Getting FDA approval on a brand name for vandetanib, AstraZeneca’s very first orphan drug, isn’t the only challenge the company has faced during launch. The size of the patient population eligible for Caprelsa is decidedly small, but ultimately fuzzy. “We don’t really know how many patients there are at any given time,” says Eric Vogel, executive director of oncology, at AstraZeneca. “In some reports its 1,000 [in the US], and the FDA thinks it may be 2,000 to 2,500.” Compounding the difficulties presented by a tiny patient population, relatively speaking, is the fact that not all medullary thyroid cancer patients would benefit from Caprelsa; the drug is indicated only for patients whose cancer “has progressed to the point where surgery is no longer an option.”

Vogel says the company is “learning as we go” during the launch. “We believe that roughly half of the patient population will end up in the major treatment centers around the country, but that the other half may or may not continue to be followed by the community endocrinologist or medical oncologist,” says Vogel. Traditional market research hasn’t uncovered a network of physicians treating medullary thyroid cancer, since Caprelsa represents the first pharmaceutical treatment option for those patients, says Vogel. “There are some things that we can do to find physicians that look like they might be treating [medullary thyroid cancer], but it’s an inexact science at this point.”

AstraZeneca signed an exclusive distribution deal with Biologics, an oncology management company and specialty pharmacy, last April. Biologics also distributes AstraZeneca’s Arimidex, as well as Novartis’ Afinitor, Gleevec and Tasigna, Bayer/Onyx’s Nexavar, Celgene’s Revlimid, BMS/Otsuka’s Sprycel, Pfizer’s Stutent, Merck’s Zolinza, Roche/Genentech’s Xeloda and others, according to an “in stock” list on the company’s website. The decision to partner with Biologics for distribution had to do with the size of the patient population, and the amount of support that patients using Caprelsa would need, says Vogel. “We’re pleased with the relationship. [Biologics] spends 45 minutes, on average, with each patient, according to the reports we get from them,” Vogel says. Biologics, for its part, provided a team of 10 nurse liaisons tasked with educating physicians about the drug, and easing the administrative burden on the physician’s practice, Dan Duffy, executive VP and general manager, oncology pharmacy services group, told PharmExec.

In addition to Biologics’ nurse liaisons, AstraZeneca has deployed “regional scientific managers” – physician and/or nurse-facing individuals, to “communicate to our HCP audience about risks associated with Caprelsa, the REMS programs and all of the precautions, as well as any questions they might have around the efficacy or safety of the product,” says Vogel. The REMS program has helped AstraZeneca identify customers, since physicians have to become certified through REMS before prescribing the drug. “Down the road, we may broaden our reach out to community oncologists, those who we’re already calling on with our sales forces for Faslodex,” says Vogel.

The company hopes new indications will be forthcoming, and is currently looking to Europe for the next Caprelsa launch. Laura Woodin, senior manager, corporate affairs, said in an email that Caprelsa is being evaluated in “more than 40 early-stage studies” and various tumor types, including pancreatic, glioblastoma (brain), biliary tract (liver duct), as well as two other forms of thyroid cancer, papillary and follicular. “We’re trying to take our learnings from the US and apply those to other markets,” says Vogel. In terms of a possible launch in the EU, Vogel says the patient population size across Europe is roughly the same as the US patient size, but right now, “it’s not efficient to commercialize [Caprelsa] country by country.” “We will commercialize it country by country as we get new indications, but we have to look at it more broadly by much larger markets” for now, says Vogel.

Caprelsa is currently under review with the European Medicines Agency (EMA) and Health Canada, according to Woodin.

Under the Labour government, the time that it took for a patient suspected of having cancer to be referred from a GP to a specialist was set at two weeks maximum, and the Party promised in its April 2010 election manifesto to further reduce this to one week.

Despite the coalition government’s ring-fencing of healthcare (and pledge to increase it, in “real terms”, by 0.4%), the Spending Review’s retention of the old target is no great surprise. The Tories made no indication of matching Labour’s cancer diagnosis promise in their election manifesto, and, back in July, House of Commons Leader Sir George Young announced that the two-week waiting time was “clinically justified”. Nor is it a surprise to hear Andrew Lansley, the coalition Health Secretary, complain that Labour had never actually identified how the one-week target would be paid for or provided in the first place.

