Barri Blauvelt is CEO of Innovara, a global pharmaceutical business and management development firm. She can be reached at Innovara@innovara.com.

Barri Blauvelt

	The announcement by the US FDA on May 23 of the accelerated approval of Merck’s newest master brand Keytruda (pembrolizumab) 

 was a wonderful surprise to most. This was because to those involved in genetic and clinical research, they had low expectation that government agencies would do the logical thing and approve cancer treatment based on a common biomarker instead of approving one tumor type at a time.

	Accelerated approvals of targeted therapies are not new, but until now targeted solid-tumor therapies have tended to be site specific. The first of these genetically-targeting master brands was Herceptin (trastuzumab).  When Herceptin was 

, the challenge to Genentech was whether or not to launch with the FISH test. Launching with it, the market value was estimated to be about 70% lower than without it.  However, governments felt that due to the high price, it was obligatory for Genentech in the US and its partner Roche outside of the US to provide FISH tests so that the drug would be used only in patients who were likely to respond.  Genentech/Roche’s decision to launch with the FISH test set the course for future targeted therapies to be approved along with biomarker diagnostics.  

	Today we say, “Of course!” to the expectation for companion diagnostics. Yet it was not an obvious choice 20 years ago. FISH tests were simply not available around the globe. Moreover, oncologists weren’t used to asking for it to be done. And finally, women with breast cancer themselves were demanding to be given Herceptin, not understanding that the drug would only help them if they were HER2 positive.

	Why is it, then, that even today, new genetically-targeting therapeutics continue to be challenged by limitations of biomarkers at launch? 

The Case of Familial Hypercholesterolemia: 

, the benefits of the new class of PCSK9-inhibitors in preventing cardiovascular death and stroke were demonstrated as early as within one year of adding a PCSK9 inhibitor to statin therapy.

An editorial on this (in the same issue) concluded, “It is anticipated that the results of the FOURIER trial will soon be implemented in international guidelines regarding the treatment of high-risk patients, directing clinicians in the use of this new and expensive class of drugs.”

	The findings of the FOURIER trial were not that surprising to most cardiologists. Yet uptake of this potential class of drugs has been slow, even in countries willing to reimburse for it.

	To better understand why uptake has been so slow, we look to NICE, CDC and other agencies. The EU approved the first of these drugs in 2014.  At that time, NICE, the CDC and other agencies called for not only the testing for gene-encoding proprotein convertase subtilisin–kexin type 9 (PCSK9), but that this should be followed by 

cascade testing in suspected cases of Familial Hypercholesterolemia (FH)

.  However, according to Stanford University, at the time of launch, there were 

only a few laboratories in the US and internationally that could test for PCSK9

.  So along with high price, lack of such testing being able to be done in accordance with NICE and other guidelines helped governments and physicians alike not to prescribe and reimburse for a potential new master brand for FH.

Diagnostic challenges for master brand Keytruda

	So let’s turn again to Keytruda (pembrolizumab). Keytruda helps the body’s immune system fight cancer cells by blocking the cellular pathway PD-1/PD-L1. The FDA previously approved Keytruda for the treatment of patients with metastatic melanoma, metastatic non-small cell lung cancer (NSCLC), recurrent or metastatic head and neck cancer, refractory classical Hodgkin lymphoma, and urothelial carcinoma testing positive for PD-L1. Keytruda targets MSI-H and dMMR tumors containing abnormalities that affect the proper repair of DNA inside the cell. These are most commonly found in colorectal, endometrial and gastrointestinal cancers, and may also be found in breast, prostate, bladder, thyroid gland and other primary sites and in metastatic cancers. So the FDA’s 

 approval to allow for use based on a tumor’s biomarker instead of prolonging the inevitable approval of one tumor at a time is a huge leap forward.

approved for use with a companion diagnostic

, the PD-L1 IHC 22C3 pharmDx test (the first test designed to detect PD-L1 expression). However, PD-L1 testing is largely prognostic for patients beginning pembrolizumab treatment. This is because PD-L1 assays are unable to conclusively identify non-benefitting patients. How can that be?

