Wednesday, April 30, 2008

"Selective Reporting of Study 329"

A new study in a rather obscure journal has revealed more about the now infamous study 329. [Jureidini JN, McHenry LB, Mansfield PR. Clinical trials and drug promotion: selective reporting of study 329. Int J Risk Safety Med 2008; 20: 73-81. Link here.]

For the background, let me take the easy way out, and quote Ed Silverman from PharmaLot:

Back in 2001, an infamous study was published in the Journal of the American Academy of Child and Adolescent Psychiatry that declared Glaxo’s [GlaxoSmithKline, GSK] Paxil antidepressant - called Seroxat in the UK - [paroxetine] was “generally well tolerated and effective for major depression in adolescents.” Known as study 329, the findings were used to widely promote the drug, which became a huge seller.

Of course, the study was later held in disrepute after it was learned the results didn’t tell the whole story. In fact, 329 was one of three studies cited by former New York Attorney General Eliot Spitzer, who filed a suit charging Glaxo with “repeated and persistent fraud,” alleging the drugmaker had promoted positive findings, but hadn’t publicized unfavorable data (back story).

As it turns out, study 329, ... already had a sordid history that included ghostwriting charges (here’s some background)....
We did cover this issue in the past (here) on Health Care Renewal.

Furthermore, we can now turn to the Clinical Psychology and Psychiatry Blog for an analysis of what is new about the study by Jureidini et al. The main points were -

The study report (in the Journal of the American Academy of Child and Adolescent Psychiatry) featured results of manipulation of the measures used to assess efficacy to make the drug appear more efficacious:

  • Study 329 was designed to employ 8 measures of drug efficacy. It turned out that paroxetine was not statistically significantly superior to the comparator using any of these 8 measures.
  • After the study was underway, the authors added a bunch of new measures, including new instruments, and modifications of instruments used in the original 8 measures. Only when using some of these new measures did the drug exhibit any efficacy.

To summarize how the Clinical Psychology and Psychiatry blog put it:

Devising various cutoff scores on various measures on which victory could be declared, as well as examining individual items from various measures rather than entire rating scales, the authors were able to grasp and pull out a couple of small victories. In the published version of the paper, there is no hint that such data dredging occurred. Change the endpoints until you find one that works out, then declare victory.

Worse, the study report simply omitted mention of the data that serious adverse events were more common in patients treated with paroxetine than with placebo, making the drug appear safer than it really may be. Jureidini et al noted that the following phrase,

worsening depression, emotional lability, headache, and hostility were considered related or possibly related to treatment

was omitted from the published report. Furthermore, per Jureidine et al,

Suicidal thoughts and behavior were grouped under the euphemism of 'emotional lability'

Yet the final JAACAP paper only stated,

Only headache (1 patient) was considered by the treating investigator to be related to paroxetine treatment

Jureidini et al concluded,

The published conclusions of study 329 and information provided by GSK to health professionals understated adverse effect rates and emphasized post-hoc measures that were not consistent with the unpublished, protocol-defined primary and secondary outcomes.

The article by Jureidini et al adds to our understanding of the various devious ways commercial sponsors of clinical research and the supposedly independent academic investigators who collaborate with them may manipulate the design, implementation, analysis and reporting of clinical studies to make the sponsors' products look better.

As we have said again and again, patients and physicians require the best possible information about benefits and harms of treatments to make the best decisions about such treatments. When those with vested interests in supporting a particular treatment distort the information available to make such decisions, they risk harming patients. In addition, manipulation of clinical studies violates the trust of study participants who thought they were taking part to advance science or health care.