What does seem a tad incongruous is Lansley’s comment on Sunday that the coalition government is “fully committed to improving early diagnosis for people with cancer. Up to 10,000 lives a year could be saved if England’s survival rates were brought up to the best levels in Europe…”

With, according to a 2009 government report*, only 15 of England’s 152 healthcare trusts matching the highest survival rates in Europe for patients suffering from the three most common forms cancer (colorectal, lung and breast), it’s clear that the country was lagging significantly behind Europe even when Labour was tripling the NHS budget and promising swifter diagnosis for cancer patients. On the report’s publication, the then-Health Secretary Andy Burnham said: “I hope the publication of this data combined with the Prime Minister’s pledge to give patients key diagnostic tests within one week of seeing their GP will save thousands more lives.”

Considering the strong arguments that swifter diagnoses at this vital early stage make a huge difference to cancer survival rates, perhaps the one cut the coalition government should be making is to cancer testing times.

*Cancer Reform Strategy, UK Department of Health, December 2009.

Confounding perceptions that oncologists are a pampered group able to set the terms of their engagement with patients—and to command high fees from compliant insurers—the survey tells a different story. Most cancer practices are working at full capacity, with a growing “triage” problem leading to variations in the quality of care for some patients, while grappling simultaneously with a troubled bottom line as payers ratchet down on costs. Significantly, that bottom line still depends heavily on reimbursement for medications—anywhere from 60 percent to 75 percent of revenues is the average per practice. Thus, the impact of health reform on the in-office specialty drugs used widely in treatment is a major uncertainty on the financial health of cancer practices going forward.

“Demand for oncology services is overwhelming the health care system and many of the professionals we surveyed see the future of cancer care as a low-margin, high-volume business in which active management of the practice will be critical to survival,” said NCCN spokesman Patricia Goldsmith. The contrast between commitment and compensation is increasingly stark. While the average working time for oncology specialists engaged in private practice is now 60 hours per week, it has been accompanied by a pronounced decline in per-patient revenues. Coping trends under way include relying more heavily on mid-level professionals to monitor care and limiting the range of non-essential services available to Medicare patients who do not have supplemental private insurance cover.

So what are the key issues that keep cancer care professionals up at night? Fears of forcing patients out of treatment due to cost and insurers who impose diminishing returns; Medicare reimbursement cuts for infusion drugs and other mainstays of treatment; alignment of private payers with Medicare around low Medicare fee-for-service rates; vanishing professional and personal time; and difficulty in attracting qualified professionals to the cancer space.

Overall, manpower shortages are an increasing reality, with the survey posting findings that indicate a 50 percent gap in surgical specialists versus current need, and more than 60 percent for specialists in gynecological cancers. The shortages are destined to grow as health reform expands the insured population. Unless this is redressed through new incentives to fix a deteriorating financial picture, it will impact everything from the quality of care available to patients to the ability of the drug industry to interact with cancer professionals.

This is a huge problem for Roche who purchased the treatment as part of its merger with Genentech. The drug firm could see sales drop by $1 billion if FDA agrees with the panel and ceases use of the drug for breast cancer. The drug earned Roche $5.7 billion in 2009.

“We are disappointed by the committee’s recommendation and believe Avastin should continue to be an option for women with this incurable disease,” stated Sandra Horning, Roche’s global head of clinical development hematology/oncology, in a release. “We will continue to discuss the data from the more than 2,400 women who participated in three Phase III studies with the FDA. This recommendation does not impact Avastin’s approved uses for other cancer types.”

Avastin (in combination with chemotherapy) was given fast-track approval in early 2008, because it treated HER2 negative breast cancer, a form of the disease with few treatment options. FDA requested that Genetech release the results of two post-market trials to determine how effective the drug is at improving patient lifespan.

