Health Care in America - The Sword of Damocles - Antibiotics

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The Broken American Health Care System

Classics scholar Daniel Mendelson on the metaphor of the Sword of Damocles from the ancient Greek parable by Cicero:

"The real point of the story is very clearly a moral parable. It's not just, oh, something terrible is going to happen, but it's about realizing that what looks like an enviable life, a life of wealth, a life of power, a life of luxury is, in fact, fraught with anxiety, terror and possibly death."

What are Antibiotics?

Bacteria are everywhere, including on the skin and in the digestive system of humans. While bacteria are critical to normal bodily functions, some types can cause illness. In humans, antibiotics are used to treat health conditions caused by bacteria, including ear and skin infections, food poisoning, pneumonia, meningitis and other serious illnesses. Antibiotics are also used to treat or prevent infections that can complicate critical medical procedures including surgery, cancer therapy, and transplants.

Antibiotics belong to a category of drugs called "antimicrobials," and include penicillin, tetracycline, amoxicillin and many other formulations that can kill or inhibit the growth of bacteria without causing significant harm to the patient. Antibiotics were initially derived from natural compounds. Many organisms, including various types of fungi, produce substances that destroy bacteria and prevent infection.

Penicillin, perhaps the most famous of all antibiotic drugs, is derived from a common fungus called Penicillium. Many other fungi also produce antibiotic substances, which are now widely used to control diseases in human and animal populations. The discovery of antibiotics revolutionized health care worldwide.

Today, there are hundreds of antibiotics in use, most of which are synthetically produced.

What are Antibiotic-Resistant Bacteria?

Just as immunization helps the human body fight disease by exposing the body to small amounts of a virus or bacteria, when bacteria are continually exposed to small amounts of antibiotics they can develop immunity to them. Over time this leads to the development of new, stronger strains of bacteria, with the antibiotic immunity passed on to subsequent generations.

It's a case of "survival of the fittest," with the strongest bacteria, that are least susceptible to a specific antibiotic, living on, adapting and multiplying. These are called "resistant bacteria" because they have adapted to the point where antibiotics can no longer kill them. As a result, some antibiotics have lost their effectiveness against specific infectious diseases. For example, certain strains of tuberculosis are now resistant to antibiotics that were previously effective in fighting them.

Another example is staphylococcus aureus, a bacteria that is the most common cause of staph infections, and that can cause pneumonia, meningitis, toxic shock, skin abscesses, heart valve infections and other serious and deadly medical conditions. In the United States, almost every strain of s. aureus is now resistant to the antibiotics oxacillin, penicillin and amoxicillin, and strains of the disease have begun developing resistance to newer drugs like methicillin and vancomycin. The threat of prolonged illness or death from an s. aureus infection has increased as it has become more resistant and fewer drugs are able to effectively control or eliminate it.

Antibiotic resistance has been accelerated by extreme overuse of antibiotics in humans and animals. Over-prescribing antibiotics for viral-caused conditions like the flu or common cold, against which antibiotics are useless, contributes to antibiotic resistance. As the American Academy of Pediatrics notes, "When antibiotics aren't used the right way, they can do more harm than good."

For example, children who are given antibiotics for ear infections are more likely to get another ear infection, sooner, than those who are not prescribed these drugs. In recent years the academy has urged its members to drastically reduce the antibiotic prescriptions they write.

Penicillin: the first miracle drug

Many of you are here only because penicillin saved your life, or the life of one of your parents or grandparents. Penicillin's ability to cure people of many once-fatal bacterial infections has saved so many lives that it is easy to understand why it was once called a "miracle drug".

Antibiotics are chemicals, effective at very low concentrations, created as part of the life process of one organism, which can kill or stop the growth of a disease-causing microbe--a germ.

In 1929, Alexander Fleming, a doctor and researcher at St. Mary's Hospital in London, England, published a paper on a chemical he called "penicillin", which he had isolated from from a mold, Penicillium notatum. Penicillin, Fleming wrote, had prevented the growth of a neighboring colony of germs in the same petri dish.

Dr. Fleming was never able to purify his samples of penicillin, but he became the first person to publish the news of its germ-killing power. Howard Florey, Ernst Chain and Norman Heatley expanded on Fleming's work in 1938, at Oxford University. They and their staff developed methods for growing, extracting and purifying enough penicillin to prove its value as a drug.

World War II (1939-1945) had begun by the time their research was showing results. The main research and production was moved to the United States in 1941, to protect it from the bombs pounding England. Work began on how to grow the mold efficiently to make penicillin in the large quantities that would be needed for thousands of soldiers.

As the destruction of the war grew, so did interest in penicillin in laboratories, universities and drug companies on both sides of the Atlantic. The scientists knew they were in a race against death, because an infection was as likely to kill a wounded soldier as his wound.

Creating the right environment for growth was the first step in producing enough penicillin to be used as a drug. In Oxford, experiments showed that Penicillium notatum grew best in small shallow containers on a broth of nutrients. Penicillium need lots of air. In the United States, it was discovered that huge "deep fermentation" tanks could be used if sterilized air was pumped continually through the tanks.

