Eidetics and drug/diagnostic combos	February 2009

Med Ad News spoke with Robert Pearlstein, VP of Eidetics, about the transformative significance of drug/diagnostic combinations, examples of successfully marketed combos, and the work his company has done in this area.

Med Ad News: What strategies might pharma marketers and agencies have to use to effectively market the new generation of drug/diagnostic combos?

Robert Pearlstein: Marketing a pharmaceutical, as with any other product, requires establishing a perception of value. For biopharmaceuticals, that “perception” has a tangible definition: how well does it work? It is “tangible” because it is actually measured and judged in formal ways, i.e., via clinical trials, the results of which are evaluated by national regulatory agencies. Indeed, every stakeholder across the planet agrees that innovative preventive or therapeutic products are highly desirable and should be encouraged, nurtured, and made available to all who would benefit. In light of the tremendous growth in our knowledge of molecular biology, the central question is: why is this not happening?

The essential limitation is an inability to create therapeutics that have broad “value.” In truth, most drugs available today: (i) are only obviously beneficial in a subset of patients; (ii) typically demonstrate mere marginal value across “all” patients; and (iii) lose most of their value if they produce adverse events in even a tiny percentage of patients.

The entire circumstance we have today has been created because the value of what is being brought to market is “non-obvious.” The global structure is fundamentally a series of adversarial “gatekeepers,” each charged with the responsibility of assessing product value: (i) the approval / regulatory bodies, including the entire and cumbersome clinical-trial structure that has evolved; (ii) the healthcare payers of all types, including CMS, managed care organizations, formulary/evaluative bodies such as NICE; (iii) the internal resource-allocation executive committees of biopharmaceutical companies; and (iv) frontline clinicians who make product choice decisions.

At the most fundamental level, the key is creating products guided by the use of R&D and clinical biomarkers (“companion diagnostics”). Of critical and paramount importance is the ability to target therapeutics to those specific patients who will benefit greatly, and avoid targeting therapeutics to those patients who will either gain no benefit or even be harmed.

If achieved, the “value” of any given new product will be far more obvious to all stakeholders, including the entire global “gatekeeper” organization.

We are diluting the value of novel therapeutics (and therefore the key incentives to pursue them) by judging them against what they can do across all plausible patient populations. The relevant thought experiment is this: if you had the proverbial cure for cancer, would we be engaged in thinking about its value? If it was truly curative in only a discrete and definable subset of cancer patients, would we be engaged in thinking about its value? Obviously, the question answers itself: the value would be almost incalculable and all gatekeepers would be compelled to provide immediate and universal access to it. The problem is that all the current mechanics underlying drug discovery, commercialization, regulation, and access exist because almost all drugs are not the therapeutic equivalents to “the cure for cancer” of this thought experiment.

The problem is not a lack of “innovation” but a lack of “navigation.” In the current situation, everything about biopharmaceuticals is depressingly “empirical.” That means we lack the tools to guide our efforts at every level: to know both what to create and for whom to prescribe it. Without that, the risks involved in the enterprise are unacceptably daunting and the failure rates unacceptably high.

This problem is truly fundamental: creating innovative therapeutic products that focus on the differences between “patients” at a molecular level. The central reality is that each person is a new, unique throw of the proverbial genetic dice. (These genetic differences explain how we can definitively identify individuals using “DNA fingerprinting.”) The variations are usually subtle; consider eye color for example. But, collectively these differences are enough to make any given drug only work in a subset of patients. If this issue can be solved, all the rest of the pieces will fall into place. It is the one that needs to be the organizing principle around which all of the other initiatives can rationally be built.

The “Elevator-Speech” Version: at root, “drug/diagnostic combos” are the answer to the “value” question: if such a new combo delivers high therapeutic value – even in a relatively small but defined subset of patients – you can charge a significant premium for it, i.e., pro rata to its value. Payers well understand this: the inability to cure or manage disease is itself extremely expensive. Drugs that significantly lower that cost are inherently and obviously worth a premium. The drug/diagnostic (“Rx/Dx”) combo is a plausible, logical, and now technically tractable approach to delivering a far higher level of value. In that way, it offers the pharmaceutical marketing executive “real” value to sell – and to a willing world of customers.

