Monday, August 20, 2012

Spare the Rod, Spoil the Child - How the Prescription Pad Replaced the Paddle.

Fifty years ago, if a child misbehaved, he got a good paddling. Today, society frowns on slapping and spanking kids, with corporeal punishment outlawed in all but 19 states.

If we no longer feel comfortable using the rod to combat misbehavior, what do we do when kids misbehave?  Our society has discovered a very unique solution for dealing with irritating, moody and temperamental kids.

Risperdal, Zyprexa, Abilify, Geodon, Seroquel. Atypical antipsychotics (often called second-generation agents) are now the fifth top-selling drug class in the United States, with sales of $18.2 billion in 2011, according to IMS Health. Their use in children with behavior and emotional problems is now as American as apple pie. Last, year, in fact, Americans spent about as much on antipsychotic drugs as we do on drugs for cancer or diabetes.

First introduced in the 1990s for schizophrenia – atypical antipsychotics were promoted as being relatively benign – with fewer side effects than older drugs like Haldol, Thorazine and Mellaril.  Due to the perception of enhanced safety (promulgated by the pharmaceutical industry), use of atypical antipsychotics has skyrocketed in children and adolescents in the past 15 years. Today atypical antipsychotics are used for a myriad of off-label indications (with questionable supporting evidence) in children and adolescents, including ADHD, mood disorders and oppositional behaviors such as aggression, arguing with parents, having angry outbursts or being defiant. While the rates of psychiatric drugs have mushroomed in both privately and publicly insured youth, psychiatric medication use is especially high in kids in foster care. The excessive rate of psychiatric medication use in foster children - with some states reporting overall psych med use as high as 66% in adolescents 12 to 17 years old - has resulted in several high-profile national investigations leading to Medicaid taking a variety of measures to try to regulate antipsychotic prescribing.

Why are psych medications so popular for treating emotional and behavioral issues in youth in the U.S?  Some researchers attribute it to reimbursement policies, diagnostic classification systems or cultural beliefs regarding the role of medication treatment. Most see aggressive marketing as a factor in the rise of antipsychotic prescribing to kids. But whatever the reason, prescribing psychiatric drugs to manage childrens' emotional and behavioral conduct is a trend that is much more popular in America than Europe. American children are about three times likelier to be prescribed psychiatric meds compared to children in Western Europe, with use of antidepressant and ADHD medications three or more times greater in the U.S. than in the Netherlands and Germany.

So while using a hair brush to whack a kid at school is prohibited, you may find some of the facts and figures regarding antipsychotic drug use hair raising!
Today, Americans no longer reach for the paddle to punish misbehavior in children. Instead, we reach for the prescription pad. Perhaps someday we will look back and question the practice of using powerful psychiatric medications to manage emotional and behavioral problems in children. For now, we seem to accept a cultural norm that judges corporeal punishment as cruel and abusive, but sees medicating bad behavior as an  acceptable way of dealing with troubled kids.

Sunday, January 31, 2010

All that Glitas is Not Gold – Musings on Pharma Marketing & Type 2 Diabetes

In the past several years, the second-generation glitazones Avandia (rosiglitazone) and Actos (pioglitazone) - once touted as breakthroughs that could reduce cardiovascular mortality in patients with type 2 diabetes - have been tarnished by controversy. The story of the glitazones (also known as thiazolidinediones or TZDs) reflects everything that is good, bad and ugly about the pharmaceutical industry.

When pharmaceutical manufacturers first started investigating rosiglitazone and pioglitazone, I am sure they had good intentions, thinking that these two agents would offer benefits over drugs like metformin. In the late 1990s, optimism about the potential of these second-generation TZDs grew as liver toxicity associated with troglitazone (Rezulin, a first-generation TZD) resulted in Rezulin's withdrawal , in 1997 in the United Kingdom and in the United States in 2000.

The bad and the ugly about TZDs is that despite the fact that glitazones have not lived up to their potential and despite the fact that leading American diabetologists have stated publicly that their risks outweigh their benefits (particularly in the case of rosiglitazone), the drugs continue to be aggressively promoted and prescribed.

Many readers will peg the debate regarding glitazone safety to Dr. Steve Nissen’s 2007 meta-analysis in NEJM indicating that rosiglitazone increases the risk of myocardial infarction (MI) by 43%. Not everyone agreed with Dr. Nissen's conclusions and there continues to be debate and disagreement over the cardiac safety of rosglitazone and the significance of PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events). PROactive is a study whose methodology sparked debate when the investigators substituted a more favorable secondary endpoint for a primary endpoint that failed to reach statistical significance. A critique of PROactive is elucidated in this commentary in Clinical Diabetes by Dr. Jay Skyler.