Production increased even more when corn steep liquor, a thick, sticky by-product of corn processing, was added to the tanks. Corn steep liquor contained concentrated nutrients that increased the yield 12-20 times. Formerly considered a waste material, corn steep liquor became a crucial ingredient in the large-scale production of penicillin.

Scientists were also determined to find another strain of Penicillium that might grow better in the huge deep fermentation tanks. Army pilots sent back soil samples from all over the world to be tested for molds. Residents of Peoria, Illinois, were encouraged to bring moldy household objects to the local U.S. Department of Agriculture laboratory, where penicillin research was being conducted. Laboratory staff members also kept an eye out for promising molds while grocery shopping or cleaning out their refrigerators.

In 1943, laboratory worker Mary Hunt brought in an ordinary supermarket cantaloupe infected with a mold that had "a pretty, golden look." This Penicillium species, Penicillium chrysogenum grew so well in a tank that it more than doubled the amount of penicillin produced.

The deep fermentation method, the use of corn steep liquor and the discovery of P. chrysogenum by Mary Hunt made the commercial production of penicillin possible. Researchers continued to find higher-yielding Penicillium molds, and also produced higher yielding strains by exposing molds to x-rays or ultraviolet light.

Penicillin kills by preventing some bacteria from forming new cell walls. One by one, the bacteria die because they cannot complete the process of division that produces two new "daughter" bacteria from a single "parent" bacterium. The new cell wall that needs to be made to separate the "daughters" is never formed.

Some bacteria are able to resist the action of antibiotic drugs, including penicillin. Antibiotic resistance occurs because not all bacteria of the same species are alike, just as people in your own family are not exactly alike. Eventually, the small differences among the bacteria often mean that some will be able to resist the attack of an antibiotic. If the sick person's own defenses can not kill off these resistant bacteria, they will multiply. This antibiotic-resistant form of a disease can re-infect the patient, or be passed on to another person.

Taking antibiotics for viral illnesses like colds can also cause antibiotic resistant bacteria to develop. Antibiotics have no effect on viruses, but it will kill off harmless and even the beneficial bacteria living in the patient's body. The surviving resistant bacteria, free from competition, will live and multiply and may eventually cause disease.

Patients with bacterial infections, who don't finish their antibiotic prescriptions completely, also allow resistant bacteria to develop. This happens because a small number of semi-resistant bacteria, which needed the full course of antibiotics to kill them, survive. Instead of being a small part of the bacteria causing an infection, the more resistant bacteria take over when sensitive bacteria are killed by the antibiotic.

Today, in the United States, deaths by infectious bacterial diseases are only one-twentieth of what they were in 1900, before any antibiotic chemicals had been discovered. The main causes of death today are what are referred to as "the diseases of old age": heart disease, kidney disease and cancer. We would be shocked to hear of someone dying from an infection that started in a scratch, but, before antibiotics like penicillin, it was common for people to die from such infections.

Humans can slow the creation of antibiotic resistant diseases by understanding the uses and limits of antibiotics. Take all of an antibiotic, and only take them when prescribed by a doctor. Research to develop new antibiotics to treat resistant bacteria continues, but research takes time. Time is running out because the world's biodiversity is decreasing--the source of half of our disease-fighting chemicals.

How antibiotics are used and abused

Perhaps you are wondering about the use -- and abuse -- of antibiotics in general. Let me give you an example. One of the most common diagnoses given at a doctor’s office is the upper respiratory infection (URI). It accounts for up to 70 percent of all antibiotics dispensed (Annals of Internal Medicine. American College of Physicians. American Society of Internal Medicine. March 20, 2001).

However, according to Dr. Carol Kauffman, most URIs are not caused by the bacteria that antibiotics are designed to fight. Rather, Kauffman says, they are caused by fungi. So, unless a secondary, bacterial infection presents itself -- and even then, the rules change -- most URIs do not require the use of antibiotics.

Regarding ear infections, in one study, children administered antibiotics for acute otitis media suffered double the rate of adverse effects compared to children in the study who took placebos (Clinical Evidence. 2000). The difference in outcome for those children in the study who took antibiotics compared to those who do not was almost negligible. Some scientists counter that children who take antibiotics run lower risks of secondary ear infections such as meningitis or mastoiditis (infection of the angular bone located behind your ear).

Of course, the landscape is complicated by noncompliance. The portion of people who take their antibiotics as prescribed has been estimated at anywhere between 8 to 68 percent. So it’s difficult to say just how effective antibiotics actually are.

Antibiotics in use today

Alexander Fleming, by the grace of God, brought us a mixed blessing in 1928 with his accidental discovery of penicillin produced by, of all things, a fungus. Medicine’s interest treating people for exposure to fungi dropped dramatically in succeeding years, until the microbes were only thought important insofar as their ability to produce increasingly diverse varieties of antibiotics.

