The Lifecycle of Cipro

Franchise Architect. Alan Westwood, vice-president of global strategic marketing, anti-infectives, says Cipro is Bayer’s proud history, but Avelox is its promising future.

In 1982, Alan Westwood, brand new to a medical affairs assignment in Bayer's UK division, was going through his desk. He discovered a document for an antibiotic compound called BAY o9867. Westwood, a microbiologist, started reading. "I was rather amazed by its in vitro activity," he says.

Westwood, who today is vice-president of global strategic marketing for Bayer's anti-infectives franchise, ran down to the marketing group to find out the story on the compound. Looking back, he realizes that 20 years ago that was a surprising thing for a medical-affairs type to do. "It was very unusual, and it was one of the pivotal parts of my career," he says.

Team Cipro. Seated, left to right: Jonathan Harris, deputy director, anti-infective marketing; Jennifer Stahl, director, US oncology, new business development and former director, anti-infective marketing, Cipro/Cipro XR; Carol DEugenio, deputy director, marketing research. Standing, left to right: Steven Kowalsky, PharmD, global medical director, global clinical development; Marc VanUnen, director, anti-infective marketing, Cipro/Cipro XR; Eric Zalamea, deputy director, anti-infective marketing, Cipro; Carol Sever, deputy director, regulatory affairs.

Westwood's reach across disciplinary lines was prophetic. BAY o9867, better known as Cipro (ciprofloxacin), launched in 1987 and turned out to be one of the great medicines of the 20th century. Partly that was a matter of the molecule itself, an exceptionally useful, powerful broad-spectrum antibiotic. But it was also a product of something Westwood set in motion that day: a textbook example of how R&D and marketing can collaborate on an extraordinary product. Among Cipro's accomplishments, it was:

• the first antibiotic to launch (in 1987 in the United States) with five separate indications—urinary tract infections (UTIs), lower respiratory tract infections (LRTIs), skin and skin structure infections, bone and joint infections, and infectious diarrhea

• the first antibiotic to reach sales of $ 100 million in its first year on the market

• the subject of 40, 000 research publications

• available in four tablet dosages (100, 250, 500, and 750 mg), five formulations (tablets, IV, ear drops, and oral suspension), and an extended-release form

• a drug with 16 approved indications in the United States, the last of which—pediatric use for complicated UTIs—extended its patent exclusivity for six months in late 2003.

Throughout its history, Cipro has been a compelling case study in how to manage a drug over the course of its lifecycle, through reformulation, research, and promotion. It has also been a kind of training ground where a whole generation of Bayer marketing professionals learned their craft.

On December 9, 2003, the patent for Cipro twice-a-day (BID) tablet expired in the United States, but it was extended when FDA granted Bayer six-month pediatric exclusivity. Other patents remain, including one for its extended-release formulation CiproXR, and Bayer is exploring the possibility of others. But for many observers, June 9, 2004—the date the extension expired—was the end of an era. To mark the event, eight Cipro veterans, past and present, gathered to recall the drug's history and what it meant to them.

As Good as an IV

As a product, Cipro was a blend of marketing pluses and minuses. The second approved drug in the fluoroquinolone class, it was effective against the organism

Pseudomonas aeruginosa

, which causes hard-to-treat hospital-acquired infections. Its broad-spectrum efficacy on other bugs including

Escherichia coli

earned it the respect of physicians. On the other hand, it is less potent against streptococcus—and thus respiratory infections, the biggest chunk of the anti-infectives market.

Cipro's main advantage was strength: It was comparable to the IV antibiotics that ruled the field at the time. "That was key for clinicians," says Steven Kowalsky, PharmD, global medical director for global clinical development. "The idea of being able to have a drug that you can give orally that is as effective as a parenteral meant a huge cost savings."

This was before the heyday of managed care formularies, but the Cipro team was already making a pharmacoeconomic argument. "The quinolones were expensive drugs," says Carol D'Eugenio, deputy director of marketing research. "The economic story was that we kept you out of the hospital, so you saved $5,000 a day." And there was another problem. "In some cases the reimbursement system was not ready for the idea of putting a patient on an oral tablet in the hospital and then sending them home," says Jennifer Stahl, current director of oncology new product development, previously director of anti-infective marketing for Cipro/CiproXR.