While diabetologists may disagree about the cardiac risks of rosiglitazone, virtually every thought leader, and reputable drug information source, concludes that rosiglitazone and pioglitazone increase the risk of heart failure and fractures. In 2009, these findings led the American Diabetes Association to release consensus guidelines unanimously advising against the use of rosiglitazone.

What is less well known is that the second-generation glitazones - which cause weight gain and edema and significant adverse events - were originally positioned as being cardioprotective in patients with type 2 diabetes. In other words, they were touted to prevent the very problems that they now seem to promote.

To understand how and why glitazones were launched with the perception of improved cardiac health, we need to go back to the early 1990s when U.S. pharmaceutical companies conducted animal research to elucidate the mechanisms of action for rosiglitazine and pioglitazone [e.g. peroxisome proliferator-activated receptor (PPAR) agonism] and to the late 1990s, when a diabetologist at University of North Carolina School of Medicine almost lost his job for disclosing negative data about rosiglitazone at a national medical conference.

The early years - glitazones and animal research
In 1996, researchers investigating the effects of PPAR-gamma agonists discovered that adding pioglitazone to aortic rat smooth muscle cells inhibited abnormal cell proliferation. This research, published in the American Journal of Hypertension, concluded that glitazones may be more useful than commonly-prescribed diabetes drugs, such as metformin, for inhibiting atherosclerosis, a process that frequently occurs in diabetic patients. In another article published that same year in American Journal of Physiology, researchers showed that when pioglitazone was administered to Dahl-S rats (an animal model for hypertension), the drug inhibited normal vascular responses to norepinephrine and angiotensin II. This, along with other studies conducted with troglitazone, opened up a wave of speculation that since PPAR-gamma agonists seemed to have a cardioprotective effect in diabetic rats, they had the potential to improve hypertension and cardiovascular disease progression in humans.

Fast forward to 1999, and we see more glitazone animal research appearing in the scientific literature. In one article, the authors examined the effects of rosiglitazone on blood pressure and endothelial function in fatty Zucker rats (an animal model for obesity, hypertension and diabetes). The authors postulated that since rosiglitazone prevents hypertension in insulin resistant rats, the drug might reduce cardiac risks associated with obesity and insulin resistance in humans. What is apparent from reading this Diabetes article, but is not apparent from the abstract, is that GSK funded the research and that 3 of the 4 authors were paid advisors to, or owned stock, in the company.

The later years- glitazones and surrogate endpoints
With the launch of Avandia and Actos in 2000, GSK and Merck continued their efforts to show that pioglitazone and rosiglitazone could prevent complications beyond those achievable by glucose lowering alone. Since cardiovascular disease is the leading cause of death in type 2 diabetes, the possibility that glitazones might prevent heart attacks or strokes in patients with diabetes was very exciting. As with many pharmaceutical agents, the focus of research was “surrogate endpoints”. In other words, clinical researchers tried to suggest that glitazones could reduce cardiac morbidity and mortality by showing that the drugs impacted surrogate measures of cardiac disease, primarily triglycerides, LDL and HDL cholesterol. This research produced conflicting reports. While studies like this retrospective study of medical records from 605 primary care practices suggested that pioglitazone improved LDL, HDL and triglycerides, the findings for rosiglitazone were not so rosy. This observational study, however, co-authored by a Glaxo employee concluded that "no differences in changes in LDL-C or HDL-C could be discerned between patients treated with rosiglitazone compared with pioglitazone." Finally, while research showed that pioglitazone did exert favorable impact on lipids, there was no certainty that such improvements in surrogate endpoints would translate into improved clinical endpoints. Around this time, rosiglitazone received another blow when John Buse, a prominent endocrinologist from University of North Carolina School of Medicine, presented negative findings about the drug at national medical conferences of the Endocrine Society and the American Diabetes Association (ADA)

The recent years - The glitazones lose their luster
Glitazones' association with fluid retention started to appear in the literature as early as 2002-2003. By 2008, a steady stream of clinical publications linked glitazones with congestive heart failure. Additional data indicated that the drugs increased the risk of fractures in women.

When Dr. John Buse first presented negative data about rosiglitazone back in 1999, senior executives at GSK tried to get him fired from his job, accusing him of being a liar and stating that he was accountable for a $4 billion dollar loss in market capitalization. The Senate Finance Committee's Report on the incident can be found here. Fast forward to 2009 and John Buse is a member of the ADA consensus committee issuing national guidelines on treatment of type 2 diabetes. These new guidelines recommend that rosiglitazone not be used. This time, GSK says very little other than defending Avandia in a letter to the editor and stating that "GlaxoSmithKline regrets the recommendation of the recent American Diabetes Association/European Association for the Study of Diabetes consensus statement against the use of rosiglitazone for treatment of type 2 diabetes because it is contrary to scientific evidence.”

