More pediatric drug studies have been completed in the past five years than in the previous 30. Sales of children's medicines are growing even faster than Rx sales for the elderly and are expected to reach $23.1 billion by 2006.

And, on average, pediatric patients spend $2.12 a day compared with seniors' average of $1.29. Tailoring products to this young demographic is a marketing strategy that pharmaceutical companies can't afford to ignore. It can enhance the product's therapeutic effectiveness, improve brand awareness and loyalty from prescribers and consumers, and increase revenue for a therapeutic franchise. 

Government agencies are behind much of the push—encouraging development of pediatric formulations with both the 

 of extended patent exclusivity and targeted R&D dollars and the 

, in some cases requiring pediatric studies before approval. (See "Pediatric Push.") Pediatric formulations of approved products offer multiple advantages:  							

But unlike products for other demographic segments, pediatric drugs require additional investment in formulation, clinical research, and manufacturing start-up. The market opportunity justifies the cost and effort, but the link between strategy and implementation for pediatric products must be especially tight. 

Until recently, most drugs were not subjected to clinical testing in pediatric patients, meaning that pediatric use of most medications is off label. "Eighty percent of the drugs used in pediatrics still don't have a label with pediatric information," says Cameron Durrant, president of PediaMed Pharmaceuticals. 

Because pharma companies conducted few pediatric clinical tests, children sometimes were given medications later found to be harmful. The most notorious example was the antibiotic chloramphenicol, which led to "gray baby syndrome" and the death of 23 infants because they could not metabolize the drug. On the other hand, some drugs that eventually proved effective for pediatric patients, such as potent AIDS medicines, went unused for years. 

When specific formulations and/or label instructions are not available for pediatric patients, physicians have to rely on their own clinical judgment to determine how to administer a drug that was intended for, and only tested on, adults. This approach is fraught with risks: Too much of a drug can be toxic, too little can mean ineffective treatment. 			

Dosing for children is more complicated than simply adjusting for the body weight or surface area of a smaller person. Accurate and effective dosages for children depend greatly on metabolism, absorption rates, rates of elimination from the body, and a host of other factors that distinguish young persons from adults. And these factors differ markedly within age classes of young people: adolescents (12â16 years), children (2â12 years), infants (1 month to 2 years) and neonates (0â1 months). 

Aside from pharmacologic issues, physicians prescribing adult medications to children seldom consider the practical issues of dosing compliance. Taste, texture, and ease of administration are among the important factors in ensuring that kids will be able to comply with dosing regimes. The reluctance or inability of children and infants to swallow pills is a special challenge. Older children are notoriously adverse to swallowing bitter-tasting tablets. 

Many therapies also require frequent dosing that can interrupt normal school day and afterschool activities. Social reasons make it undesirable in many instances for students to leave class and visit the school nurse three or four times a day because of dosing requirements. This constant interruption would be eliminated with a pediatric dosage form allowing administration during the time at home. 

A 2003 survey of pediatricians by the American Association of Pediatrics found the biggest barriers to completing treatment included the frequency and duration of the dosing schedule (96 percent), the unpleasant taste (91 percent), and the palatability of the drug (87 percent). 

Traditional child-friendly approaches to the problem have not always provided a satisfactory solution, especially because they make accurate dosing problematic. Tablets may have to be broken into pieces to get the child to take them, resulting in a loss of the drug—with no assurance that the child will consume all of the pieces. Spillage (or spit-out) can be a problem with orally delivered liquids, one of the most common pediatric formulations. Dosing implements such as droppers or medical spoons can aid in precise dose delivery, but for some drugs, liquids raise challenges relating to long-term stability. 

To overcome the challenges of treating children, pharma companies must formulate products that achieve and balance several key objectives: 			

 The formulation and administration method must ensure that children get the right amount of drug each time they are dosed and that they can comply with the daily dose regime. If these objectives are not met, patients may not get the full therapeutic effect. 

 This is critical for compliance with the dosing regime. Dosing frequency is a major concern: If dosing is too frequent or at an inconvenient time (in the middle of the school day), doses will be missed. Practical consideration must be given to both the parent (who is often giving the drug) and the child (who must swallow it). 

