Tracking new therapies as they wind their way through development, regulatory approval, and payer acceptance can be like waiting for paint to dry and then repainting in a different color. It's a slow process and far from linear. 

This is especially true for potentially groundbreaking drugs, disruptive technologies that completely upend  markets and patient care. The lag time between that first flickering glimmer of hope and an accepted therapy can be measured in decades. And, all too often, agents that seem hopeful in the lab and early clinical trials fizzle on further investigation. 

But then there are those rare moments when the stars align and truly astounding therapies make their way into the world, providing improved care and big returns. In the next few years, cancer immunotherapies seem likely to enter the pantheon of big winners. And they may not be alone. Besides the buzz around a cure for hepatitis C virus, there are exciting drugs for heart failure and cholesterolemia coming into play. On a smaller scale, companies are embracing new therapies for rare diseases. Stem cells are making real forays into late-stage trials.  

This year's pipeline report will check in on these emerging technologies, as well as potential therapies to address metabolic and neurodegenerative diseases. There's a lot to like in the pipeline and more than a little competitive drama to make it really interesting.  

For Trekkers, there's nothing better than watching a Klingon or Romulan ship lose its invisibility cloak and get blasted out of space. On the cellular level, similar action is driving the excitement around programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) checkpoint inhibitors: the opportunity to reveal cancer and unleash the immune system against it.

"There's genuine enthusiasm among oncology experts," says Seamus Fernandez, managing director of Major and Specialty Pharmaceuticals at Leerink Partners. "There's evidence of activity in more than five different tumors and signals of activity in as many as 14. We forecast a $36 billion immuno-oncology market by 2025."

That's a large pie and there's been a lot of jostling to get the biggest piece. Bristol-Myers Squibb's cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor 

 (ipilimumab) was first out of the gate, but there are several other agents poised to hit the market. 

 (pembrolizumab) received accelerated approval from the FDA to treat melanoma and the company is researching the drug against non-small cell lung cancer (NSCLC) and other indications. In its World Preview 2014 Outlook report, EvaluatePharma forecasts 

That's a great start, but it's unclear whether Merck's advantage will hold out over the long haul. The competition will be fierce in the PD-1/PD-L1 space. With the huge potential market, this could be the equivalent of the Oklahoma land rush for the usual pharma titans. However, Stephanie Hawthorne, senior director at Kantar Health, notes that, for now in melanoma, Merck is in the driver's seat compared to BMS's PD-1 inhibitor 

(nivolumab), which is a few months (or possibly longer) behind 

"It's a big advantage for Merck being first-to-market," says Hawthorne. "Based on the available data, they both look really efficacious, and they're fairly well tolerated compared to 

. BMS's saving grace might be the combination of 

 they are studying. The survival data we've seen for it so far is really impressive, and that could trump Merck's lead." 

Hawthorne's point was underscored in late September when BMS released data at the European Society for Medical Oncology (ESMO) showing that 

achieved a 32% response rate against advanced melanoma in patients who had previously been treated with

. The control group, which received traditional chemo, had an 11 % response. 

 was approved for melanoma in Japan in July, under a deal with BMS partner Ono Pharmaceuticals. The ESMO data will only support BMS's showing in the US. The FDA has given 

 fast track designation in NSCLC, melanoma, and renal cell carcinoma (RCC) and breakthrough therapy designation for Hodgkin's lymphoma. In September, BMS announced that both the FDA and European Medicines Agency (EMA) have accepted 

 for accelerated review for melanoma. The FDA PDUFA date is March 30, 2015. 

is the most valuable pipeline drug in development at the moment," says Lisa Urquhart, editor of Evaluate's editorial team, EP Vantage. "The data from studies is showing some impressive advances in both overall survival and disease progression." 

's potential sales at $6 billion by 2020. The company believes 

 could be approved for melanoma in the US next year. Meanwhile, Hawthorne expects approval for the 

 may even have a more clear-cut advantage in being first-to-market for NSCLC, where BMS has already submitted its drug for approval while Merck is still completing Phase III  trials.  

The PD-1/PD-L1 approach is generating a lot of enthusiasm for good reason. Early results have shown great efficacy in many indications, including underserved areas, such as bladder and head and neck cancers. The possibility of producing an agent that can target multiple cancers is raising heart rates throughout the pharma industry. 

"These drugs are all across the board," says Hawthorne. "I'm not sure there's a tumor type that's not being touched: renal cell cancer, head and neck, bladder, and Hodgkin's lymphoma. It's just an indication of how huge and impactful these could be for patients."   

Again, this is underscored by Merck results, also released at ESMO, which showed a 24% response rate for 

Genentech/Roche's PD-L1 offering, MPDL3280A (RG-7446), is in trials for NSCLC, melanoma, RCC, and bladder cancer. The company received breakthrough designation for this last indication. EvaluatePharma puts sales at $2.93 billion by 2020, while the Thomson Reuters Cortellis database puts them at $1.2 billion by 2019. 

MedImmune/AstraZeneca is also in the race with PD-L1 drug MEDI-4736, primarily targeting NSCLC. Also shared at ESMO, a small 18-person study showed a 28% response to MEDI-4736 combined with the CTLA-4-directed antibody tremelimumab. Cortellis projects MEDI-4736 sales at close to $1.1 billion by 2019. 

"We're just at the tip of the iceberg for immuno-oncology, but the enthusiasm is certainly warranted because of the kinds of responses and the tumors being opened up," says Fernandez. "The field is about as exciting and confusing as you could possibly imagine." 

With these fantastic response rates in aggressive cancers, how will PD-1/PD-L1 inhibitors redefine patient care? As monotherapies? In combination with other types of immuno-oncology drugs? Or will they be combined with the new generation of targeted chemotherapies? 

"The best-case scenario, these agents are working in 35 to 50% of melanoma patients as single agents," says Fernandez. "Worst-case scenario, maybe they're working in 15 or 20%. There's a strong conviction that multiple mechanisms are going to be relevant in various different tumors." 

How this will play out is subject to much debate. If Fernandez's more optimistic scenario proves accurate, these checkpoint agents could be extremely successful monotherapies, which could have a profound impact on standards of care. 