Antibiotics and the Animal Industry

Industrial farms have been mixing antibiotics into livestock feed since 1946, when studies showed that the drugs cause animals to grow faster and put on weight more efficiently, increasing meat producers' profits. Today antibiotics are routinely fed to livestock, poultry, and fish on industrial farms to promote faster growth and to compensate for the unsanitary conditions in which they are raised.

Modern industrial farms are ideal breeding grounds for germs and disease. Animals live in close confinement, often standing or laying in their own filth, and under constant stress that inhibits their immune systems and makes them more prone to infection. According to the Union of Concerned Scientists, as much as 70 percent of all antibiotics used in the United States is fed to healthy farm animals.

When drug-resistant bacteria develop at industrial livestock facilities, they can reach the human population through food, the environment (i.e., water, soil, and air), or by direct contact with animals (i.e., farmers and farm workers).

Industrial livestock operations produce an enormous amount of concentrated animal waste, over one billion tons annually—that is often laden with antibiotics, as well as antibiotic-resistant bacteria from the animals' intestines. It is estimated that as much as 80 to 90 percent of all antibiotics given to animals are not fully digested and eventually pass through the body and enter the environment, where they can encounter new bacteria and create additional resistant strains.

With huge quantities of manure routinely sprayed onto fields surrounding CAFOs, antibiotic resistant bacteria can leech into surface and ground water, contaminating drinking wells and endangering the health of people living close to large livestock facilities.

Antibiotic Resistance, Public Health and Public Policy

Antibiotic-resistant bacteria is a growing public health crisis because infections from resistant bacteria are increasingly difficult and expensive to treat. As of this writing, the U.S. Congress was considering legislation, staunchly opposed by industrial farm lobbyists, which would ban seven classes of antibiotics from use on factory farms and would restrict the use of other antibiotics. This is a response to the fact that modern industrial livestock operations threaten to increase the prevalence of antibiotic-resistant bacteria.

Thousands of Americans die every year from drug-resistant infections. In addition, the National Academy of Sciences calculates that increased health care costs associated with antibiotic-resistant bacteria exceed $4 billion each year in the United States alone—a figure that reflects the price of pharmaceuticals and longer hospital stays, but does not account for lost workdays, lost productivity or human suffering.

Although everyone is at risk when antibiotics stop working, the threat is greatest for young children, the elderly, and people with weakened immune systems, including cancer patients undergoing chemotherapy, organ transplant patients and, in general, people whose health is compromised in some way.

The following excerpt is from an article by Carol R. Goforth.

The headlines are sensational enough that it wouldn’t be surprising to see them in the most notorious supermarket tabloids. The stories behind the headlines are scary enough that they might be the plot of a horror movie. Unfortunately, it is often the scientific press that is reporting on the spread of antibiotic-resistant bacteria, and the threat to human health and life is very real and growing.

The increase in public awareness about the spread of antibiotic-resistant bacteria has been occasioned by a significant increase in the number of reported cases of human illness associated with antibiotic resistance. Studies show that infectious disease mortality rates have risen nearly 60%, with the Centers for Disease Control (CDC) estimating that more than half of the infection-related deaths involve resistant bacteria.

Dubbed “super-bugs” in the popular press, multi-drug resistant bacteria are becoming more and more common. Newspapers and magazines carry stories of bacterial infections that do not respond to the antibiotics typically prescribed to control them. As one legal commentator observed, “many of the killer diseases of the past such as tuberculosis, typhoid fever, diphtheria, and pneumonia have returned to wreak havoc as bacteria are increasingly resistant to antibiotics.” While antibiotics were once regarded as an unending miracle of modern medicine, we are fast approaching a time when the miracle may come to an end.

While there are doubtless many factors contributing to the spread of multi-resistant bacteria, one factor appears to be the widespread addition of antibiotics to livestock feed. A wide range of antibiotics are currently added, in subtherapeutic amounts, to animal feeds. A growing volume of research suggests that this practice is having devastating and potentially irreversible effects on the viability of antibiotics as agents to effectively treat diseases in human beings, but the legal community appears to be lagging far behind scientific experts in calling for an end to this practice in the United States.

At the current time, there are three primary uses of antibiotics in animal agriculture: therapeutic, prophylactic (to prevent potential infection), and growth promotion (with both of the latter two categories being at subtherapeutic concentrations).

The use of antibiotics to ward off infections and to promote growth in livestock is not new. For more than 40 years many farmers have fed their animals a diet laced with small, subtherapeutic doses of antibiotics.

The discovery that antibiotics could be used for prevention of infection and growth promotion was serendipitous. Veterinarians began administering antibiotics to sick animals in an effort to determine whether the “miracle drugs” that were saving human lives could also help livestock.

These experiments led to the discovery that feeding animals small doses of the drugs not only inhibited diseases but also enhanced growth. This discovery led in turn to an agricultural revolution, with farmers—especially those in very large operations relying increasingly on subtherapeutic doses of antibiotics to keep their livestock healthy and to promote animal growth.

