Marshall Plan On Climate Related Diseases

To effectively address the looming problem of climate related diseases, a global strategy should be put in place. A "Marshall Plan" on Climate Related Diseases could be a good model to follow. If action is taken now by the large pharmaceutical sector, via active lobbying at the UN, and appropriate funding mechanisms put in place, there is a viable chance that the number of climate related diseases could be halted or reversed. Failure to adopt the WSSD targets of reversing the disease figures by 2015 will make the task almost impossible.

Conclusion - Climate change is with us and will grow increasingly important in this century. The predicted impacts will grow in intensity and severity as well geographically and climate change may not just affect the developing world. By virtue of its global reach and changing weather patterns, climate change may allow developing world diseases to visit the developed world in the coming century. The pharmaceutical industry, funding agencies and governments are in a unique position to find viable treatments for many of the leading diseases of the future.


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Chapter 35. Pharmaceutical Productivity - The Imperative for New Paradigms

George M. Milne, Jr- Boca Grande, Florida

Introduction - Despite dramatic increases in R and D investment, the promise of the genomics revolution, and the remarkable array of new technical tools available to the discovery scientist, the record of industry productivity over the past decade as measured by drug approvals has, if anything, declined (Figure 1). During this same period, the unpredicted rise of blockbusters and mega-blockbusters, a direct result of improved R and D/Marketing partnerships, has driven unprecedented revenue expansions, while the vigor of the generic industry has placed an exclamation point on sustainability. The expanding forward productivity gap, which has resulted, is painfully obvious to all of us who are actively engaged in the operation or leadership of biomedical R and D enterprises. Indeed, to maintain biopharmaceutical industry prospects for sustained growth and to meet the palpable healthcare needs of a global and aging population, increases in productivity on the order of 2 to 4-fold are required - and urgently. So why haven't we made more progress? Where might we go to seek the new concepts, the new assemblies of technology, different organizational concepts best suited to the creation of a breakthrough in R and D productivity? This is a core defining issue for the biopharmaceutical industry for the coming decade and the focus of this chapter.

Industry Productivity vs. Investment The Innovation Imperative

i-14-l uUl

Source: PhRMA Annual Survey, 2000

Figure 1. Industry NCE Productivity

The source of the answer lies, as we all know, in overcoming the unrelenting attrition statistics we experience as we go from therapeutic hypothesis to hit, to lead, to drug candidate, and, finally, to man. The attrition statistics have not improved despite a number of incremental advances and in many cases have been eroded due to ever more stringent regulatory hurdles and the increasing numbers of unprecedented targets emerging from genomics (Figure 2). With the unrelenting expiration of the patents on key products, the challenge is both compelling and urgent. The challenge is also quantal which should free us intellectually from just working harder on more conventional approaches to productivity since the risk of failure from persevering along the current path is arguably absolute. This gives us the opportunity and, indeed, the mandate to venture forth along unproven paths - to


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challenge conventional thinking while doing what motivates all of us - making a difference in health.

Attrition Curve: The Reality

Ideas •> Leads ■* Dev. Candidates Ph2a Clin. *#■ Products

Figure 2. Project to Product Attrition Curve

Ideas •> Leads ■* Dev. Candidates Ph2a Clin. *#■ Products

Figure 2. Project to Product Attrition Curve

The success rate for a specific therapeutic lead is the product of the odds that the target will be valid as a point of therapeutic intervention - often referred to as confidence in rationale - and the odds that the selected chemical will prove to react favorably with not just the desired molecular target, but with related targets, sites of toxicity, its own metabolism and the metabolism of other drugs, distribution, absorption and stability, etc., i.e. does the series confer true chemical drugability. As

SUCCESS RATE = (confidence in rational) X (chemical drugability)

outlined above the overall industry statistics for success is about 1 in 100 for programs starting at the hypothesis level. Only about one quarter of the time do we identify true candidate quality leads or strengthen the hypothesis during the screening phase which still leaves a survival rate from preclinical candidate to approved product of about 1 in 25, The component reflecting the odds of confirming the confidence in rationale for a nominated candidate averages about 25%, but can vary from unity for highly precedented targets to infinity for an unproven orphan receptor. However, by far the largest routine hit to survival (75%) comes because we have simply selected a chemical or chemical series that is not truly drugable. Indeed, if we return to the many screens that fail to yield viable leads, the contribution of chemistry to the outcome exceeds 85%. While chemistry must take a leadership role, it is important to emphasize with HTS displaying reproducibility in the 30- 70% range for some tests, the final solution will lie with the disciplined application of highly discriminating chemistry and biological test systems.

As we will discuss below, this low level of precision and overall success is unacceptable given the paucity of great targets. This dissection of the current hurdles for success serves as the outline for the four themes that are explored in this essay: 1. expanding the number of high confidence in rational targets, 2. a central role for chemistry and chemical diversity, 3.enhanced lead identification and parallel optimization of hits, and 4. creating connectivity - target hopping and data mining. An important sub theme is that while success will require that we push existing technologies, the real breakthroughs will come from fundamental challenges to how we assemble the technology and to the culture and practices that are so embedded in our upbringing that they are invisible - and that chemistry and chemists are at the heart of both the opportunity and the challenge.

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