"This could be very disruptive," says Hawthorne. "Whereas you're used to treating lung cancer with cisplatin or carbo-taxol first line, you might get 

Hawthorne anticipates that both clinical and commercial factors will drive companies to test their more traditional therapies in combination with the emerging checkpoint inhibitors. 

"If the drug has the potential to displace you, then it makes sense to go in combination with it," says Hawthorne.  

In addition, there's the long-term possibility of pairing a PD-1/PD-L1 with emerging immunotherapies that target different mechanisms. Just over the horizon, chimeric antigen receptor (CAR-T) therapies could make a big impact. Unlike PD-1/PD-L1 inhibitors, which unchain immunity, CAR-Ts activate the immune system, which offers intriguing possibilities, as well as possible dangers. 

"My wariness would be around the potential side effects," says Hawthorne. "If you're simultaneously upregulating the immune system and taking the brakes off, that could go kind of crazy." 

At this point, Novartis is first in the CAR-T line with CTL019, which received breakthrough designation from the FDA in July for acute lymphoblastic leukemia (ALL). The drug is currently in Phase II trials. 

However, CAR-T therapy may not have an easy path. A Juno Therapeutics/Memorial Sloan-Kettering study for aggressive non-Hodgkin's lymphoma (NHL) was halted recently after two patients died from cytokine release syndrome, one of the apparent risks of taking the brakes off the immune system. While the study was only delayed, this event underscores potential concerns about CAR-T therapies. 

Another interesting immuno-oncology therapy is Amgen's blinatumomab, a bi-specific T-cell engager (BiTE).  Blinatumomab received breakthrough therapy designation for ALL in July, and Amgen has filed for early approval. At Leerink Partners' Healthcare Insights Conference in July, a number of experts expressed their belief that this drug is an interesting proof-of-concept; however, they were also concerned about neurotoxicity. Thomson Reuters puts potential sales at $325 million by 2019. 

There are too many immunotherapies to list here, which is great news for cancer patients. Ultimately, PD-1/PD-L1 may form the backbone for a variety of combinations. This is based on efficacy, as well as a complementary mechanism of action, but there's also a practical measure. With so many different combinations, it would be virtually impossible to test them all. 

There are also cell-based therapies that look promising. For example, Aduro BioTech recently received breakthrough designation for its combination immunotherapy CRS-207 and GVAX. CRS-207 uses engineered Listeria to stimulate an immune response against mesothelin. GVAX is made from pancreatic cancer cells modified to secrete GM-CSF, which also provokes an immune response.

"They did a very small phase I study: seven patients were treated and some lived for two or three years," says Ravi Kiron of BioPharma Strategy Advisors. Phase II results from early 2014 were also quite promising. They showed the combination therapy doubled one-year survival for patients with metastatic pancreatic ductal adenocarcinoma. The combo is currently in a phase IIb trial. "These cell-based therapies have a lot of potential," adds Kiron.

"The stakes get a lot more interesting and a lot more confusing," says Fernandez. "We are going to see a significant number of mixed successes and disappointments as we move forward with these different combinations." 

While immunotherapies may hold the greatest upside, there are still a variety of more traditional treatments in the oncology pipeline. 

First on the list are the poly ADP ribose polymerase (PARP) inhibitors, which encourage cancer cell death by limiting this DNA-repair enzyme. They include veliparib from AbbVie; rucaparib from Clovis Oncology/Pfizer; 

 (olaparib) from AstraZeneca; and BMN-673 from BioMarin. Their oral administration makes them particularly exciting. 

Veliparib is being developed for triple-negative breast cancer and NSCLC. The drug showed a 52% response rate against breast cancer in a study that combined it with carboplatin and paclitaxel. AbbVie recently announced a pivotal Phase III study for patients with advanced breast cancer. The company is also conducting a Phase II  trial for NSCLC. Thomson Reuters projects sales at $350 million by 2019. 

Meanwhile, in a Phase II study, rucaparib showed a 93% disease control rate in BRCA-positive ovarian cancer. Thomson has rucaparib at $414 million by 2019. 

Clovis has also earned breakthrough designation for its epidermal growth factor receptor (EGFR) blocker CO-1686 for lung cancer. At the  2014 ASCO Annual Meeting, Clovis unveiled excellent progression-free survival in a combo Phase I/II study. 

The company will have major competition from AstraZeneca's AZD9291, which targets both EGFR and the resistance mutation T790. AstraZeneca is partnering with Roche, and the drug is currently in pivotal trials. They plan to file with regulators in the latter part of 2015, which seems like a long way off. Thomson Reuters estimates $761 million in sales in 2019. 

Articles

Features

The science of drug discovery is back on script-and the stars are cued up for a new generation of breakthrough therapies. But is pharma ready to raise its game and cut a deal with all those "prove it to me" payers?

2015 Pipeline Report: Burning Bright

The European Medicines Agency (EMA) really is between a rock and a hard place. Its earnest efforts to satisfy the critics who accuse it of obsessive secrecy seem to do little more than open it up to further criticism for not having done enough. And at the same time, drug firms—and many patient groups—become increasingly wary of the implications of the agency's direction of travel. 

The agency might have expected that the latest stage in this continuing saga—the publication in October of its plan for proactive release of clinical reports—would receive a warm welcome. The agency aimed to assuage the appetites for data disclosure, and also to mollify the patients and drug producers who are anxious, each for their own reasons, to maintain a minimum degree of privacy. The plan is, after all, a judicious blend of ambition and caution. It goes further—the agency claims—than any other drug regulatory authority in providing access to the information on which marketing authorization decisions are based. Yet it simultaneously offers some safeguards for industry and some discretion for trial subjects. 

But the outcome is far from a roaring success. The critics continue to allege that the agency is conspiring with industry to conceal the important data. Industry says it needs to see how the plan works. And patients want guarantees of protection of their data, and more of a say in its functioning.  

The most strident reaction has come from health campaigners, who have pointed to what they see as crippling deficiencies—a long list of historic failings that have now been consolidated by the EMA's new policy, so that they will stretch into the future too. A coalition of health campaigners, health insurance agencies, doctors and academics says that "for more than a decade, the EMA has failed to comply with EU rules on freedom of information," by neglecting to set up a register of documents that it holds—making it difficult for citizens to determine which document to request. The result, they say, has been endless exchanges with the EMA before documentation is provided.  

