Glaxo and the Making of a Blockbuster Drug

GlaxoSmithKline (GSK) announced results yesterday. As expected, there was plenty of good news. Sales are brisk. Profit was up 5%.

And among those numbers was a once little known drug, called Requip, that is now performing spectacularly well. Total sales for Requip in 2006 topped out at $496 million. And to think that Requip is aimed at a disease few people knew about only five years ago. This did not happen without some help from the marketing groups at Glaxo.

Restless Leg Syndrome, also known as Ekborn's syndrome, was first described in the mid-1940s by Swedish neurologist Karl A. Ekborn. He described a disorder characterized by sensory symptoms and motor disturbances in the limbs, mainly during rest. Early descriptions of such a condition date back to the 17th century, and some credit the English anatomist and physician Thomas Willis, who lived from 1621-1675, for first describing the condition.

Alleviating Restless Leg Syndrome
The National Institute of Neurological Disorders and Stroke at the NIH describes RLS as follows: RLS is a neurological disorder characterized by unpleasant sensations in the legs and an uncontrollable urge to move when at rest in an effort to relieve these feelings. The sensations are described as burning, creeping, tugging, or like insects crawling inside the legs. These sensations are known as abnormal (paresthesias) or unpleasant (dysesthesias) in the medical literature.

Many people experience an occasional leg cramp while in bed, and cramps in the lower extremities are more common in patients suffering from kidney disease and other electrolyte disturbances. The latter can be a side-effect of medications such as calcium-channel blockers. Cramps can also occur when a muscle is overworked due to exercise or an aberrant load. The latter can happen following an injury to another part of the limb. People also occasionally experience leg symptoms when sitting down for a long time in a cramped place such as an airline seat. Walking about provides some relief in all these situations.

However, prior to 2004, these conditions were rarely labeled RLS, and RLS as a whole was largely unknown. That is no longer the case. Restless legs are on the nightly news and feature prominently in newspapers and magazines. The "patients" are good looking young to middle-aged persons describing common symptoms interfering with their daily lives.

But it isn't just on the news. A recent Google search for restless leg returned about 1,240,000 pages mentioning RLS. That includes several sponsored links all promising to alleviate this condition. Not all links are affiliated with Glaxo, and many point to companies touting herbal remedies, massage, yoga, pilates, and supplements. It looks as if everyone is suffering from an ailment few had known existed.

It has struck some people that RLS was largely unknown until drugs became available to treat it. Consumers Union says patients are convinced by "Glaxo's marketing machine, which has persuaded many consumers and physicians to accept restless-legs syndrome, or RLS, as a real condition warranting treatment."

Marketing a Malady
A UK industry watchdog reprimanded GlaxoSmithKline last year for promoting an unlicensed drug "to treat the disputed condition." Disputed, because many doctors claim the condition has been concocted or at least exaggerated to help sell drugs, according to the UK's Sunday Times. And unlicensed because ropinirole was not approved for restless-legs in the UK at the time. A similar sounding story appeared in the Wall Street Journal several months ago under the title, "How Glaxo Marketed a Malady to Sell a Drug."

GSK began running ads between September 2004 and November of 2005 to raise awareness of RLS. Glaxo began by advertising the disorder to doctors in medical journals. The ads started months before the company had regulatory approval to begin selling ropinirole (known as Requip in the U.S.). It then sent specialists to discuss the condition with general practitioners. It sponsored seminars and continuing education in desirable locations. This apparently became so pervasive that some doctors accused Glaxo of disease mongering.

In May of 2005, the FDA approved a Parkinson’s Disease drug, ropinirole or Requip, for Restless Legs Syndrome. The Ekborn Support Group started promoting Requip, known as Adartrel in the UK, on its website and in publications. Following a complaint in the UK, GSK admitted to giving the group administrative help, paying for its stationery and the installation of broadband access. The Ekborn Support Group, in 2006, said 5% of the population suffered from the condition. At the time, doctors in the UK put the number at less than 3%, with only a small minority requiring treatment.

The Restless Legs Syndrome Foundation in the U.S. similarly started promoting the medication and raising awareness. And GSK set up a website, called restlesslegs.com as a resource for people with RLS. The GSK site claims RLS affects up to 10% of American adults. Only a few studies done in North America show such high prevalence. Interestingly enough, all these studies were done after the ad campaign had been in full swing for a while.

The Sleeptionary™, an independently created site by the National Sleep Foundation, is focused on RLS. It calls RLS a common and under-diagnosed and treatable condition, affecting about 10% of the adults in North American and Europe and increasing with age. The Sleeptionary™ is supported by an unrestricted grant from GlaxoSmithKline. The web publication Bandolier, promoting "Evidence Based Thinking about Health Care," also has a big section on RLS. It too is made available by an unconditional educational grant by GlaxoSmithKline.

Prevalence of RLS: Big Study Discrepancies
Bandolier found that prevalence of RLS varies widely in studies, from 1-14%, but that the two largest studies show a prevalence of about 6%. More recent studies found higher rates. Rates in Japan where Glaxo's marketing has no reach, were found to be lower at 1%. Bandolier also cites a large survey that found 2.7% of adults in Western countries had RLS as diagnosed by the standard criteria. It found that quality of life is impaired in people suffering at least moderate symptoms at least twice a week. Prevalence in this group was much lower.