	We have to remember that the PD-L1 gene is not typically mutated or amplified and is constantly evolving as part of the immune system. This means that PD-L1 expression can be ever changing in space and over time, as well as be impacted by other treatments, such as radiation or chemotherapy. Finally, there are challenges as to diagnostic accuracy based upon assay testing variability, concerns about quality (e.g. variability in staining intensity and patterns) and lack of standardization pertaining to tissue fixation, storage, and antigen retrieval resulting in PD-L1 degradation. These combined effects may explain why PD-L1 positivity 

has had such widely varying clinical significance

So over the past 20 years, what have (or haven’t) we learned?  

	It’s a simple, yet surprisingly often-overlooked critical success factor: In the era of genetically targeted therapies, companies developing potential master brands need to begin work much earlier in the clinical development program to ensure that reliable diagnostics will be available to all potential patients when the therapeutic is approved. 


	
	1.     Sabatin MS, Guigliano RP, Keech AC, et al. "E volocumab and Clinical Outcomes in Patients with Cardiovascular Disease". 

	2.     Dullart, RPF. "PCSK9 Inhibition to Reduce Cardiovascular Events". 

Articles

Companies developing potential master brands need to begin work much earlier in the clinical development program to ensure reliable diagnostics will be available to all potential patients, writes Barri Blauvelt.

Diagnostic Challenges in the Era of Genetically Targeting Master Brands

A decade ago, pharma companies typically launched new products, observed how well they sold, and, if necessary, modified their marketing strategy and launched again. In today's competitive marketplace, there is only one rule: Get it right the first time.	

Increasing price pressures in Europe, Japan, and the United States make it tough for companies to command the new-product premiums they need to sustain high levels of investment. So they must find new ways to justify their products' value and to maximize ROI as quickly as possible. Sometimes they must establish a product's market position in as few as 36 months. After that, according to IMS data, the ability to rapidly acquire share and defend price premiums diminishes sharply.	

To find out what pharma companies must do to launch products successfully, Innovara conducted a global benchmarking study between September 2001 and April 2002. (See "Study Parameters," page 48.) Based on the results, this article examines	

how major pharma companies are organized and managed globally to develop and bring new products to market 

the relationship between companies' R&D/commercialization interface processes and their commercial results/market leadership

the key components of their new global product commercialization success.	

Companies such as AstraZeneca and Pfizer, the study's two mostly highly rated, identify the unique medical and scientific rationale for their products, then work to create the need for whatever that advantage may be well in advance of commercialization. 	

John Patterson, AZ executive vice-president of product strategy and licensing, believes that shaping the product and its market early are key to his company's success. "We were fortunate," he says, "following our 1999 merger, to retain the top global marketing talent from both Astra and Zeneca. We also have a strategic global planning group that assists our R&D and global marketing teams in producing target product profiles (TPPs) and target product claims (TPCs) early in each candidate's lifecycle. The thinking behind those TPPs and TPCs is not only the foundation for the success of our brands but for the success of our business."  	

The classic case for the result of that kind of thinking comes from the other top-rated company: Pfizer. Before commercializing Lipitor (atorvastatin), Pfizer created a perception of the importance of triglycerides, which, at launch, seemed to be the only medical differential between the new medicine and other leading statins. During that time, Pfizer underspent the competition in basic R&D and, instead, invested heavily in  Phase III studies that would, on approval, be necessary to support the commercial-medical position through launch and post-launch phases.	

Three main operating principles appear to shape products and markets to assure global commercial success:	

Medical and scientific excellence and creativity to establish the rationale for the product

Highly skilled commercial personnel to prepare the market for the new brand, accelerate market adoption, and maximize share of voice at launch

Seamless organizational alignment and cross-functional teamwork to minimize time to launch and maximize medical and commercial impact.

"What is most surprising about this study is not that Pfizer was crowned as the leader of best practices," says David Beadle, executive director of global pharmaceutical research for UBS Warburg, "but rather the extent of its lead over the majority of other industry players. Pharma companies must be prepared to manipulate decades-old marketing rules to create the blockbusters of the future." 	

So, what are the new rules? Following, in the order of importance, are the 12 best practices in which companies must excel to create blockbusters.	

As soon as a company suspects it has a major new drug-as early as Phase I-the patent-life clock is ticking. From that moment on, everyone even remotely involved in new product commercialization must focus on developing the product's potential. And all participants in the three operating principles-medical/scientific excellence, aggressive commercial execution, and seamless organizational alignment-must not only know what they need to do but how to do it quickly.				