The coalition consists of well-respected and well-informed organizations—although all with a strong declared interest in protecting the patient, the citizen, and independent research: Association Internationale de la Mutualité, the Medicines in Europe Forum, Health Action International-Europe, the International Society of Drug Bulletins, and the Nordic Cochrane Center. They say the new policy will not provide adequate transparency. The criticisms center on the scope of the EMA plan: it will cover the reports only of trials submitted in support of centralized marketing authorization procedure, and it offers no proactive access to clinical reports for medicines already on the market. In addition, the redaction it provides for "can hinder the interpretation of data (e.g., in the interpretation of a serious harm narrative) or delay access to information of public interest (e.g., redaction of results on exploratory endpoints)," they argue. Allowing redaction is a licence for "censorship by pharmaceutical companies under the guise of protecting commercial confidentiality," they say: "The policy gives pharmaceutical companies the upper hand in deciding the contents of the clinical reports by allowing them to redact data." And they fear that companies will adjust the content of their clinical study reports to conceal as much as possible: "They will be written and structured in such a way as to withhold vital details of a pharmaceutical drug's effects or present them in the best possible light." 

To compound the alleged felony, the EMA has abandoned other plans, announced in November 2012, to routinely require pharmaceutical companies to submit all original clinical trial data in a format that would allow the EMA to re-analyze the data, complain the critics. This means that a medicine can still be approved by the EMA on the basis of incomplete evidence, say the campaigners. Pierre Chirac, coordinator of the Medicines in Europe Forum, comments: "It seems that the EMA has found an easy solution to avoid having to release much clinical data: by just not requiring it from pharmaceutical companies in the first place..." At the very least, as some small compensation, the EMA should now proactively provide a numbered, standardized table of contents for clinical study reports (including a list of appendices and attachments containing information on study design, conduct or results), so that researchers can identify relevant additional information that they might wish to request under freedom of information rules, says the coalition. 

The critics have the wind in their sails. The EU Ombudsman, Emily O'Reilly, now on the brink of a further term of office and acclaimed for her energy, has already announced her engagement. She says she will monitor how the EMA deals with access to documents requests, and will verify the justification for the redaction of information and the conditions attached to gaining access to documents. The Ombudsman's office has had the EMA in its sights for a long time. "Transparency is a vital means by which EMA can ensure the accuracy of its decisions," it said earlier this year, and transparency "serves to foster scientific discussion and progress, by enabling independent scientists to scrutinize the conclusions of EMA, and the data and arguments taken into consideration by EMA when reaching those conclusions." 

Further support for the pro-transparency camp is sure to come from the left wing of the European Parliament, now jubilant at its successes in resisting the shift of pharmaceutical policy (and control of the EMA) from the health portfolio to the industry portfolio in the new European Commission. And the new health commissioner, Vytenas Andriukaitis, is likely to be respectful of the views of the strident MEPs who have led that campaign, and accordingly vigilant in defending the information rights of the public and independent researchers. 

On top of that, the World Health Organization (WHO) has just issued a statement supporting the disclosure of clinical trial results, to enhance transparency for the public.  It has launched a public consultation on its official position—which has already been welcomed by the UK's prestigious Health Research Authority (HRA). Tom Smith, HRA's director of quality standards and information, has greeted the WHO initiative as "a key step" along the road to seeing "all clinical trials results made available globally with parity in timescales." This, he added, would boost public confidence and reduce waste in research. 

WHO's statement is a follow-up to the International Clinical Trials Registry Platform that it established to improve research transparency nearly a decade ago, based on its conviction that "the registration of all interventional trials is a scientific, ethical, and moral responsibility." This scheme has, however, proved insufficient, and WHO is now beefing up its approach. "Concerns have been raised that there may be selective publication of trials dependent on their results, with particular concern that trial results which may be viewed as 'negative' are less likely to be submitted, or accepted, for publication in the scientific literature or made public in other ways," it says. 

"Multiple analyses have confirmed that a substantial number of clinical trials remain unreported several years after study completion, even in the case of large randomized clinical trials," states WHO. So it is now insisting that "all clinical trial registry sites are to be updated as necessary to include final enrollment numbers achieved, and the date of actual study completion." Trial results are to be reported within 30 months of the study completion date, both through submission for publication in a peer reviewed journal and through an open access mechanism. Key outcomes are also to be made publicly available by posting on the primary clinical trial registry. And it's not over yet. WHO also says it is "actively engaged with multiple initiatives related to data sharing, and supports sharing of health research datasets whenever appropriate."  

On every front, the EMA risks looking as if it is dragging its feet rather than leading the pack in the search for appropriate transparency. At a recent hearing on clinical trials data disclosure in the European Parliament, the EMA executive director, Guido Rasi, was quietly composed and confident in setting out the complex pressures and duties that EMA has to balance as it moves into a new era of access. But in a sound bite-dominated world, where it is often easier to transmit radical positions than calibrated compromises, even the equable Rasi was less compelling to most of the audience than the critics of the EMA approach.  

Column

Agency's plan for reporting clinical trial data has sparked strong reactions from health campaigners, industry, and patients.

EMA—a Pioneer Permanently At Bay

It may be time for pharmaceutical executives to devise a new rationale for drug pricing other than the need for high returns to support research and innovation. The important benefits of new cancer treatments and hepatitis cures diminish when physicians and patients find the medicines unaffordable, and Medicaid officials predict that soaring prescription drug outlays will undermine state education and safety net programs. Americans are angry that drugs cost less in Europe and object to funding biopharmaceutical development for the world. Last month's "60 Minutes" expose of soaring cancer drug prices was not a new story, but the discussion of "financial toxicity" for expensive oncology therapies clearly resonated with the public.

Public and private payers have been willing to pay high prices for certain new drugs and orphan therapies that offer important benefits for very sick and targeted patient populations. In an analysis in the October issue of 

 on the value and cost of specialty drugs, James Chambers and colleagues at the Tufts' Center for Value and Risk in Health found that specialty drugs approved by FDA from 1999 to 2011 offered greater gains in quality-adjusted life-years (QALYs) compared to traditional medicines; although specialty drugs often cost more, they offer "reasonable value for money." Another article by researchers at Prime Therapeutics supported the use of specialty drug coupons to lower patient out-of-pocket costs and support adherence, even though that strategy discourages the use of cheaper drugs and ultimately boosts costs for insurers. 