PLoS medicine's April 2006 article was focused on "disease mongering," a way to broaden the market for a drug "with the selling of sickness that widens the boundaries of illness and grows markets for those who sell and deliver treatments." According to PLoS, GSK started marketing ropinirole for the syndrome in 2003 with a press release entitled "New survey reveals common yet under recognized disorder -restless legs syndrome - is keeping Americans awake at night."

The Glaxo release was followed by 33 newspaper articles, 97% of which uncritically accepted the definition in the press release. All of this was not without consequence, and sales for Requip have quadrupled since it was approved for RLS. In its first year, illustrated in the annual report for 2005, GSK reported sales rising 34% to 156 million British pounds ($300 million) following its launch in the second quarter. The company spent $27 million on ads promoting the drug. Requip is one of the fastest growing drugs in Glaxo's portfolio and it reached nearly $500 million in 2006.

The story is somewhat reminiscent of Warner-Lambert's (now Pfizer (PFE)) Neurontin. Neurontin was a little known epilepsy drug with sales well below $100 million, when WL found they could promote it for neuropathic pain. The significant differences are that WL promoted a drug off-label, an illegal act, and that neuropathic pain was an underserved condition with few good options. But Neurontin swiftly became a blockbuster drug.

Blockbusters and the Market
Today's pharmaceutical companies depend on blockbusters to survive. Their whole sales and marketing model is based on it. Compounds without blockbuster potential are often abandoned early on, regardless of medical needs (see Blockbuster Drugs: Good or Bad?). The success of the model has also led to a focus on side-effects rather than efficacy. Because so many people with minor symptoms are taking drugs, everyone became a lot more worried about side-effects. Over the years we have seen progressively more drugs fail over toxicity rather than efficacy. It is not as if compounds became more toxic suddenly, but that is another story altogether.

But what to do with a drug that does not deliver? Companies are far more reluctant to kill a drug once it is on the market. In the current setup, money and people are allocated to a drug franchise once approval seems likely. The closer the drug gets, the more money there is to spend. When the drug gets approved but does not perform as expected, these resources often get busy. Much like the soldiers in "Desert of the Tartars," who go looking for an unseen enemy if none can be found, these marketers go look for a disease.

Disease Mongering?
"Disease mongering" is the effort by the medical and pharmaceutical community to enlarge the market for a treatment or drug (see Does Pharma Invent Disease?). It works by convincing people they are suffering from an undiagnosed little known illness and they need intervention either to feel better or to prevent worse things from happening, or both. Often the "patients" and their family are only too happy to oblige. And other groups, such as personal injury lawyers, also stand to gain in many cases. The curious recent epidemic of whiplash syndrome in Scandinavian countries, where it was once unheard of, is a good example of this phenomenon. When the government changed reimbursement rules, the incidence suddenly spiked.

Typically, the ailment in question is a chronic condition that is non-progressive but causes significant suffering in some cases. It may be seen as a precursor or risk factor to worse conditions, or it may be statistically correlated with a higher incidence of certain diseases.

The malady typically has a small core group of patients whose complaints are severe, verifiable, frequent, and whose quality of life is clearly affected. Good examples are migraine headache, neck pain, heartburn, low back pain, wheezing, etc. Surrounding these is nearly the entire adult population, who at one time or another experiences or has experienced similar but often vague manifestations, often so slight that many would not call them "symptoms."

When a drug exists that has some effect on this condition, if often becomes a catalyst for rapid changes. Studies start appearing linking the condition to all kinds of severe problems or showing correlations to shorter life-expectancies.

Redefining Behavior as Pathologic Conditions
What then follows is usually a redefinition of health so these formerly normal conditions and behaviors get labeled as pathologic and thus within the realm of medicine. As mentioned above, people with these conditions help the situation along by preferring the label of patient. That can be seen in obese people who get teased by co-workers, or alcohol abusers, who end in police custody. Formerly accepted behaviors such a smoking have quickly become medical entities labeled nicotine addiction.

Family members also play a role in this, and they often prefer to see their kin as suffering from some ailment, rather than being personally responsible for the same condition. Being a patient has short-term benefits and enables access to health care dollars. But the drug companies are often the ones who stand to gain the most.

Alternatively, the definition of the disease is expanded to include earlier, milder, or even asymptomatic groups with no complaints whatsoever. Something like it has been happening with blood pressure, cholesterol, and other commonly measured parameters, for some time now.

In almost all cases, drugs affecting these parameters exist and become the focal point of studies. This type of market enlargement is common for blockbusters closing in on a plateau in sales. Underperforming drugs are more likely to be shuttled to previously unknown or little known conditions where a market can be created de novo, as in RLS, erectile dysfunction, and neuropathic pain.

Today's Wall Street Journal examines the role of the drug industry behind antismoking policy and new "guidelines" advocating "cold turkey" cessation. The advent of the nicotine patch and similar products is playing a big role in all this. Investors should be aware that there will eventually be a big backlash against all this.

Disclosure: none.

Comments

[Tom B:]

Several smoking cessation treatments work significantly better than willpower. If I reacll correctly, Buspar is the best. If I were a smoker and trying to quit, I'd be happy to pay for a little help.

2007 Feb 12 12:40 PM