Articles

Thanks to managed care's efforts to steer patients into the least intensive treatment settings, primary care practitioners (PCPs) play an increasingly important role in prescribing. A case in point: PCPs write more than 70 percent of the prescriptions for selective serotonin reuptake inhibitors (SSRIs) used to treat depression, according to a September 2002 article in the Psychiatric Annals. Their patient load places PCPs in a pivotal role as major prescribers for many other medications as well. Yet, frequently pharma marketers have only a fuzzy understanding of what makes primary practitioners tick. To successfully target doctors in that desirable group, industry needs to better understand them.	

But they can be difficult to reach. Many PCPs do not belong to the American Medical Association. Only about half are members of a specialty organization such as the American Academy of Family Physicians (AAFP) or the American Osteopathy Association (AOA). And most caregivers who practice on the east and west coasts are employed by managed care organizations that operate as intermediaries, often raising barriers that reduce access to physicians.	

The situation frustrates PCPs as much as it does industry. At grand rounds, dinner programs, and other medical meetings, physicians complain of increasing patient loads, reduced time with each patient, reduced authority in determining treatments, and shrinking financial compensation. Many feel like they are on a treadmill, and some fear that they will never be able to regain their focus on what attracted them to a medical career in the first place: protecting the welfare of their patients. This article: 	

explains how primary care practices differ from specialty care

outlines approaches pharma companies can use to develop relationships with those caregivers

highlights the potential benefits to industry. 

In addition, it presents data from a survey of more than 8,000 PCPs nationwide that reveals the relative value they place on educational programs, services, clinical research, and samples. (See "What PCPs Value," page 64.)	

Despite the fertile opportunity, the pharma industry has traditionally harbored biases against primary care that limited PCPs' involvement in research and on advisory boards, according to industry representatives who attended 2001 and 2002 Primary Care Network advisory board meetings.				

Currently, only field sales reps routinely develop relationships with primary care physicians. Industry decision makers and policy setters most often consult with "thought leaders" and researchers who live in a world entirely different from that of the busy primary practitioner. That "super specialist" perspective gives industry a distorted view of actual medical practice.	

Industry gives tertiary specialists its ear in part because of a mistaken assumption that knowledge and expertise follow the four-level structure of the medical pyramid. (See "Pyramid of Care," page 66.) Industry executives assume that thought leaders know more than tertiary care specialists who know more than specialists who know more than primary care physicians.	

Although that hierarchy may be valid in the treatment of a specific disease, the expertise level reverses when it comes to treating a whole patient who has multiple medical conditions. Primary care has more insight into a patient's overall health than the specialists further up the pyramid. Consider, for example, someone with a parathyroid tumor who also has hyperlipidemia, hypertension, a difficult marriage, and a mood disorder. The primary care physician refers the patient to the subspecialist who treats the tumor. However, the PCP retains responsibility for the management and integration of the patient's entire medical, psychiatric, and psychosocial make-up. 		

In fact, an increasing number of patients with complicated medical problems are never referred up the pyramid because none of their multiple complaints meets managed care's criteria for subspecialty referral. Moreover, many patients prefer to receive treatment from their family doctor. A depressed person, for instance, may want to avoid the perceived stigma of referral to a mental health professional.	

Because primary care doctors represent such a large potential market, pharma companies should develop disease management strategies that apply to the family practice setting. Education based on those strategies would help PCPs treat the whole patient and would include nonpharmacalogical as well as pharmacological approaches.				

Such strategies also need to recognize three significant differences between primary and specialty practice. PCPs typically have much less time with each patient; only five to seven minutes compared with the specialist's 45–60 minutes. Another major difference is the patient's expectation of the clinical encounter. In one family practice residency program, patients presented an average of 4.3 complaints per visit, while they typically consult with a specialist for a single complaint. Finally, the diagnostic approach often differs between the two clinical settings. PCPs tend to rely on a working diagnosis that they confirm through treatment response, while specialists typically rely upon tests and diagnostic procedures.	

It's no wonder that many primary practitioners are slow to adopt new treatments when they hear presentations only from the top of the medical pyramid. Specialists lecture primary care doctors with in-depth details of a specific disease and provide evidence-based treatment guidelines. Those guidelines are often derived from results of clinical trials done with "clean" patient populations, those with the specific disorder under investigation but with no other confounding conditions. PCPs value that clinical information, but when they return to their offices, they need principles of patient management that they can generalize to a wide variety of medical scenarios. Survey respondents considered lectures from their primary care peers nearly as important as clinical trial data. 	

A 2001 survey of Primary Care Network (PCN) members found that 88 percent of PCP respondents want educators who understand and appreciate the unique nature of primary practice and who can recommend practical solutions to their real-world patient care dilemmas. When they attend medical seminars, they want information they can apply to the next three patients they see with that condition. If those patients respond, PCPs immediately see the value to their practice and will likely change their treatment or prescribing approach.	

When developing medical research programs, pharma companies typically go to the top of the MD hierarchy. Industry researchers ask thought leaders to write protocols, and they employ specialists and tertiary super-specialists as investigators. Clinical trial subjects typically come from specialty practice populations, and those with co-morbid conditions are excluded. Eventually, the new data trickle down to primary care physicians, but only after undergoing lengthy compilation, analysis, and publication. 				

It's not surprising then, that PCPs question the relevance of such academic findings to their diverse patient populations, and they may hesitate to integrate new approaches into their practices. Their own experience may conflict with "evidence based" guidelines, and in such cases, primary practitioners will typically follow their own clinical experience.	

One way to involve PCPs is for pharma companies to sponsor clinical integration trials-those conducted within a primary practice that test drugs in patients with complex medical problems. Integration trials can answer questions such as:	

Is this new drug safe for patients who have concomitant diseases and use other medications, such as antihypertensives or birth control pills? 

Does this new therapy treat the medical condition in such patients within a reasonable amount of time without many side effects? 

In Germany, general practitioners test new therapies in primary care settings in addition to research settings, reports Ulrich Goldman, MD, vice-president of Schering AG. That helps German pharma companies more accurately predict a drug's safety and efficacy and gives PCPs confidence that the medication will work with their patients.	

