Sunday, July 31, 2011

When Drug Companies Commit Crimes, Should CEOs be Held Accountable?

A recent Businessweek article reminds us of the illegal activities that have become common among drug companies, and the issues associated with holding them accountable for their crimes. The article by Dune Lawrence provides us with this list of recent settlements with the Department of Justice, mostly involving marketing drugs for unapproved uses.

2007: Bristol-Myers Squibb: Abilify: $515 million
2008: Cephalon: Gabitril, Actiq, Provigil: $425 million
2009: Pfizer: Bextra, Geodon, Zyvox, Lyrica: $2.3 billion
2009: Eli Lilly: Zyprexa: $1.4 billion
2010: Allergan: Botox: $600 million
2010: Astra-Zeneca: Seroquel: $520 million
2010: Novartis: Trileptal, Diovan, Sandostatin, Zelnorm, Exforge, Tekturna: $422.5 million
2010: Forest: Celexa, Lexapro, Levothroid: $313 million

Drug companies are forbidden from directly marketing their products for applications for which they do not have FDA approval. Unfortunately, there is no restriction on what doctors can do. They are allowed to prescribe any drug for any application. Drug manufacturers try to skirt the legal restrictions by paying doctors to do their marketing for them.

The seemingly heavy fines that have been levied are really quite small in terms of the cash flow that companies derive from unapproved usage. Of what value is a fine if it does not affect the practice it is trying to punish? The Office of Inspector General (OIG) handles waste and fraud cases for the Department of Health and Human Services. It fears that drug companies see these fines as just another cost of business that can be passed on to the consumer. OIG is contemplating inserting a small level of accountability by letting it be known that they are considering holding executives of the offending companies responsible for the illegal behavior. It is thought that Howard Solomon, CEO of Forest Laboratories, will be the first target, with OIG “excluding” Solomon from participating in government programs. This means that Forest Laboratories would be excluded unless Solomon is fired.

“Exclusion is common enough; the Health and Human Services Dept. punishes about 3,000 people a year this way, often because of criminal convictions. Solomon stands out because the Justice Dept. has never charged him with wrongdoing, nor has he ever admitted to wrongdoing, not even in Forest’s $313 million settlement last year on charges related to the marketing of antidepressants and the distribution of an unapproved drug, the thyroid medication Levothroid.”

Some are aghast that the leader of a large business should be held responsible if he was not personally guilty of direct criminal behavior. Before we weigh in on this issue, let’s see exactly what Forest has admitted to, and learn more about the nature of their actions and the consequences of their illegal activities.

“....Forest Pharmaceuticals pleaded guilty to three criminal charges and settled civil claims filed by the Justice Dept. Forest admitted it obstructed the FDA by concealing information, distributed an unapproved thyroid drug, and illegally promoted Celexa for use by children and adolescents. While Forest applied to the FDA for pediatric use of Celexa and was eventually denied, the company admitted it had marketed the drug to doctors by hiring speakers to tout its benefits for young patients. Forest also admitted it had suppressed the negative results of research in Europe that found Celexa was no more effective in treating depressed children and adolescents than a sugar pill. Fourteen young patients in that study attempted suicide or contemplated suicide, compared with five in the placebo group, court records show.”

To find out more about Celexa we will turn to Marcia Angell’s New York Review of Books article: The Epidemic of Mental Illness: Why? Angell refers to three recent books on the subject of psychoactive drugs:

The Emperor’s New Drugs: Exploding the Antidepressant Myth by Irving Kirsch Anatomy of an Epidemic: Magic Bullets, Psychiatric Drugs, and the Astonishing Rise of Mental Illness in America by Robert Whitaker Unhinged: The Trouble With Psychiatry—A Doctor’s Revelations About a Profession in Crisis by Daniel Carlat.
I have read the latter two books and highly recommend them.

First let us listen to what Carlat, a psychiatrist, has to say about drug companies and their marketing practices. He points out that while companies often claim that their large R&D costs justify the prices they charge for their product, they actually spend twice as much on marketing (in 2007 alone: R&D: $30 billion, marketing: close to $60 billion). It is incredible to assume that a CEO of a drug company would not have any personal responsibility for an activity twice as large as its R&D effort.

Carlat further adds that some 90% of these marketing costs are directed at convincing or bribing doctors to use their products. As a psychiatrist, Carlat is well aware of how this activity affects his profession. Celexa is an antidepressant. There is no scientific justification for its use as an antidepressant, and as we shall see, there is no evidence that it acts in any beneficial manner other than as a placebo. Yet there is a lot of money to be made by confusing both the public and medical professionals. That is the function of marketing. Again, from Carlat:

“Since all the drugs within a therapeutic class seem equivalent, there is little scientific reason to choose one over another. And where there is a scientific vacuum, drug companies are happy to insert a marketing message and call it science. As a result, psychiatry has become a proving ground for outrageous manipulations of science in the service of profit. Many of the leaders of our field have allowed themselves to become paid puppets of the pharmaceutical industry....psychiatry is in the midst of a crisis in ethics, and it is not clear if the profession will survive this crisis intact.”

One might conclude that some over exuberance in marketing is allowed if the drug provides some benefit. But doe a drug like Celexa provide a benefit? Angell turns to Irving Kirsch’s book for an answer.

