Drug firms helped create $3 billion overactive bladder market

• Nearly 20 years ago, the condition known as incontinence got a makeover that vastly expanded the market for drugs to treat it.
• Two doctors with financial ties to the drug industry gave it a new name -- overactive bladder -- and an expanded definition was created.
• The number of adult Americans said to have the condition went from 12 million to 33 million. A newer estimate puts it at as many as 46 million.
• Though best treated without medication, sales of overactive bladder drugs reached nearly $3 billion in 2015.

In 2001, an automated telephone survey paid for by a drug company asked adults a simple, uncomfortable question: How often do you go?

The results produced a striking number: Nearly 17% of adults in the United States — some 33 million people — were declared to have overactive bladder disorder.

And a massive new market for drug sales was born.

Last year, sales of drugs to manage overactive bladder, once simply known as incontinence, reached nearly $3 billion — even though experts in the field say the condition is best managed without drugs at all.

At the center of the issue are two urologists, known as the “godfathers” of overactive bladder disorder: Alan Wein of the University of Pennsylvania and Paul Abrams of the University of Bristol in England. The two researchers re-named the condition, developed a definition for it and organized drug-company sponsored conferences that advocated for using drugs to treat it.

Both have longstanding financial ties to companies that market overactive bladder treatments, including more than $60,000 that Wein has received in the last three years alone, according to federal reports on drug company payments to American doctors.

Even Wein concedes the initial estimate, drawn from a paper on the national survey that he and Abrams co-authored, “overstates the market.”

“If I call you up on the phone and asked if in the last month you’ve ever had a really strong desire to urinate, and you say that’s happened, then theoretically you would qualify as (having) overactive bladder,” he said in an interview.

Kari Tikkinen, a urologist and clinical epidemiologist at the University of Helsinki, conducted his own analysis in 2007 using a detailed questionnaire sent by regular mail to 6,000 people in Finland. He found the prevalence was closer to 8%.

Tikkinen, who received no drug company funding for his research, said labeling patients with minimal symptoms as having a disease “risks causing healthy people to consider themselves sick, and exposes them to needless drug side effects.”

That is what has played out, a Milwaukee Journal Sentinel/MedPage Today investigation has found.

While overactive bladder is not a life-threatening condition, the drugs used to treat it have been included in more than 12,000 reports of problems to the U.S. Food and Drug Administration since 2013. That includes nearly 200 deaths and more than 700 hospitalizations.

Among them:

• A 77-year-old man died from kidney failure after taking the overactive bladder drug VESIcare and several other drugs.
• A 51-year-old woman was hospitalized with paranoid delusions and difficulty urinating after taking the generic overactive bladder drug oxybutynin and other drugs. 
• An 81-year-old man was hospitalized with high blood pressure after taking the overactive bladder drug, Myrbetriq. 

In a statement, the FDA said the benefits of the drugs outweigh their risks when they are used as instructed. A spokeswoman for Astellas, which makes VESIcare and Myrbetriq, said the company complies with all regulatory safety reporting requirements.

“Patient safety is our No. 1 priority,” spokeswoman Candace Johnson wrote in an email.

The drugs themselves work moderately better than a placebo, studies show, but not more effectively than non-drug treatments that pose no risk. Such behavioral therapies include bladder training, pelvic muscle exercises, weight loss and fluid management.

“It’s easier to prescribe medications than to explain the non-pharmacological treatments,” said Amir Qaseem, vice president of clinical policy at the American College of Physicians.

There are now more than a dozen overactive bladder drugs and treatments on the market, ranging from Botox injections and prescription patches to Myrbetriq, which uses an advertising campaign featuring a cartoon bladder.

“The pharmaceutical industry does play a major role in pushing some of these drugs,” said Qaseem.

‘Creating a Disease’

For decades, bladder problems were identified as incontinence or “detrusor instability.” The detrusor is the bladder muscle, which can squeeze too often — or without warning — and lead to feelings of having to go.

