In 2001, a drug company funded automated telephone survey 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 had a simple answer: too often.
Just that simply, 33 million people had a new diagnosis: overactive bladder disorder -- and a massive new market for drug sales was born.
Last year, sales of drugs to treat overactive bladder reached nearly $3 billion, even though some experts say the condition is best managed without drugs at all.
At the center of the issue are two researchers, known as the "godfathers" of the condition: Alan Wein, MD, PhD, a urologist at the University of Pennsylvania, and Paul Abrams, MBChB, MD, of the University of Bristol in England. The two named the condition, developed a definition for it, and organized drug company-sponsored conferences to advocate 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 received in the last 3 years alone, according to federal reports on drug company payments.
But even Wein concedes the initial estimate, drawn from the national survey 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, MD, PhD, a urologist and clinical epidemiologist at the University of Helsinki in Finland, conducted his own analysis in 2007 using a detailed questionnaire sent by regular mail to 6,000 people in Finland. He found that 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."
And that scenario is exactly what happened, according to a MedPage Today/Milwaukee Journal Sentinel investigation.
While overactive bladder is not a life-threatening condition, the drugs used to treat it have been included in more than 12,000 adverse event reports to the FDA 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 solifenacin succinate (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, mirabegron (Myrbetriq).
FDA Responds
In a statement, the FDA said the benefits of these drugs outweigh their risks when they are used according to the product label.
A spokesperson for Astellas, the company that makes Vesicare and Myrbetriq, said the drug maker complies with all regulatory safety reporting requirements.
"Patient safety is our No. 1 priority," Candace Johnson said in an email.
The drugs themselves work moderately better than a placebo, studies show, but are not more effective than various treatments that involve exercises or other changes in behavior. 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, MD, vice president of clinical policy at the American College of Physicians, which has issued a guideline on managing incontinence in women.
There are now more than a dozen overactive bladder drugs and treatments on the market, ranging from Botox injections and Medtronic's implantable neuromodulation device InterStim, to a prescription patch and an over-the-counter patch, as well as the drug Myrbetriq, which uses an advertising campaign featuring a cartoon bladder.
"The pharmaceutical industry does play a major role in pushing some of these drugs," Qaseem said.
'Creating a Disease'
For decades, bladder problems ranged from detrusor instability to incontinence. These conditions were generally considered a consequence of aging.
To use a popular term, that "paradigm shifted" when Wein and Abrams joined forces. They held their first overactive bladder conference in June 1997. It was sponsored by Pharmacia, which had an interest in the OAB market.
In December of that year, the field's major journal, called Urology, published a special supplement on overactive bladder with about 30 articles. The introduction, written by Wein and Abrams, talked about a "promising" new drug for the treatment of overactive bladder -- 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, a guideline issued by the International Continence Society.
Then came the 2001 phone survey -- named the NOBLE trial -- also sponsored by Pharmacia. It asked 5,204 adults questions about how often they needed to urinate, whether they had to get up at night, whether they felt urgency and if they had incontinence.
While the paper about the survey's conclusions does not say all of the nearly 17% of adults with overactive bladder needed to be treated, that has been the implication when drug companies have used the number in subsequent years.
"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 that year from Neil Wolf, then a vice president of Pharmacia, who was in charge of the global launch of another bladder control drug, tolterodine (Detrol), showed how the company tried to drum up a market.
Its title: "Positioning Detrol"
Its subtitle: "Creating a Disease"
The slide presentation, which was later 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 definition of overactive bladder subsequently expanded "dramatically and rapidly."
The company wanted the condition to be recognized by both patients and primary care doctors, to reach the widest audience. One slide describes how the company wanted to "create an environment where PCPs 'own' OAB."
In an interview, Wolf said the presentation was tailored to a group of industry leaders in market research, and that 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."
For years, Detrol was the main drug on the market, racking up $400 million in 2001. But it soon had competition and it faced a limited lifespan. The drug's patent was set to expire in 2012, which as a generic, would lower the cost for consumers, but meant Pfizer, which now owned Pharmacia, faced a substantial loss of revenue.