The industry is also coming under regulatory pressure to assess the frequency of adverse events, which means pharma companies in general are becoming more concerned about how pharmaceuticals work in diverse patient populations. As first-line healthcare providers, PCPs are in a unique position to detect treatment outcomes and side effects early, before they become complicated and difficult to manage. Those physicians may be the first to see the benefits of new treatments and to identify treatment opportunities for new drugs. They are also likely to be the first to identify potential complications and patient subtypes at risk for side effects. Identification of both benefits and risks in clinical integration studies conducted early in the drug development process may lead to treatment guidelines that doctors can quickly adopt in real-world medical practices.	

Investigator-initiated studies can also increase PCP involvement by enabling physicians to test the validity of a concept or an observation. For example, midwestern primary practitioner Roger Cady, MD, repeatedly heard his patients say that if they "catch the headache soon enough" they could prevent it from building into a full-fledged migraine. Acting on a hunch, he orchestrated a small study in which practitioners studied early interventions. The findings, which were later corroborated in a larger study, showed early treatment enhanced the efficacy of an anti-migraine drug and reduced adverse events and recurrence.	

The primary care world is an untapped opportunity for pharma companies. Because PCPs write the majority of prescriptions, they are in an ideal position to monitor adverse events. Because they treat patients with multiple medical conditions, PCPs are in a position to observe possible drug interactions. Primary Care Network has suggested to pharmaceutical executives, managed care, and FDA that a network of PCPs who are trained in drug safety could test newly approved drugs in their own practices. 				

Research suggests that approach could provide multiple benefits for pharma companies, PCPs, and even regulators. PCPs like getting in on the ground floor and helping to shape research, regulators say they like the idea of sharing the burden of responsibility for drug safety, and pharma companies like the prospect of reducing unanticipated post-approval drug problems.	

Industry observers anticipate that significant increases in user fees during the next several years will enable FDA to expand agency oversight of marketed medications. And recently FDA commissioner Mark McClellan expressed interest in ways Medicare and Medicaid programs might collaborate with FDA in the safety surveillance of pharma products. Those events affirm the potential benefits of conducting clinical integration trials in primary care settings before drug approval. It fact, some observers predict that eventually, FDA will require industry to provide patient data from actual medical practices. Pharma companies can take the lead by expanding the role of primary care physicians, who have not previously been involved in assessing the value and risk of prescribed products.	

PCPs' involvement in pre-approval trials could ease FDA's heavy burden, reported participants in PCN's spring 2003 advisory meeting. They also suggested augmenting MedWatch, the form FDA requires that physicians use to report an adverse event. Because filling in the form is so time consuming, only an estimated 1 percent of adverse events ever get reported. By streamlining the form and allowing online completion, FDA could make reporting adverse events easier and thus improve risk management. In addition, involving primary care givers could help communicate various risks to physicians, which, in turn, could modify their prescribing behavior. Perhaps best of all––for industry as well as for regulators––the use of clinical integration studies would clarify appropriate prescribing limitations, thus increasing regulators' options for market approval.				

Another way for pharma companies to involve PCPs in product research is to select some thought leaders from the specialty of primary care. Research designs would then more effectively weave clinical experience into the evidence-based studies, making clinical trials relevant to the population that primary care manages. The findings of primary practice can even suggest important research questions. PCPs have observed, for example, that many chronic medical conditions are co-morbid in a minority of individuals. Such a constellation of disorders calls for further medical and product research.	

Bob Ingram, vice-chair of GlaxoSmithKline and executive committee member of the Pharmaceutical Research and Manufacturers of America (PhRMA), says that when the industry is criticized for its methods, the public assumes guilt by association and blames healthcare providers as well. That perception makes PCPs and pharma natural allies. Clearly, working more closely with PCPs will provide numerous benefits to industry. 	

It will increase the likelihood that products succeed in the marketplace while providing a scientific basis for balancing risks with benefits. It could improve pharma companies' image by demonstrating concern for patient care while heightening the public image of new products and the healthcare delivery system. Not only could that collaboration help integrate new patient-care approaches into primary care more rapidly, it would enable pharma companies to identify a medicine's problems earlier in the product lifecycle and allow for earlier development of treatment regimens that reduce patient risk. Equally important is the cultivation of positive relationships with PCPs. By joining forces with primary care, pharma companies can turn a source of criticism into a resource of expertise and support.	

Those approaches will also help pharma companies demonstrate that their corporate culture does not match media stereotypes, and they will help build a trustworthy, people-friendly reputation that will help them weather tough times. Public relations consultants tout that kind of systematic approach to reputation management as the best strategy for enhancing shareholder value, attracting and retaining high-quality employees, and minimizing the impact of a crisis on company operations. In the face of increasing market, regulatory, and customer pressures, pharma companies are looking for ways to maximize results. Working more closely with primary practitioners can help build company reputation, prevent expensive surprises, and improve physicians' prescribing behavior. 	

Features

Thanks to managed care's efforts to steer patients into the least intensive treatment settings, primary care practitioners (PCPs) play an increasingly important role in prescribing.

The Pivotal Prescribers

How should drug companies and physicians interact? And if something is wrong with the relationship, who's to blame? 	

Some of the best thinking I've seen on that important issue comes in the British Medical Journal, which devoted most of its May 31 issue to teasing out the complexities of how for-profit drug companies alter medicine's playing field. It's a project that could have fallen into pharma bashing-and some individual pieces come close. But it's saved by a willingness to look past the surface to figure out how the pharma-medical system really works and why. 	

"This relationship isn't a Manichean battle between good and evil," writes deputy editor Jane Smith, "but the entwinement of individuals from different backgrounds and value sets who get to know, and often to like each other and therefore want, as humans do, to reciprocate friendships and favors." 	

The contributors don't let pharma off the hook, but they generate some fascinating insights into how the world works-and how hard it is to fix:	

An article on the use of third-party spokespersons zeroes in on the technique's double-bind: Pharma companies need physicians to speak on their behalf, because the companies' self-interests undermine virtually anything they could say. But because the third parties are working on behalf of drug companies, their own credibility erodes. One general practitioner says: "Either you are not aware that this is going on-in which case you trust everything and then people are harmed by prescribing medicine that has damaging side effects. Or, if we are aware of it, then we don't know who we can trust. This can lead to us being too sceptical so we don't prescribe good new drugs as soon as we should. Either way it's a no-win situation for patients and GPs." 

Several articles examine doctors' interactions with drug company sales reps. Some of the results are unsurprising: Doctors who interact weekly with them are more likely to prescribe new drugs-and to be isolated from colleagues and to work in poorer areas. For some of them, the authors argue, visits from drug reps "possibly fulfill a pastoral rather than an educative role." More troubling are data cited in another study that suggest that the more doctors accept gifts from drug companies, the more they (inaccurately) feel they are unaffected by them. 