Because prescription drug sales are so profitable, many medications without clear advantages are aggressively marketed, and prescribed, even though they have no proven benefits over older, existing treatments. In the past, drug companies had so much clout – and so much marketing muscle- that they could effectively drown out naysayers with multi-million dollar advertising campaigns and educational programs. Now the tide seems to be turning, although I cannot say for sure how many primary care physicians, who treat most patients with type 2 diabetes, have read the 2009 ADA guidelines.

All these musings remind me of that age-old riddle, "If a tree falls in the forest and no one hears it, did it really fall?" Medical evidence is a bit like that proverbial tree - whether physicians hear it depends on whether a pharmaceutical company will benefit from the sound of the fall. When clinical data promotes use of a drug, manufacturers will go our of their way to make sure that doctors hear about it - in advertising, medical education, scientific articles and speaker programs. In contrast, medical evidence with the potential to negatively impact sales often falls on deaf ears.

Thursday, December 31, 2009

Type 2 Diabetes, Evidence-Based Medicine & The Reign of Confusion

Evidence-based medicine (EBM) is getting a lot of attention these days. Like most topics, it has its ardent fans and die-hard opponents. To some, EBM is cookbook medicine, with too many rules and too little room for individual clinical judgment. On the other side of the controversy are EBM proponents who feel that arming physicians with guidelines, best practices and protocols brings a much needed dose of standardization into the Wild West world of healthcare decision making.

Why the sudden attention to EBM? The rising cost of healthcare expenditures –along with health care reform - means insurers want to be certain of the value of the pharmaceutical treatments they pay for. Clinicians, living in a post-Vioxx world, want assurance that the medications they prescribe are safe and effective . While the FDA tells us that drugs are efficacious compared to placebo (or as Jerry Avorn jokingly says, ‘probably better than nothing’), there is often little or no evidence that these new treatments are effective clinical interventions (e.g. able to reduce disease morbidity and mortality).

What some physicians do not realize is that many drugs are approved on their ability to improve surrogate endpoints – markers such as LDL-cholesterol, hemoglobin levels or HbA1c. Proving that a drug actually saves lives or prevents disease complications is another matter all together.

This is one reason why large-scale epidemiological studies that look at the impacts of clinical interventions on disease progression, disease complications and mortality rates wind up causing so much confusion. These study findings, along with their interpretation and the subsequent recommendations regarding treatment, often come into conflict with the medical status quo, either by contradicting clinical standards promulgated by thought leaders and medical associations and/or the marketing messages of pharmaceutical and medical device companies whose products, although improving surrogate endpoints, do not necessarily impact survival. One example of this was the assumption that intensive glucose-lowering regimens can reduce the incidence of cardiovascular mortality, the leading cause of death in patients with type 2 diabetes.

Up till recently, standard thinking was that intensive glucose control - targeting the HbA1c to around 6.5% or 7% - would prevent development of cardiovascular complications in people with type-2 diabetes at high-risk of heart disease. Intensive treatment (vs standard treatment which lowers HbA1c to 7.0% or 7.5%) often involves higher doses and/or combinations of hypoglycemic medications, as well as more frequent glucose monitoring at home.

In the last five years, evidence from 5 large-scale epidemiological studies turned the world of type 2 diabetes upside down when they suggested that intensive treatment does not reduce cardiovascular mortality. These studies include: UKPDS (United Kingdom Prospective Diabetes Study), ACCORD (Action to Control Cardiovascular Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation), PROActive(PROspective PioglitAzone Clinical Trial In MacroVascular Events), and VADT (Veterans Affairs Diabetes Trial). These studies followed patients, in some cases up to 10,000 patients for up to 10 years, in order to compare cardiac death rates for standard vs intensive treatment.

In one of the studies, ACCORD, there were actually more cardiac deaths in patients assigned to intensive therapy. The median HbA1c level achieved was 6.4% for the intensive treatment group and 7.5% for standard treatment. The trial was stopped after 3.5 years because 41 more patients in the intensive treatment arm (median HbA1c of 6.4%) had died from strokes, heart attacks, congestive heart failure, and arrhythmia than in the standard therapy group (median HbA1c of 7.5%) . These results have engendered debate as researchers try to understand the factors behind the increased death rate in patients on intensive therapy with hypoglycemia, weight gain and fluid retention being possible contributing factors. (Note: Since clinical trial interpretation is highly complex and requires in-depth knowledge of study design and sub-group analysis, I will leave more detailed analysis of these trials to clinical thought leaders)

While everyone agrees that managing plasma glucose is important, the question is how tightly? Years ago, an HbA1c around 8% was considered acceptable. In more recent years, clinical guidelines from the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE) have recommended tighter glycemic targets, in some cases as low as 6.5%. In a market-driven healthcare system, these recommendations have serious financial implications for pharmaceutical companies, insurers and consumers.