According to the two trials, the treatment only slowed cancer progression by approximately a month and didn’t do anything to boost patient survival. Additionally, patients taking Avastin had more adverse reactions than patients taking chemotherapy alone.

FDA will give a final ruling on Sept. 17.

The data was released at the annual meeting of American Society of Clinical Oncologists. According to Roche, Genentech’s parent company, patients treated with a combination of Avastin and chemo, followed by the continuation of Avastin alone, survived more that 14 months without seeing symptoms worsen. Comparatively, patients on chemotherapy alone were progression-free for about 10 months.

Roche studied 1,873 untreated patients with advanced ovarian cancer. Patients taking Avastin with chemo saw a higher frequency of adverse events including low white blood cell counts, pain, gastrointestinal problems, and hypertension.

Here’s a run down of the other news coming out of Chicago:

•Argos Therapeutics released positive Phase II data about its AGS-003 drug in combination with sunitnib for the treatment of advanced renal cell carcinoma. “Sunitinib has been shown to modulate the immune system by decreasing T-regulatory cells that can potentially suppress immune responses in the tumor microenvironment,” said Asim Amin, co-director, Immunotherapy Program for the Blumenthal Cancer Center.

•Novartis announced that a Phase II trial involving the drug Afinitor showed positive results in dropping the size of benign brain tumors caused by tuberous sclerosis. Of the 28 patients in the study, 75 percent saw a decrease of around 30 percent in size.

FDA, on Monday, announced that it was reviewing whether a certain class of prostate cancer drugs could lead to diabetes, stroke, death, or heart problems.

The drugs in question are gonadotropin-Releasing Hormone (GnRH) agonists, marketed under a number of monikers, including Vantas and Lupron. These treatments are used to slow the growth of prostate cancer by decreasing the amount of testosterone created by the body.

“While our review of these prostate cancer treatments is ongoing and there are some limitations to the data, FDA believes it is important to tell patients and health care professionals that there may be an increased risk of serious side effects,” stated Robert Justice, director of the Division of Drug Oncology Products in FDA’s Center for Drug Evaluation and Research.

Doctors are being told not to suspend treatment, but to be aware of the risks and watch patients closely for diabetes of cardiovascular disease.

Together, the three drug giants will pull together an undisclosed dollar amount in seed funding and create the independent, non-profit Asia Cancer Research Group (ACRG). The new company’s purpose is to grab Asia’s lung and gastric cancer problem by the horns.

Neil Gibson, chief scientific officer of Pfizer’s oncology research unit, pointed out that there’s a “huge unmet need and a disproportionate health burden to Asian patients.” A significant portion of lung cancer in Asia seems to be related to a mutation in a gene that helps regulate cell growth and division—a mutation far more common in Asia than the West. Gastric cancer shares this skew, accounting for 630,000 deaths each year.

The ACRG will have a six-person research-specific board (two experts from each company) to approve major decisions and material. Lilly will provide virtual access through its research site in Singapore. Researchers can cull from at least 2,000 tissue samples as part of the ACRG’s two-year plan to create the biggest pharmacogenomic cancer database in the world. While research avenues into other cancers are a possibility in the future, the group’s focus for now is on lung and gastric cancer.

This is just the latest example of a pharma “open source” policy, a concept adopted by the techies long ago. Open-sourcing takes some of the pressure off R&D units, which have sustained heavy losses the last couple quarters.

“Hans’ extensive and successful global commercial experience will add tremendous value to Dendreon’s already strong executive team as we prepare for the launch of Provenge in the coming year,” Dendreon CEO Mitchell H. Gold stated in a release. “Hans’ deep knowledge of sales and marketing, manufacturing and operations will be integral to our success as we transform Dendreon into a commercial organization and work to fulfill our mission of transforming the lives of patients with cancer.”

Until recently, Bishop served as president of Bayer’s specialty unit where he gave a huge boost to its hemophilia product line, helping bump sales to $3 billion. Here’s our profile of Bishop from the June 2009 issue of Pharmaceutical Executive Magazine.

