to the pharmaceutical companies on a silver platter. Some was the focus of the neoKraepelinians on the biological aspects of mental illness. But the main gift was the creation of the diagnosis – Major Depressive Disorder [MDD] – that could be expanded to fit the majority of patients showing up for treatment. The combination of the SSRI’s greater tolerability and the catch·all MDD diagnosis was a recipe for success. These are not potent drugs nor is MDD a solid diagnosis, so the challenge was getting through the Clinical Trials for approval.

With the "Atypical Antipsychotics" there were different bridges to cross. At least in terms of felt adverse effects, the incidence of neurological side effects was more in the background than with the older drugs. The dangers were metabolic and insidious – often taking longer to develop than the duration of the usual Phase 3 Clinical Trials. Antipsychotics are potent drugs and Risperdal was no exception. So unlike the Antidepressants, getting a treatment effect in an RCT wasn’t really a problem. But in the words of J&J Sales Manager, Tone Jones, "You can’t make a blockbuster [> $1 B/YR] out of a 1% disease [incidence  of Schizophrenia]." They weren’t handed much of a market, unlike the Antidepressant makers. They had to create their own. They aimed for a particular set of situations where the drugs were sought by someone other than the patients themselves: mentally impaired children; autistic children; the kids with "Super angry/grouchy/cranky irritability" that Joseph Biederman called Bipolar Kids; elderly people in long term care; psychotic and others in government facilities including prisons – something like captive audiences.

They put Alex Gorsky in charge of Risperdal sales. Gorsky was a lifelong Boy Scout, still active in the national organization:
    Boy Scout Promise:
    On my honor, I will do my best. To do my duty to God and my country and to obey the Scout Law; To help other people at all times; To keep myself physically strong, mentally awake and morally straight.
He was a West Point graduate and later Army Ranger:
    Cadet Honor Code:
    A cadet will not lie, cheat, steal, or tolerate those who do.
    Ranger Creed:
    Recognizing that I volunteered as a Ranger, fully knowing the hazards of my chosen profession, I will always endeavor to uphold the prestige, honor, and high esprit de corps of the Rangers.
    Acknowledging the fact that a Ranger is a more elite soldier who arrives at the cutting edge of battle by land, sea, or air, I accept the fact that as a Ranger my country expects me to move further, faster and fight harder than any other soldier.
    Never shall I fail my comrades. I will always keep myself mentally alert, physically strong and morally straight and I will shoulder more than my share of the task whatever it may be, one-hundred-percent and then some.
    Gallantly will I show the world that I am a specially selected and well-trained soldier. My courtesy to superior officers, neatness of dress and care of equipment shall set the example for others to follow.
    Energetically will I meet the enemies of my country. I shall defeat them on the field of battle for I am better trained and will fight with all my might. Surrender is not a Ranger word. I will never leave a fallen comrade to fall into the hands of the enemy and under no circumstances will I ever embarrass my country.
    Readily will I display the intestinal fortitude required to fight on to the Ranger objective and complete the mission though I be the lone survivor.Rangers Lead The Way!!!
and he worked for Johnson & Johnson [the company whose last name was Baby Oil], coming up through the ranks to this challenging position.
    The Johnson and Johnson Credo:
    We believe our first responsibility is to the doctors, nurses and patients, to mothers and fathers and all others who use our products and services. In meeting their needs everything we do must be of high quality. We must constantly strive to reduce our costs in order to maintain reasonable prices. Customers’ orders must be serviced promptly and accurately. Our suppliers and distributors must have an opportunityto make a fair profit.
    We are responsible to our employees, the men and women who work with us throughout the world. Everyone must be considered as an individual. We must respect their dignity and recognize their merit. They must have a sense of security in their jobs. Compensation must be fair and adequate, and working conditions clean, orderly and safe. We must be mindful of ways to help our employees fulfill their family responsibilities. Employees must feel free to make suggestions and complaints. There must be equal opportunity for employment, development and advancement for those qualified. We must provide competent management, and their actions must be just and ethical.
    We are responsible to the communities in which we live and work and to the world community as well. we must be good citizens — support good works and charities and bear our fair share of taxes. We must encourage civic improvements and better health and education. We must maintain in good order the property we are privileged to use, protecting the environment and natural resources.
    Our final responsibility is to our stockholders. Business must make a sound profit. We must experiment with new ideas. Research must be carried on, innovative programs developed and mistakes paid for. New equipment must be purchased, new facilities provided and new products launched. Reserves must be created to provide for adverse times. When we operate according to these principles, the stockholders should realize a fair return.
And so armed with a thorough understanding of the Clinical Trial process, a medical writing firm less than a mile away [Excerta Medica] turning out journal articles faster than they could locate KOL authors to sign up, a keen sense for backroom wheelings and dealings, and winning interpersonal ways, Gorsky set out to create the markets needed to become a blockbuster and then some. The story is masterfully told in the Huffington Post fifteen part series by Steven Brill. It’s all on-line just waiting for you to read it. And you won’t have a bit of trouble understanding why he called it America’s Most Admired Lawbreaker
    Katie Tierney Higgins RN
    October 5, 2015 | 1:49 AM

    Hmmm did Gorskey create the markets that made Risperdal a blockbuster?

    The way I read the story, Gorskey pitched the deals with the actual creators of the markets — mainly, psychiatrists, Biederman got his own play station, for instance.– Allen Frances got — something else for TMAP.

    I missed the science behind Biederman’s invention of C&A bipolar disorder–and still wonder why there is no emphasis on his experimenting on kids with powerful drugs based on his theories about their problematic (for caregivers/teachers, etc) behavior– . His may be the most heinous example of bad medicine based on pseudoscience.

    “For more than a decade, Biederman had done pioneering work on the theory that behavior disorders among children and adolescents–such as attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD)—were the result of chemical imbalances in the brain that could be addressed with strong prescription drugs, such as Risperdal.” ( Steven Brill)

    — Paging Ron Pies !!

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