In the past three decades, agricultural use of antibiotics has increased exponentially. One article has estimated that in the past thirty years, farmers have increased their use of penicillin-type antibiotics in farm animals by 600% and their use of tetracycline by 1500%. Recent statistical research continues to show an increasing reliance on the routine use of antibiotics for pigs and cattle. Larger operations also continue to be more likely to use antibiotics, and many rely on additives for periods of time in excess of ninety days.

Part of the increase in antibiotic use is attributable to the declining effectiveness of the drugs as growth promoters. Over time, the amount of antibiotics needed to promote growth in farm animals has increased significantly. Some sources have suggested that “roughly 10 to 20 times the amount used four decades ago were required to produce the same level of growth in the 1990s.”

Moreover, even at concentrations approaching therapeutic levels, “the benefits of growth promotion are less now than those reported several decades ago.”

Antibiotic use and abuse

There has been an astonishing increase in the use of antibiotics in spite of the dangers of abuse.  In 1954 2 million pounds of antibodies were produced inn America, while today estimates of production exceed 50 million pounds.

Approximately 16 million pounds are used on humans, the remaining 34 million pounds are used on livestock in our food supply, most used as a food supplement.

Included in the list of antibiotics used as food additives in American agriculture are a number of drugs that are either themselves used as drug therapies for human patients or are closely related to such drugs. Amoxicillin, ampicillin, erythromycin, neomycin, penicillin, and tetracycline are all used to treat human illness as well as being used in animal agriculture.

US General Accounting Office Report - GAO-11-406

July 1, 2011

Infections that were once treatable have become more difficult to treat because of antibiotic resistance. Resistance occurs naturally but is accelerated by inappropriate antibiotic use in people, among other things.

Questions have been raised about whether agencies such as the Department of Health and Human Services (HHS) have adequately assessed the effects of antibiotic use and disposal on resistance in humans.

GAO was asked to (1) describe federal efforts to quantify the amount of antibiotics produced, (2) evaluate HHS's monitoring of antibiotic use and efforts to promote appropriate use, (3) examine HHS's monitoring of antibiotic-resistant infections, and (4) describe federal efforts to monitor antibiotic disposal and antibiotics in the environment, and describe research on antibiotics in the development of resistance in the environment.

GAO reviewed documents and interviewed officials, conducted a literature review, and analyzed antibiotic sales data.

Federal agencies do not routinely quantify the amount of antibiotics that are produced in the United States for human use. However, sales data can be used as an estimate of production, and these show that over 7 million pounds of antibiotics were sold for human use in 2009.

Most of the antibiotics that were sold have common characteristics, such as belonging to the same five antibiotic classes. The class of penicillins was the largest group of antibiotics sold for human use in 2009, representing about 45 percent of antibiotics sold. HHS performs limited monitoring of antibiotic use in humans and has implemented efforts to promote their appropriate use, but gaps in data on use will remain despite efforts to improve monitoring.

GAO did not address the millions of pounds of use on livestock including beef, pigs, fish and chicken nor the implications of transferring drug resistant bacteria from animals to humans since 1946.  Nor did it address the huge discrepancies in the amount of antibiotics produced by pharmaceutical companies.

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Health Care in America - Big Pharma Fraud, Cover Ups & Corruption

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The Hals Report

 
Fraud, Cover-Ups, and Corruption: Welcome to the Drug Industry

Erik Hals,  January 6, 2011

The Broken American Health Care System

There are no short cuts to the truth, and especially when it comes to the cutthroat world of big pharma and big bucks.  In this article we take a story that appeared in The Hals Report by Erik Hals.  It is another example of the extent big pharma is willing to go to secure business in the ruthless legal drug addiction market in America.

 

The United States health care industry is one of the largest in the world, with over 300 billion dollars spent on prescription drugs per year. (1) For many, these drugs have brought undeniable benefits, but in recent months the health care industry has fallen upon scandal after scandal.

Recently, two of the worlds largest pharmaceutical companies were fined billions of dollars after investigations into their secret working practices brought several fraudulent activities to light. Now, new revelations have emerged including pervasive fraud, corruption and huge kickbacks which were paid to doctors.

So, what do doctors receive kickbacks for and how do they work? We will begin with a man named David. A decade ago David was prescribed Risperdal for a psychiatric illness, a drug made by Johnson and Johnson. U.S. authorities never approved Risperdal for treating his disorder but the doctor prescribed it to him anyway, it had devastating consequences. He is now in a wheelchair with diabetes and Parkinson’s. In a current lawsuit against Johnson and Johnson, he blames Risperdal. (2)

The pharmaceutical companies didn’t trick the government though. U.S. regulators ruled Johnson and Johnson misled doctors about potential fatal risks associated with the drug, including diabetes. (3) There are more than 2,000 people bringing legal actions against Johnson and Johnson. The company claims the actions are without merit. (of course they do!) The U.S. government and several states are also suing the company in related cases.