In 2008, Pfizer won FDA approval of a second agent, fesoterodine fumarate, marketed as Toviaz. This drug is in the same class of drug as its Detrol brand, but is slightly different chemically.
Toviaz sales grew from $76 million in 2010 to $238 million in 2015, according to IMS Health, a drug market research firm.
Growing the Numbers
A year later, a study funded by Pfizer pushed the number of people said with overactive bladder to nearly 19% of American adults -- more than 42 million. Three of the six authors of that study were paid consultants to Pfizer; a fourth was a Pfizer employee.
Where do these growing numbers come from?
In effect, they take a smaller group of mostly older people who had incontinence, or leakage, and add to it a larger group of middle-age and older people who have problems with urgency and going often, with or without incontinence.
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, age 40 and older, 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 the number was funded by Pfizer and two of the six authors were listed as Pfizer employees. Three of the four remaining co-authors listed affiliations with United BioSource, which does work for the pharmaceutical industry.
Pfizer officials declined to comment on its support of research on estimates on how many people have the condition, or on 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 that their "safety and efficacy profiles are well-established."
Carl Elliott, MD, PhD, 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," Elliot 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 with 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.
Wein 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.
Pharmaceutical companies pushed their overactive bladder drugs in extensive advertising campaigns, starting with Pharmacia's Detrol. One staple was an ad with the memorable "gotta go right now" jingle that depicted a crossing guard stopping traffic so she could run to a nearby restroom.
Allergan, which makes Botox, ran a series of "calm your bladder" ads targeted at people who were frustrated with their existing bladder medications.
Indevus Pharmaceuticals, which makes the drug trospium chloride (Sanctura), ran journal ads featuring a giant four-leaf clover that claimed the drug "stands alone" when compared with other treatments. But the FDA issued a warning in 2009 that said the ads overstated the drug's effectiveness and omitted information about its risks.
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.
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 2 years.
"It seems like the disease has already been created," Elliott said. "Pharmacia already did it when they re-branded incontinence as OAB for Detrol, and it seems like [pharmaceutical 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 frequency or urgency.
And there could be various reasons why people have to urinate a lot, from organ prolapse and prostate disorders to neurological dysfunction -- conditions that may have nothing to do with the bladder. That, in turn, leads to the treatment of symptoms, but doesn't actually cure anything.
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 issued a guideline on diagnosing and treating overactive bladder.
Eight of the 11 experts on the panel listed financial relationships with companies that market treatments for overactive bladder.
While the guidelines say nondrug behavioral training should be the first treatments offered, it also says patients can be put on the combination of drugs and behavioral therapy right away.
The guideline also devotes only about one page to those therapies while spending about 20 pages discussing drugs and other treatments, including Botox injections.
E. Ann Gormley, MD, of Dartmouth, who headed 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 assessed by the panel.
Gormley 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.
They emphasize pelvic floor muscle exercises and bladder training, and recommend against using drugs for stress incontinence. 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
Many studies have shown that overactive bladder drugs perform no better than a placebo, but at the same time they often have potentially serious side effects. (See Sidebar)
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, the FDA began requiring drug companies that make anticholinergic overactive bladder drugs to add a label warning about such side effects after conducting a "comprehensive evaluation of post-marketing reports."
Yet the MedPage Today/Journal Sentinel review of FDA records found reports of problems related to the drugs are continuing -- since 2013, anticholinergics were cited in nearly 200 cases, with patients noting confusion, a "confusional state" or feeling abnormal.
The analysis included only cases reported medical professionals and drug companies. Since drug companies are the only ones that are required to file reports they receive, the real total likely is much higher.
Another side effect of many of the anticholinergic drugs is dry mouth. In clinical trials, it was reported 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, PhD, president of the National Center for Health Research, noted there is another factor that argues against the use of the drugs.
And in the Final Analysis ...
While incontinence episodes are reduced moderately, they are not eliminated, which means that 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."