 There are many considerations here: ensuring that children do not receive a toxic dose, preventing them from choking on the medication, and prohibiting kids from taking the product when they are not supposed to. These are matters of formulation, packaging, and labeling. (See "Packaging for Safety.") 

 Even with the benefits of novel drug delivery technologies, the price of such products cannot be out of line with the adult version or with pediatric competitors. Manufacturing and packaging costs need to be consistent with a retail price point that can deliver the target unit volume. 

Novel oral delivery technologies offer pharma companies a range of options for producing products that meet those objectives and appeal to children, their parents, and prescribers. Such technologies include taste masking, chewable tablets, and controlled-release formulations. 			

This has evolved as an important formulation technology because children have a pronounced aversion to bitter-tasting medicine. Flavors, sweeteners, and coatings are standard approaches to masking otherwise unpalatable tastes. Excipient suppliers offer ion-exchange resins that, by absorbing the drug, make it mostly tasteless while in the mouth. Another approach is to reduce the rate at which a drug dissolves in the mouth. That can be accomplished by modifying the pH of the active ingredient to render it less soluble or by containing the active ingredient in tiny, microencapsulated spheres. 

 These are an increasingly popular option as a child can break the tablet or capsule into discrete pieces by chewing and can swallow the pieces with less chance of gagging or choking. As might be expected, chewables usually incorporate taste masking and other formulation characteristics that give the product a pleasing texture. 

 These can offer multiple benefits, depending on which technologies are used. Sustained-release technologies make small amounts of the drug substance continuously available over an extended period of time, typically by incorporating the active ingredient in a polymer matrix or applying a special coating. Sustained-release products can reduce dosing frequency to once or twice a day, offering a regimen that is easy to comply with. 

 These produce tablets that disintegrate in the mouth in just a few seconds with small amounts of saliva. The resulting small particles are very easy to swallow. In fact, for some drugs, the need to swallow is eliminated by pre-gastric absorption, which has the added benefits of quicker absorption and increased bioavailability. Fast-dissolving formulations often incorporate taste-masking features. 

There are many examples of drugs on the market that incorporate these technologies. One is the antihistamine/nasal decongestant Viravan (pyrilamine), a grape-flavored chewable tablet from PediaMed Pharmaceuticals, a specialty company whose products feature "Kidpliance" technologies that offer child-friendly drug delivery. 

Another example is Schering-Plough's Claritin (loratadine) Reditabs, a formulation of its antihistamine that incorporates Cardinal Health's Zydis fast-dissolving technology. Claritin Reditabs, which were originally introduced in 1997, reached sales of $300 million by 2001, and estimates say that nearly 75 percent of those sales were for pediatric use. For more recently approved pediatric formulations, see "New Labels."

In adopting these new formulation technologies, pharma companies face a set of considerations that must be balanced against their strategic and marketing objectives: 			

 The new delivery technologies will require more complex processing steps, more expensive excipients, and in some cases royalties and licensing fees, all of which can drive up the cost of manufacture. Those expenditures must be balanced against the benefits of higher revenues from better pricing and improved market share. 

 A proprietary technology provides better product differentiation and a more defensible market position. However, it will probably raise costs and may require partnering with a technology provider. Nonproprietary technologies are less costly but provide fewer competitive advantages. The decision about which technology to use may depend in large part on the degree of patent protection the active drug substance still has. For instance, a pediatric version of acetaminophen will be more defensible if formulated using a proprietary delivery technology, but the cost of the technology must not drive the price of the product beyond other over-the-counter versions. 

 To take advantage of a new delivery method, the active ingredient must be compatible with the technology. For instance, if the amount of drug per dose is large, it might not be accommodated in a dosage formulation that requires a large amount of excipient. Some active ingredients are not stable in water, ruling out the use of liquid formulations and some gelatin dosage forms. Thorough preformulation testing will determine if the technology and active ingredient are compatible. 