But the specialty drug model was upended by approval of Gilead's Sovaldi, indicated to treat some 3 million Americans with hepatitis C virus (HCV) at $1,000 per dose. The heated debate over Gilead's pricing rationale has escalated since last month's approval of Harvoni, the company's new combination HCV pill that is even more expensive, although it could end up reducing total treatment costs. Insurers and payers see these new drugs as the tip of the iceberg for an anticipated surge in high-cost therapies for chronic conditions such as Alzheimer's and high cholesterol, which would stress health systems even more. 

The attack on rising drug prices led by insurance companies has notable support from state Medicaid agencies, pharmacy benefit managers (PBMs), and consumer groups. At the annual fall Medicaid conference sponsored by America's Health Insurance Plans (AHIP), Sharon Levine of the Permanente Medical Group complained that costly specialty medicines will erode California's education system, and Michael Weinstein, president of the AIDS Healthcare Foundation, raised the specter of $10,000 pills:  "If we don't draw the line somewhere," he warned,  rising drug prices "will never end."  

CVS Health chief medical officer Troyen Brennan noted at last month's 

 briefing that pharmaceutical companies are "less than transparent" about pricing and development costs, and that Americans have a right to question whether industry's high revenues and profits reflect a reasonable rate of return. 

Industry's response is continued emphasis on the value of life-saving therapies for individual patients, that prescription drugs account for a small portion of healthcare spending, and that further biomedical innovation is critical to improving health. Just after the "60 Minutes" broadcast, the Pharmaceutical Research and Manufacturers of America (PhRMA) released a report on nearly 800 cancer medicines and vaccines in development, along with an analysis of failed cancer drugs over the last 15 years to illustrate the many costly setbacks involved in discovering new treatments. And a new study from the Partnership to Improve Patient Care warns that alternative payment models, such as bundled payments, medical homes, and accountable care organizations, could diminish patient choice and impose "one-size-fits-all" cost containment tools. 

Many experts thus are looking for new ways to address these issues. Mark McClellan of the Brookings Institution proposed at the AHIP conference that "better evidence" on which drugs are more effective could support higher prices and lead to new pricing models for personalized medicines. At the 

 briefing, Peter Bach of Memorial Sloan Kettering, who was featured in the "60 Minutes" report, urged a serious rethinking of coinsurance strategies and an end to Medicare Part B drug distribution, which tends to encourage physicians to administer high-cost therapies. 

There's much discussion about altering how Medicare pays for drugs covered by Part D. And the Medicare Payment Advisory Commission (MedPAC) has been assessing the viability of a "least costly alternative" (LCA) approach that would align payments for certain Medicare Part B drugs administered in doctors' offices to the least expensive medicine in a class, an admittedly tricky approach, which was applied to a handful of Part B drugs between 1995 and 2010, but halted by legal action.  

A recent conference on ways to "Turn the Tide Against Cancer" sponsored by the Personalized Medicine Coalition ended with a frank discussion of cost containment pressures. Stephen Eck, vice president of Astellas Pharma Global Development, described the complexities of drug pricing: that R&D costs are incurred long before a drug comes to market when it's hard to know it's full effect and value, and that current prices actually pay for the next drug development program—not the last one. 

Richard Schilsky, chief medical office of the American Society of Clinical Oncology (ASCO), urged an end to all the finger-pointing between pharma and insurance companies over high co-pays and high prices. He suggested a "value pricing" approach that allows different prices for different uses of the same drug, depending on documented effectiveness for each indication. Aetna medical officer Michael Kolodziej agreed that it's probably better to examine the "global cost of care" than the "sticker price" of drugs. And CancerCare CEO Patricia Goldsmith complained that the high cost of drugs and biologics should not be the "lightening rod" in all discussions about the high cost of care.  

Pharmaceutical executives might agree, but more transparency on pricing methods and unbiased assessment of the varying value of drugs is key to gaining public understanding of this complex market. 

's Washington correspondent. She can be reached at 

Insurers, physicians attack high-cost therapies in anticipation of specialty drug surge.

Outrage Grows Over Drug Pricing

Structural transformations in the life sciences industry have put the traditional sales role under increasing scrutiny, with the most prominent change being a drastic reduction in field force deployments in the US and Europe. This, argues Hay Group's Ian Wilcox, is where opportunity lies. By rethinking the role of the sales rep and the new skills it demands—and then executing boldly around a new customer-driven master plan—pharma companies can put themselves in a prime competitive position.

Among all the changes that the commercial side of the pharmaceutical industry has undergone in the last decade, the most impactful has been the redistribution of customer influence. There's been a shift away from individual physicians and towards payers (as well as medical institutions and patients). The result of this change? The roles of the sales rep and the commercial organization behind it need to change—and not just incrementally. 

Today's customers focus on value. This certainly includes the most time-honored sales factor—therapeutic efficacy. But today, cost issues have become more prominent and problematic—complicated by different customer needs and different socioeconomic factors. And beyond this, customers are looking for value that extends beyond straight measures of efficacy or cost—extending to ancillary services that may benefit patients, providers, and payers alike. Examples include resources that make sure patients take the right dosage of their medication, or online tools for medical professionals that are effective and user-friendly—or, better yet, innovative.    

The classic rep activity of "detailing" a specific product's benefits to customers is now almost an artifact of a previous era. This information is available in other ways and there are other important factors to emphasize in the new value proposition. 

While there's general agreement on the issues pharma companies face, many executives still aren't clear (or decisive) about how to improve their commercial organizations or the role of the sales rep.   

That said, there certainly have been discussions and experiments. For instance, organizations have added required competencies like resilience to the existing rep role—not a bad thought, but not a bold move either.  

Moving from the usual "regional sales manager" 

model to an "account manager" model that expands the individual rep role.

—for instance, through so-called e-detailing or Skype sessions or by transitioning the focus of the role to more of an "information broker." 

 that focuses on dropping samples and keeping contact, while reserving significant interaction for a higher-level rep/team with sophisticated medical knowledge and strategic focus.  

But in many cases, these kinds of changes just aren't far-reaching enough. They may not be staffed for success. Or, they're moving too slowly (see sidebar). 