Pharma vet Hans Bishop readily admits to being ruthless in his career. “If you’re ruthless about seeking out challenges that you’re not quite ready for, that will make you grow,” he says. This tropism toward uncertainty is a trait shared by many young guns who come to Big Pharma embracing its medical mission only to find how resistant to risk the structure can be.

So Bishop also admits to being restless—and his career trajectory betrays the sense of a man on the move. After training in organic chemistry, he was too restless for a life in the lab. Being a sales rep at Glaxo Wellcome benefited by comparison. Soon Bishop was managing the major launch of game-changing migraine drug Imtrex (sumatriptan). From sales and marketing he jumped to spin off a joint-venture between Glaxo and Reuters called Diversified, dealing with then-emerging PBMs. Next the British drug giant handed him its entire UK marketing business to manage. “But the company had a crazy idea about how to run the business,” he says. “I spent months trying to change management’s mind, lost the argument, and left.”

Other tracks left by this restless spirit: SmithKline Beecham, Chiron—and Sonera Zed, a global mobile-telecom startup.

In 2007 Hans Bishop finally jumped the pond, leaving London to take the to spot at Bayer’s worldwide headquarters for hematology and cardiology in Berkeley, CA—the company largest division within the company. “When I arrived, we had a fantastic product, Kogenate {Factor 8}, but I was quite surprised at how little we were doing to develop it, let alone meet what were very significant needs for hemophilia patients,” he recalls.

His effect on the company was one of immediate and disruptive innovation. Bishop has transformed Bayer’s hemophilia franchise and increased annual global sales to $3 billion; at the same time, he is revitalizing both its R&D to cover the entire spectrum of hemophilia-related conditions and its commercial approach. Bayer can now boast the only long-acting version of Factor 8 in the clinic, a major leap in convenience and compliance over the standard thrice-weekly infusion regimen.

Bishop also pressed his diversified expertise into service to innovate his business unit’s approach to customer service, including funding grants for research into how to better manage the disease, from drug discovery to patient empowerment.

As he refines the model, he plans to apply it to the three other therapeutic areas under his wing, oncology, neurology, and early-stage ophthalmology. For the moment, Bishop seems too busy to be restless.

Steven Paul, Lilly

Last week, Lilly announced a major restructuring plan focused around the creation of one Developmental Center of Excellence and several individual business units. The media (Pharm Exec included) focused on the news that 5,500 jobs were being cut as part of the plan. This week, we’re talking to Lilly to find out what the company’s R&D structure will look like beyond the elimination of positions.

Steven Paul, president of Lilly Research Laboratories and executive vice president of science and technology, filled Pharm Exec in on the details.

Could you clarify the role of the new Developmental Center of Excellence? Is it simply a coordination vehicle?

Its main purpose is to speed innovation to patients and to the market. Yes, it is a coordinating vehicle—we have put there the key functions for clinical development, including all the key elements such as process research development, regulatory, safety, and project management. There is going to be a single operating model at Lilly, which we piloted for the past 12 to 18 months, and that’s something we call critical chain, which is a way of seamlessly developing drugs.

Why the change?

The reason we are doing this is because we have a terrific Phase I and II pipeline—we have 64 individual molecules in development, 21 in oncology, and our goal is to get those molecules into Phase III and into the marketplace and to patients.

There are three key pillars from a technology and methodology perspective. One is critical chain methodology—a project management tool that we piloted. One hundred percent of the projects using critical chain methodology are on track, either at or ahead of their milestones, as compared to about 60 percent of our traditional development projects. We will expand this to all of our projects by the end of this year.

The other pillar is something we call advanced analytics. This is the use of clinical trial modeling and simulation, as well as adaptive, seamless design. In other words, moving from Phase I to II and from Phase II to III without stopping.

We piloted this on four projects. We literally determined the dose in Phase II—in a multi-arm study—moved the two doses that were optimal into Phase III without stopping, and continued on with the commercial development of the molecule.