Cipro was known around the world but had different names in different countries—in Germany, it was known as Ciprobay; in Japan, as Ciproxan; in Latin America, as Ciproxina; and in France, as Ciflox. Whichever the name and nation, Bayers message was always the same: Cipro meant power.

The key, for Jonathan Harris, deputy director of anti-infective marketing for Cipro/CiproXR, was the support of an international network of opinion leaders. "They believed in the studies," he says. "Almost every key thought leader had been involved in them. They were the ones saying, 'Look, you have got to believe this. I know we have never seen it before, but trust us. We have done the studies.'"

The result was a launch that surprised even insiders. "Just before launch in 1987," says D'Eugenio, "our German colleagues had presented a model, which was the first time we would forecast by indication. The model came out that Cipro would reach $100 million in its first year. Everybody said, 'Yeah, right.' It had never been done before."

But this time it was. Within six months of launch, Cipro was on 99 percent of hospital formularies, and by year end, the forecast had proven true.

Fund Everything

In the 1980s, Bayer put Cipro in the hands of a project team with membership from the key clinical functions, preclinical functions, and marketing. Cross-functional teams always sounds good but often fail. For Marc VanUnen, the current director of anti-infective marketing for Cipro/CiproXR, what made the approach work was accountability.

"In the old model," explains Harris, "if it's a marketing objective, it still comes back to marketing—'Oh, it's marketing's fault.' Cipro's model is: Get everyone in a room, and if you cannot come to a decision or cannot do it because of a guideline, you find a way that fits the guidelines or the timelines or the restrictions. If a medical person says they cannot do it, it's not, 'Oh, you're going to do it.' Rather, it is, 'Let's find a way of making it work.'"

In a sense, though, the team also included the substantial participation of the global community of microbiologists and infectious-disease specialists. Key thought leaders came to Bayer with ideas for new indications and formulations, and the company funded everything that came its way—including preclinical studies. At one point, according to Westwood, every hospital in the United Kingdom was testing Cipro for one thing or another. "I had something like 60 studies running," he says. "In the US, we blanketed the country, clinical and preclinical, in vitro, animal models, pharmacokinetics, and pharmacodynamics.

"Cipro was a very hands-on experience for many physicians. They understood how it worked. They recommended it in the hospital environment and then transferred that endorsement to community use. At one meeting in 1986, there were 113 presentations about Cipro—just to give you an idea of how many people were involved."

This Drug's Life. Reinvented, repositioned, and relaunched, Cipro lived long, and Bayer prospered.

The Case for Quinolones

Almost from the start, Cipro used its research base to add indications: typhoid fever, chronic bacterial prostatitis, intra-abdominal infections, sinusitis, febrile neutropenia, and of course the disease that added the drug's name to the vocabularies of late-night comedians: anthrax. The drug dominated the field of UTIs, but in 1996–1997, the team wanted a larger share of the respiratory market. That was doubly important, because of another upcoming Bayer quinolone, Avelox (moxifloxacin), which was expected to do well in the respiratory arena. By building the case for quinolones in RTIs, Bayer could pave the way for Avelox.

The result was the Cipro Oral Launch Team (COLT) campaign. The team built pulmonary advisory boards and collected "a ton" of publications. "Without that, it would have been difficult," says Harris. "A lot of physicians were like, 'Wait a minute—Cipro effectively covers strep?' The reps were not just pulling out reprints of one clinical study, they were pulling out four and five. They had slide kits and other support material. We had unbelievable support from top pulmonologists and infectious-disease people."

The campaign was designed to gain Cipro one point of market share. In practice, it gained two. More important, it taught the team a way to support the product. "We would meet weekly to say, 'What else can we do? What haven't we thought about?" says D'Eugenio. Adds Harris, "If we did not have the data, we would generate it. We would do a study."

What the team learned became a core Bayer strategy. "The study we did for COLT is tiny compared to what we do now," says Kowalsky. "A lot of brands within the Bayer franchise—Levitra and Avelox, for example—learned from COLT."