Data Reveal More Sales Rep Status Quo than Sales Rep Revolution			

The rep role that previously focused on exerting influence and providing guidance is now becoming a service model. This means the rep acts as a conduit to help physicians and related customers access information and resources.  

, Dr. David Nash, Dean of the Jefferson Medical University School of Population Health, said "The most disruptive action a pharma company can take is to trump the competition with new and more effective tools to educate the patient. It's very simple: the most sensible investment is one which will contribute to making patients better consumers of medicine." 

Back up the commercial organization chain, anecdotal evidence suggests that managers are becoming less focused on "pull through" (numbers of prescriptions) and are managing the business relationship with pharmaco-economic data. When doing this, they use analytical tools to help payers/institutions see how a portfolio of products benefits them.  

Your 'To-Do' list for the commercial organization and people in sales

Building an effective response to these strategic challenges requires a clear plan and laser-like focus that starts with the assertion that success depends ultimately on the way management communicates with this valuable storehouse of human capital. 

Most prevalent ’primary’ performance measures to determine incentive payout 			

 The commercial organization for 2014 and beyond must:  

			» Connect with customers (through all your services) to make sure you know what they value. 

			» Make sure everyone in your company knows what your customers value (and that they all agree on it).

			» Focus more on your key accounts than geography. 

			» Arm your sales force with a clear, attractive value proposition that can be communicated at all levels—describing what you offer, in both your products and related services. 

			» Find ways to open sustainable communications channels, so that you can keep up to date with what your customers want. Work closely with other parts of the organization—especially R&D,  R&D partners, and market access teams.  

 A successful new commercial organization will need people with skills that current reps may not possess. These people are no longer just reps in the classic sense. They provide a conduit of sorts for physicians and other healthcare providers to gain access to resources and tools within their companies' networks. So, what qualities should the core people in sales possess?

			» A strong medical science background, so they can understand and communicate sophisticated and complex information about advanced therapies. 

			» Outstanding relationship building skills, but more on an institutional level than the interpersonal level that has characterized the traditional rep. 

			» The ability to adapt to changing situations and provide different levels of discourse and service depending on the audience. 

			» A strategic orientation that enables them to confront issues and find solutions at a higher level. 			

» A level of technical knowledge and understanding that will allow them to team with technical professionals to provide solutions (as opposed to handing them off). 

A key factor here is to re-assess current reps for their suitability to this new role. Their previous success working under an old model (likely with performance measures that no longer fit the new role) is no guarantee of future success. Not all will have the new skills, behavioral characteristics, or motivation to  be able to develop them quickly enough. 			

Getting moving: Some things to think about

Companies that rethink the commercial organization correctly in the context of a good understanding of relevant market dynamics and then move the fastest to apply this to the revamped rep role will have the competitive edge. 

 To help you work out what you should do, there are some basic steps and questions to consider: 

			» Determine the true level of commitment within your organization to this kind of meaningful change.  

			» Think about the changes in your commercial organization from the years before the economic crisis of 2008-2009 through to today. Which changes would you classify as stopgap and which would you classify as forward thinking?				

			» Which of those stopgap measures (perhaps cuts or re-organization or re-distribution of people) have been re-visited and how? 

			» What effect did the more progressive or experimental changes have? 			

			» Where changes weren't successful, what were the reasons? Cultural resistance? Lack of clarity? Not enough people or money? Or were they poorly thought through? 

			» For those changes with potential, how could they be adapted? 

			» Consider the pros and cons of each change. 

Once you've found a scenario that you think would work, ask yourself whether you have enough of the right people to follow through on it and how you might obtain appropriate resources if you come up short.  

By rethinking the role of the sales rep and the new skills it demands, pharma companies can put themselves in a prime competitive position.

Sales Reps and the New Commercial Organization

Thirty-nine years ago this past June, an article appeared in 

that offered readers what was for its time a startling degree of foresight. Four paragraphs down, just above their first historic mention of what they called "the paperless office," the authors of "The Office of the Future" passed along a prediction by George Pake, head of Xerox's Palo Alto Research Center: 			

"Pake says that in 1995 his office will be completely different; there will be a TV-display terminal with keyboard sitting on his desk. 'I'll be able to call up documents from my files on the screen, or by pressing a button,' he says. 'I can get my mail or any messages. I don't know how much hard copy [printed paper] I'll want in this world.'" 

Coming in a time when the typewriter was still 

in any modern office, the first part of Pake's prediction was far-seeing—and quite correct. The integration of computers into office environments may seem like a self-evident development with hindsight—but I don't recall anyone predicting the future ubiquity of smartphones or social media 20 years ago. So the first part of Pake's prediction should be considered one of the more impressive in the history of business prophecy. 

The second part of Pake's prediction—the bit about paper—is more troublesome. In the same 20 years that saw Pake's display terminal prediction come true, the use of paper in North American offices actually rose. And while paper use in offices has declined somewhat since the 1990s, overall world consumption of paper has grown by four times since Pake made his prediction. 

Why the history lesson? Because we as marketers need to get out of our heads the idea that the advent of digital technologies means the immediate irrelevance of more traditional forms of communication. 

We as marketers can achieve extraordinary things with digital tools. They have transformed the business of health, greatly for the better, and will continue to do so in ways that we can barely imagine today. 

But no matter how enthusiastic we are about the shiny new tools in our toolbox, and no matter how much we talk to each other at digital conferences about how digital and mobile and social have grown from mere tactics to Capital-S Strategy, vast swaths of our audience are still consuming vast swaths of content via traditional channels. 

Why? Because in today's world, the speed of technology evolution is outpacing human habits, and human nature. People have been reading and writing and sketching on paper for nearly two thousand years, and on a variety of other non-digital tactile media for unknown thousands of years before that. We'll probably reach the age of the paperless office and fully paperless content consumption someday, but it'll most likely be after everyone who reads this article is dead.  

Any evolution in the fundamentals of ways humans communicate and perceive their world takes a long time—generations steeped in the old ways must pass and new generations be born, often several times over, before such an evolution can be considered complete. Even evolution itself is an evolution—"On the Origin of Species" was first published more than 150 years ago, and still only about six in ten Americans—or so says Pew Research—believe in its fundamental assertion. 