Some of the most interesting analysis was devoted to medical journals. Several studies questioned whether there was something wrong with sponsored research or the articles that report on it. The situation is complex. Most sponsored research tends to be favorable to the sponsor's product, but not because such research uses inferior methodologies. Concerns include whether negative results are withheld and the comparisons experimenters choose to make in their studies. In general, the authors find problems that trouble them-and that threaten the ability of scientists to reach valid conclusions based on a review of the literature. But they have no easy solutions.

The editors may have set out to critique pharma, but by refusing to settle for obvious answers they've begun to sketch the realities of an industry that mixes public and private interests in ever more complex ways. Anything that gives all the players a more realistic sense of what's wrong and how the pieces are connected serves us all.	

Columns

How should drug companies and physicians interact? And if something is wrong with the relationship, who's to blame?

Pharma-Physician Conundrum

Paramus Road in New Jersey is a construction zone, filled with cars edging their way past lots slated for shopping plazas, food joints, and industrial office parks. Along that thoroughfare-near small pharma companies like Faulding and Synaptic and just a few miles away from Roche-lies Yama-nouchi Pharma America (YPA). Like the environment unfolding around it, YPA is in the process of becoming.	

Roger Graham, senior vice-president of sales and marketing; Akihiko Matsubara, president; and Robert Desjardins, MD, president of research and development, converse in the courtyard of their new Paramus, New Jersey facility.	

The company now occupies several floors of a new building, a substantial expansion from one year ago. Weekly management meetings have given way to daily updates informing executives of the company's latest marketing and execution plans. Industry analysts from Merrill Lynch, Datamonitor, and Decision Resources, among others, have already published their predictions for competitive sales.  	

That is a snapshot of a pharma company in waiting. Having submitted their first new drug application (NDA) to FDA for the investigational compound YM905, also known as Vesicare (solifenacin), a product to treat overactive bladder, YPA executives are gearing up for the agency's decision. 	

"We're moving full speed ahead with prelaunch preparations," says Roger Graham, YPA senior vice-president of marketing and sales. "We're excited about the compound and energized by the opportunity. And we don't expect good things-we expect great things."	

Vesicare may be at the crux of Yamanouchi's US expansion plans, but gaining FDA approval for the product is only the first step. 	

"The move to contain drug prices in Japan and the strengthening of US and European firms have made the Japanese pharmaceutical market increasingly competitive," says Akihiko Matsubara, YPA president. "In such a climate, Japanese companies need to capitalize on global opportunities." Matsubara points out that the course Yamanouchi took, like other Japanese pharma companies before it, was to establish an independent US marketing and sales organization that allowed for continued growth. By doing so, Yamanouchi can: 	

gain US marketing experience so it can one day market its products without splitting profits with licensing partners

increase returns on its R&D investments because it will have a US infrastructure from which to launch additional products

reduce its reliance on the Japanese market

"There is more out there than just marketing in Japan," says Michael Ferguson, a senior analyst specializing in Japanese pharmaceuticals and biotechnology for Wood Mackenzie. "Japanese companies must sell products in all markets. Global companies have special opportunities. They are likely to attract more successful products and partners and, by doing that, make more money and profit."	

Yamanouchi is not the first Japanese company to set up shop in the United States, but the establishment of its US subsidiary exemplifies the wider reality of Japanese pharma companies' flight to globalization. However, it learned some lessons from the companies that came before it, like Fujisawa, Eisai, Sankyo, and Takeda. 		

"It's interesting that Yamanouchi is going at it alone and not relying on partners," says Joanna Lawrence, a Datamonitor healthcare analyst. "By forming their own company, they can get the maximum sales profits from every product."	

Yamanouchi is similar to other Japanese companies in that it will try to use globalization to carve its way out of the increasingly hostile Japanese market. 	

It used to be easy to run a pharma company in Japan. Before 1983, the Japanese government prohibited foreign companies from filing new drug applications unless they had a Japanese partner. 			

"That meant Japanese pharma companies had a conveyor belt of innovative drugs coming in from Western companies to be co-marketed," says Ferguson. "They didn't need to sell anywhere else because they were doing nicely."	

Groomed by government, the Japanese pharma industry thrived in a system that favored domestic producers, placed enormous emphasis on safety-sometimes at the expense of efficacy-and, because the government-run National Health Insurance (NHI) picks up the healthcare tab for the entire population, kept companies insulated from the demands of the market. "Those factors combined to create an uncompetitive industry," says Todd Clark, president of VOI Consulting and editor of the Pharma Handbook: A Guide to the International Pharmaceutical Industry. 	

But megamergers and generic competition spurred western pharma companies' drive for profitability, and they clamored for Japan, the second largest pharma market, to let them in. With an economic recession in full spate, the Japanese government agreed to repeal many of its protective restrictions on industry to bring investment into the country from outside, says Clark. 	

The Japanese Ministry of Health, Labour, and Welfare reduced the review time for new drug approvals to 12 months. In addition, it adopted the International Conference on Harmonization (ICH) guidelines in 1998. Under the old rules, companies had to fully repeat clinical trials with Japanese patients-a major barrier to entry that kept brands like Tylenol out of Japan until very recently. ICH allowed researchers to use some data from clinical trials conducted in other parts of the world in the Japanese approval process. Pharma companies needed only to complete a bridging study that showed that the product worked in the population.			

"In the early days of ICH, the attitude in the United States and Europe was very skeptical," says Robert Desjardins, MD, president of YPA's R&D. "We thought, 'There is no way they can implement this stuff. It's going to be hard enough to harmonize Europe and the United States. There's no way we can harmonize Japan.' 	

"But it turns out that we were dead wrong. Japan implemented ICH requirements and guidances faster than we implemented them in the West. There was a recognition-typical of the Japanese, perhaps-that in the long term, this would help the Japanese pharma industry by forcing it to globalize."			

Under ICH, it was feasible for western pharma companies to launch both new products and a backlog of therapies that had not been marketed in Japan before. That increased the competition, says Lawrence, and caused "Japanese companies to feel threatened on their own ground." 	

In the same way that Yamanouchi seeks to market its products in the United States, Big Pharma companies may forgo contracting with indigenous companies and sell their drugs directly in Japan. Considering the dearth of NDAs at FDA during the last few years, that means growth opportunities for western pharma companies, according to Datamonitor. It remains to be seen if their growth comes at the expense of revenue for Japanese pharma companies-but it was that threat that finally ushered Japanese companies onto the world stage. 	