The determination of the HBA1c target, for example, dramatically impacts the sales of drug and device companies because a shift in HBA1c targets as small as .05% translates into gains (or losses) worth billions of dollars to the drug and device companies that produce type 2 diabetes medications as well as monitors and glucose test strips used for self-monitoring at home. Emphasis on tight glucose control, for example, is a major reason why we have seen a near doubling of annual costs of prescription diabetes drugs in the past decade. According to a 2008 article, published in Archives of Internal Medicine, expensive medications such as glitazones, Januvia (sitagliptin) and Byetta (exenatide) have driven up costs for treating patients with type 2 diabetes - from $6.7 billion in 2001 to $12.5 billion in 2007.

While older, generic drugs such as metformin or glipizide cost less than $20.00 for a 30-day supply, newer drugs can be 8 to 12 times that. For example, a 30-day supply of Januvia is $194, a month’s supply of Actos (pioglitazone ) is $149.00 and a 30-day supply of Byetta, $245.00. (Pricing Information: Epocrates Rx and

A recent editorial in the Canadian Family Physician points out that the culture of tight glycemic control "tyrannizes patients with little gain". A December 2009 article published in Circulation states, "based on limited evidence, self- monitoring [in type 2 diabetes] has failed to show consistent benefits in terms of quality of life, patient satisfaction, hypoglycemia, long-term complications of diabetes and mortality."

I doubt whether the average physician has heard much about the intensive therapy debate. Pharmaceutical companies spend millions of dollars promoting evidence that supports use of their products. When the evidence could hurts drug sales, companies tend to say little. Therefore, do not hold your breath waiting to see Lilly or Merck "twittering" about the risks of intensive treatment. It is more likely that the industry spinmeisters will be spending their money warning doctors of the risks of 'cookbook medicine'.

Sunday, November 29, 2009

Playing With Fire –The State of Pediatric Mental Health in America

Shire Pharmaceuticals recently introduced the first selective FDA-approved alpha-2A adrenergic receptor agonist for treatment of ADHD (attention deficit hyperactivity disorder) in children. Alpha blockers have been used for years off label. Intuniv (guanfacine), which is thought to stimulate receptors in the pre-frontal cortex, claims efficacy for children with ADHD who display a subset of symptoms that include “arguing with adults, deliberately annoying others, losing one's temper, and being easily frustrated or irritable."

I tend to make mountains out of molehills. A friend of mine, who also over thinks everything, jokingly refers to us as ‘The Ruminators’. I don’t need a psychopharmacologist to tell me that my brain chemistry is different from some of my friends who are perpetually cool, calm and collected.

Most adults I know at times argue, blame others, throw temper tantrums and act irrationally. Fortunately, most of us learn to restrain our tongues when annoyed or irritated. Call it what you like – self control, self mastery or self modulation. Everyone at some point, from the CEO of a multimillion dollar company to the barista at Starbucks, learns it is best not to call the boss an idiot or scream at a customer.

Maturity is about learning to regulate your emotions, thoughts and social interactions. Many childhood emotional disturbances, from bipolar disorder to ADHD, involve an inability to do so. For the past 25 years, America has blamed this dysregulation on biological causes. Why do we so fervently pursue this“blame the brain” theory? One contributing factor is the tremendous profits made by drug companies in the area of pediatric mental health.

The Economics of Psychotropic Drug Use in Kids
Pathological behavior in kids has become a mega-billion dollar industry. From the astounding amounts of money spent on DTC advertising to the skyrocketing use of atypical antipsychotics in kids, the numbers are staggering. In 2008, spending on atypical antipsychotics, frequently used in children who are emotionally disturbed, was a mindboggling $14.6 billion. In 2004, three of the top five drugs prescribed for children 17 years and younger were ADHD drugs: Concerta at $.49 billion, Strattera at $.43 billion, and Adderall ranked fifth at $.41 billion.

An article published in Archives of Psychiatry reported that between 1993 and 2002, there was a 6-fold increase in pediatric office visits resulting in an antipsychotic prescription, from 201,000 in 1993 to 1.2 million in 2002. As Julie Zito had pointed out, the rate of psychotropic drug prescribing for children is much higher in the United States than other country. This is especially true for children in foster care.

ADHD medications and atypical antipsychotics are also some of the most heavily promoted, with 2007 DTC advertising expenditures for Concerta of $5.5 million (Source: Medical Advertising News, May 2008). In that same year, BMS spent $105.8 million on DTC advertising of the atypical antipsychotic Abilify (Source: Medical Advertising News, May 2008). Astonishingly, nearly 25% of children taking antipsychotic medications were under 9 years of age in a 1-year study looking at prevalence of psychiatric drug use in an outpatient prescription claims database of a large pharmaceutical benefit manager.