According to the AMA's Physician Master File, 47.4% of all active physicians were age 50 and up as of 2012. So nearly half of our single most important constituency are old enough to remember watching the Apollo 11 mission on television. Also, more than half of physicians regardless of age—55%, according to Kantar's latest survey—still read articles from medical publications in physical form, nearly double the number who read such articles on a tablet and well more than double the number that read them on a smartphone. 

Patients too. While the median age of the American population is 37, the use of healthcare isn't distributed evenly across that population. According to one published study, only a fifth of the average person's lifetime medical expenditure will be spent during the first half of his/her life, and nearly half of that expenditure will occur after age 65. That's not to say that young people don't consume plenty of healthcare services—of course they do. But older people consume a lot more. And in ten years, older people will still consume a lot more, and those older people will still be old enough to have begun their professional lives well before the advent of the desktop computer, let alone the smartphone or tablet or social media. These are people whose formative years were spent consuming information via traditional, non-digital means, and a large number of them still prefer to consume information that way. 

All this being the case, when considering the proper place of digital media in any marketing mix, we need to go back to basics. The question for marketers is the same today as it was in 1914 and will be in 2114: Who is our audience, and what is the best way to communicate with that audience? Now, brand audiences are not monolithic—they include all sorts of internal variations depending on the variables of each brand's labeling and value proposition, not to mention the variability of people and their information consumption habits. That's why one needs a marketing mix. But if we really know our audience, we can at least draw certain basic conclusions. Such as: if our median audience member is more than 50 years old, it would be foolish for the center of gravity of our marketing mix to lie on the digital side of the scale. 

So why the rush to digital? We as marketers are suffering from a cognitive bias—a bias in favor of our own preferences. We are by nature creative and innovative people, and it's our responsibility to stay abreast of new developments in marketing, so we surround ourselves with the new, the innovative, the transformative. Digital turns us on. So we have a tendency to place our audiences in our shoes, rather than the reverse. We see our audience not as they are, but as we are. In so doing, we run the risk of failing to place our messaging in front of large numbers of people who might well benefit from it, people who don't correspond to our own biases about media consumption. 

To avoid the effects of this cognitive bias, we need to reacquaint ourselves with our brands' audiences. The emergence of digital media and research tools offers us greater capacity than we've ever had before to find out as much as possible about our audiences' individual content delivery preferences. Then, we can go about the task of defining—or redefining—our marketing mix, incorporating digital and traditional elements as the audience's nature dictates. That mix will likely include a majority of one and a significant minority of the other, depending on the nature of the audience. But it will always be a mix, strategically appropriate content passing through a carefully balanced recipe of the various forms of media delivery, digital and otherwise. 

Yes, digital is the future of marketing. But brands and the people that use them don't live in the future— they live now. To be successful as marketers, we need to remember two things: 1) that our messages belong where our audience is today—not where they may be in the future and 2) because our target audiences are not homogeneous, applying a balanced marketing mix is crucial. Whether the medium is stone, papyrus, paper, billboards, bus stops, television, desktops, smartphones, the Oculus Rift, or little chips embedded in the brain—wherever our audience is today, in all its infinite variations, that's where our message belongs. 

 is the founder and president of Excitant Healthcare Advertising. He can be reached at 

The rush to digital will continue at a fast clip, but marketers need to reacquaint themselves with their brands' audiences.

Digital's Place in the Pharma Marketing Mix

Tuberculosis (TB) advocacy campaigner Treatment Action Group (TAG) has reached a milestone in improving access to TB treatments. The efforts of the research and policy think tank were fruitful as Sanofi reduced the 340B federal discount program price of

 (rifapentine) from $73 to $51 and further in January to $32 per box, according to TAG's website. The collective action resulted in a historical win for the TB community with a 57% reduction in 

's cost, says Erica Lessem, TB/HIV project assistant director. And in spite of the aggressive stance taken by TAG, including two open letters to Sanofi and pressure by way of the #shameSanofi twitter countdown, the Paris-based drug company is today "more committed than ever to TB treatments." 

"TAG vows to do more than just get in the room" to drive drug development for TB elimination, says Colleen Daniels, TB/HIV project director. TAG wants to be certain, she says, that its presence isn't merely a box for drugmakers to check, but a signal for meaningful engagement around a patient-centered approach. 

Using similar bold and direct tactics for 

 (bedaquiline), TAG and a TB coalition sent an open letter to Janssen in September appealing for a reduction in the drug's price for all non-high-income countries as well as a meeting with the company, policymakers, and key funders of TB drug procurement. Janssen has indicated interest in negotiating on the price of 

, says Lessem. TAG has been involved in the design of the next set of 

's studies and has pushed Janssen to assure trials that are rigorous scientifically and ethically, she notes. 

In contrast to the collaboration between TAG and Janssen, Japan's Otsuka has taken a more closed-door approach to working with the think tank. Lessem says the lack of openness and responsiveness to the TB advocacy community is an indicator of a less rigorous trial protocol, and ultimately, the result has been less success with regulatory agencies for Otsuka's 

 (delamanid), which only has approvals in Europe and Japan so far. 

TAG's roots date back to the early era of AIDS activism. In 1992, several members of the Treatment and Data Committee of ACT UP (the AIDS Coalition to Unleash Power) left to establish TAG, to push for clinical trials and evidence-based approval of HIV drugs. Now the science-based think tank divides its efforts across HIV, and its deadliest co-infections, TB and hepatitis C, according to Daniels. 

There are around two billion people with latent TB infection, and we need to be able to prevent them from developing active TB, which kills around 1.5 million people a year, says Daniels. There are not enough efforts in pharma working on preventing TB activation, especially for those possibly infected with drug-resistant strains of the disease. 

In endemic areas like South Africa with simultaneously high rates of TB and HIV, patients take drugs that have been in use for 60 years. The drugs have major toxicity and tolerability issues and must be taken in sequence under close supervision; stopping the drug results in loss of the treatment's effect, Daniels explains. 

We need drugs that can be taken for shorter duration with better tolerance and adherence, but there are few prospects for improved therapies, she says. 