"Yamanouchi is a name that is unknown in the United States as a corporate entity," says Graham. "One of the biggest challenges is to establish it among US healthcare professionals so that when YPA launches a drug, it can focus on product education and selling." 				

It is true that the company's products have greater name recognition than the corporate brand. Consider Flomax (tamsulosin), a well-known treatment for the symptoms associated with benign prostatic hyperplasia, now marketed by Boehringer Ingelheim. Credit for that goes, in part, to Yamanouchi's business development division which was established in the United States in the early 1980s. Yamanouchi's first agreements from that office also resulted in the licensing of future megabrands such as Cardene (nicardipine) to Syntex (now Roche) and Pepcid (famotidine) to Merck.				

Ten years later, Yamanouchi expanded that office to include clinical development capabilities and called it Yamanouchi USA. YUSA consisted of a dozen employees-almost all Japanese expatriates-who worked closely with a clinical research organization to oversee Flomax's development. Despite being new to the agency's guidelines, that group successfully pulled together an FDA submission.  	

"Unfortunately, we didn't anticipate the opportunity Flomax created early enough to build a [sales and marketing] business for the company," says Desjardins. "Even though it was successful, it had to be out-licensed for marketing. It was clear to me when I interviewed here that Yamanouchi had no intention of letting that happen again." 	

Although Yamanouchi was one of the first big Japanese companies to arrive in the United States, it was among the last to establish a fully integrated pharma company. But it took steps along that path by creating Yamanouchi Pharma Technologies, which develops drug-delivery systems, in Palo Alto, California, in 1997 and a manufacturing center in Norman, Oklahoma, the following year. In 2000, Yamanouchi Venture Capital opened its doors with the goal of strengthening the company's investments in early-stage biotechnology companies throughout the world.	

Although Matsubara, who company executives affectionately refer to as "Mat," worked at Yamanouchi's Japanese headquarters from 1977 until he came to the United States in 1999, he runs YPA with a decidedly American spirit. 				

"I didn't find a cultural gap between myself and the American people after I relocated," says Matsubara. "Instead, I feel right at home." 	

Desjardins says, "Because it is a Japa-nese company, I was concerned that it might be tightly controlled from headquarters or excessively hierarchical. But the style of management is very open and communicative and enjoyable to work in."	

Graham adds, "YPA offers the best of both worlds. You are working for an organization which is just getting started in the United States, but there are vast resources to support you."	

YPA executives attribute the subsidiary's independence to Takenaka's vision. "In my earliest interview with Dr. Takanaka," says Desjardins, "he said he understood that if we met the standards of product development of the US FDA, we'll meet them anywhere in the world. Certainly, the company has embraced the concept of global product development. And because FDA drives those standards, that places us in a key position here in the United States."	

Desjardins adds that, although YPA will increasingly play a leadership role, the company will continue to work cross-functionally with its colleagues in Japan and Europe. After all, Yamanouchi conducts all of its discovery research in Japan, but development takes place across the globe. He says, "The ability to file applications for a new chemical entity in many markets at once speaks well of the company's coordination of its development systems and is evidence of its ability to work globally-not a trivial undertaking."				

"We were very close to submitting Vesicare in Europe at the same time as in the United States," says Matsubara. "Japan was somewhat later, but in the future we will make product submissions simultaneously."	

It is through such thinking that the divisions between Yamanouchi and YPA begin to melt away. "Yamanouchi products and YPA products are really one and the same," says Graham. "Right now, we want to establish Yamanouchi and Vesicare as truly global."	

Vesicare is an ideal therapy for Yamanouchi's first US marketed product. Yamanouchi scientists discovered solifenacin in Japan, where the overactive bladder (OAB) market is not yet established. However, the company transferred development of the product to the United States, where analysts expect the market to grow as awareness of the condition increases and the stigma decreases. Graham says, "There are 17 million patients who suffer from OAB in the United States, but only 20 percent receive treatment. Part of growing that market is to get the other 80 percent of patients to seek treatment."								

The Prostate Cancer Education Council reports that overactive bladder affects all ages and both sexes, although women are twice as likely as men to have the condition. The council estimates that 15–30 percent of people over the age of 60 who live at home are incontinent as well as at least half of the 1.5 million Americans who reside in nursing homes.	

"It is possible that the size of the market may double over the next ten years," says Kat Neumeyer, a Decision Resources analyst specializing in the OAB market. "There is the baby boom factor. We know the marketers of drugs that target 'old age indications' are going to be very successful. A lot of that has to do with a change in attitudes about medical treatments for non-life-threatening conditions. That growth will be primarily driven by the US because it doesn't have the same issues as Europe does with pharma reimbursement cost control."  	

Paramus Road in New Jersey is a construction zone, filled with cars edging their way past lots slated for shopping plazas, food joints, and industrial office parks. Along that thoroughfare-near small pharma companies like Faulding and Synaptic and just a few miles away from Roche-lies Yama-nouchi Pharma America (YPA). Like the environment unfolding around it, YPA is in the process of becoming.

Company in Waiting

Looking back on 2003, biotech industry insiders and the analysts who cover them would agree that the opening line from Charles Dickens' A Tale of Two Cities aptly describes the current biotech market: "It was the best of times, it was the worst of times." 	

Institutional investors' and analysts' views of the market reflect their different investment styles and time horizons for holding individual portfolio positions. A hedge fund manager-for whom a week is long term-views the market differently than an investor looking for relative value within a sector or a peer group of companies whose investment time horizons are between two and five years. Those differences further exacerbate the volatility of the biotech market, in which some companies succeed and others fail for reasons that have little to do with quality research and development.	

Based on the results of an informal survey of financial community representatives, this article highlights the key challenges and opportunities in biotech today. For some, the news is encouraging: the world of biotech investing has never been more exciting and positive. Survey respondents said:	

There are more attractive companies than ever-innovative, cash rich, and virtually unknown to most investors.

Valuations are at their most reasonable in a long time.

Pharmaceutical companies faced by pipelines problems have no choice but to search for biotech companies and products that complement their own efforts.

Revolutionary technologies and products are on the verge of reaching the patients who need them.

FDA finally has someone at the helm, indicating a new era for biotech companies and their products.	

Yet, at the same time, biotech companies without a positive cash flow or products in Phase III have never faced such intense scrutiny by institutional investors:	

After 20 years, the investment community is savvier about biotech's clinical development process. As a result, companies must work harder for a piece of the funding pie.