 Projected sales must be large enough to support development and manufacturing costs. If projected volumes are too low, the manufacturing costs may be too high to justify rolling out the new dosage form. This dictates focusing a pediatric strategy either on products with large markets or on smaller markets in which surveys indicate the reformulated product can command a substantial market share. 

Although new pediatric products have been introduced for diabetes, AIDS, asthma, and many other diseases, many opportunities remain. But it's important to remember that implementing a pediatric strategy requires the integration of skills in drug development, packaging, and marketing. Success in this market is a true test of companies' efforts to become market driven. To that end, companies must do the following: 			

 Children are not small adults: They have different dose response ranges and different preferences regarding dosage form, taste, and other product characteristics. The therapeutic dose and toxic dose can be very close, and within the pediatric population, the appropriate dose for a 3-year-old will be very different from what is appropriate for a 15-year-old. 

 Teenagers can safely take tablets and capsules, but these conventional solid-dose forms will usually be inappropriate and/or less effective for younger children. Also, different dosage forms may have different concentrations of the drug substance, which can lead to overdosing and underdosing if a formulation meant for one age group is given to another. Appropriate labeling and packaging that distinguishes products is critical. And using different formulations or delivery technologies for different age groups distinguishes them further. 

 In the absence of alternatives, physicians will use adult formulations to treat pediatric patients. Safety data on pediatric patients, even when a pediatric formulation is not available, can provide physicians with guidance on how to use the drug appropriately for children. Conducting the necessary bridging studies in early development stages is inexpensive compared to having to run the studies after approval. 

Consider taste masking and excipient choices early.

 Taste masking should be incorporated into excipient testing during preformulation studies. Technologies like the "electronic tongue" can be used to match desirable taste characteristics. Child sensitivity to different excipients can be identified through literature searches. Drug stability can be a major issue: Drugs not stable in water don't lend themselves to being formulated as solutions, as suspensions, or in gelatin dosage forms. 

In terms of size, need, and public policy focus, the opportunity for pediatric formulations is substantial. By meeting the needs of an underserved population, pediatric drugs offer pharma companies an opportunity to do well while doing good. 

Articles

Features

Pediatric drugs require investments in formulation, but the market opportunity is worth the cost.

The Growing Pediatrics Market

When the Department of Health and Human Services (HHS) sent out a video news release (VNR) in January called "Government Answers Questions About New Medicare Law," the agency thrust that public relations tool into the spotlight. 

The video, which aired on about 50 small- to mid-market stations, featured HHS Secretary Tommy Thompson and Leslie Norwalk of the Centers for Medicare and Medicaid Services touting the benefits of the new Medicare discount cards. It was voiced by a woman who signed off, "In Washington, I'm Karen Ryan, reporting." 

But then came the backlash. Ryan, a former TV news reporter and anchor and current president of the Karen Ryan Group, was vilified in some quarters as a shill for the Bush administration. As the story of "deception" gained momentum, several TV stations claimed they didn't know they were running a VNR. They thought it was "legitimate" news because they took it off of CNN's news feed service. (CNN declined to comment to 

for this story.) HHS says, given the title, TV stations were aware of the material's origin and had the opportunity to edit it if they wished. 

Eventually, the General Accounting Office ruled that the VNR was an illegal use of taxpayer funds for government propaganda. However, what's less certain is the controversy's effect on TV stations' appetite for pharma-funded VNRs. 			

In response to questions about the HHS VNR, former colleagues and current video news release users act as if they have been asked about their sex lives or tax returns: "I can't comment about that, but maybe I can find you someone who can," says one high-powered news executive. "Can I do it off the record?" says another. "I'll talk to you, but don't use my name," says one anchor. 			

So, what's the big deal? "Everyone uses them, but no one wants to admit it. Otherwise, there wouldn't be so many companies putting them out," says Christina Summers, a colleague of mine at the Manhattan Bureau and one of the few people willing to comment on the record. 

Few TV stations admit that they air VNRs word for word, but tracking reports indicate that the tactic is quite common. One medical news producer, who wishes to go unnamed, says, "We are very conscientious about what we put on the air. We don't use cut [pre-voiced] stories. And we don't retrack [replace the announcer's voice word for word] with our own reporter. We do our own research, but we are happy to look at VNRs and use the b-roll [secondary footage] when needed." 