Surprisingly, most of the leading pharmaceutical companies in the United States have been fined for fraud in the past. One of the most common types of fraud in the pharmaceutical world is known as off-label marketing. Off-label marketing is a technique in which pharmaceutical companies advise doctors to prescribe drugs for unapproved uses. This is known as fraud against the government because medicare ends up paying the expense for the drugs if they do not work.

Sharon Ornsby, a member of the FBI financial crimes unit, in an interview on Al Jazeera television said, “pharmaceutical fraud is one of our top three threats.”

The U.S. government is slowly beginning to show a fighting facade, but is that all it really is, a facade? In the last 2 years alone the U.S. government has fined six of Americas top ten pharmaceutical companies for fraud. Ongoing investigations continue against three of the four remaining companies. During this specific period in time the industry has paid out over five billion dollars in fines.

In September of 2009 Pfizer settled civil and criminal charges in the amount of 2.3 billion dollars with the federal government for illegally marketing four types of drugs. (4) The Pfizer corporation made over 180 billion dollars selling twelve twelve kinds of drugs and only paid 2.3 billion dollars in fines, talk about a phenomenal business plan!

Details of Pfizer’s behavior came to light when several insiders decided to become whistleblowers. Glen Demott was a top Pfizer representative selling the drug Bextra while earning 100,000 dollars per year. He claims he was trained to lie to physicians, “they were training us to say things to physicians that weren’t accurate. Bextra was not approved to be used for acute pain and we were out there trying to get standing orders for acute pain.” Eventually, Demott was forced out of his position with Pfizer. (5)

Demott is one of a growing number of whistleblowers exposing medical corruption across America. This is largely thanks to a U.S. law called Qui Tam. The law allows individuals with knowledge concerning fraud against the government to bring a legal case on its behalf and share in the proceeds.

Lewis Morris is chief lawyer for the U.S. health department and increasingly uses Qui Tam to expose drug industry corruption. Today there are over 1000 outstanding Qui Tam cases in the United States and they are slowly beginning to open up the secretive world of big pharma. For the first time, we can see millions of dollars in payments to doctors throughout the U.S.

Drug companies now publish physician payment figures online and in 2009 just a few companies paid doctors in the United States over 200 million dollars. (6) These giant sums of money pouring into the medical field will inevitably lead to corruption on every level of the pharmaceutical industry. (if it hasn’t already?)

We already know Risperdal can cause diabetes and Parkinson’s as we saw in Davids case, but now there is evidence the drug can cause serious complications in adolescent boys as well. (Gynecomastia: breast development.) (7) As we speak, federal investigators are still looking into claims concerning Johnson and Johnson. They believe the company illegally marketed Risperdal for use in children, including those with ADHD. But with so many drug scandals flooding the news, the countries regulators have begun to run low on resources.

Avandia used to be the worlds best selling diabetes drug for years. It earned its maker Glaxo Smith Kline billions of dollars, but now it is linked to over 100,000 heart attacks in the United States.

In July the U.S. food and drug administration held hearings related to the dangers of Avandia. (It’s license has already been suspended in Saudi Arabia) An investigation by the U.S. senate finance committee found the totality of evidence suggests Glaxo Smith Kline was aware of the possible cardiac risks associated with Avandia years before the evidence became public. (8) Glaxo Smith Kline also tried to prevent heart attack warnings from being printed on their products box.

Many of Americas leading pharmaceutical corporations appear distraught and amass in corruption. Will fines alone prevent this?

The U.S. government is continually reaching for stronger powers and controls over the industry. The department of health is even considering breaking up drug companies found guilty of corrupt and unethical practices. In the meantime, 1000′s of doctors continue to take cash payments from the drug industry and would argue they are doing nothing wrong. This deeply entrenched culture of corruption within the drug industry is a serious problem that will inevitably cripple our healthcare system beyond repair if something isn’t done about it . Say NO to big pharma.

Sources:
1. Reuters: prescription drug sales 300b$
2. Health Freedom Alliance
3. J&J Told to Pay $257.7 Million Over Risperdal Marketing Tactics
4. Pfizer pays a record $2.3 billion to settle criminal charges
5. Whistleblower Glen DeMott on False Claims Act Settlement Reached
6. PFIZER INC Officers & Directors
7. RISPERDAL
8. Avandia Maker Hid Risks for Years, Probe Finds

© The Hals Report 2012. All rights reserved.

http://www.thehalsreport.com/

Health Care in America - Illegal "Off-Label" Conspirators

The Broken American Health Care System

Big Pharma Promotes Illegal “Off-Label” Drug Uses

When Drug Makers’ Profits Outweigh Penalties

By David Evans

Washington Post

Originally Published in Bloomberg News

Sunday, March 21, 2010; G01

http://www.washingtonpost.com/wp-dyn/content/article/2010/03/19/AR2010031905578.html

On the morning of Sept. 2, 2009, another Pfizer unit, Pharmacia agreed to plead guilty to the same crime. This time, Pfizer executives had been instructing more than 100 salespeople to promote Bextra — a drug approved only for the relief of arthritis and menstrual discomfort — for treatment of acute pain of all kinds.

