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May 30,2007 Salk Institute

Transforming Pharma I Bio • May 30, 2007

.Table of Contents

Agenda 2

Welcome Letter 3

Event Hosts 4

Partner Organizations 5

Dinner sponsored by Goodwin Proctor 6

Panel 1 - Discovery 7

Sponsored by SDSU 9

Panel 2 - Definition 10

Sponsored by Comerica 12

Panel 3 - Development 13

Sponsored by Covance 15

Panel 4 - Delivery 16

Sponsored by BioMed Realty Trust 18

Notes 19

1


Agenda 8:00a.m.

9:00a.m.

9:15a.m.

10:15 a.m.

11:00 a.m.

12:00 p.m.

1:00 p.m.

2:00p.m.

3:00p.m.

3:45p.m.

4:00p.m.

Registration and networking - Auditorium Foyer ntin nt 1 r akfa t

Welcome - Auditorium ntH

Panel1 M d rat r: David Hale, hairman , Hal Bi Pharm V ntur

Norrie Russell, Ph.D., ntr pr n ur in R id n , NN Bartfai Tamas Ph.D. ir tor, Har ld L. Neur g n rativ R arch nt r,

he cripp Resear h In titut Christina Waters Ph. ., Pr id nt & yr Ph rm Inc.

Break

Panel2 Moderat r: Paul Kedrosky, Ph.D. , Executive Direct r Th on Liebig enter at U an 1eg

Darren Carroll, Seni r Managing Director, illy V nture John Reed, M.D., Ph.D. , Pre ident and CEO, Burnham In titute £ r Medical Re ear h Jay Short, Ph.D., Co-Owner and Leader, Bi Atla

Lunch - Auditorium Foyer

Panel3 Moderator: David Johnson , Pre ident and CEO, Bi

Craig Davis, Ph.D., Executive Direct r, The Chao Center £ r Indu trial Pharmacy & Contract Manufacturing

Francois Ferre, Ph.D., Co-Founder, Co-Pre ident/CEO, Althea Techno! gie , Inc. Dan Peterson, Vice President, Indu try & G vernment Affair , k roup, Inc.

Panel4 Moderator: Steve Burrill, CEO, Burrill & C mpany

Jack Bailey, Vice Pre ident, Busines to Bu iness Divi ion, Eli Lilly & Company Lynn Kippenhan, Global Vice Pre ident, Sale Marketing & Commercial Development,

Covance Central Laboratory Services John Lally, Regional Manager, Customer Bu iness Unit, Pfizer, Inc.

Wrap-up Panel Moderator: Joe Panetta, President & CEO, BIOCOM

Steve Burrill, CEO, Burrill & Company David Hale, Chairman, Hale BioPharma Ventures David Johnson, President and CEO, BioCrossroads Paul Kedrosky, Ph.D., Executive Director, The von Liebig Center at UC San Diego

Closing Remarks Event I-Iost

Networking Cocktail Reception - Auditorium Foyer

2


Members of the San Diego Life Sciences Community,

We are pleased to welcome you to this important summit, "Transforming the BioPharma Risk Distribution Model."

This summit will examine how to finance the four Ds of bringing an innovative life sciences product to market:

discovery, definition, development, and delivery. Within the scope of this conference, individual panels will assess each

of these four stages in the life cycle of innovation and explore new ways of partnering that can lead to greater efficiency

and proportional risk sharing.

Our ability to finance the rising costs of bringing an innovative life sciences product to market requires that we

continually seek creative models that will attract investment, particularly in the early stages. This summit will attempt to

define one such model, termed "distributed partnering," and compare it with historical models: that is, the fully

integrated "do everything" model that erved as the dominant model of Big Pharma through the 1970s and the "co

partnering" model that emerged with the advent of the Biotech industry in the late 1970s. The "distributed partnering"

model will focus on the culture and expertise best suited to each phase of innovation-discovery, definition,

development, and delivery-as well as the risk -adjusted financing and potential return on each phase of investment.

The diverse assembly today includes members of industry, academic research centers, professional service providers, and

the finance community. We are confident that, together, our interactions today will provide thoughtful critique on, and

evaluation of, the critical issue of financing life sciences innovation. We hope that through discussing and refining these

ideas in this public forum we can establish a blueprint for advancing America's competitiveness in the global market.

We would like to thank the speakers and members of the community who are here today. We would also like to express

our gratitude to our sponsors for supporting our efforts to ensure the collaboration that leads to competitiveness.

We hope that you enjoy this conference and thank you for your continued support.

Steve Burrill

CEO, Burrill & Company

David Johnson

President and CEO, BioCrossroads

foe Panetta

President & CEO, BIOCOM

Duane f. Roth

CEO, CONNECT

3


Event Hosts

Steve Burrill, C 0 Burrill & ompany Mr. Burrill h n in 1 d in th gr wth n f th i t hn 1 gy in d u try £ r r 40 y ar . Pri r t £ unding urrill h p nt 2 r with rn t & ~ ung ir cting nd rdinating the firm' ervice t eli nt in th bi /high t hn 1 g I w rldwid . In 2 02, Mr. Burrill wa r gniz d th n r y th pr tigi u i ntific American 50).