Below the Belt

By 1999, Bayer was ready to rethink its approach to Cipro's main indication: UTI. This was a time when resistance to the TMP-SMX class of anti-infectives was emerging as a true and growing global public health threat. And that created an opportunity.

"Physicians would try Bactrim (trimethoprim/sulfamethoxazole) or penicillin first, then move on to a quinolone like Cipro," says Stahl. "We wanted physicians to think of Cipro more in first-line use. Economic models show that if you are in an area of high levels of resistance, it is more economical for the physician and the patient to start with Cipro first."

The goal was to grow Cipro's UTI use from 48 to 56 percent of the drug's prescriptions. The team treated it like a relaunch, developing an internal icon and logo and conducting a huge Phase IV study of resistance rates. Called Strategic Urology Relaunch and Growth Effort (SURGE), the campaign gave birth to a catchy slogan for Bayer's two quinolones: "Avelox above the belt, Cipro below the belt."

SURGE succeeded in part because the team had already learned some important lessons from previous efforts that aimed to grow their UTI share. One had to do with the disappointing launch, in 1996, of the Cipro Cystitis Pack, a three-day regimen offered in packaging specially designed for women. "We didn't stay true to our branding," says Stahl. "All of a sudden, it was not the standard Cipro blue. As a product manager, I would never again walk away from my branding colors. That is your signature in the marketplace."

There were other issues raised by the pack. Pharmacies were already carrying 250-, 500-, and 750-mg tablets and resisted adding another SKU. Physicians, accustomed to a four- to seven-day course of therapy, balked at the pack's three-day dosing. And because reps were compensated based on dollar volume, they didn't have the proper incentives to push the lower-priced Cystitis Pak. Step by step, by learning from their mistakes along the way, the team mastered the art of managing new formulations and indications.

Anthrax Attack

Some of the most striking—and unexpected—lessons came in the wake of the anthrax attacks of October 2001. Cipro's effectiveness against anthrax had been known since the early 1990s, after the Department of Defense did animal studies to determine its utility. In the first Gulf War, it was used by the troops in Kuwait and Iraq. "Bayer worked continuously with the government to provide Cipro as needed," says Stahl. That paved the way for Bayer's regulatory submission for approval of a new indication. Andy Verderame, director of regulatory affairs, remembers believing that it was a toss-up whether FDA would think it was a good idea or simply laugh in their faces. But, in 2000, Bayer got approval for its anthrax indication.

When the US public became aware of anthrax as a potential threat, Bayer answered the governments call, but it put the company in the controversial position of having to authorize a generic version of Cipro.

Stahl says that when the public suddenly became aware of anthrax as a potential threat, "we answered the call of the government, but it put us in another predicament."

A major part of the national discussion was the idea that the government should break Bayer's patent so other manufacturers could make Cipro, because there were concerns that the company simply couldn't make enough for the entire country post 9/11. Bayer reassured the public that the supply wouldn't be a problem, but also became one of the first companies to authorize a generic. This has become a more common practice among pharma companies battling generic competition. It's also become more controversial.

By the Book

As Cipro moved into the latter phases of its lifecycle, Bayer looked for an analogous product to study in order to learn how to manage the product. The company chose the antibiotic Augmentin, which handled its patent expiry well; the team was encouraged to see that Augmentin grew 6 percent after the launches of the generic and its own extended-release formulation. And Bayer ended up doing pretty well too, with Cipro sales actually flattening out since the generic and extended-release launches, compared with where they were last year. The best part is, CiproXR is doing well so far and Avelox, the "above the belt" part of their franchise, is gaining market share in RTI prescriptions—and making up for the company's losses in Cipro BID sales.

Stahl says that the team "did it by the book, even though they didn't mean to." Some of her colleagues say the lifecycle of Cipro actually helped write the book, because they had no cases to learn from in those early years. In a world where the global market for existing antibiotics is estimated at $25 billion, few companies are undertaking antibiotic research, despite the urging of public health officials and physicians. And in an economic environment that is increasingly discouraging the industry's investment in research and development for anything other than new molecular entities, few companies are doing lifecycle management for their currently marketed products. Bayer is doing both, a testament to its commitment to its products, its pipeline, and the public health—but not necessarily in that order.