Who has it? Genentech does. Dr. Colin Goddard, CEO of OSI Pharmaceuticals, who selected Genentech over many larger oncology companies to license Tarceva (erlotinib), gives the best example of what a sense of urgency means: "Speed of development, willingness to invest heavily in the development of the product, talent, and a bet on who would be the market winners were the main ingredients we were looking for. What made the difference for us was that, at Genentech, speed was seen as a key reason not to lose the deal. "	

Yet, companies need to balance medical and ethical responsibility with their desire to maximize a new product's lifetime value or to boost shareholders' flagging confidence in the company.	

For new products,  three public relations strategies are critical to global commercial success: 	

consumer-to-patient preparedness-educating consumers so they are prepared to convert to the product at launch.

What comes easiest to most companies is the development of medical community advocacy and thought leadership. Even the strictest governments allow pre-launch PR for major new products through medical congresses, research, and more. In that respect, companies must merely match share of voice and share of spend in pre-launch PR-related medical marketing activities to be fairly assured of achieving the 60 percent unaided recall brand awareness level that most companies aim for by launch time.	

But the effectiveness of pre-launch PR depends on nurturing and using global, regional, and local medical thought leaders as advocates. From a PR perspective, those thought leaders must rally around a common message that is highly credible while helping to prepare a global platform for the company's brand. Pfizer, 	

AstraZeneca, and-until recently-BMS have been masters at that.	

More challenging is the PR mission to the investment community, which begins with the earliest clinical testing-or even with discovery and translational research. The companies that do that well take it seriously, right from the top. Merck's Ray Gilmartin, Pharmacia's Fred Hassan, and Genentech's Art Levinson are three CEOs known for their strong shareholder loyalty and investment community PR skills. As a result, they are able to sustain the shareholder community's confidence, even through periods of dry pipelines. 	

Finally, PR preparedness-so necessary in today's DTC-driven marketplace as a way to raise physicians' interest and to expand the market- is often the industry's Achilles heel. The well known story of Novartis' Gleevec (imatinib) provides a stunning example of how important it is for companies to monitor-and respond to-patients' reactions to a product.  	

Says Gloria Stone, director of global PR for Novartis Oncology, "With Gleevec, public relations proved to be one of the most effective means of communicating the drug's status to a global audience." 	

"First and flexible" describes a company's willingness to try new things. Specifically, it means being top of mind with biotech companies and inventors when they are ready to sell or license new technologies. How does a company get to be first on their list?				

Dr. Jason Fisherman, managing director of Advent International, a global venture cap firm that works with biotech companies and biotech-related funds, explains: "A critical factor in the decision process is identifying a partner, who not only has a real commitment to scientific and clinical innovation but who can relay a clear vision for how the alliance will lead to mutual commercial success. That includes a shared sense of 'disciplined urgency' and focus as well as an openness to bi-directional learning."	

Only two companies make it to best-practice status in that regard: Genentech and Pfizer. Genentech's ability to come through with a thorough and flexible offer shows the licensor they genuinely care for mutual success and rapid commercialization. And, being able to take the plum oncology product Tarceva away from bigger contenders also showed a willingness to build an oncology program around high science that many larger companies would find too complicated or beyond their core therapeutic areas of interest.	

Pfizer makes the "first considered" list as an acquisition partner for a different but compelling reason. Five of six of its most recent product launches have come from other companies' R&D efforts.	

Many companies want to be on the "preferred partner" list but fall short for two main reasons: First, they have no processes to enable them to rapidly consider new technologies or products outside of defined therapeutic franchises. Second, they are much more rigorous in their analysis of external candidates than they are of their own R&D products, making the hurdle for a positive evaluation  much higher-sometimes impossibly so. After one or two rounds of negotiations, licensors quickly lose interest.	

Retail guru John Wanamaker is famous for saying, "Half the money I spend on advertising is wasted. Unfortunately, I don't know which half." The same could be said of R&D's "deep pockets." Ken Kaitin, director of Tufts University's Center for the Study of Drug Development, estimates that, of the total R&D spending on new products, less than half relates to the cost of developing the successful compound. "Of every five products that enter human testing, only one will succeed," reports Kaitin. Then, each of those must be approved by a country's regulatory agency. And the odds of success after approval are even worse. The study shows that, in the increasingly generic market, only one in twelve newly approved products will survive five years of commercialization and only one in sixty will become a new market leader.				