Many companies that skated through the 1990s with a compelling story are on thin ice as institutional investors, analysts, and FDA now demand high-quality product development packages and publication of peer-reviewed data for validation.

The survey's institutional investors reported the following issues as the most challenging to the industry right now:				

Limited funding options. A glut of companies have depleted their IPO proceeds and still need to raise money before they can take their products through FDA approval. Many of those companies have not yet reached, and in some cases are not even close to beginning, their Phase III trials, decreasing the likelihood that they will be able to access additional funds in the current negative economic environment. At the same time, Big Pharma, which in the past provided biotech companies with an exit strategy and funds to fuel product development, is also under pressure to produce consistent earnings growth. 	

As a result, that group has grown more selective about taking stakes in companies in which the synergies are not obvious. Without those two traditional sources of funding, it seems likely that intra-biotech mergers and acquisitions will continue. Several institutional investors also mentioned that venture capital firms (VCs) are likely to take a few of the more stable biotech companies with limited cash private again.	

Unforgiving climate. Most respondents felt that the current market dynamics made anything less than perfect performance and meeting every expectation unacceptable. Consequently, investors overreact to negative news and often ignore positive or expected news.	

Economic cycle new to most CEOs. Many of the executives running biotech companies seeking to raise capital have never had to look for cash during a negative economic cycle. That inexperience is challenging when they must deal with sophisticated biotech investors who have experience in both bull and bear markets. 	

Zero tolerance for fuzzy communications. Against the backdrop of increased investor scrutiny and dwindling goodwill, companies must communicate their news clearly and accurately because the perception of any risk will send investors running to the exits. Although negative news will cause a sell-off, the decline will be exacerbated if the investment community perceives that management is glossing over or distorting the facts. 	

Phase III premium. Dedicated biotech investors increase their stakes and access to capital increases measurably when a company gets a product into Phase III. Moreover, the broad base of general healthcare funds open up to those companies as additional sources of funds and potential shareholders. 	

This trend is fueled by two factors: Until they cross the Phase III hurdle, biotech companies don't offer investors much trading liquidity. And compared to two years ago, later-stage companies are trading at much more attractive price/earnings ratios.	

Macro economic environment. The build up to the war in Iraq and the war itself posed both economic and operational challenges as the market reacted to news  in the Middle East. For biotech companies, the best way to navigate such macro-economic issues is to provide news about how their business remains on course.	

The current biotech market presents opportunities for both astute investors and nimble biotech companies. Respondents named the following trends as positive:				

Undervalued equities with strong pipelines: The converse of the Phase III premium mentioned earlier is that investors see significant potential in undervalued companies with strong pipelines in growing therapeutic areas such as cardiovascular and oncology.  Those companies will deliver value to shareholders based on their solid scientific foundation, respected management, and quality clinical plans. For investors with longer time horizons, the market has rarely been so attractive.	

Significant discounts for biotech investors. Many of the big biotech companies (like Genentech and Amgen) are currently trading at a significant discount to their true market value. That poses high-reward investment opportunities for investors who are not dedicated to the biotech and healthcare sectors and are looking to get into a sector with upside potential. 	

New FDA leadership. With the new commissioner, biotech investors hope to see more decisive action in the form of approvals, streamlined procedures, and updated protocol parameters in promising areas such as oncology and biologics. Although most investors hope for a swifter approval process, they are realistic and respect FDA's authority and fiduciary duty to safeguard US citizens. In survey conversations, most investors were cautiously optimistic about the perceived positive changes taking place in the agency. 	

Consolidation and partnership deals. In recent months, the market has seen a spate of mergers and acquisitions mainly by pharma companies but also by intrepid biotech players. Survey respondents anticipate that, because of increased pressure on earnings, the deal-making bonanza will flourish, fueling pharma companies' ability to take strategic stakes in biotech firms rather than acquiring them outright. Also, to reduce the expense and time of raising capital, several biotech companies chose to merge this year. The pace of such deals is likely to accelerate, especially if the financing window remains jammed and companies need cash to move products through the pipeline. 	

Overall, recent market action has led to a scenario in which the "dream factor" is no longer a component of biotech valuation models. The "story stocks" of the late 1990s and early 2000 have been cast aside in favor of companies with solid science, honest management, and transparent communication programs. For companies that fit that profile, this can be the best of times. 	

Looking back on 2003, biotech industry insiders and the analysts who cover them would agree that the opening line from Charles Dickens' A Tale of Two Cities aptly describes the current biotech market: "It was the best of times, it was the worst of times."

Best of Times, Worst of Times

Pharma companies seem to have forgotten one key lesson: Blockbusters are made, not discovered. Few drugs achieve top sales based on their initial formulation and indications. Instead, most major products succeed because of a company's concerted efforts to expand and extend their application through product lifecycle management (PLM). Pharma powerhouses Pfizer and Novartis have reaped superior rewards by balancing their efforts in pursuit of both new chemical and biological entities (NCEs/NBEs) and line extensions. They pursued PLM to capture the full value of the products they already had, while continuing to investigate novel NCEs. 	

This article outlines how pharma companies can use enhanced PLM opportunities for growth and profitability. During the ten years of additional patent life that reformulation can bring, the average blockbuster earns more than $2 billion in net profits. Although other avenues-a switch from brand-name prescriptions to over-the-counter products, branded generics, and combination products-are applicable for a few medications, reformulation is a cost-effective way to extend the lifeline of most brand-name therapies.	

During the patent exclusivity period, companies can increase sales through eight PLM strategies:				

Marketing. By developing prelaunch awareness, taking the product launch global, and creating marketing and promotional alliances, companies can ensure the broadest access to the available customer base and thus the fastest ramp-up in sales. Warner-Lambert/Pfizer's co-promotion efforts for Lipitor (atorvastatin), and Pharmacia/Pfizer's for Celebrex (celecoxib) are good examples of how companies can join forces to create "category killers."	

Indication expansion. Maximizing the label before patent expiry-the preferred approach of many franchises-is another way to enhance brand image and sales. Companies should always consider that development option, assessing both the therapeutic area and cross-therapeutic area opportunities of their candidates and targets. (See "Reformulating Rewarded," page 74.) 	

Pediatric or orphan indications. These can speed approval time and bring six months or seven years of market exclusivity, respectively, but in most cases they expand the market only marginally, because children don't take many medications and orphan products have small markets.	