The ongoing revelations about study 329 unfortunately remind doctors and patients who skeptical they must be about how well drugs and devices really are supported by clinical research. Combined with numerous other reports of manipulation and suppression of research, they suggest that:
  • medicine, and particularly academic medicine ought to do a far better job of policing itself to ensure the integrity of clinical research
  • pharmaceutical, biotechnology and device companies lead by businesspeople and lacking strong corporate cultures and explicit codes of conduct supporting ethical conduct may not deserve our trust
  • government regulation of drug and device companies need to be far more stringent
  • consideration ought to be given to require that all clinical research be conducted at true arm's length from organizations and people with vested interests in promoting particular products or services assessed by such research
I must note that there is also a local angle to this. As Jureidini et al wrote, "in 1992 Martin Keller MD, Chairman of Psychiatry at Brown University, Rhode Island and colleagues successfully proposed to SKB [SmithKline Beecham, the predecessor of GSK] a multi-site study of a selective serotonin reuptake inhibitor and tricyclic antidepressant in adolescent major depression."

As PharmaLot reported, "The latest study prompted a complaint concerning possible scientific misconduct to be leveled against study 329’s lead author, Martin Keller, a psychiatry professor at Brown University, by David Egilman, a clinical associate professor in community health at Brown. We are awaiting a reply from Keller and Brown provost David Kertzer, who was sent the complaint by Egilman. UPDATE: A Brown spokesman declines to comment."

As I noted in my previous blog post, I am currently on the voluntary faculty of Alpert Medical School of Brown University. I am a former full-time faculty member, and an undergraduate and medical school alumnus of Brown. I am saddened to see the ongoing damage to the reputation of the institution from this case. I do believe that Dr Egilman's complaint warrants full, open, and transparent investigation.


Anonymous said...

I see this in a much more disturbing light, encompassing the concept of disease mongering. A pharmacist friend bluntly states I would be shocked by the number, and who, are taking this and related medications. Police and teachers being but two groups. Friends in the mental health field are concerned that these drugs are being given with little or no professional follow up. A seven minute visit, every few months, does not really allow for a good patient doctor interaction involving such a complex issue as mental health.

I have been pressed, and pressed hard, about my personal life and how one of these medications would be of benefit, just to help me through the difficulties of everyday life. The one common factor in all of these situations is we are all dealing with suburban doctors, are covered by insurance, and we all have incomes allowing us the ability to make the required co-pays.

Equally disturbing to me is when I state my financial situation and marriage are secure I find a very slick answer raising doubt as to my veracity. The withholding of date, combined with the marketing of these drugs, not only is ethically wrong, but is putting patients at risk. The insistence that everyone would benefit from this class of pharmaceuticals may create a market, but again, the with held negative side effects place patents at risk. One drug, I cannot find the reference, looses effectiveness after about six weeks, again putting the patient at risk.

At what point does the risk to the patient become the driver in their treatment?

Steve Lucas

Anonymous said...

Current Depression Medications: Do The Benefits Outweigh the Harm?

Presently, for the treatment of depression and other what some claim are mental disorders, some of which are questionable, selective serotonin reuptake inhibitors are the drugs of choice by most prescribers. Such meds, meds that affect the mind, are called psychotropic medications. SSRIs also include a few meds in this class with the addition of a norepinephrine uptake inhibitor added to the SSRI, and these are referred to SNRI medications. Examples of SNRIs are Cymbalta and Effexor

Some Definitions:

Serotonin is a neurotransmitter thought to be associated with mood. The hypothesis was first suggested in the mid 1960s that this neurotransmitter may play a role in moods and emotions in humans. Yet to this day, the serotonin correlation with such behavioral and mental conditions is only theoretical. In fact, the psychiatrist’s bible, which is the DSM, states that the definite etiology of depression remains a mystery and is unknown. So a chemical imbalance in the brain is not proven to be the cause of mood disorders, it is only suspected with limited scientific evidence.
Norepinephrine is a stress hormone, which many believe help those who have such mood disorders as depression.

And depression is only one of those mood disorders, yet possibly the most devastating one. An accurate diagnosis of these mood conditions lack complete accuracy as they can only be defined conceptually, so the diagnosis is dependent on subjective criteria, such as questionnaires. There is no objective diagnostic testing for depression. Yet the diagnosis of depression in patients has increased quite a bit over the decades.

