Novartis Head Of Pharma Development James Shannon: An Interview With “The Pink Sheet” DAILY (Part 2 of 2)

The company is moving forward with a new drug development paradigm and its “category captainship” program.

Novartis Head of Pharma Development James Shannon sat down with "The Pink Sheet" DAILY to discuss the company's strategic priorities for drug development and in-licensing. This is the second of a two-part interview (see related ¹ (Also see "Novartis Head Of Pharma Development James Shannon: An Interview With “The Pink Sheet” DAILY (Part 1 of 2)" - Pink Sheet, 21 Jul, 2006.)).

"The Pink Sheet" DAILY : At the May Bank of America Healthcare Conference, Novartis Drug Regulatory Affairs Global Head Mathias Hukkelhoven highlighted a new two-phase drug development paradigm (building/testing of model and confirmation of model, followed by staggered release). How far has Novartis progressed on this project?

Shannon: The concept....is a project which has been running in Novartis development for about the last year and we give it the name DELPHI for Development Excellence Productivity and Innovation. In March 2004...the FDA produced the Critical Path white paper, basically saying the current model of drug development is the same as it's been for the last many, many decades and actually does not really leverage all of the technology that we have available to us today. It really is a rather low-tech business and needs to change.

But in March 2004, there weren't any real details about how it would change. We've been working with FDA...but also with the European Medicines Agency, which came a little bit later to the party, but has a roadmap for future development. And all of us, FDA, Novartis, EMEA and other companies believe that there are a number of areas in which we could change substantially drug development. Those would be in the better use of biomarkers, be they genomic technologies, proteomics, images, etc., which could either better select patients for efficacy or be used as markers for safety. With genomic or proteomic markers, we could potentially get indications of [drug toxicity] before we would put patients at risk.

Many industries have moved to...modeling and simulation so most of the planes which fly today have been modeled on a computer before ever a prototype is built. The difficulty, as far as biology is concerned, [is that] biology has been relatively unpredictable up to now. With the work we're doing with [Novartis Institutes for Biomedical Research President] Mark Fishman, we're trying to get down to the pathways of disease and understanding really what goes on within the cell at the subcellular level in disease, [so] that we can differentiate different types of patients and different types of mechanisms for the same outward appearance of a disease (same phenotype).

We're trying to make the biology much more predictable, almost to the level of physics or chemistry so we know what's going to happen. Therefore, we can bring more computer models into play and we can simulate what would happen in humans...based on knowledge of what happens in a cell or a test tube. Both FDA and we want to have more use of IT tools and computer tools.

"The Pink Sheet" DAILY : How would this work in clinical trials?

Shannon: Up to now, we've done Phase I in normal volunteers to look at safety and tolerability. We've gone to Phase II to do dose ranging. We've done Phase III where we do two repetitive studies with statistics which look at p-value <.05, which is a very arbitrary cutoff level. What we want to do is have more progressive statistics using all of the data which we generate throughout the development program and much more use of Bayesian statistics, which takes and adds data as you go along.

The more data you have, you can combine it all together and get a better outcome prediction. But also the use of adaptive trial designs, so that as you learn something you start with a fairly wide selection criteria and then gradually as you learn more about the drug, the dose, the types of patients in whom it is effective or safe, then you narrow down the criteria to get to the real benefit of the drug in a patient population in whom the drug is very highly effective and also highly safe.

[FDA announced recently that it would develop five guidance documents related to adaptive clinical trial design (² (Also see "FDA To Issue Five Guidances On Adaptive Clinical Trial Design" - Pink Sheet, 10 Jul, 2006.)).]

The concept [Novartis' Hukkelhoven] talked about was really taking the preclinical environment in the early human data, building this computer model, and simulating what might happen into a Phase II/III environment. Taking that computer model to the FDA, as would Boeing take a computer model to the [Federal Aviation Administration], and saying this is what we attempt to build. If we can prove that our computer model is correct and this is how the drug behaves in humans, will you approve it?

And then we would go forward with an adaptive trial based on that simulation....[We would] go from a very sequential 1-2-3 phase to more of a 2-phase, and a much more simulated environment.

"The Pink Sheet" DAILY : What types of drugs would you consider using for this paradigm?

Shannon: The most likely area is in drugs where we have clear biomarkers for either efficacy or safety, where we can drive a very large patient benefit. I would ultimately like to come out and say this drug is effective in 100% of the patients based on this marker. It really would be in life-saving drugs where we get the initial take-up, but then going forward from that, it could be into more or less life-threatening diseases, but diseases in which we would offer very substantial patient benefit based on better efficacy and much less safety concern.

"The Pink Sheet" DAILY : In January, Novartis Pharma CEO Thomas Ebeling announced a "category captainship" program to enhance the company's position in hypertension. How has that worked?

Shannon: The concept of category captainship is really where you can have a very comprehensive offering to the patient and physician and marketplace. It's only possible to do it where you have a very strong offering to make. It combines not only the therapeutic product but also educational materials or services to the patients and physician.

The concept in hypertension, where we have a very large offering of products...is we offer to a physician almost guaranteed success as far as treatment of hypertension is concerned with Novartis products.

[Novartis' best-selling product is the angiotensin receptor blocker Diovan (valsartan) (³ (Also see "Novartis’ Diovan Growth Bolstered By Awareness Program, Part D" - Pink Sheet, 17 Jul, 2006.)). The company has two hypertension NDAs pending at FDA, the Diovan/amlodipine combination Exforge and the first-in-class oral renin inhibitor Rasilez (aliskerin). The company anticipates launching both drugs in 2007 (⁴ (Also see "Novartis’ Exforge Has Late December User Fee Date" - Pink Sheet, 27 Apr, 2006.)).]

Alongside that, we offer educational products to patients. We offer them assistance in managing their blood pressure. Blood pressure is one of those diseases that many patients don't even know they have and they don't know what their target blood pressure should be. We offer blood pressure monitors, information services, an educational website for the patient. For the physician, we offer tools to help patients manage their blood pressure.

So really the idea is that we offer it as part of a hypertension package - not only do we come and sell you a drug, but we offer you a complete solution for the hypertensive patient.

"The Pink Sheet" DAILY : Does Novartis anticipate expanding this concept into other therapeutic areas?

Shannon: We are not able to expand that into areas where we don't have complete offerings. So right now, we do it in hypertension. It is possible that as we move forward, we would expand that to those patients who have the combined diseases of hypertension and diabetes. So that's the idea that the physician would recognize [Novartis] as a solution provider rather than simply a seller of pills....

We would want to be, in essence, the market leader. At the end of the day, what it is all about is trying to improve the lives of patients, or extend their lives. If we can do that by having a great offering to physicians, then that's what we mean by category captainship.

- Jonathan Block