Combination products. Although attractive as a way to extend a therapy's life, combination products are difficult to develop because FDA treats them almost as though they are new NCEs. Although GlaxoSmithKline's Combivir, which combines Epivir (lamivudine) and Retrovir (zidovudine), is a success story, Merck and Schering-Plough' s difficulties in combining Singulair (montelukast) with Claritin (loratadine) highlights the challenges of this approach. Because these combinations are treated as new NCEs, they must go through lengthy trials to show they are more efficacious than their individual active ingredients.	

New forms. These include salts, co-crystals, and hydrates that have benefits of their own or enhance the effectiveness of a drug delivery technology. 	

New formulations. Many successful product extensions come through formulation changes such as:	

chiral forms/isomers and active metabolites

process technologies, such as purification and expression systems

drug delivery systems such as patches, devices, and implants.

Of those enhancements, drug delivery technology has traditionally held the greatest promise. By marrying an off-patent opiate with a novel, transdermal drug delivery system, for example, Alza created a $1 billion-a-year blockbuster in Duragesic (fentanyl patch). Still, drug delivery systems often have considerable limitations, such as utility with only certain types of compounds and challenges in delivering the dosage desired. Those factors can add significantly to cost and regulatory complexity.	

Switch from Rx to over-the-counter. Although an Rx-to-OTC switch can be lucrative, only a few types of medication are suitable for OTC sales: those for non-serious conditions and those with good therapeutic to toxicity ratios. Antihistamines, H2 blockers to relieve heartburn and gastroesophageal reflux disease, and antidiarrheals are three common success stories. Other potential categories-such as statins, antibacterials, and hormones-may not be successful because of concerns about self treatment, toxicity, and misuse.	

Branded generics. Given Big Pharma's limited success in competing with generics companies, few innovator pharma companies have pursued this approach, but there are exceptions: Bristol-Myers Squibb (Coumadin/warfarin), Pfizer (Dilantin/phenytoin), Novartis (Tegratol/carbamazepine), Abbott (Depakote/divalproex), and GlaxoSmithKline (Dyazide/hydrochlor-othiazide/triamterene). Many products that have crossed over to OTC status still have some innovator-only dosage forms. In other cases, only the innovator's original product has been approved for a particular indication. Either situation can be the basis for branding a generic. 	

Patent expiry is not the only threat to a company's products. If competitors find novel, commercially relevant forms of an active ingredient, those new formulations can erode the market share of the originator. In the worst case, a competitor could find novel forms, formulations, or delivery systems for a molecule and block the company that owns it from using those forms or formulations as part of its own products' lifecycles. Sepracor used that strategy to identify isomers or metabolites of other companies' drugs and to license them back to the owners of the original molecule.				

The same potential exists with novel solid forms-polymorphs, salts, hydrates, and co-crystals-and drug formulations. Aggressive generics and specialty pharma companies have begun to exploit that potential, filing rafts of patent claims on others' molecules. In that way, such "upstarts" can skirt the patent process of mature companies.	

Three such examples are Pfizer's Zoloft (sertraline) and Norvasc (amlodipine) and GlaxoSmithKline's Paxil (paroxetine). In each case, one or more competitors claim to have identified an alternative solid form of the active ingredient that is bioequivalent to the brand-name product. In each case, the competitors seek to launch these products before the innovator's patents on the specific solid form of the compound expire. 	

Pfizer and GSK made themselves vulnerable to such attack by failing to patent-protect, in a timely fashion, all of the forms with potential commercial value.  That is not surprising, because there is little internal incentive, given the time and expense of conventional "low throughput" screening, for innovators to keep looking for every way to develop an acceptable version of a drug once they have identified one acceptable form. But that might be penny wise and pound foolish. Although both companies benefit from exclusivity until their NCE patent expires, they may lose several years of additional exclusivity on preferred solid forms of their compounds because they failed to identify and patent all other viable alternative forms.	

To prevent other companies from prematurely entering their markets, innovator companies must investigate their drug molecules thoroughly before they bring them to market, then file patent claims on all commercially relevant and potentially beneficial solid forms and formulations of each one, as well as delivery systems that might be used with the compound. Otherwise, they risk losing a piece of the pie at later stages of their products' lifecycles.	

One way innovator pharmas can address this issue is by employing the kinds of sophisticated high-throughput screening techniques and informatics that they typically reserve for new product discovery. Traditionally, form and formulation experiments have been done in a manual, low-throughput manner, involving only tens of experiments per compound.	

By using high-throughput techniques, companies can conduct thousands of experiments on compounds that are already patented in search of nonobvious forms as well as synergistic, excipient combinations for use in product extension and enhancement. Using such an approach, companies with approved products could harvest significant additional lifecycle opportunities. 	

New technologies are also increasing the range of possibilities for biologics, and that is critical, because many major first-generation biologics are under generic threat. In this arena, too, companies have several ways to extend patent life:  				

post-expression modifications, such as glycosylation

targeted coupling, conjugation, and fusion of molecules to enhance therapeutic value

expression system improvements, including molecular biologic approaches

drug-delivery systems, such as depot, needleless, and inhaled/nasal forms.  

A majority of biological products currently on the market are glycoproteins-proteins with attached sugar chains. Glycosylation is critically important in the pharmokinetics, bioactivity, solubility, and immunogenicity of such products. Its critical role enables companies to improve the performance of therapeutic proteins and extend their intellectual property life. Neose's GlycoPEGylation technology, for instance, has been shown to significantly improve the pharmacokinetics of many products, including several currently marketed glycoprotein blockbusters such as erythropoietin and follicle-stimulating hormone.	

Amgen's Neulasta (pegfilgrastim), a pegylated version of Neupogen (filgrastim)-the man-made form of granulocyte colony-stimulating factor-is another example. It offers a more convenient dosing schedule and a longer half-life for the compound, which stimulates production of white blood cells in users, most of whom are cancer patients. With Aranesp (darbepoetin alfa), Amgen's follow-on product to Epogen (epoetin alfa), the company reengineered the basic protein to create a "next generation" drug. Aranesp has an additional two N-linked glycosylation sites beyond Epogen's three sites. These sugar molecules attached to the protein significantly increase half-life and reduce dosing frequency for the red blood cell-producing protein.   	