Med Ad News: What are some examples of well-marketed drug / diagnostic combos, and why?

Robert Pearlstein: For many complex reasons, Rx/Dx combo successes are still relatively few. This reflects the state of commercial reality, the state of the science, and the state of the regulatory mechanics needed to foster their growth. The latter includes programs such as FDA’s Critical Path Initiative and the Biomarker Consortium. At present, the best examples are probably in oncology.

The paradigm example is the breast cancer drug Herceptin. This agent is effective in just the 25% to 30% of patients whose tumors express a specific protein, HER-2neu. After nearly stopping the Herceptin clinical program, the company developing it realized it could create a companion diagnostic to detect Herceptin-sensitive patients. Herceptin has gone on to become a major product, as well as one of the first examples of personalized medicine, i.e., matching a drug to an individual’s specific tumor genotype.

A stunning recent example is the finding that the effectiveness of monoclonal antibodies which target the epidermal growth factor receptor (EGFR), such as Erbitux and Vectibix, are far more effective in patients with colorectal cancer whose tumor cells lack a mutation in a gene called K-ras. In less than a year, assaying for K-ras status has been widely adopted in both the United States and the European Union. We believe part of the appeal is the unambiguously binary, “on-off” nature of the mutation: patients’ tumors are either positive or negative for so-called “K-ras wild type” status. The logic is compelling: if K-ras is mutated so that it is constantly “turned on,” trying to shut it off by targeting the “upstream” epidermal growth factor receptor won’t help. The simplicity of the science, the companion diagnostic, and the therapeutic result are so straightforward, the paradigm has been adopted with lightening-like speed across the world.

Unfortunately, this has all been discovered after the approval by FDA of both agents and their pricing in at least the U.S. marketplace. As such, the case also illustrates the commercial and regulatory complexities surrounding Rx/Dx combos. For example, there was a recent FDA ODAC Advisory Board meeting to evaluate how to think about such retrospective clinical findings and their place in the label.

Nonetheless, the K-ras finding is an unambiguous signal of things to come. Recently, drug manufacturers have been acquiring diagnostics companies at a rapid rate; e.g., Roche’s acquisition of NimbleGen, Ventana Medical Systems, and 454 Life Sciences in the past several years. Roche also signed an agreement with DxS for rights to the TheraScreen K-ras mutation assay.

Med Ad News: What work has Quintiles done in this area? What did you learn from the experience?

Robert Pearlstein: First of all, the Eidetics division of Quintiles Consulting has been in the business of helping clients assess product value for several decades. The “Rx/Dx combo” issue is an evolutionary aspect of that work: “value” is the essential defining quality of such combos. It is also a vital one going forward.

Secondly, we are working with a variety of clients to evaluate just such Rx/Dx combos for agents in their pipeline portfolios. We have identified four fundamental and interacting variables which condition the commercial significance of Rx/Dx combos:

Breadth: What percent of all patients screened by the assay will benefit?
Depth: How large will the therapeutic effect be in assay-positive patients?
Modality: How intrusive is the assay modality?
Criticality: How big are the therapeutic stakes involved in the specific disease?

Third, we have been helping clients with the very difficult strategic business issues surrounding Rx/Dx combos. The provisional answer (still evolving) is: make extremely informed decisions, based on all the complexities of regulatory mechanics, the science, and payer relationships that are all still in flux. Our greatest contribution so far is providing the framework and commercial/therapeutic-area experience to bring rigor to the process.

In the end, the potential upside is a new generation of biopharmaceutical products with substantially greater therapeutic power, safety, and evident value. Quintiles is exceptionally positioned to accelerate and enable this process worldwide because it uniquely has the real world combination of strategic, analytic, regulatory, commercial, and clinical-development experience needed to both “advise” and “do” in the new and exciting frontier of Rx/Dx biopharma.