This can save enormous amount of time, and you can do it on the front end. For a few molecules you could probably do it for Phase I, II, and III. Not all molecules will meet the criteria for this. It obviously requires that you have enough clinical trial material. But when you have a validated target and the molecule is behaving very well in Phase I through proof-of-concept, at that point, these kinds of trials can literally cut years off the development time of a molecule.

The third pillar of this Center of Excellence is the idea of tailored therapies. Lilly has been very successful with tailoring, but we now believe that it needs to be applied across the portfolio in a much more robust way, beginning in Phase I and not after a drug is in Phase III or on the market. Tailoring the right patient, right dose—these are essential for determining whether a drug works.

Are you altering the end points in a trial as a molecule is moving through the trial?

Not necessarily the end points. For example, because the purpose of Phase II is to pick the dose of a molecule—and to confirm efficacy and safety—you usually stop at the end of it. You look at the data, look at the best two or three doses, and move into Phase III. This way you can stop the doses that you don’t want and enroll patients into the programs that you do want.

You can also do this on the basis of tumor response. Let’s say you are in Phase II for an oncology drug that works in breast cancer. Now we know that virtually no oncology drug works for all people that have breast cancer. But let’s say you have a marker—logical or molecular—now you can determine which type of breast cancer is responding to your drug and without stopping. You literally keep enrolling patients that have that type of breast cancer.

CNS doesn’t seem to have its own business units, yet it has been a major Lilly franchise.

I think this was misinterpreted in the press release and something we are trying to clarify with the public. We are very interested in CNS, and the biggest products we have right now are CNS drugs—Zyprexa, Cymbalta, etc. But they are mature products that will lose patent protection over the next few years, beginning in 2011, so they were put into the developed markets business unit. But we have a very robust science pipeline. In fact, we have two Phase III molecules for Alzheimer’s disease. So we have not, by any means, lost interest or enthusiasm for CNS.

How are your business units different from similar models in other companies, such as J&J and Pfizer?

When we make a commercial decision on a molecule—traditionally after Phase II—at that point the molecule will move into the business unit with two exceptions. In oncology we will move all Phase I molecules into the business unit, because we often do Phase I trials for cancer in cancer patients. The other business units will pick up the molecules at the commercial decision time.

What about benchmarks? Is it all about speed to market or the number of new compounds being commercialized?

We have an unprecedented amount of molecules in early stages and mid stages, so our success as company as we transverse the patent cliffs is going to require that we speed innovation to patients. If you didn’t have enough good stuff to speed to patients, none of this will be effective. We feel we’ve got the quality molecules we need to make this work.

Is there a deadline for the restructuring plan?

This is all going to occur by January 1, 2010. We are well on our way for the Development Center of Excellence because we’ve been piloting critical chain, adaptive designs, and tailored therapies for some time. We are ready to go, and this will be rolled out at our analyst meeting in December.

Have you substantiated the number of people being laid off as opposed to positions being eliminated?

No. Frankly, we don’t have the answer to that question. We’ve done very well over the years with attrition. We’ve already reduced by 7,000 people by attrition over the last few years. We hope this predominately occurs by attrition, but obviously it might not. We don’t know the percentages, but that will all be worked out in the next few months.

The warning comes after two separate analyses of lymphoma and leukemia in children and teens being treated with TNF blockers such as Enbrel, Remicade, and Humira. Last year, FDA requested that all TNF blocker manufacturers submit lists of all cancer-related cases in which children were being treated with such medications.

Of the 48 cases submitted, about half the children had different versions of lymphoma; 11 died from the disease. In the leukemia study, the feds reviewed 147 cases of patients on TNF blockers. Thirty of those patients died, 26 from leukemia associated with TNF blockers.

In both cases, the patients were being treated with other medications, and linking the cause of death to TNF blockers is difficult. However, FDA feels there’s enough information to warrant a warning that taking these treatments could boost risk of leukemia or lymphoma.

“Additional data are expected from the ongoing long term, observational, postmarketing studies and registries that are being conducted by the TNF blocker manufacturers,” FDA stated in a release. “In addition, FDA is working with TNF blocker manufacturers to explore new ways to further define the risk of malignancy in children and adolescents using TNF blockers.”