The Pathologizing of Childhood Misbehavior
Fueled by an unholy alliance of the pharmaceutical industry and third-party advocacy groups like National Alliance for the Mentally Ill (NAMI), our culture has come to see emotional and behavioral problems in children as pathological processes caused by neurobiological defects.
Now, the launch of Intuniv gives parents and physicians license to treat defiance, temper tantrums and misbehavior with psychiatric medications that work in the pre-frontal cortex.

Yet, how sure are we that there are no long-term consequences of medicating children while their synaptic pathways are still developing and forming neuronal connections? Is it possible that administration of these potent medications could interfere with the normal maturing process? In fact, could our preoccupation with biologically-based behavior management lead to irreversible changes in the neurobiological processes that underlie normal development in children?

Stimulating The Pre-Frontal Cortex
Is drugging childrens' cortical areas playing with fire?

Our pre-frontal cortex brain carries out important executive functions that we associate with maturity, like thinking through consequences and exerting control over impulses. In adults, the pre-frontal cortex inhibits aggression and modulates social judgment. Lesions of this area may result in antisocial and aggressive behavior and exaggerate responsiveness in excitatory circuits.

Children with ADHD have deficits in executive function and so find it difficult to regulate emotions and control their impulses. A functional neuroimaging study published by Crow and Blair in 2008 shows a decreased responsiveness in regions of the frontal cortex in children with mood and anxiety conditions such as bipolar disorder and PTSD.

There is no doubt that this area of the brain is influential in determining how we think, act and behave. The issue is whether children and teenagers challenges with frustration, irritability and impulsivity is a psychiatric illness or the immaturity of youth.

Children in Crisis - A Public Health Perspective
Our society chooses to see bad behavior in kids as emotional disturbances due to abnormalities in dopamine and serotonin pathways and physiologic brain functions. Even if children with bipolar disorder or ADHD display abnormal functioning of prefrontal cortical and striatal circuits, we ought not assume that ADHD is biological/genetic at its core. In fact, a large body of scientific research provides convincing evidence that familial, psychosocial and environmental factors play a significant role in pediatric disorders like ADHD. Unfortunately, such research receives short thrift in American culture where our "blame the brain" mentality has transformed our views on childhood mental health.

If the medical and consumer media disseminated more scientific research showing that nurture, not nature, contributes to psychiatric illnesses in kids, society might change its responses to the alarming rates of children with emotional disturbances and the high rate of psychotropic drug use in kids. Perhaps, we might transition from a biomedical model where we "blame the brain" to a public health perspective where we "blame ourselves."If this occurred, we would place greater emphasis on prevention. Instead we worship at the altar of psychopharmacology, pathologizing misbehavior and drugging kids to get them to act more maturely.

While many factors contribute to the development of ADHD , several are substantiated in the medical literature.

Television Watching
Children spend an average of 3 to 4 hours per day watching TV. Several researchers, including Chrisakis, Miller & Marks and Hamer, have shown that early exposure to violent or non-violent entertainment television (more than 2.7 hours per day according to one author) leads to attentional and behavioral problems, as well as higher levels of psychological stress, in children. A study conducted by Johnson in adolescents reveals similar findings, with frequent television viewing during adolescence (more than one hour daily) associated with elevated risk for subsequent attention and learning difficulties, even after family characteristics and prior cognitive difficulties were controlled.

Also fascinating are the findings from this study, which followed a sample of boys and girls 6 to 10 years of age growing up in the 1970s and 1980s to determine whether watching television violence as a child would be associated with later adult aggression. Follow up data revealed that childhood exposure to media violence predicts future aggressive behavior for both males and females. The relationship between exposure to violence on television and aggression was observed even when socioeconomic status, intellectual ability, and a variety of parenting factors were controlled.

These associations are concerning, especially when one considers how television has intruded into the life of children in the past sixty years. In 1946, only 0.5% of U.S. households had a television in 1946. By 1962, that number was 90%.

Tobacco Smoking
Prenatal cigarette smoke exposure (PCSE) is associated with ADHD, aggression and conduct disorders in children. In the past this association was ascribed to the effects of nicotine on the developing fetal brain. A 2008 article published in Journal of Psychiatry and Neuroscience hypothesizes that maternal cigarette smoking inhibits brain monoamine oxidase (MAO) during fetal brain development. Inhibition of MAOs is known to result in an aggressive phenotype in laboratory animals. According to Baler et al, cigarette smoke-induced inhibition of MAO in the fetal brain, may result in morphologic and functional changes that enhance the risk of irritability, poor self-control and aggression in the offspring.

Don't expect to see health care policy that restricts TV watching in young children. Or laws that make it a misdemeanor to smoke while you're pregnant. It seems that we would rather feed our children a steady diet of prescription drugs than take a hard look at how our culture and lifestyle contributes to the alarming number of children with mental health issues. While writers like Edward Shorter (A History of Psychiatry) consider the biological approach to mental illness a "smashing sucess", future generations of children may feel otherwise. Although the biomedical paradigm of childhood mental illness is widely accepted today, someday we may consider it a failed experiment.