The controversy over the Medicare VNR ballooned in the face of online news sources pointing to specific stations that were "lazy enough to run parts of the segment as news," according to 

's campaigndesk.org. Despite that, few industry observers think that will change stations' VNR pick-up practices.  

"I think it's had no impact," says one New York anchor regarding the Medicare VNR. "Stations have more and more hours to fill and producers have less time to vet the stuff. That's the fact, that's the bottom line." He goes on to explain why some pharma VNRs do so well: "Medical stories are very teasable so you're going to be drawn to them."  

The HHS VNR serves as a case study for industry and highlights important issues for executives to consider when using the tool. The first is to underscore the media's responsibility in how they use information transmitted through VNRs. Lisa Kovitz, director of brand marketing at Burson-Marsteller, says, "What we do is provide the expertise of our spokesperson or the unique finding of a survey or special b-roll that they couldn't get themselves, and then it's up to the journalists to decide what to do with it." 			

ABC News' managing editor for medical coverage, Roger Sergel, says, "The responsibility here is upon news people to be sure that they understand what it is that they are bringing to the public and that they make efforts to ensure that the information is accurate and balanced."

However, Sergel uses the word "deceptive" several times to describe medical VNRs. He sees public relations firms and drug companies using that video as a tool to get to the local affiliates that are more likely to run the material without question. 

Sergel's perception demonstrates how pharma-sponsored news feeds can backfire without complete transparency. "It's always very important when one is doing a VNR, press release, or setting up an interview to have full disclosure," says Novartis executive director of public relations Gina Moran. 

Other media, such as CBS News—which has its own paid VNR feed—have institutionalized the full disclosure process regarding VNRs. The organization's spokesperson, Sandy Genelius, says that, even before the HHS incident, "CBS Newspath already had in place an extensive set of safeguards to ensure that VNR material was clearly marked, and it would be virtually impossible for Newspath clients to mistake it for anything else." 

But if healthcare VNRs are so common and everyone claims to have a hard and fast policy about their use, why was the Medicare VNR such a big deal? 

"Perhaps in the HHS incident, it may have had more to do with politics than the use of a VNR as a public relations tool," concludes Moran. 

Ryan concurs: "The reason it got so much publicity is that it was political. I don't think it was so much that it was the VNR, it was the subject and the fact that it was an election year." 

It's back to business as usual for the parties involved in the Medicare VNR. HHS still runs VNRs. Ryan admits only one concession: "I won't sign off 'reporting' anymore." 

In an election year when the industry is a favorite punching bag, there are lessons to be learned. To be up front with TV journalists, ensure that editorial contact information is listed on the tape label and title slate in case reporters have questions. Watch networks' coverage of drugs. Is your VNR just as balanced? As clear and engaging? Would you be proud if the VNR's transcript was printed in the 

? If your answer is "no" to any of those questions, you might be heading for trouble. 

Backlash from a government VNR provides lessons for pharma PR.

Rx, Lies, and Videotape

Roger Newton and David Scheer were the co-founders of Esperion. Newton now leads Esperion as a unit of Pfizer’s global R&D. Scheer is president of Scheer & Co., a venture capital consultancy.

Every year, 1.5 million people cross a threshold into a dangerous disease. The plaque lining the inside of their arteries becomes thick or unstable enough to put them at risk for a heart attack. Known as atherosclerosis, the condition affects 12â15 million people worldwide and has a high mortality rate. In addition, hundreds of millions of patients suffer from high cholesterol levels, which cause that plaque to form. The pharmaceutical industry has produced a group of statins—all with blockbuster sales—to lower cholesterol levels, but so far, a medicine that reverses the buildup of plaque has been elusive. 

Such a product may now be in sight. Several of the scientists who developed Lipitor (atorvastatin), an anti-cholesterol drug that became the best-selling prescription product in the world at $9 billion a year—have wowed clinicians with their next breakthrough. The new therapy, which includes a recombinant form of apolipoprotein A-I, known as Apo-I Milano, has demonstrated in a small Phase II clinical trial that it can reverse plaque buildup by an average of 4 percent in five weeks. 			