Pharmaceutical executives must play a critical role in rejuvenating interest in PLM within their companies. They must understand new technologies but also be aware of opportunities for, and threats to, the company's products. They need to ensure that their companies maintain an appropriate balance of PLM, drug discovery, and innovation. Here's how:				

Prioritize franchise development. Both commercial and R&D executives must stop giving automatic priority to "sexy" new NCEs and NBEs over lifecycle extension efforts. The typical rationale is that NCEs and NBEs are the future and that line extensions lack strategy. That is false. In fact, the latter may have earlier and more certain market impact. 	

Line extensions are part of protecting and building a hard-won franchise. Often, when companies trade off valuable line extensions for more risky new products, they fail to ensure funding for important line-extension activities. The two should not be mutually exclusive. Executives need to balance those interests and their impact on returns, costs, risks, and timing and use the best evaluation tools to do so. That means protecting their portfolio investment opportunities by growing and protecting franchises as well as by creating new markets.	

Integrate marketing and R&D during development. Involvement of a company's commercial groups is critical to developing the best PLM approach. Marketing executives traditionally pay scant attention to early-stage drug discovery activities. To provide high-quality input and strategies, most companies need to greatly enhance connectivity between these two halves of the company. Earlier commercial involvement will ensure that more attention is placed on how to create PLM product ideas through form and formulation opportunities.	

Integrate lifecycle management into product planning. PLM must be integral to the process of drug development and not just an add-on a few years before patent expiry. Ideally, companies should consider PLM during the target validation period pursue it aggressively thereafter.	

Refine and integrate late-stage drug discovery and early development plans with product lifecycle plans.

Modify stage gates to include consideration of projects' lifecycle potential.

Consider product lifecycle options at each stage of development, not only in Phase III. In the earlier phases, companies should consider follow-on targets, based on the target family opportunities, and follow-on compounds. In Phase III, as success seems more assured, companies could explore follow-on indication and form and formulation opportunities. 

Refine portfolio and productivity management systems to reflect the lower risk and faster return of PLM efforts. Allocate enough R&D budget to line extensions, which have lower risks and faster returns. 

Improve functional acceptance. Too often, R&D functions are not interested in PLM and would rather work on novel compounds. In addition, the technologies are rejected and seen as threatening by the very R&D and formulation groups that could best use them. To move forward and exploit new opportunities for growth, companies must change any destructive, not-invented-here attitude.

Improve partner relationship management. Many key technologies come from companies outside Big Pharma. To move projects forward successfully, Big Pharma must work seamlessly across teams and functions, both internally and with partners.

Reward successes for product lifecycle management "genius." Too often, R&D incentives, such as professional recognition, patents, and financial rewards, favor those who come up with NCEs and NBEs. But companies should reward all contributions to product success, including pursuit of opportunities through inventive use of PLM tools and techniques. 

Companies that follow those guidelines can greatly expand their ability to explore new product forms and formulations to build, sustain, and preserve their product franchises. But to succeed in today's marketplace, they must plumb the opportunities inherent in the full range of product lifecycle management. In the face of competitors' aggressive attempts to sidestep or overtake originators, few companies can afford not to. 	

Pharma companies seem to have forgotten one key lesson: Blockbusters are made, not discovered. Few drugs achieve top sales based on their initial formulation and indications.

Extending the Product Lifeline

Partnerships between pharmaceutical (Rx) and diagnostic (Dx) companies are difficult to achieve because most managers don't understand what it takes to make them work. 

Some pharma executives see diagnostic tests as a double-edged sword. On the one hand, tests can diagnose patients who should take a particular medication, thereby expanding market share. Yet, diagnostics threaten to limit market share by inhibiting doctors from prescribing a medication without a confirmed diagnosis. (See "Double-Edged Sword," page 50.) 

And when a pharma company does decide to partner with a diagnostics company, it often has completely unrealistic expectations about how long it takes to develop and launch a product. The pharma partner typically wants a market-ready test in six months, but even when that is possible the diagnostic partner knows that the situation is no better from the diagnostic angle. With increasing regulatory demands, more sophisticated technology, and low profit margins, Dx companies do not have the marketing, sales, or development resources they need to make a new test commercially successful in a short time. Typical diagnostic test development and market acceptance time lines range from two to ten or more years, and most new diagnostic tests take at least three to five years to become established and used regularly by physicians. Even large integrated companies with both Dx and Rx divisions, such as Roche, Abbott, and Bayer, have been unable to find the ideal synergy between their diagnostic tests and their drugs. But there is still hope for bringing the two sides together. 

The good news for partnerships is that the very factors that make Dx companies hesitant to form pharma alliances also represent significant opportunities for both parties. When the might of a pharma marketing and sales force is combined with the technology of a strong diagnostic test, the potential to increase market share is significant. 

Consider what the cholesterol test did for Mevacor (lovastatin). (See "Slow Road to Acceptance," page 52.) Merck spent millions on a "know your number" campaign to make HDL and LDL household words. In return, the diagnostic tests helped Mevacor achieve blockbuster status in a relatively short time. 

Changing dynamics in both the therapeutic and diagnostic industries will make partnerships an even more important strategic move in the future. As disease awareness expands and therapeutic interventions become more specific and customized to individual patients, the need for diagnostic tests that help a physician select specific drugs will also expand. 

Successful partnerships can bring significant rewards to both parties, so it pays to invest the time and effort needed to get them right. (See "It Takes Two to Tango.") This article discusses the steps necessary to make that happen. 

Pharma companies must understand and respect that Dx development and marketing time lines and activities-although they are more similar to pharma now than they were during the past decade-still take a different approach to gaining physicians' acceptance and use. Partners must begin working together as early as possible in the development process-even during the pre-clinical stage.  

Small and large diagnostic companies and large reference labs bring different attributes to the table. Large, integrated Dx companies have sales forces and marketing budgets large enough to promote their tests and educate physicians. They also tend to have greater flexibility in developing tests for a variety of therapeutic areas. However, because of the need to run such new tests on instruments previously placed with their customers, large Dx companies ultimately limit their degree of flexibility. Thus, a pharma company may need a diagnostic test to identify patients allergic to dust mites, but such a test may not be adapted to run on the established test platforms of the large diagnostic companies, thereby limiting the use of such a test. 

Conversely, because they have fewer resources and don't want to spread themselves too thin, small diagnostic companies tend to specialize in fewer therapeutic areas. Yet they can develop tests to fit specific treatment outcomes and are thus more technologically flexible. Because of their size, however, they may lack the marketing power and direct sales force support required to drive a new product to commercial acceptance. (See "No Promo, No Uptake," page 56.) 