Sunday, October 25, 2009

Risky Business – How Buying a Ford Explorer is Like Taking Zometa

Last week, Peggy Stevens, a woman in Missoula, Montana who developed osteonecrosis of the jaw (ONJ) while being treated for lymphoma, was awarded $3.2 million. The settlement was based on Ms. Stevens'claim that Novartis did not disclose risks associated with the bisphosphonate, Zometa (zoledronic acid).

Imagine this scenario.

You walk into your local Ford dealership intending to buy a Ford Explorer for your daughter’s 17th birthday. The salesman says he’s happy to help. With this scenario in mind, which of the following questions do you think the salesman is least likely to ask?

a. How much do you want to spend?

b. What options are you looking for?

c. Did you know that Ford Explorers are notorious for overturning at low speeds, that SUV rollovers account for 33% of passenger vehicle fatalities and that close to 10,000 people died in SUV rollover crashes in 2002 alone?

Dollars to doughnuts, you answered C. How do I know that? Because it is obvious that a Ford Explorer car salesman is not going to bring up the subject of rollover fatalities with someone about to buy an SUV for their teenage daughter.

Unlike car salesman, however, drug companies are FDA mandated to communicate safety risk information regarding the drugs they market. Unfortunately, like the car salesman, the drug company has a financial stake in framing information about their products in the most appealing way possible. And in a profit-driven health care industry, who can blame them?

This tendency to present safety risk information in a favorable light, however, does come with a price tag. It means that companies downplay the risks of the drugs that we take. This tendency to minimize concerns about drug safety is typical of pharmaceutical advertising and promotion, as well as industry-supported CME (continuing medical education). Medical communication firms and ad agencies do not go out of their way to bite the hand that feeds them, so pharmaceutical copywriters and medical writers are well versed at presenting efficacy and safety information about prescription drugs in ways that minimize the negative and accentuate the positive.

An industry-sponsored online CME program on bisphosphonates illustrates this point. Below is the introductory paragraph to a CME program "Advances in Treating Metastatic Bone Cancer" sponsored by InforMEDical Communications, Inc and funded by Novartis Pharmaceuticals, Amgen, Inc. and Merck & Co., Inc. The original version mentions ONJ in the middle of the introductory paragraph to the program. In my rewrite below, I present the same information. However, in my revision, I reorder and reframe statements, and also use formatting and subheads, to bring the physicians attention to ONJ, rather than burying it in the middle of the paragraph.

Bisphosphonate therapy, the current standard of care for metastatic bone cancer, has been shown to decrease SREs by up to 50% and also to slow the rate of development of SREs. While this therapeutic advance is significant, bisphosphonate therapy does not completely block the process of bone metastasis; despite treatment with bisphosphonates, approximately 20% of patients with bone metastasis still have elevated bone resorption markers.In addition, bisphosphonate therapy is associated with renal toxicity and the emerging problem of osteonecrosis of the jaw (ONJ), which is causing deep concern among patients and dental care professionals who fear development of ONJ following dental procedures or even basic dental cleaning. Addressing these issues and finding treatments that more effectively prevent and suppress the bone metastatic process are needed.

Risks of Bisphosphonates Administered to Patients With Metastatic Bone Cancer
  • There have been a number of published studies that highlight the incidence of osteonecrosis of the jaw (ONJ) in cancer patients receiving bisphosphonate therapy for metastatic bone cancer.
  • While bisphosphonates have been shown to decrease SREs by up to 50%, approximately 20% of patients still have elevated bone resorption markers.
  • Because of bisphosphonates association with ONJ, it is critical to consider this adverse event, and communicate the risk of ONJ to patients, before initiating therapy.

Whether you are Republican or Democrat, for single-payer health care or against it, support private health insurance options or prefer a government run system, it all comes down to this. In a market-drive health care system, drug companies make money by selling drugs and insurance companies make money by restricting care. Is that good? Is that bad? I am not always sure. I do know, however, it is an inescapable fact of life in the good ole USA.

Sunday, October 18, 2009

In Brain Chemistry We Trust - The Gospel According to Pharma

The rise of the biopsychiatric model of mental illness
If anyone has doubts about America’s faith in a Higher Power, all you need to do is to take a look at how we have come to worship the biomedical model of mental illness. This biomedical model is so entrenched in our culture that it has become gospel.

Drug companies have a vested interest in this biomedical model of mental illness, one that promotes a neurobiological basis to most emotional disorders. Since the 1980s, when the biomedical model became popular, drug companies have spent billions of dollars to educate us about our impaired brain chemistry and how it is the cause of our depression, our bipolar disorder and our ADHD. In 2008 alone, we paid back industry's efforts by ingesting $5 billion dollars worth of antidepressants and an additional $19 billion of antipsychotic medications such as Abilify, Risperdal and Zyprexa[Source: IMS National Sales Perspectives™]. In our culture, the dark side of the human psyche has become material, not so much for novelists, but for the machinations of the pharmaceutical industry.