The conditions were generally considered a consequence of people getting older.

What followed was an example of illness inflation — an effort driven by drug companies to create or expand the definition of conditions that are part of everyday life and to create guidelines that call for treatment with drugs that are expensive and often dangerous.

Wein and Abrams held their first overactive bladder conference in London in June 1997. It was sponsored by Pharmacia, which helped pioneer overactive bladder drugs.

In December of that year, the field’s major journal — Urology — published a special supplement on overactive bladder with about 30 articles on the condition. The introduction, written by Wein and Abrams, talked about a “promising” new drug — Detrol, which was manufactured by Pharmacia.

The FDA approved the drug the following year and by 1999 a new definition — which expanded the number of people who met the criteria — was being written by the International Continence Society.

Then came the 2001 national phone survey, which asked a variety of questions about the urinary habits of Americans, also sponsored by Pharmacia.

The survey asked 5,204 adults questions that included how often they needed to urinate, whether they had to get up at night and whether they felt urgency.

While the paper from Wein and Abrams about the survey did not say all of the 17% of adults with overactive bladder needed to be treated, that was the implication when drug companies began using the number.

“The pharma people would love it if that prevalence is in fact the market for treatment, but it’s not,” Wein said. “There are many more people who qualify than who need treatment.”

In 2002, a slide presentation from Neil Wolf, then a Pharmacia vice president who was in charge of the global launch of Detrol, showed how the company tried to drum up a market.

Its title: “Positioning Detrol.”

Its subtitle: “Creating a Disease.”

The slide presentation, which later was posted on the website Slideshare, describes how Pharmacia started to target “key opinion leaders” among doctors in 1996. It boasts how the International Continence Society's definition of overactive bladder subsequently expanded “dramatically and rapidly.”

One slide shows the company wanted the condition to be recognized by both patients and primary care doctors, to reach the widest audience. Another describes how the company wanted to “create an environment where PCPs (primary care providers) ‘own’ OAB.”

In an interview, Wolf said the presentation was tailored to a group of industry leaders in market research and said the subtitle “was not a good choice of words.”

"We didn't create a disease,” he said. “We created awareness of a condition so that people who suffered from the condition could recognize themselves and talk with their doctors."

Growing the numbers

In 2009, a study funded by Pfizer, which bought Pharmacia, pushed the number of people said to have overactive bladder to more than 42 million — or nearly 19% of American adults. Three of the six authors were paid consultants to Pfizer; a fourth was a Pfizer employee.

Where did the growing numbers come from?

In effect, they took a smaller group of mostly older people who had incontinence, or leakage, and added to it a larger group of middle-aged and older people who simply have problems with urgency and going often.

Indeed, the drug company Astellas, which makes the two top-selling overactive bladder drugs, highlights on its website an even larger industry-funded estimate — that 46 million Americans age 40 and older "sometimes" felt overactive bladder symptoms.

The number came from an internet survey in which 37% of respondents said they experienced symptoms “sometimes.” But only 25% said their symptoms occurred often. And an even smaller number, 23%, said they had “bothersome” symptoms.

The 2011 survey that created that number was funded by Pfizer and two of the six authors were listed as Pfizer employees. Three of the four remaining authors listed affiliations with United BioSource Corp., a firm that does work for the pharmaceutical industry.

Pfizer officials declined to answer questions about the company’s research that boosted estimates of how many people have the condition, or about Pharmacia’s marketing push for Detrol.

In a statement, the company said its drugs “serve as an important treatment option for patients with OAB,” and their “safety and efficacy profiles are well-established.”

Carl Elliott,  a bioethicist at the University of Minnesota, called overactive bladder a primary example of “disease-mongering.”

“The basic idea is selling a drug by selling a disease,” he said. “You expand the diagnostic category to create a larger market for the drug.”

 A major marketing push 

The very name “overactive bladder” was created with marketing in mind.

Compare that to “incontinence,” or to the formal name of “detrusor instability.”

