2004N-0181 - Critical Path Initiative; Establishment of Docket
FDA Comment Number : EC39
Submitter : Dr. Jeffrey Schmitt Date & Time: 08/02/2004 07:08:20
Organization : Targacept, Inc.
Drug Industry
Category :
Issue Areas/Comments
Comment Issues
2. Please rank each hurdle identified in Question 1, above, in priority order according to which hurdles create the most severe product development problems.
1. Currently, two-thirds of the staggering $837 million cost of bringing a drug to market (http://csdd.tufts.edu/NewsEvents/RecentNews.asp?newsid=29, 15 May 2003) is spent on unanticipated failures in research and development prototyping.
2. Expenditures have risen approximately 5 to 7-fold since 1970 without an increase in the rate at which new drugs are brought to market (H. Gabrowski, The Changing Economics of Pharmaceutical R&D in The Changing Economics of Medical Technology 1991, National Academy Press, 1991; R. Frank, J. Health Economics 22, 2003).
3. This trend remains salient even after adjustment for economy-wide inflation. Additionally, the average time needed to bring drugs to market in the U.S. alone is 12 years and rising.
4. A further challenge is the current drug failure rate: only 21.5% of the drugs that begin Phase I human trials are eventually approved for marketing (J. DiMasi, R. Hansen and H. Gabrowski, J. Health Economics 22 (2003) 325-330).

3. For each problem identified, please indicate the type of drug, biologic, or device to which the hurdle applies.
All areas of drug discovery would be made more efficient, moving needed pharmaceutical products to market in a shorter time frame, with enhanced predicatability of effectiveness with the ability to better predict or eliminate side effects.
4. For each problem identified, if a solution would facilitate the development of drugs, biologics, and/or devices for a particular disease or categories of disease, please indicate which diseases would be affected?
All disease indications responsive to pharmaceutical treatment would be positively affected, especially those diseases with the greatest worldwide impact (and afflicting, perhaps, the most neglected populations) such as AIDS, malaria, Alzheimer's disease, etc.
6. For each solution identified, please indicate which could be accomplished quickly, in less than 24 months, and which require a long-term approach?
All of the above could be accomplished in less than 24 months given appropriate funding.
5. Nature of the Solution. For each problem identified, please describe the evaluation tool that would solve the problem and the work necessary to create and implement the tool/solution. For example, would a solution come from scientific research to
In response to these challenging factors, we propose a solution that involves the development of effective, reliable simulation tools to accurately predict successful drug candidates.

While other high technology industries rely heavily upon simulation to evaluate development candidates, the pharmaceutical industry still relies on expensive candidate prototyping. Physical prototyping is inefficient, both in terms of time and cost, but is, unfortunately, and for lack of a better alternative, the way the pharmaceutical industry operates. The proposed simulation methodology circumvents many of the encumbering compromises that scientists face in computational drug design.

Within the pharmaceutical industry and academia, there is a revitalized interest in simulation technology, aimed not only at efficient simulation- based design but also at the prediction of a compound's "drugability" i.e. predictive ADMET (absorption, distribution, metabolism, excretion, and toxicity).

The introduction of these new technologies is anticipated to have an impact similar to the introduction of computer assisted design (CAD) and computer simulation on the aerospace and automotive industries. Prior to CAD and computer simulation, prototypes of new aircraft and cars were built and tested in expensive laboratories at tremendous costs in terms of dollars, time, manpower, and with lengthy timelines to actual product introduction. A fitting analogy is the revolution brought about by the introduction of finite-difference methods and high performance numerical simulation in the aerospace, automotive and other high-tech industries? where the motto has become "fail in simulation rather than in prototyping."

Recent progress in computational drug design is, indeed, very promising, especially given the concurrent dramatic improvements in the performance of affordable computer hardware. However, there remains a vital need for significant funding opportunities for the development of tools to provide investigators insight using novel and robust theoretical underpinnings. Based on our extensive experience in rational drug design and our collaborative efforts with numerous research institutions worldwide, we propose to solve numerous problems within the basic physical, biological and computational sciences related to drug design. Our specific aims are to:

Develop nonlinear statistical methods for modeling structure activity and structure property data;

Develop systems modeling and/or metamodeling approaches for metabolism, cellular function and gene regulation;

Develop new quantum mechanical methods of simulation, including dynamics and novel descriptor calculation;

Develop efficient high-throughput virtual protein docking methodologies; and

Create software that will provide an innovative, fundamentally distinct platform to improve the design and delivery of effective and affordable drugs

We anticipate that these technical advances will make dramatic improvements to:

1. Reduce the drug failure rate (currently an average of 1 in 5 products that reach Phase I human trials actually reach the market)

2. Significantly reduce the cost of developing all drugs (currently an average of $837 million per compound)

3. Dramatically shorten the time-to-market for all drugs (currently an average of 12 years per compound)

Providing a solution to the staggering challenges of affordable, effective, efficient drug design will directly and positively affect the entire world's population. At a time when 13,000 people per day in third world countries die from AIDS, malaria, or tuberculosis (http://www.wsws.org/articles/2003/jan2003/drug-j17.shtml), such accurate and predictive tools have the potential to dramatically improve, even transform, the health situation of third world countries in particular, and, by extension, the entire global population.
7. For each problem identified, what role should FDA play and what role should be played by others?
The FDA should assist competent, knowledgeable, passionate experts to find NIH Roadmap funding to support such projects, then assist them in identifying key constituents who would urgently need and increase their efficiency through use of such a software tool once it is available.
8. What factors should guide FDA in setting priorities among the hurdles and solutions identified?
The FDA should be guided by: Unmet medical need statistics; future projections of growing unmet medical needs, including population growth and aging as factors in those projections; and other, newer threats such as weapons of mass destruction that may require new pharmaceutical responses to be available to large populations worldwide.
1. Hurdle Identification. Please describe the product development issue, the nature of the evaluation tool that is out-of-date or absent, how this problem hinders product development, and how a solution would improve the product development process.
The Need for Radical Advances in Simulation Tools to Revolutionize Drug Discover

Rather than addressing a single health problem, Targacept proposes the use cutting edge research based on recent genomic discoveries, molecular biology, pharmacology and quantum mechanics to develop powerful, effective simulation tools for rational drug design. There must be a reduction in unanticipated failures, research and development (R&D) costs, and time-to-market for all drugs so that the pharmaceutical industry can address global health issues in an effective and sustainable manner.

Extremely significant, given current drug design costs and timelines, is the pharmaceutical industry's inability to treat all but the most profitable diseases, i.e. diseases of the developed world, resulting in a limited focus on the immense pharmaceutical needs of the third world countries.

The emergence of resistant 'super strains' of infectious organisms as well as a revolution in our understanding of genomics and signal transduction has led to increasingly complex scientific challenges in drug discovery. Targets are also requiring ever-greater levels of specificity? affecting one of many enzymes or receptor isoforms is now a commonplace pursuit. Additionally, the multifaceted theme of 'modulation' is becoming more prevalent, especially in the arena of receptor-based therapeutics. Thus, R&D costs in the pharmaceutical industry are rising, highlighting a need for new depths of mechanistic understanding. There is overwhelming need for radical advances in simulation tools to aid the drug discovery process.
If you have questions or need clarification, please contact me at 336-480-2100. Please engage me in further discussion of such projects.