For this new felony, Pfizer paid the largest criminal fine in U.S. history: $1.19 billion. On the same day, it paid $1 billion to settle civil cases involving the off-label promotion of Bextra and three other drugs with the United States and 49 states.

“At the very same time Pfizer was in our office negotiating and resolving the allegations of criminal conduct in 2004, Pfizer was itself in its other operations violating those very same laws,” Loucks, 54, says. “They’ve repeatedly marketed drugs for things they knew they couldn’t demonstrate efficacy for. That’s clearly criminal.”    

The penalties Pfizer paid for promoting Bextra off-label were the latest chapter in the drug’s benighted history. The FDA found Bextra to be so dangerous that Pfizer took it off the market for all uses in 2005.

Across the United States, pharmaceutical companies have pleaded guilty to criminal charges or paid penalties in civil cases when the Justice Department finds that they deceptively marketed drugs for unapproved uses, putting millions of people at risk of chest infections, heart attacks, suicidal impulses or death.

It used to be legal for companies to promote drugs in the United States for any use. Congress banned the practice in 1962, requiring pharmaceutical companies to first prove their drugs were safe and effective for specific uses.

If the law is clear, why do drug companies keep breaking it? The answer lies in economics. Pharmaceutical companies spend about $1 billion to develop and test a new drug. To recoup their investment, the companies want doctors to prescribe their drugs as widely as possible.

Since May 2004, Pfizer, Eli Lilly, Bristol-Myers Squibb and four other drug companies have paid a total of $7 billion in fines and penalties. Six of the companies admitted in court that they marketed medicines for unapproved uses. In September 2007, New York-based Bristol-Myers paid $515 million — without admitting or denying wrongdoing — to federal and state governments in a civil lawsuit brought by the Justice Department. The six other companies pleaded guilty in criminal cases.

 In January 2009, Indianapolis-based Lilly, the largest U.S. psychiatric drugmaker, pleaded guilty and paid $1.42 billion in fines and penalties to settle charges that it had for at least four years illegally marketed Zyprexa, a drug approved for the treatment of schizophrenia, as a remedy for dementia in elderly patients.

In five company-sponsored clinical trials, 31 people out of 1,184 participants died after taking the drug for dementia — twice the death rate for those taking a placebo, according to an article in the Journal of the American Medical Association.

“Marketing departments of many drug companies don’t respect any boundaries of professionalism or the law,” says Jerry Avorn, a professor at Harvard Medical School. “The Pfizer and Lilly cases involved the illegal promotion of drugs that have been shown to cause substantial harm and death to patients.”

The widespread off-label promotion of drugs is yet another manifestation of a health-care system that has become dysfunctional.

“It’s an unbearable cost to a system that’s going broke,” Avorn says. “We can’t even afford to pay for effective, safe therapies.”

About 15 percent of all U.S. drug sales are for unapproved uses without adequate evidence the medicines work, according to a study by Randall Stafford, a medical professor at Stanford University.

 As large as the penalties are for drug companies caught breaking the off-label law, the fines are tiny compared with the firms’ annual revenue.

The $2.3 billion in fines and penalties Pfizer paid for marketing Bextra and three other drugs cited in the Sept. 2 plea agreement for off-label uses amount to just 14 percent of its $16.8 billion in revenue from selling those medicines from 2001 to 2008.

The total of $2.75 billion Pfizer has paid in off-label penalties since 2004 is a little more than 1 percent of the company’s revenue of $245 billion from 2004 to 2008.

Lilly already had a criminal conviction for misbranding a drug when it broke the law again in promoting schizophrenia drug Zyprexa for off-label uses beginning in 1999. The medication provided Lilly with $36 billion in revenue from 2000 to 2008. That’s more than 25 times as much as the total penalties Lilly paid in January.

Companies regard the risk of multimillion-dollar penalties as just another cost of doing business, says Lon Schneider, a professor at the University of Southern California’s Keck School of Medicine in Los Angeles. In 2006, he led a study for the National Institute of Mental Health of off-label use of drugs, including Zyprexa.

“There’s an unwritten business plan,” he says. “They’re drivers that knowingly speed. If stopped, they pay the fine, and then they do it again.”

Paying the doctors

In pushing off-label use of drugs, companies find ready and willing partners in physicians. Under the fragmented system of U.S. medical regulation, it’s legal for doctors to prescribe FDA-approved drugs for any use. The FDA has no authority over doctors, only over drug companies, regarding off-label practices. It’s up to the states to oversee physicians.

“I think the physician community has to take some ownership responsibility and do their own due diligence beyond the sales and marketing person,” says Boston’s former U.S. Attorney Michael Sullivan.