The drug development process in TB is "absolutely broken," adds Lessem. "The incentives for R&D are all in the wrong way so that it's not actually about getting drugs into patients. Its about making money in the big markets," she says. "There are few companies actually investing in TB research, and we've actually seen, recently, that Pfizer and AstraZeneca have pulled out." Last year, TAG reported the first decline in global funding for TB research since the organization began tracking numbers in 2005. This decline was driven primarily by pharmaceutical companies abandoning TB research. With total investments under $100 million, private sector companies spent less on TB research in 2013 than they did in 2009, at the peak of the economic crisis. Many in the TB community are pessimistic when talking about controlling the disease. "We want to change the discourse in TB so that we coalesce around a vision," says Daniels. "We can get to TB elimination." 

TAG works globally but has a domestic focus working with minority populations on drug pricing and access in the context of the Affordable Care Act and different state exchanges. The organization looks at how structural and social factors prevent treatment and care from being implemented effectively in the US, notes Jeremiah Johnson, HIV prevention research and policy coordinator for TAG. 

A major topic the group has confronted has been pre-exposure prophylaxis (PrEP), says Johnson. A big problem is that those who would most benefit from PrEP still need greater access to accurate information about their risks for acquiring the virus as well as all of their options for avoiding seroconversion. 

 from Gilead has hit a political "minefield," says Johnson. "I think there is some interest in the market," he notes. "But it's hard to gauge what Gilead's real perspective is. The community isn't completely behind pre-exposure prophylaxis and there are fears around reducing condom use, and questions around how the therapy works with existing prevention efforts."  

Gilead has been willing to help sponsor community organizations to create their own PrEP campaigns, but lately is taking a more hands-off approach, says Johnson. 

Treatment Action Group (TAG) reaches a milestone in improving access to much-needed treatments for tuberculosis.

Advocacy Beat: Progress in Global Access to TB Drugs

 about the potential of medicines to manage—even cure—a growing number of once untreatable conditions. That's the simple takeaway from 

's annual review of what's coming up next from the industry's $60 billion pipeline of drugs in development. As contributing writer Josh Baxt notes in this month's cover feature, "immunotherapy is unlocking its promise as a safer way to fight cancer, we are seeing the first new treatments for heart failure since the 1980s, and gene therapy—the ultimate guarantor of personalized medicine—is finally approaching the clinic." 

Yes, it's a good time to be a patient. The larger question is whether the times are as good for the industry that accounts disproportionately for the task of rendering basic science into therapeutically effective medicines, able to perform consistently across a target patient population. The truth is there are some real tears in the patchwork gauze that binds a new entry to the commercial market. Many of these fissures lie hidden from public view, characterized only in vague terms like long lead times to market and high "sunk" costs. Yet, combined, they amount to a smoldering challenge to the current approach to drug development, a silent reminder of the necessity to embrace a different, perhaps more frugal model. 

Here are a few "grand challenges" that drug developers in this new world of science face in moving a compound forward, from bench to bedside:  

While time-is-money problems continue to rise in late-stage development, initial work in de-risking an asset for human trials is also slowing progress. One major challenge is the failure of traditional animal models to keep pace with the proliferation of testable drug candidates in certifying whether such candidates are likely to work safely when transposed to humans. No compound can progress toward regulatory approval without this essential benchmark being met, yet the predictive capacity of the "oncomouse" and other genotyped rodent models—their ability to yield an objective clinical response—is still quite low. In key areas like cancer it is getting lower as researchers attempt to develop models that can accurately mimic the contours of ever more complex tumors. The result is lengthy delays in progressing assets to crucial Phase IIb work and beyond: scientists say it's one of the less recognized roadblocks in that race to de-risk. 

Next, consider the mounting complexities in the conduct of clinical trials, as a new generation of biologic drugs demand significant investments in pinpointing and recruiting the right patient candidates; appropriate monitoring, across multiple sites; data retention and evaluation; and extraordinary levels of physician supervisory engagement. Trials centered on the "one drug/one condition" methodology are becoming irrelevant. To satisfy the exacting expectations of trial reviewers coping with compounds that embody new science and an unconventional therapeutic approach, drugmakers seek to cover many bases at once, leading to internal process irregularities, data silos, and mid-course protocol adjustment snags that the Tufts Center for the Study of Drug Development (TCSDD) estimates costs the industry $6 billion a year in unnecessary spending.   

What happens after approval may be even more significant. A nod from the FDA is only the beginning of a mounting series of regulatory obligations designed to evaluate the safety, efficacy, and "medical need" for a medicine under real-world clinical conditions. These often involve the preparation of large-scale studies in multiple locations—or, alternatively, among highly selective small subpopulations—that can go on for years, exceeding even the length of the drug's patent and costing many millions of dollars.   

Unfortunately, industry has failed to highlight what it is taking on to comply with these post-approval mandates. The long time frames for this work may also mean study conclusions are less relevant to the current state of therapy, which can lead to pressures for withdrawal of the product from the market.  And how many promising drug development leads will be sidelined due to the priority all this post-approval work gives to the perspective of the regulator, whose role in many jurisdictions is morphing from simple registration approval to gatekeeper on pricing and reimbursement as well? What was once predictable is increasingly uncertain: the days when approval boundaries were fixed and finite, as exemplified by the slogan "We won, so we're done," are clearly over.  

Finally, there are the usual competitive challenges, although this time the threat may be extramural, led more by countries than companies. China, with its huge market size and scale, is beginning to demonstrate the capacity to develop innovative drugs at lower cost than its Western equivalents. Science is not going to get any easier, so finding ways to economize through process innovations may end up being the stitch that saves the industry. 

From the Editor

Amid a resurgence in drug development for hard-to-treat conditions, the bigger question is whether the times are as good for the industry tasked with rendering basic science into therapeutically effective medicines.

Pharma Science: It's Hard

Everyone knows that Novo Nordisk is a tightly focused enterprise neatly matched to a big disease footprint—diabetes, where it commands nearly 50% of the global insulin market. A critical—and less apparent—driver of the company's success has been its long journey to build a viable presence in the US, a market whose size and reach makes it a proving ground for any business with global aspirations. Prior to 2001, Novo Nordisk was just a bit player here, with annual sales below the $300 million mark. Paced by some risky investments to build a US sales force literally from scratch, the company raised that number tenfold in the years up to 2008, and then more than doubled it again after the introduction in 2009 of its breakthrough glucagon-like peptide-1 (GLP-1) analogue, 

. This year, Novo Nordisk's US sales are slated to surpass $7 billion, with 

 alone racking up a 60%-plus share of the GLP-1 market.  