David Johnson, President and CEO, BioCro sroad Mr. John n' leader hip f Bio ro r d ntinu t furth r ignifi ant pr gr and to expand and prom te Indiana' life cience indu try thr ugh it bi ph rm euti 1 manuf: cturing initiati e, ntinued gr wth fit tart-up bu ine e , the launch of two venture fund and rai ing in e ce of $100 milli n :f; r n w inv tment in Indiana life cience opportunitie .

Joe Panetta, President & CEO, BIOCOM Mr. Panetta is Pre ident and CEO and a member of the Board of Director of BIOCOM, the outhern California advocacy association representing more than 500 companie , ervice ector firm , univer itie and re earch in titute working within the biotechnology and biomedical device arena. In addition, hi a ociation involvement ha al o included serving as founding member of the International Biotechnology Forum under the auspice of the Biotechnology Industry Organization.

Duane J. Roth, CEO, CONNECT Mr. Roth also serves as CEO and Chairman of Alliance Pharmaceuticals Corp. He serves on a number of boards and committees dedicated to issues of financing and developing biotechnology, including the Independent Citizens Oversight Committee for the California Institute of Regenerative Medicine, to which he was appointed in 2006 by Governor Schwarzenegger. He also serves as a member on the Governor's Commission For Jobs and Economic Growth.

4


Thank you to the partner organizations who helped make this meeting possible.

fB COM BIOCOM ha become the large t regional life cience a ciation in the world, proudly representing the Southern California life science communitie and more than 550 member companie . Highly focu ed on the uccess of it member and the life cience c mmunity, BlOC M c n i tently create alue through it program and relevant member benefits . The BIOCOM mi ion i to po ition the S uthern Cali£ rnia life cience community to achieve individual and collective ucce on the world tage f cientifi and techn l gical inn vati n and to de elop pr duct that impro e global health and quality of life.

BioCrossroads® BioCro road i Indiana life cien e initiati e, a publi -pri ate collab rati n that upp rt the regi n, re earch and corporate trength whil n uraging n w bu ine d el pm nt. i r r ad pr vid m ne and upp rt t life cience bu ine e , laun he n w life ien bu ine e , and mark t Indiana' life ci nee indu tr . The organizati n

pro ide additi nal upp rt t th tat ' xi ting li£ ien indu try b panding ien e educati n pp rtuniti expanding uni er ity techn l g tran £ r apabiliti , and building trat gi uni er ity!indu tr partn r hip .

LIFE SCIENCES; VENTURE CAPITAL, MERCHANT BANKING, MEDIA

Burrill & m r h nt b nk £

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c mp ni nd i wi l r g rd entrepren ur with th r th entrepr n ur and r d li r cr ati n, tr ining nd du ti n, nd r

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The Panelist Dinner was Generously Sponsored by

6


Panel1

Pharma I Bio vs. Academic research: Who is leading discovery?

• Why has the productivity for New Molecular Entities dropped off over the past decade, and will

the primary engine for discovery over the coming decade be Pharma/Bio or research

institutions?

• How has the discovery and development culture changed over the past several decades in

Pharma/Bio and in academic research centers?

• Is the US losing or gaining ground in discovery in a global context?

• How are the pressures of the marketplace - industry consolidation, payer consolidation,

increased regulatory requirements - impacting drug discovery?

• How will legislation currently being considered- namely, repeal of non-interference, follow-on

biologics, etc. - affect the research institutions and small companies performing

discovery work?

7


Panelists Pharma I Bio vs. Academic research: Who is leading discovery?

Moderator- avid Hal h irman, Hal BioPharma V ntur Mr.H 1 t h r n ur wh , in 1 2 j in d y rit h In r ) an 1eg ' fir t i techn 1 gy

mpan, nd th n 1 t r h ln n n t u rb part f v r 14 bi tech mpan1 n 1 g r

Tamas Bartfai, Ph.D., Director, Harold L. Dorri Neurological Re earch enter, The Scripp Research Institute Dr. Bartfai i th dir t r f th Har ld rn

h ir in ur 1 gi l R ar h nt r cnpp R arch In titute. In

additi n, h h ld th H r ld . rn nerv u tern r ear hatH ffm n-L academia in t cl<h lm Uni r ity.

ur h in B

i n . ri r t

l, witz rl nd. M

Norrie Russell, Ph.D., Entrepreneur in Residence, CONNECT

ming t cripp , he wa the head f central t f hi pr fe i nal career wa pent in

Dr. Russell ha more than 25 year experience in drug di c ery, including a 1 ng career at A traZeneca, where he was Global Head, Biol gical Science and Technol gy, with re pon ibility for the application f genomic , proteomics and genetic to the entire re earch and devel pment proce .

Christina Waters, Ph.D., President & COO, aTyr Pharma, Inc. Dr. Waters brings nearly twenty years of research and management experience to aTyr, in both early stage and large pharmaceutical companies. Prior to joining aTyr, she was the Director of Scientific Development at the Genomics Institute of the Novartis Research Foundation.