To get a drug approved by the FDA, one needs two clinical trials showing a benefit. However, companies are allowed to have as many tries as necessary to get those two positive results. Tests with negative results are considered proprietary information and are not available to the public. They can be buried, while the drug companies go on to write numerous articles about only the positive results.

Kirsch was troubled by two findings from the available data. The first indicated that placebos (sugar pills) were 75% as effective as the antidepressant drug in treating the depressed subjects. Kirsch obtained all the data drug companies had submitted to the FDA through the Freedom of Information act. There were 42 studies for the six most widely used antidepressants: Prozac, Paxil, Zoloft, Celexa, Serzone, and Effexor. Most of the studies yielded negative results. Kirsch determined that the placebo was 82% as effective as the antidepressant based on this data set.

The second finding that puzzled Kirsch was that in treating depressed subjects, any medications

“such as synthetic thyroid hormone, opiates, sedatives, stimulants, and some herbal remedies —were as effective as antidepressants in alleviating the symptoms of depression.”

These tests are performed in a double blind mode. Subjects are told that they may receive a placebo rather than a drug, but neither the participants nor the tester know who receives which. Kirsch hypothesized that these seemingly irrelevant drugs were working because they produced a side effect. If a subject took a pill and observed a side effect they could reasonably conclude that they had received the drug rather than the placebo. The net result is that a placebo with a side effect is a “super placebo.” Kirsch demonstrated this effect by doing a study where the placebo was laced with something that would provide a dry-mouth sensation. This placebo worked just as well as the drug.

Others have performed similar studies and reached the same conclusion: if you tell a person with a mental problem that you are giving them a pill that should make them feel better, they will tend to feel better even if there is no real medication present.

These types of studies form the basis for the statement above that claimed that antidepressants like Celexa were no better than a placebo. But a placebo is harmless, antidepressants are not.

Let us now turn to Whitaker’s book.

Drugs like Celexa are referred to as SSRIs: selective serotonin reuptake inhibitors. Serotonin is a neurotransmitting chemical used to transmit signals from one neuron to another across the synapse separating them. Serotonin is the chemical chosen by evolution in several regions of the brain. It is produced when needed and either reabsorbed for reuse or discarded. Celexa will alter the level from a normal level to an abnormal level; it does not correct for an abnormality as generally believed. It is not surprising that a drug like Celexa will cause a new set of symptoms to appear which can in some cases appear to be beneficial. However, the brain tries to respond to these enforced new serotonin levels by modifying its own serotonin management system. The longer these modifications are in place the less likely they are to be reversible. In other words, long-term usage can lead to addiction and increasingly adverse outcomes including cognitive impairment.

Whitaker’s thesis is that the drugs prescribed for mental illness are actually causing more harm than good and contributing to outcomes requiring a lifetime of drug dependence and functional disability. He points out that conditions such as depression were once rare, episodic, and usually self-limiting before the introduction of drugs. Depression is now common (depressingly so), it tends to be chronic, and the outcome is often partial or total disability.

Consider this study by the National Institute of Mental health (MIMH).

From Whitaker:

“In 1955, there were 38,200 people in the nation’s mental hospitals due to depression....Today, major depressive disorder is the leading cause of disability in the United States for people ages fifteen to affects 15 million American adults....58 percent of this group is “severely impaired.” This means nearly nine million adults are now disabled, to some extent, by this condition.”

Not everyone who is now disabled is so because of the recurring bouts of depression. Long-term effects of the SSRI medications like Celexa also play a role.

“SSRIs cause a multitude of troubling side effects. These include sexual dysfunction, suppression of REM sleep, muscle tics, fatigue, emotional blunting, and apathy. In addition, investigators have reported that long-term use is associated with memory impairment, problem-solving difficulties, loss of creativity, and learning deficiencies.”

Forest and its executives, researchers and marketers cannot be unaware of these results. Also recall that the crime Forest admitted to was the illegal marketing of Celexa to children and adolescents. How would you feel if someone tried to give your child a pill that produced the long-term effects listed above?

Businessweek presents a rather balanced article on Howard Solomon and Forest Laboratories, but it is still sympathetic to Solomon’s plight (he is eighty-three years old and may be forced to retire). I am not. The behavior of the drug companies is so reprehensible and harmful that a much more extreme measure is appropriate. Solomon is responsible for criminal behavior and for the irreparable harm caused by his company’s activities. Criminals should be treated as criminals—even eighty-three year old criminals. Until drug company executives begin spending some time in prison, there will not be sufficient motivation for them to change their business practices.

Psychoactive drugs can alter the behavior of a patient, but they cannot cure the patient. There are ill people who are so out of control that they are a danger to themselves or others. It is an appropriate short-term solution to render such people harmless and controllable with medication. Prescribing drugs to less severely symptomatic patients, while convenient and profitable, is a dangerous practice. As Carlat pointed out, there are serious ethical issues associated with the alliance between the profession of psychiatry and the drug companies.

I was surprised to learn that this is the eleventh article I have written related to drugs and mental illness. I am sorry if some find this subject less compelling than I, but my sense of outrage is undiminished. I believe I have one more article left in me—at least. Please bear with me—and share the outrage if you feel it.

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