To take a closer look at Novo Nordisk's blueprint for the US, 

met last month with Senior Vice President for North America Jesper Hoiland. Hoiland, 54, a 27-year company veteran who assumed his post in August 2013, is the first native Dane to lead the US business. It's a distinction that Hoiland sees as an opportunity to create a broader cross-cultural perspective and promote better understanding of a complex—and often non-transparent—operating environment for medicines. In the following Q&A, Hoiland discusses his first year on the job at the company's regional headquarters in Princeton, including an unsettling initial encounter with the growing clout of pharmacy benefit manager (PBM) medicines gatekeepers; looming price wars; observations on the vital importance of stakeholder outreach in a transactional health system driven largely by relationships; all the advance planning required to unleash the promise of the eight to 10 new compounds Novo Nordisk hopes to commercialize by the end of the decade; and implementing what he sees as the three essential contributors to CEO leadership success: People. People—and People. 

 You joined Novo Nordisk in 1987. What was your first assignment? How have the company's clinical and business practices changed over the past 27 years? 

 My first job as a young manager at Novo back in 1987 seems inconceivable today. The interesting part is that I was assigned to the US, at a time when we had virtually no presence here. Between Novo and Nordisk, which were still separate companies then, we had less than 75 people, including sales reps. Among other things, I was tasked to estimate the number of cattle Novo would need each year to fill the demand for human insulin, which was mostly extracted from cow glands. This depended, in turn, on accurate forecasts of the growth of the US diabetes market. Getting the right estimate was also important because in the 1980s the US dollar was highly volatile. All that seems fanciful now given the advances in both science and information.  

Looking back over the years, our business practices have been affected most notably by information technology. In the 1980s, as the youngest manager on staff, I was good at adapting to the new data management tools coming on stream, which explains why I became the first person outside the finance department to be given a personal computer. I recall being asked by my supervisors to figure out what other uses Novo could find for it. Ironically, today I hardly use my desktop because I prefer to meet and talk to people directly. Personal interactions are the basis of my management style. 

Further to business practices, hasn't Novo Nordisk's longstanding status as having a foundation as its majority shareholder kept it remarkably stable over the years, particularly compared to the short-term business pressures that confront publicly held enterprises?   

Our company history is unique. We began as two companies, Nordisk and Novo, founded in 1923 and 1925, respectively, led by Danish physician researchers and pharmacists with a passionate scientific interest in diabetes—a condition that, due to the discovery of the insulin hormone by two Canadian researchers, was then just emerging as a treatable chronic disease. The two new companies led the world in turning this discovery into a product with clinical—and commercial—applications. Ninety years later, and as a combined company since 1989, we are still the leader, not just in Europe, but globally. We are able to build on decades of work in progressing the treatment of diabetes, from the accessibility, safety, and stability of man-made insulin to innovations in therapeutic delivery devices as well as investments in diabetes control and prevention in diverse community settings—our products are now marketed in 180 countries.   

The focus on diabetes was made possible by the decision of both companies to structure themselves as a foundation under Danish law, Nordisk in 1926 and Novo in 1951. This allowed profits to be plowed back into research and treatment activities rather than be subject to tax. Dr. Hans Christian Hagedorn, a co-founder of Nordisk and inventor of the first bulk manufacturing process for insulin derived from the bovine pancreas, put most of the company's early revenues into research, including founding the Steno Memorial Hospital, which exists to this day and has had a distinguished record over the years in treating more than half of the diabetic patients in Zeeland and Copenhagen. The Foundation was also the force behind our very early investments in the enzymes that trigger many metabolic processes, the understanding of which paved the way for the development of reliable, artificially derived sources of insulin. That sister company, Novozymes, is now the world's largest producer of enzymes for industrial and human uses; as with Novo Nordisk, the Foundation is the majority shareholder.    

At present, more than 70% of votes are controlled by the Novo Nordisk Foundation. This gives management the ability to deflect two negative influences on proper business planning: M&A pressures driven by activist shareholders, whose only motive is scoring a run-up in the stock price; and financial reporting biased toward short-term quarterly results at the expense of long-term performance. Novo Nordisk has never been for sale, even though over the years some prominent competitors have tried to buy us. We are one of the few multinational companies operating on a 10-year planning cycle.    

Status as a foundation also colors the approach to corporate responsibility, where we adhere to "triple bottom line" reporting, which includes financial, social, and environmental performance metrics. We put that in place back in 2004, when we were the first major pharmaceutical company to do so. The commitment also shows in our record on executive compensation, where we have one of the lowest differential in this industry between our CEO's pay package and the pay of workers on the shop floor.    

 Now that you are leading a transformed US organization for Novo Nordisk—it ranks today as the company's largest foreign operation—what lessons do you draw from that first assignment in the US market?

My initial training in sales gave me basic knowledge about the pharmaceutical business that I continue to apply today. I still count as one of my proudest achievements the diploma I received after completing an arduous six-week course to obtain certification as a sales rep. I had to pass that test in order to keep my job. But that was only the beginning. Working in the field, meeting customers, and reacting spontaneously to their tough questions, convinced me that success does not come from sitting in an ivory tower.    

Since I arrived as head of North America in August 2013, I've spent most of my time out of the office. I make an effort to visit and mingle with the sales force, whose numbers I have increased by nearly a fifth in the past year. I am reaching out to pharmacy benefit managers, payers, physicians, and nurses. I ask every diabetes patient I meet for their perspective on treatment. To the extent I can, I try to dialogue with regulators. I make it a point to be a guest lecturer at business schools, which I believe are a great source of ideas as well as giving me a chance to meet the next generation of managers. Because the US market is changing so quickly, it is important to possess a holistic, 360 degree view of what forces are shaping that change, especially because most of it is taking place outside our own narrow segment of the health system. To that end, this month, Houston became the first US city to join Novo Nordisk's "Cities Changing Diabetes," a global partnership focused on diabetes lifestyle education and fighting the rise in urban diabetes. 

Jesper Hoiland, Novo Nordisk's President for North America, assesses the challenges and opportunities during his first year at the helm of the diabetes franchise leader's biggest affiliate market.

Pharmaceutical Executive-11-01-2014