"The results were as spectacular as any I have ever seen," says Steve Nissen, MD, of the Cleveland Clinic, who designed, conducted, and reported the trial. "They've set the research world on fire. People will be talking about this for a long time." 

 Cholesterol Cycle. High-density lipoprotein (HDL), otherwise known as "good cholesterol," enters the arteries where it converts cholesterol to a new form, then carries it away from the arteries to the liver, where it is processed for disposal. Low-density lipoprotein (LDL) or "bad cholesterol," on the other hand, delivers cholesterol to the arteries, where it can build up in the form of plaque. Esperions pipeline candidates mimic the action of HDL, and Apo-I Milano takes it a step further by reducing the volume of plaque that has already built up.

Before the Apo-I Milano champions could bring the protein to that point, they had to license the compound and start their own company, Esperion. But this story really begins long before that in a small town in Italy. 

Limone sul Garda sits high in the mountains of Northern Italy on the western shore of Lake Garda. In the 1970s, two scientists from the University of Milano, Guido Franceschini and Cesare Sirtori, discovered that 44 of its inhabitants had dangerously low levels of high-density lipoprotein (HDL), also known as "good cholesterol." 			

What's good about HDL is that it converts and carries cholesterol away from the arteries to the liver, where it is processed for disposal. Low-density lipoprotein (LDL) or "bad cholesterol," on the other hand, delivers cholesterol to the arteries, where it can build up in the from of plaque. (See "Cholesterol Cycle.") 

 The Arsenal. Esperion has a full line of cholesterol-regulating candidates in development to beat the war on plaque.

But despite their lack of HDL, these Italians—and their ancestors before them—lived long, healthy lives and had few heart attacks: the type of contradiction that makes researchers say "hmm." So Franceschini and Sirtori looked closely at the subjects' HDL and discovered that it was a little different from the norm, that it was, in fact, extremely efficient at its job, so very little of it was necessary. The researchers recognized a drug in the making, bonded the protein to a phospholipid, patented the combination, named it Milano, and in 1985, licensed it to Pharmacia (which was still based in Sweden). 

Then in the late 1990s, a round of acquisitions and restructuring shook loose both the protein and the people with the skills to develop it. Pharmacia merged with Upjohn, and the Milano protein, which had been largely ignored for a decade, was targeted for divestiture. David Scheer of Scheer & Co., a venture capitalist firm and consultancy, was hired during the Pharmacia Upjohn merger to evaluate those back-burner projects. 

"We looked at 14 and came to the conclusion that the Apo-I Milano protein was the most interesting," Scheer recalls. But at the time, Pharmacia wanted to focus on small molecules, not proteins, which are more difficult to develop and manufacture. Says Scheer, "They were interested in developing pills in a bottle." 

Scheer and his company had grander plans: "We had vision that this project deserved a platform, a company that had as its focus HDL as the next frontier in the cardiovascular arena." So they developed two scenarios to present to Pharmacia. Both had Apo-I Milano as a core candidate with other HDL therapies to be acquired or discovered, but one was designed as a Pharmacia management buyout or spin-off, and the other was a separate company founded by Scheer and a team of independent HDL experts, who would license the compound. 			

"We essentially had a bake-off at the 11th hour," Scheer recalls. "The fact that Roger Newton was half Swedish worked in our favor." 

The independent scenario won out. Around the same time, Warner-Lambert initiated a restructuring that limited the research activities of the team that had developed Lipitor, which was led by Newton. Scheer contacted Newton, who he saw not only as a expert in the field of dyslipidemia, but as an "entrepreneur, someone with charismatic leadership qualities who was under-appreciated by Warner-Lambert." Newton, with a PhD in nutrition with an emphasis on lipid metabolism, had headed the Parke-Davis/Warner-Lambert Atherosclerosis Drug Discovery Program for 12 years, including championing the discovery and development of Lipitor. He was ready for a change. 