“A lot of people, when they heard it, thought it had a psychiatric connotation, which we didn’t think was very good,” said Wein, who helped launch the condition to prominence.

In contrast, he said, the term “overactive bladder” was “pretty intuitive.”

“You hear ‘overactive bladder’ and immediately it puts in your mind a picture of something you can recognize,” he said.

Experts say the name change helped make the condition more acceptable for public discussion, including patients bringing it up with their doctors. Those doctors, meanwhile, were encouraged to screen patients for the condition — and to keep them on their medication once it was started.

The drugs became a staple in magazine and TV ads.

The campaign for Detrol featured the memorable “gotta go right now” jingle and a crossing guard stopping traffic so she could run to a nearby restroom.

Allergan, which makes Botox, ran a series of “calm your bladder” TV ads targeted at people who were frustrated with their existing bladder medications.

Indevus Pharmaceuticals, which makes the drug Sanctura, ran medical journal ads that featured a giant four-leaf clover and the claim the drug “stands alone” when compared to other treatments. But the FDA issued a 2009 warning that said the ads overstated the drug’s effectiveness and omitted information about its risks. The agency told the company to immediately cease its use of the ad.

More recently, Astellas has been promoting Myrbetriq in a television ad that shows a woman being tugged away from a bowling match by her cartoon bladder.

Video: TV commercial for Myrbetriq

Sales of Myrbetriq jumped from $134 million in 2013, the first full year after it was approved, to $553 million in 2015, according to data from IMS Health. That is a 312% increase in two years.

“It seems like the disease has already been created,” said Elliott, the University of Minnesota professor. “Pharmacia did it when they rebranded incontinence as OAB for Detrol.

“It seems like (drug companies) are just piggybacking on top of the work that’s already been done.”

Differing recommendations

The official definition of overactive bladder says patients must have “urgency with or without urge incontinence, usually with frequency and nocturia.” That’s the feeling of having to go, with or without leakage, and going frequently during the day and having to get up several times at night.

The condition is typically diagnosed only by a patient’s report of symptoms.

But many experts say there’s a big difference between having incontinence, or leakage, and just having the urge to go frequently.

And there could be various reasons why people have to urinate a lot that have nothing to do with the bladder — prostate disorders and neurological dysfunction, even “organ prolapse,” in which organs fall from their normal place in the body and push on other structures, such as the bladder. All can happen with aging.

When these conditions are missed, doctors say, and patients are deemed to have overactive bladder, it leads to the treatment of symptoms, but doesn’t actually cure anything.

In 2012, the American Urological Association and the Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction together issued new guidelines to be used by doctors for diagnosing and treating overactive bladder.

Eight of the 11 experts on the panel listed financial ties to companies that market treatments for overactive bladder.

While the guidelines say behavioral training should be the first treatment offered, they also say patients can be put on a combination of drugs and behavioral therapy right away.

The guidelines devote one page to behavioral therapies while spending 20 pages on drugs and other treatments, including Botox injections and nerve stimulation.

E. Ann Gormley, who chaired the panel and who does not do any drug company speaking or consulting, said more space was devoted to drugs because there were more than 100 drug-related studies reviewed by the panel.

Gormley, a professor of surgery at the Geisel School of Medicine at Dartmouth, said she does not think the guidelines were overly favorable to drug companies.

Once the guidelines were issued, the American Urological Association put out a pocket guide for primary care doctors summing up the recommendations. It was paid for, in part, with money from Astellas — the company that makes the two top-selling overactive bladder drugs.

Two years later, a panel of experts put together by the American College of Physicians issued recommendations on treating urinary incontinence in women.

The emphasis in the guidelines: Behavioral therapies.

Those guidelines emphasize pelvic floor muscle exercises and bladder training, and recommend against using drugs for incontinence caused by stress. They say drugs can be used in some cases, but only if bladder training proves unsuccessful.

Of the six authors, one reported owning some drug company stock. The number that reported working as speakers or consultants to drug companies?

Zero.