Doctors generally don’t tell people they’re prescribing drugs pitched to them by pharmaceutical salespeople for unapproved treatments, says Peter Lurie, former deputy medical director of Public Citizen, a Washington-based public interest group. Most doctors don’t keep track of FDA-approved uses of drugs, he says.

“The great majority of doctors have no idea; they don’t even understand the distinction between on- and off-labeling,” he says.

Pfizer’s marketing program offered doctors up to $1,000 a day to allow a Pfizer salesperson to spend time with the physician and his patients, according to a whistle-blower lawsuit filed by John Kopchinski, who worked as a salesman at Pfizer from 1992 to 2003.

“By ‘pairing up’ with a physician, the sales representative was able to promote over a period of many hours, without the usual problems of gaining access to prescribing physicians,” Kopchinski says. “In essence, this amounted to Pfizer buying access to physicians.”

Pfizer spokesman Chris Loder says the company stopped what it calls “mentorships” in 2005. He says Pfizer paid doctors $250 a visit. The goal was clear: Get doctors to prescribe a new drug as widely as possible.

Pfizer’s Neurontin is a case in point. The FDA approved the drug as a supplemental medication to treat epilepsy in 1993. Pfizer took in $2.27 billion from sales of Neurontin in 2002. A full 94 percent — $2.12 billion — of that revenue came from off-label use, according to the prosecutors’ 2004 Pfizer sentencing memo.

Since 2004, companies that are now Pfizer divisions have pleaded guilty to off-label marketing of two drugs. Pfizer continued off-label promotions for these medications after buying the firms, according to documents.

Pfizer first stepped into an off-label scheme in 1999, when it offered to buy Warner-Lambert, based in New Jersey. Prosecutors charged that Warner-Lambert marketed Neurontin off-label between 1995 and 1999.

Warner-Lambert admitted doing so for one year in a May 2004 guilty plea for which Pfizer paid $430 million in fines and penalties.

When the FDA approved Neurontin in 1993 to be used only along with other epilepsy drugs, the agency wrote that as a side effect, the drug can induce depression and suicidal thoughts in patients.
The whistle-blower

Much of what prosecutors learned about Warner-Lambert’s marketing of Neurontin comes from a former employee, David Franklin, who holds a Ph.D. in microbiology.

Franklin, 48, whose title at Warner-Lambert was medical liaison, says his job involved more salesmanship than science. He told doctors that Neurontin was the best drug for a dozen off-label uses, including pain relief, bipolar disease and depression.

“Technically, I had responsibility for answering physician questions about all of Parke-Davis’s drugs,” Franklin says. “In practice, my real job was to promote Neurontin for off-label indications heavily — to the exclusion of just about everything else.”

Franklin says he knew such uses of the drug had no scientific support for effectiveness and safety.

 “I was actually undermining their ability to fulfill the Hippocratic oath,” Franklin says, referring to a physician’s pledge to “First, do no harm.”

After working for Warner-Lambert for three months, Franklin quit and filed a whistle-blower lawsuit on behalf of taxpayers to recover money the government paid for illegally promoted drugs. He stood to collect as much as 30 percent of any settlement the company made with the government.

Franklin had to wait four years — until 2000 — before the Justice Department began a criminal investigation. In November 1999, Pfizer made its public offer to buy Warner-Lambert. In January 2000, a federal grand jury in Boston issued subpoenas to Warner-Lambert employees to testify about the marketing of Neurontin.

That March, Warner-Lambert’s annual report disclosed that prosecutors were building a criminal case. Undeterred, Pfizer bought Warner-Lambert in June for $87 billion — the third-largest merger in U.S. history.

More sales than Viagra

A year after the acquisition, the FDA discovered that Neurontin was still being marketed off-label. In a June, 2001 letter to the company, the agency wrote that Pfizer’s promotion of the drug “is misleading and in violation of the Federal Food, Drug and Cosmetics Act.”

Pfizer marketed Neurontin off-label after receiving that letter, agency records show. For 2001, Pfizer reported revenue of $1.75 billion from Neurontin sales, making it the company’s fourth-largest-selling drug that year, ahead of impotence pill Viagra, which Neurontin topped for four years.

As Neurontin sales soared to $2.27 billion in 2002, the FDA found that Pfizer was improperly claiming that the drug was useful for a broader range of brain disorders than scientific evidence had established.

The agency sent a letter dated July 1, 2002, that said the company’s marketing practices were in violation of FDA rules. It asked Pfizer to stop using misleading promotions. Pfizer reported $2.7 billion in revenue from Neurontin in 2003. Overall, the drug has provided Pfizer with $12 billion in revenue.

Pfizer spokesman Chris Loder says, “Regarding the 2001 and 2002 FDA letters, we do not believe that they were suggestive of any continuing off-label promotion.”

For blowing the whistle on his employer, Franklin collected $24.6 million under the False Claims Act.

Prosecutors Loucks and Sullivan got involved in the case after Franklin filed his suit, relying on information from Franklin and their own investigation. Before 2004, prosecutions for off-label marketing were rare.