"The experience I gained prepared me, at the Lipitor chapter close, to consider options outside of a large pharmaceutical company," Newton recalls. "At that time, genomics was very much a focus of preclinical research, and I wanted to be able to do what I did with Lipitor, but instead of focusing on LDL, I wanted to focus on HDL. And it became obvious that the better way of doing that would be to work in a smaller, specialized, company." 

Knowing he would need a great team of scientists, Newton persuaded three of his colleagues from Warner-Lambert's atherosclerosis program to join him. In May 1998, he and Thomas Rea, Charles Bisgaier, and Michael Pape left Warner-Lambert, and in July, the group launched Esperion in their hometown of Ann Arbor, Michigan. "We were all introduced to our entrepreneurial spirit," Newton says. "It's a different way of living your life, no question about it, but a very exciting one." 

To fund the company, Scheer (who until recently was Esperion's chairman) raised $15.5 million in venture capital from groups such as Oak Investment Partners, Healthcap, and TL Ventures. The Swedish government, which had supported Sirtori's initial research on the protein, kicked in $6.5 million in the form of a "forgivable loan." Additional financing from venture capital included $22 million in Series C and $5 million in Series D funding. In August 2000, Esperion went public and raised $62 million in its IPO. After that, the company raised almost another $100 million in equity financing. 

Some of the money was used to license and develop other HDL-based compounds. And some of the scientists who had been developing those projects followed the molecules to Esperion. "With each of these programs, there were people who were so excited by what Esperion was doing that they wanted to join with their feet and head up the discovery and research in the program," says Scheer. 

In the body, HDL circulates through the walls of the arteries to scavenge surplus LDL, converts it to a new form, then transports it to the liver for elimination. The process, know as reverse lipid transport (RLT), is more efficient in some people than in others. If LDL levels are too high, plaque eventually forms within artery walls. When these plaque formations rupture, heart attacks can result. 			

Apo-I Milano (ETC-216) mimics HDL, but is in fact so efficient that it actually removes cholesterol that is clinging to the artery wall. Scientists discovered its effectiveness early in animal testing. "In one study where they used IVUS [intravascular ultrasound], the arteries in the rabbits showed changes in 45 minutes," says Mary Ann Andreach, Esperion's vice-president of marketing and product planning. "So we knew that we had a very special product candidate on our hands." For the human trials, they contacted Nissen, who specialized in cardiovascular medicine and intravascular ultrasound. Not only was he an expert at going inside the arteries to measure plaque, he had also conducted his share of clinical trials for anti-cholesterol therapy, including some for Lipitor. 

Andreach, who worked with Nissen to design the study, describes its protocol: "We decided to take a risk and do our multiple-dose study in patients with heart disease. We identified people within two weeks of either having a heart attack or being hospitalized for unstable angina. It was a double-blind, placebo-controlled trial, and we administered five treatments over four weeks. We did an IVUS of one of their coronary arteries at the beginning of the study, and we did an IVUS at the exact same spot at the end of the study." 

The study was a long shot. "I expected nothing," Nissen says. "They had very little drug and the trial was very short." But in that short time and much to Nissen's surprise, the Milano protein reduced patients' plaque by an average of 4 percent. That may not sound like much, but patients taking anti-cholesterol medicines see their plaque volume increase by half that much each year. 

"What we showed for the first time is that you can take this disease process and actually reverse it," says Andreach. As yet, the excitement is based on only one small study. But Nissen assures, "This will be evaluated in multiple clinical trials." 

So the biggest hurdles are still to come. "Our goal in Phase III studies would be to treat 1,500 or 2,000 patients, per treatment arm," Newton says, "and show the aggregate reduction of overall mortality, nonfatal MI [myocardial infarction], and revascularization procedures that often are a component of people who have acute coronary syndromes." 

"One thing we didn't want to be from the get-go was a 'one-trick pony' company," says Newton. So early on, Esperion licensed several complementary anti-cholesterol molecules. The first came from Canada's Imex. Now in Phase II, ETC-588 is a naturally occurring lipid that helps HDL remove cholesterol from arteries and other tissues. (See "The Arsenal.") Known as large unilamellar vesicles (LUVs), these "cholesterol sponges" are being tested in patients with cardiovascular disease and in patients with acute coronary syndrome. 							