Failure of pharma companies to appreciate those differences could lead to mismanagement of expectations in a partnership and, ultimately, to disappointment. Research shows that, to ensure a productive relationship, pharma companies with successful Dx alliances look for a few critical attributes in potential partners: 

strong scientific and technical capability

good reputation and track record for developing tests (See "By Reputation Only," page 56.) 

manufacturing capability needed to meet market demands

The choice of test type-laboratory versus point-of-care-also plays a key role in the success of an Rx Dx alliance. By its nature, the lab test may not be the best diagnostic to build a partnership on. Lab-based tests in which samples must be sent out for analysis often require several days' wait for results. That time lag could cause a physician to delay prescribing a drug, much to the dismay of a pharma marketer.  

Large central labs, such as Quest and LabCorp, resist doctors' attempts to specify a particular test because such requests impinge on the lab's flexibility. Yet, allowing unrestricted substitution of tests in the diagnostic environment is the equivalent of pharmacists switching a brand-name drug for a generic one without the physician's prior knowledge. FDA "approves for market" a test for a specific indication, but it does not impose restrictions on which test brand should be run if there is more than one test available for that indication. 

In the pharma realm, physicians decide what drug to select. When it comes to using diagnostic tests in conjunction with a given product, it is equally important for doctors to have the authority to select the brand used. Point-of-care tests give them that control. Physicians prefer rapid tests they can administer in their office rather than those they must send to an independent lab. With such tests there is little risk of delaying a patient's treatment while waiting for results, or worse, having the patient simply not return for treatment. In some disease areas, patients not returning for the results of a test can be as high as 40 percent. Therefore, the greatest opportunity for an integrated Rx Dx promotion lies in brand-name point-of-care tests that yield rapid results marketed with a related therapy. 

To successfully develop and market a new diagnostic test, both Rx and Dx companies must lay the foundation for the partnership as early in development as possible, preferably at the drug discovery or preclinical stages. (See "Time to Develop," page 54.) However, alliances formed three to four years before the launch of a new drug can sometimes succeed if the test is not too complicated to produce and administer and it gains regulatory approval quickly. However, with such a short timeline, it will still demand considerable sales and marketing effort from both parties.  

The use of a diagnostic test during a drug's clinical trials can help validate the test and provide sufficient usage data to support FDA approval. Furthermore, test information is often included in the submission of a new drug application (NDA), giving further credence to the diagnostic's utility. 

It generally takes at least two to three years to develop a test and get it to market and considerably more time to prepare the market to accept it. The timeline will be shorter if the new test shows an advantage over others on the market. 

Consider a new cholesterol diagnostic test in which benefits might include more accurate results in minutes rather than hours or days. Yet, if the new test offers no significant advantages over others already available, it will typically take at least five to six years from FDA approval to gain market approval. 

Rx Dx alliances, by definition, seek to identify new patients for a drug through the use of new diagnostic technologies. Thus, it is important that the partners come up with diagnostic guidelines and standards that will support the new technology. Although pharma companies can and should expect diagnostic partners to lead those efforts, it is important for both companies to work out shared costs in advance of product development. 

Of course, each side must have something the other side needs. (See "Pharma's Stake.") A good relationship between scientists on both sides of a partnership is key to success. "They must be closely aligned and always talking to one another," says one Dx company's director of marketing. Before scientists can work well together, they must have mutual trust in each other's scientific credibility.  

Also important is an open dialogue about the need for both parties to look out for their own interests. Failure to recognize that can lead to unfulfilled expectations and, ultimately, disappointment when one partner pulls out of an agreement. 

At the outset of a new alliance, companies should ask several additional questions: 

What attributes does each company offer that will make the partnership a sound fit?

Which regulatory pathway must the companies follow to bring the new products to market?

Does the pharma company have a clear vision of the disease states with a well defined need for a drug?

At what development stage is the drug company's product?  

Is the patient population clearly defined for clinical trials?

Do both the Rx and Dx companies have a good relationship with FDA?

What will the price of the test be relative to the price of the drug?

Is there already a similar test on the market? If so, will the new test be more effective or more accurate? How will it improve treatment options?

Does the Dx partner have strong scientific and developmental abilities with a good reputation and track record for developing tests?

Can the Dx company produce the number of tests needed to support the market?  

A push pull model of diagnostic commercialization illustrates the impact of various forces on market uptake and the overall commercial success of a new diagnostic test. The model includes four potential scenarios:  

Dx-only push. Products that receive marketing push from diagnostic companies alone typically take the longest time to achieve a high level of market acceptance-even when there is an added push from large diagnostic companies' sales forces. Market research and benchmark interviews indicate that tests in this category can take up to ten or more years from regulatory approval to reach acceptance in the market. Dx company marketing budgets and sales forces are not large enough to generate the necessary impact on key opinion leaders, clinicians, advocacy groups, managed care organizations, and other payer groups to make new tests widely available and used in a short time-particularly for a new disease marker. 

Dx and Rx push. If the marketing and sales push comes from a Dx and Rx co-promotion, but demand from key opinion leaders and advocacy groups is lacking, a new test can often take five to ten years after FDA approval to achieve market acceptance. Without pull from the medical community and consumers, rapid market uptake can require tre-mendous promotional resources from both partners. 

Dx-only push/medical community pull. The third scenario involves creating a strong demand in the medical community from key opinion leaders, clinicians, and patient advocacy groups. If the Dx company is solely responsible for promotional efforts with little or no marketing and sales support from the Rx company, the test may take three to five years from regulatory approval to achieve market acceptance. This scenario tends to play out in cases in which a test is developed to fulfill an unmet medical need or when it is designed to diagnose a disease or monitor treatment efficacy of a relatively new drug. (See "Getting Everyone on Board," page 58.) 

Rx and Dx push/medical community pull. The ideal scenario for achieving rapid market uptake of a new diagnostic is to combine Rx and Dx push with medical community pull. Under those conditions, a new test could be accepted within two to three years after regulatory approval. However, such a scenario requires near-perfect planning by the two companies. 

Partnerships between pharmaceutical (Rx) and diagnostic (Dx) companies are difficult to achieve because most managers don't understand what it takes to make them work.

Pharmaceutical Executive-07-01-2003

Table of Contents

The Pivotal Prescribers

Pharma-Physician Conundrum

Company in Waiting

Best of Times, Worst of Times

Extending the Product Lifeline

How to Make Rx-Dx Alliances Work