“Until a couple of these cases became public, companies were probably saying, ‘Everybody does it this way,’ ” Sullivan says.

Loucks had a track record in off-label prosecutions. In 1994, he negotiated a $61 million settlement with C.R. Bard of New Jersey, which pleaded guilty to promoting off-label use of a heart catheter that led to patient deaths.

The off-label campaign

In the January 2004 settlement negotiations with Loucks, Sullivan and two other prosecutors, Pfizer’s lawyers assured the U.S. Attorney’s Office that the company wouldn’t market drugs off-label.

“They asserted that the company understood the rules and had taken steps to assure corporate compliance with the law,” Loucks says. “We remember those promises.”

What Pfizer’s lawyers didn’t tell the prosecutors was that Pfizer was at that moment running an off-label marketing promotion using more than 100 salespeople who were pitching Bextra, according to a Pfizer sales manager who pleaded guilty to misbranding a drug in March 2009.

Pharmacia; Upjohn developed Bextra, which was approved by the FDA in 2001 for only the treatment of arthritis and menstrual discomfort.

Pfizer had by then crafted a joint marketing agreement to sell the drug. In November 2001, Mary Holloway, a Pfizer Northeast regional manager, began illegally training and directing her sales team to market Bextra for the relief of acute pain, Holloway admitted in the plea.

On Dec. 4, 2001, Pfizer executives sent Holloway a copy of a nonpublic FDA letter to the company. The agency had denied Pfizer’s application to market Bextra for acute pain. Clinical trials had shown Bextra could cause heart damage and death.

Pfizer bought Pharmacia from Upjohn in April 2003. From 2001 through 2003, Pharmacia operated first as an independent company and then as a unit of Pfizer, paid doctors more than $5 million in cash to lure them to resorts, where salespeople illegally pitched off-label uses for Bextra, it was admitted.

In her guilty plea, Holloway said her team had solicited hospitals to create protocols to buy Bextra for the unapproved purpose of acute pain relief. Her representatives didn’t mention the increased risk of heart attacks in their marketing.

They told doctors that side effects were no worse than those of a sugar pill, Holloway said.

In 2003, Holloway reported her unit’s off-label promotions of Bextra up the corporate ladder at Pfizer, according to a presentencing memo to the judge written by Robert Ullmann, Holloway’s attorney. Top managers didn’t attempt to halt the illegal conduct, the memo said.

By late 2004, Bextra reached blockbuster status, with annual sales of $1.29 billion. Holloway promoted Bextra until the FDA asked Pfizer in April 2005 to pull it from the market for all uses.

The agency concluded that the drug increased the risk of heart attacks, chest infections and strokes in cardiac surgery patients. In June 2009, Holloway, 47, was sentenced to two years on probation and fined $75,000. She didn’t return phone calls seeking comment.

‘We regret . . . ‘

By 2007, the criminal and civil cases against Pfizer, its employees and its subsidiaries had begun to mount. The tally of drugs cited by federal prosecutors for off-label promotion reached six by 2009. In April 2007, Pfizer pleaded guilty to a felony charge of offering a $12 million kickback to a pharmacy benefit manager. Pfizer paid a criminal fine of $19.7 million. In September 2009, Pfizer agreed to pay $2.2 billion in fines and penalties. Pfizer pleaded guilty to a felony charge of misbranding Bextra with the intent to defraud. After the settlement, Pfizer general counsel Amy Schulman said the company had learned its lesson.

“We regret certain actions we’ve taken in the past,” she said. “Corporate integrity is an absolute priority for Pfizer.”
 
One reason drug companies keep breaking the law may be because prosecutors and judges have been unwilling to use the ultimate sanction — a felony conviction that would exclude a company from selling its drugs for reimbursement by state health programs and federal Medicare.

At Pfizer’s Pharmacia sentencing in October, U.S. District Court Judge Douglas Woodlock said companies don’t appear to take the law seriously. “It has become something of a cost of doing business for some of these corporations, to shed their skin like certain animals and leave the skin and move on,” he said.

As prosecutors continue to uncover patterns of deceit in off-label marketing, millions of patients across the nation remain in the dark. Doctors often choose the medications based on dishonest marketing by drug company salesmen.

Loucks says that putting an end to the criminal off-label schemes will be difficult. As drugmakers repeatedly plead guilty, they’ve shown they’re willing to pay hundreds of millions of dollars in fines as a cost of generating billions in revenue.

The best hope, Loucks says, is that drug companies actually honor the promises they keep making — and keep breaking — to obey the law of the land.

As much as $100 million for health-care fraud enforcement is tied up in the stalled reform legislation, according to Loucks.

“It will be increasingly hard for the threat of exclusion to seem credible and thus serve as a deterrent to bad corporate behavior,” he says, “unless Congress supports health-care fraud prosecutions with more money.”

A version of this story originally appeared in Bloomberg Markets Magazine. It was awarded a 2010 Society of American Business Editors and Writers award for enterprise reporting and general excellence.
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