Several decades ago, less than 1 percent of the U.S. population were thought to have depression. Today, it is believed that about 15 percent of the population have depression at some time in their lives. Why this great increase in the growth of this condition remains unknown and is subject to speculation. What is known is that the psychiatry specialty is the one specialty most paid to by certain pharmaceutical companies for support of their psychotropic meds, as this industry clearly desires market growth of these products, as this objective is part of their nature. Regardless, SSRIs and SRNIs are the preferred treatment methods if depression or other mood disorders that may be suspected by a doctor.

Over 30 million scripts of these types of meds are written annually, and the franchise is around 20 billion dollars a year, with some of the meds costing over 3 dollars per tablet. There are about ten different SSRI/SRNI meds available, many of which are now generic, yet essentially, they appear to be similar in regards to their efficacy and adverse events. The newest one, a SNRI called Pristiq, was approved in 2008, and is being promoted for treatment for menopause. The first one of these SSRI meds was Prozac, which was available in 1988, and the drug was greatly praised for its ability to transform the lives of those who consumed this medication in the years that followed. Some termed Prozac, ‘the happy pill’. In addition, as the years went by and more drugs in this class became available, Prozac was the one of preference for many doctors for children.

Furthermore, these meds have received additional indications besides depression for some really questionable conditions, such as social phobia and premenstrual syndrome. With the latter, I find it hard to believe that a natural female experience can be considered a treatable disease. Social phobia is a personality trait, in my opinion, which has been called shyness, which probably should not be labeled a treatable disease as well. There are other indications for certain behavioral manifestations as well with the different SSRIs or SRNIs. So the market continues to grow with these meds. Yet, it is believed that these meds are effective in only about half of those who take them. The makers of such meds create such conditions besides depression for additional utilization of these types of medications, and are active and have been active in forming symbiotic relationships with related groups, such as providing financial support for screenings for the indicated conditions of their meds- screening of children and adolescents in particular, I understand.

More concerning, however, is the adverse effects associated with these types of meds, which include suicidal thoughts and actions, violence, including acts of homicide, and aggression, among others. While most are approved for use in adults only, prescribing these meds to children and adolescents has drawn the most attention. The reasons for this attention are the off-label use of these meds in this population, yet what may be most shocking is the fact that some of the makers of these meds did not release clinical study information about the risks of suicide as well as the other adverse events related to such populations, including the decreased efficacy of SSRIs in general, which is believed to be less than 10 percent more effective than a placebo. Paxil caught the attention of the government regarding this issue some time ago for hiding such important information, for example, some time ago.
And there are very serious questions about the use of SSRIs in children and adolescents regarding the effects of these meds on them. For example, do the SSRIs correct or create brain states considered not within normal limits? Are adolescents depressed, or just experiencing what was once considered normal teenage angst? Do SSRIs have an effect on the brain development and their identity? Do adolescents in particular become dangerous or bizarre due to SSRIs interfering with the myelination occurring in their still developing brains? No one seems to know the correct answer to such questions, yet the danger associated with the use of SSRIs does in fact exist. It is observed in some who take such meds, but not all who take these meds.

Finally, if SSRIs are discontinued, withdrawals are brutal, and may be a catalyst for suicide in itself, as not only are these meds habit forming, but discontinuing these meds leaves the brain in a state of neurochemical instability, as the neurons are recalibrating upon discontinuation of the SSRI. This occurs to some degree with any psychotropic med, yet the withdrawals can reach a state of danger for the victim in some classes of meds such as SSRIs.
SSRIs and SRNIs have been claimed by doctors and patients to be extremely beneficial for the patient’s well -being regarding the patient’s mental issues where these types of meds are used, yet the risk factors associated with this class of medications may outweigh any perceived benefit for the patient taking such a drug. Considering the lack of efficacy that has been demonstrated objectively, along with the deadly adverse events with these meds only recently brought to the attention of others, other treatment options should probably be considered, but that is up to the discretion of the prescriber.

“I use to care, but now I take a pill for that.” --- Author unknown