The lack of courage to pull the plug-especially in the earlier stages-on new therapies that fail to demonstrate strong performance throughout the development process points to a basic lack of clear decision points and other accountability measures. But the real reason for the high cost of R&D may be much simpler: "No one wants to be the bearer of bad news when it comes to a new drug that the company is counting on," says one scientist who evaluates new compounds for Pfizer. "So, at Pfizer we had to change the system. Now we do very aggressive early testing. Better an early stage "no" than an incredibly expensive later-stage one. If it passes, it is "canned," meaning it will now enter our early-stage candidate tracking system."	

Most companies face a near-term shortage of exciting new global brands, but a few not only have good new products to develop but good long-term prospects as well. They include Novartis and Wyeth, which plan to launch some exciting therapies in the next three to four years. In particular, Wyeth has new oncology and diabetes combinations and other compounds for launch possibly as early as 2004, all of which have huge global market potential. Although it has fewer new potential billion-dollar brands, GSK is collectively impressive with a range of products, each one with  a potential value of half a billion per year and co-marketing agreements for some dynamic new products that are well positioned to use the company's global marketing muscle. 	

Aventis has significant near-term growth potential with new products Lantus (insulin glargine) and Ketek (telithromycin) and new indications for Taxotere (docetaxel). AstraZeneca should blossom with Nexium (esomeprazole) and Crestor (rosuvastatin)."We all know that the secret to a successful product launch is good drug, good drug, and good drug," says AstraZeneca's Patterson. "No one disputes that our R&D has been productive."	

Most companies in the study showed the ability to develop a clear global brand commercialization strategy from a relatively early stage of development. But brand profiling is not only about name and product positioning. Companies must develop core brand marketing strategies that will shape the market to prepare for widespread acceptance of the product as rapidly after launch as possible.  				

Merck's Fosamax (alendronate) is a classic "best practice" example. If left to the definition of osteoporosis at the time of initial clinical investigations-mainly in post-menopausal women who suffer a confirmed vertebral or other fracture and other factors-the market potential for Fosamax would be tiny. However, Merck redefined the market to include both men and women at risk of osteoporosis prior to a first fracture. In doing so, it created a product potential 20–50 times greater than the previously defined market was expected to reach before Fosamax's launch.	

To be successful, companies must study a product to evaluate its ability to define and expand the market. They must establish target brand profiles early and apply them consistently throughout the development process so managers can strategically design and coordinate clinical research, brand awareness, and market shaping activities to achieve maximum commercial results. Companies must have clear global strategies that translate well into local ones and brand imagery and core messages that will essentially remain the same from country to country.	

Cross-functional teamwork and alignment with a common purpose is like good sex: everyone talks about it but few have it. One exception is AstraZeneca, whose global business teams are totally cross functional, meaning that the key decision makers are involved in all decisions about all products in all therapeutic franchises from the start. Those teams include representatives from most major countries of the world. Although at times that may appear to complicate communications, in the end it ensures top-down commitment to the new product throughout the company.								

Pfizer has such clearly established processes and discipline in evaluating and preparing new products for commercialization that cross-functional communications and effort are automatic. Only the most experienced people at Pfizer are involved in new products, and the company does not worry about therapeutic area competencies. Instead, at the corporate level, it has a highly centralized team of new product commercialization experts who can move from one product and therapeutic area to another with ease and alacrity. 	

Another question the study addressed was geography. Is it better to have a small team, centrally located, focused on decisions for only the largest markets? Or should companies have those involved in launching a new product consider input from around the world-or at least from all major markets and regional operations? 	

A clear trend is emerging to answer that question. More companies are migrating to smaller, tighter, new product global launch teams-including R&D and commercialization personnel-based in a major market. That has brought more global new product commercialization teams to the United States.	

AstraZeneca bases its global oncology team outside of Manchester, England, but its global CNS team is in the United States. "We try to locate our R&D and global marketing teams together," explains AZ's Patterson. "The United States produces most of our CNS sales, so we made it our R&D center of excellence for CNS research. That makes it easier for our CNS commercialization team to begin collaborating with the R&D team as early as possible." 	

A decade ago, pharma companies typically launched new products, observed how well they sold, and, if necessary, modified their marketing strategy and launched again. In today's competitive marketplace, there is only one rule: Get it right the first time.

Author | Barri Blauvelt

Articles

Diagnostic Challenges in the Era of Genetically Targeting Master Brands

Benchmarks for Blockbuster Launches