Results murky at best

From the beginning, studies showed many of the overactive bladder treatments did not perform much better than a placebo:

VESIcare: The FDA approved the drug, manufactured by Astellas, in 2004. In clinical trials lasting three months, it reduced the number of incontinence episodes by about 1.5 per day from an average of about 3, at the standard dose. But a placebo reduced incontinence episodes by about 1 per day.

A 30-day supply of VESIcare costs about $361.

Myrbetriq:  Astellas won approval for this drug, which works by relaxing the bladder muscle, in 2012. In the three studies that led to its FDA approval, patients who took the drug had 0.4 fewer episodes of incontinence over 24 hours compared with those on a placebo.

The drug, which can increase blood pressure, carries a retail cost of about $370 for a 30-day supply.

Botox: In 2013, Botox, which is made by Allergan, was approved to treat the condition for those who don’t get better with oral medications. The injections are needed in about 20 sites in the bladder, with clinical trial data showing the benefits diminish about six months later. The FDA says the injections can be continued indefinitely, but no sooner than every three months.

Those in the clinical trials had about 5.5 incontinence episodes per day. When treated with Botox they had 1.6 or 1.9 fewer episodes compared with a placebo, depending on the study.

But the injections carry the potential side effects of urinary tract infection, painful urination and difficulty with completely emptying the bladder. The cost of one, six-month treatment of Botox is about $1,300, according to one study.

Several overactive bladder drugs, including VESIcare, are known as anticholinergics. Labels for those drugs warn of confusion, hallucinations, disorientation and sleepiness.

That is especially concerning in older patients who are the most likely to have urinary problems and who may already have some cognitive impairment.

Starting around 2008, after conducting a “comprehensive evaluation of post-marketing reports,” the FDA began requiring drug companies that make such drugs to add a label warning about such side effects.

Yet the Journal Sentinel/MedPage Today review of FDA records found reports of problems related to the drugs are continuing — since 2013, they were cited in nearly 200 cases, with patients noting confusion, a “confusional state” or feeling abnormal.

The analysis included only cases reported by medical professionals and drug companies. Since drug companies are the only ones that are required to file reports they receive, the real total could be much higher.

Another side effect of many of the drugs linked to confusion is dry mouth. In clinical trials, it was reported in between 20% and 30% of patients, depending on the drug.

Dry mouth can lead to tooth decay, but it also makes people want to drink more — which can be a problem if a person has bladder issues.

Diana Zuckerman, president of the National Center for Health Research noted there is another factor arguing against the use of drugs to treat overactive bladder.

While incontinence episodes are reduced moderately, they are not eliminated. That means protective pads likely still are needed.

“All of these drugs have the potential for serious risk,” she said. “So what’s the actual benefit? To weigh that against risks that can be serious, it’s pretty unimpressive.”

John Fauber is a reporter for the Milwaukee Journal Sentinel. Kristina Fiore and Matt Wynn are reporters for MedPage Today.

This story was reported as a joint project of the Journal Sentinel and MedPage Today, which provides a clinical perspective for physicians on breaking medical news at medpagetoday.com.

Same condition, different drug

For years, Detrol was the main overactive bladder drug on the market, racking up $400 million in sales in 2001.

But Detrol soon had competition, and it faced a limited lifespan. The drug’s patent was set to expire in 2012. As a generic, it would mean lower costs for consumers, but Pfizer — which now manufactured the drug — faced a substantial loss of revenue.

In 2008, Pfizer got the FDA to approve a new overactive bladder drug — Toviaz. The drug is in the same class as the Detrol brand, but is slightly different chemically. Experts say the move is a common technique, as drug companies work to maintain the value of their products.

In 2010, Toviaz sales were $76 million, according to IMS Health, a drug market research firm. By 2015, they reached $238 million, an increase of more than 200%.

Read the investigation

To read past stories in the Illness Inflation investigation, and to explore an interactive database of other everyday conditions that have become medical issues, go to jsonline.com/illnessinflation.