Eli Lilly and the Growth of Serotonin Theory of Depression
Most Americans have a childlike faith in the serotonin theory of depression,a theory that states that depression is a biochemical imbalance in the brain. Antidepressants like Prozac, Paxil and Lexapro are a part of our national consciousness. If you look at how this serotonin theory of depression arose, you will find that it springs not from the labs of academic researchers, but from the labs of researchers working in the pharmaceutical industry.

As many of you know, drug companies fund most clinical trials, both in the United States and overseas. The clinical investigators who lead these trials, as well as the site monitors who track the study results, are often consultants to and/or employees of drug companies. Furthermore, the clinical data they generate is aggregated, analyzed, and prepared for publication by statisticians, medical writers and publication planners who are paid by drug companies. Today, these conflicts of interest are well known. However, when the biomedical model of mental illness first became popular, these conflicts were cloaked in secrecy.

Fluoxetine, which launched in the United States in 1988 under the brand name Prozac, was the first in a new class of antidepressants, selective serotonin reuptake inhibitors (SSRIs). Ray Fuller, a biochemist at Lilly who was co-discoverer of fluoxetine and Charles Beasley, a medical officer at Lily, authored many journal articles about the role of serotonin and selective serotonin reuptake (SSRIs) in the 1980s and early 1990s. One seminal article published by Dr. Fuller in 1991 in J Clin Psychiatry, which highlighted the role of SSRI’s in treating depression, can be read here. What is less well known is that this article was published in a journal supplement of J Clin Psychiatry, a supplement paid for by none other than Eli Lily. Furthermore, other articles about fluoxetine published at the time indicating that SSRIs offered a superior safety profile compared to tricyclic antidepressants, the gold standard before the advent of SSRIs, were also published by Lily researchers. Can we really rely on published literature written by drug company personnel? For example, Lily researchers knew in the early 1990s about the potential of fluoxetine to induce suicidality, however kept it under wraps, convincing the FDA first to ignore the data through promises of conducting additional studies and than reneging on that promise when the brouhaha died down [See Antidepressant-Induced Suicide and Tort Reform, Joseph Glenmullen, MD, Congressional Hearing, Energy and Commerce Committee, February 10, 2005.]

Most folks assume that health care treatment decisions are based on expert opinion (unbiased) and evidence-based information. Truth be told, this is far from what occurs. If you follow the money, you will find that many of our most powerful beliefs, like the serotonin theory of depression, have their roots in an unholy alliance between industry, scientific publishers and physician researchers.

Sunday, August 9, 2009

Cash For Tickers - What Would You Pay for Your Heart Attack Treatment?

When it comes to health care, most consumers worship the newer, the more technologically advanced, and the most expensive. If an X-ray is good, an MRI is better. If three Advil relieves your knee pain, arthroscopy may eliminate it completely. As long as someone else is paying, why restrict your choices? In other words, we don’t want rationing, we want everything fully loaded.

We are like folks set free at the auto mall with someone else’s credit card. We may be content with a Honda Civic, but wind up demanding the most expensive car on the lot because someone else is picking up the tab. No wonder we spend $2 trillion a year on healthcare.

If the average person is buying a new car, they research options, gather information from different sources, and comparison shop. With health care, consumers do not engage in the regular sort of cost-benefit analysis they use when shopping for a new automobile. Our health care system fails, in part, because it fails to engage the consumer in purchasing decisions. Instead, these decisions are left in the hands of doctors, hospitals, insurance companies, pharmaceutical companies and device manufacturers, all of whom have vested interests in treatment choices that are made.

Is it any wonder that managed care has stepped in to try to ration what we get?

Now let’s imagine that you are having symptoms of a heart attack and are taken to the ER. The ER doctor diagnoses you with a STEMI (a ST-segment elevation myocardial infarction). For a STEMI, there are two basic treatment options - either a combination of fibrinolytic and antiplatelet agents administered at the ER or rapid transfer to a facility, at the hospital or off-site, where a specialist will open the blocked coronary artery by performing a procedure called primary percutaneous coronary intervention (PCI), which costs around $25,000 a pop give or take. Furthermore, whether in the ER or at the PCI, you may receive additional costly biotechnology drugs, like abciximab (ReoPro®),eptifibatide (Integrilin®) or tirofiban (Aggrastat®). These drugs cost up to $500.00 per vial, with drug selection based on clinicians' preference and each patient getting multiple vials. Finally, let's imagine that you had to decide there and then, which procedure you want.