Newton describes the LUV mechanism of action: "It's a phospholipid bilayer that has an incredible capability of sequestering cholesterol. From a physicalâchemical point of view, cholesterol loves to be in such a bilayer. This infusion product is too large to get into the arterial wall itself. But the HDL particle is small enough to enter the arterial wall, pull the cholesterol out of the plaque, and then it gives up the cholesterol very readily to the LUV. For every gram of LUV that is infused, a half gram of cholesterol can be sequestered. So there is a very high capacity process here for sequestering cholesterol out of arterial walls and particularly out of atherosclerotic plaques." 

A third pipeline candidate about to enter Phase II is another cholesterol mimetic. ETC-642 is a small peptide phospholipid complex that has properties similar to Apo-I Milano. In Phase I trials, it was shown to increase HDL levels and enhance the mobilization of cholesterol. 

Although only one-tenth the size of Apo-I Milano, ETC-642 is also an infusion product, as is ETC-588. But Newton doesn't believe that administration route will hinder sales. "Of the patients who have ACS [acute coronary syndrome], up to 25 percent will come back within the year having experienced another event," he explains. "And then there are the people who have stable atherosclerosis—which may be 12â15 million patients in the US alone who have already had a heart attack and are at high risk for having another one. So there is a large potential market out there for these periodic, weekly infusions." 

Further down in the pipeline (preclinical and Phase I) is a group of small molecules that act as lipid regulators. In other words, they have the potential to be formulated as tablets that can be taken by a broad range of patients with high cholesterol and heart disease. These candidates are seen as those with the most potential to someday be combined with Pfizer's oral anti-cholesterol medicines. 

But Esperion's pipeline is no longer under Newton's control. Not long after the Apo-I Milano study was published, Pfizer—which had already acquired two of the earlier players in the Milano protein shuffle, Warner-Lambert and Pharmacia—made an offer to buy the startup for $1.3 billion. Esperion's board of directors accepted it. 			

They've kept the name, but the company now exists only in spirit—which is, ironically, what Esperion means. The R&D direction and funding are under Pfizer's governance. With a projected $200â$500 million in annual sales, the Milano protein is likely to receive the resources it needs. However, there is no certainty that all of Esperion's projects will move forward. 

"Obviously in the near term, because they are the furthest along, the large-molecule product candidates are of greatest interest to Pfizer," Newton says. "And they also have an interest in what we've been doing at the small-molecule level. But [to move forward] these product candidates must be complementary to the Pfizer strategy for their overall cardiovascular portfolio." 

Newton is optimistic about joining the fold: "It's actually very exciting, because we are a division of Pfizer. I report to John LaMattina, the president of Pfizer Global R&D, and I oversee the operations of the Esperion division. We will continue on our road to bringing HDL therapies to the marketplace. Based on our discussions so far, it looks like we will be able to continue to advance the science that we originally started six years ago." 

Staying with the project is important to Newton. "I like to finish what I start," he says. "I get a lot of pleasure out of working on the discovery and development of new medicines with talented people. To me, it's the journey and the personal relationships that are most meaningful, not getting to the end. So my commitment has not wavered a single bit since this acquisition. I was an entrepreneur when I was at Parke-Davis. I was also an entrepreneur doing what I did in Esperion. And I think I can do the same within Pfizer." 

We had a vision that this project deserved a company with a focus on HDL as the next frontier in the cardiovascular area.

Cholesterol Champions

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 

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 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 

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

 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 countriesÃ¢ÂÂ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. 			

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, 

, 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.

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 1996â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." 

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. 

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. 

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. 

Blockbusters may not grow on trees, but sometimes they hide in desk drawers. At least that's how it was for one of pharma's most enduring brands--one which, near the end of its patent life, boasts 16 indications, four formulations, and three (recent) billion-dollar years in a row.

Pharmaceutical Executive-08-01-2004

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