If you personally had to pay an extra $25,000 for PCI, wouldn't you want to know for sure that it was better?

More than 800,000 PCI procedures are performed each year, which adds up to quite a tab for insurers, whether private or public. And while PCI can be life-saving, it also can lead to serious complications. Still, the bottomline remains cost – it is more expensive to get a PCI than medical treatment.

How does the effectiveness of PCI vs medical therapy, compare in demonstrating short and long term outcomes? Most studies indicate that PCI is more effective than medical treatment. However, those benefits (e.g. reductions in 30-day mortality, likelihood of experiencing a recurrent heart attack) are very dependent on a complex set of factors, such as how soon after your symptoms started you reached the ER, your age and gender and the time delay in getting you to a PCI facility. Whether you choose to focus on the benefit of PCI, or the risks, depends to a large extent on who is in the driver seat. If you are an interventional cardiologist making $500,000 a year doing PCI, you are going to favor PCI. If you are a hospital administrator who spent millions building a state- of -the art cath lab, you are going to want as many patients as possible to use the facility. On the other hand, if you are an ER director of a hospital, your point of view may be a bit different.

Like many things in medicine, the devil is in the details. For example, while PCI may be better for most patients, there are many patients who don’t need it or in whom the risks outweigh the benefits. Ironically, one of the cheapest life-saving interventions, taking an aspirin the moment you experience initial cardiac symptoms and before you arrive at the hospital, is frequently overlooked.



Every health care treatment decision is a form of rationing. The ER doctor “rations” out STEMI treatment based on a wide array of variables, including his/her clinical judgment, the hospital guidelines, your age and health risk factors, laboratory results, geographic location, and many individual thoughts and attitudes, and institutional norms, that color the clinical decision making process. So, here begins the first part of the conundrum. Medical decisions are based on hospital protocols, in this case guided by recommendations from the American College of Cardiology and American Heart Association. However, as discussed elsewhere in these blog posts, guideline committees are frequently funded by device and drug manufacturers and made up of physicians with financial ties to industry and/or personal biases based on their medical specialty. As a result, there are likely to be more positive articles published about PCI than negative articles that highlight the dangers or the costs associated with overutilization.

Some studies address the fact that the popularity of PCI has caused a high degree of “false positives”, meaning that ER doctors send patients to the cath lab who don’t really need it. For example in this study published in JAMA, 14% of of 1,335 patients with suspected STEMI who underwent angiography had no culprit coronary artery and 9.5% did not have significant coronary artery disease. These false positives result in insurers paying for risk-prone interventions where there is no benefit to the patient (for example, patients with stable coronary artery disease). In medicine, appropriate patient selection is critical to contain costs.


Patients who undergo primary PCI are at high risk for a complication called contrast-induced nephropathy (CIN), a disorder that develops as a result of exposure to contrast agents, which are used during PCI. CIN, which has a reported incidence rate of 5% to 50%, can increase mortality up to 30% following angiographic procedures. In a small percent of cases, CIN will result in dialysis. Unfortunately, the risk of CIN in patients with renal dysfunction has remained unchanged despite advances in catheter-based technology and adjunctive antithrombotic therapy. Furthermore, while the antiplatelet drugs used in conjunction with PCI to treat STEMI may lower the incidence of cardiac mortality, these improved outcomes come at a cost. Many articles highlight the fact that these powerful drugs cause increased bleeding complications, including higher rates of intercranial hemorrhage in patients over the age of 75.

Physicians, like everybody, have differing points of view. And like all of us, their personal biases affect their attitudes, perceptions and behaviors.

Such bias is evidenced in reading comments about a June 2009 article published in Circulation. This meta-analysis, which included both randomized clinical trials (RCTs) and observational studies, compared mortality rates of PCI vs medical treatment. The authors concluded that primary PCI is associated with long-term reductions in mortality and reinfarction in RCTs, but that there is no conclusive evidence for a long-term benefit in mortality and reinfarction in observational studies. Physician raters participating in the McMaster Online Rating of Evidence (MORE) system commented about the article online.

Reading the raters interpretation of this article is a powerful example of how point of view affects perception. For example, a cardiovascular surgeon commenting on the Circulation article concludes that the analysis confirms the superiority of PCI over fibrinolysis for STEMI.

“This is a very nice collation of RCTs and observational studies showing practitioners that even in their practices, the benefits of acute intervention far exceed use of fibrinolytics for STEMI patients. This is a more expensive approach, but the data certainly supports transfer to a PCI center whenever possible and should be information about which all practitioners are aware.”

In contrast, an internist commenting on the same article online finds the analysis less convincing.

"...shows a clear early mortality benefit of primary angioplasty over fibrinolysis in STEMI. However, less convincing evidence exists that primary angioplasty in the real world is associated with a better long-term outcome."

To view McMaster comments, click here. Registration may be required.