8

Panel 1 has been generously sponsored by

Announcing a New Life Sciences MBA for Executives A Partnership Between San Diego State University and Gallup University

/

I \

•

San Diego State University (SDSU) has partnered with Gallup University to develop a new MBA for Executives in Life Sciences. The new program combines the latest academic research from a top-ranked university with the speed and business focus of a global, world-renowned consulting firm. This is the first blended model of its kind that is focused on bringing life science products from concept to market.

SPECIALIZATION. The Life Sciences MBA will incorporate courses in Biomedical Quality Systems as well as Regulatory Affairs, areas for which SDSU already offers innovative online courses and highly successful Master of Science degrees.

COACHING. Gallup University will assign an executive coach to each student for the duration of their coursework. Contact Gallup or SDSU to learn more about this.

SCHEDULE. The program utilizes the "blended learning" concept to accelerate the process for working executives. It combines on-line learning from Gallup University with three, two-week residency periods taught by SDSU professors on campus.

SKILL SETS. Many skills are necessary for today's Life Science Executive to decrease the time and increase the success of bringing products from concept to market. This program requires students to take one course from each of the following theme areas: Interpersonal Skills; Legal, Ethical, Political and Economic Environment; Information and Technology; and Globalization.

~SAN DIEGO STATE W UNIVERSITY College of Business Administration Leadership for the Global Marketplace

To be added to an interest list to receive regular updates on this new program, visit sciencemba.sdsu.edu and click on "Request Information:'

9


Panel2

Traversing the valley of death: the struggle to fund a discovery to proof-of-concept in the current climate of venture funding

• What r th k y <d finiti n' p r m t r th t r m t riti 1 t ddr b £ re inve ting in more advan d d v 1 pm nt?

• At what tag in the inn v ti n li£ y 1 d company?

n t tart a definition, r ((virtual;'

• What exp ri nc i r quir d by k y manag ment nd t am to 1 ad a definition/'cvirtual" company? (v . the traditi nal Bi techn logy E /management team)

• What will ((definition" c mpanie do, why are they nece ary, and how will they differ from current venture-backed biotech c mpanie ?

• What does the financial model of a definition/((virtual" company look like? What is the ownership structure and what is the expected return on thi type of entity?

10


Panelists Traversing the valley of death: the struggle to fund a discovery to proof-of-concept in the current climate of venture funding

Moderator- Paul Kedrosky, Ph.D., Executive Director, William J. von Liebig Center, UC San Diego Dr. Kedrosky is a venture capitalist, media personality, and entrepreneur. He is a venture partner with Ventures West, Canada's largest institutional venture capital firm. In that capacity his interests include consumer technologies, media, semiconductors, and life sciences. He is also an analyst for CNBC television; a columnist for TheStreet/RealMoney; and the editor of Infectious Greed, one of the best known business blogs on the Internet.

Darren Carroll, Senior Managing Director, Lilly Ventures Mr. Carroll leads the New Ventures Division of Eli Lilly and Company. Prior to assuming his current role, Mr. Carroll was the founding chief executive officer of InnoCentive, Inc., the first e-business venture created by Lilly. Among other positions Mr. Carroll has held at Lilly, he was the U.S. attorney for Prozac®.

John Reed, M.D., Ph.D., President and CEO, Burnham Institute for Medical Research Dr. Reed is the author of over 700 peer-reviewed scientific articles and remains an active scientist at Burnham, directing a laboratory of ~40 persons. His research interests have focused primarily on cancer, but he has also made important contributions in the area of AIDS, autoimmunity, stroke, and other disease. In 2007, he was chosen by the Achievement Rewards for College Scientists (ARCS) Foundation as their Scientist of the Year.

Jay Short, Ph.D., Co-Owner and Leader, BioAtla Dr. Short is a founder of Diversa Corporation where he served in multiple roles including CEO, President, Chief Technology Officer, and Director for the company over his 11 -year tenure. He is also currently the Founder, President, and Chairman of the E.O. Wilson Biodiversity Foundation, and a co-owner and leader of BioAtla.

11

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12


Panel3

Enter the outsourcer: Expanding availability of highly specialized firms that perform development functions on a contractual basis

• Will Big Pharma/Bio follow high-tech in outsourcing commercial manufacturing?

• Will development companies participate in "risk sharing" arrangements or will they primarily retain a fee- for-service business model?

• How will universities participate in the commercialization of discovery in the future? Will they participate more in the process?

• Will VCs invest in development companies?

• What are the drivers and what are the roadblocks to this industry becoming more "dis aggregated"?

13


Panelists Enter the outsourcer: Expanding availability of highly specialized firms that perform development functions on a contractual basis

Moderator - David John on, Pr ident nd C 0, Bio ro ro d

up bu in lit

1 d r hip f i r r ntinu t furth r ignifi nt r gr nd t xpand and pr m te i n in u tr thr ugh it bi h rn1 uti 1 m nu turing i iti tiv , ntinu d gr wth fit tartth l un h f tw nt r fun , nd r i ing in f 1 0 milli n D r n w inv tm nt in Indiana

pp rtuniti .

Craig Davi , Ph.D., Executive Director, The Chao Center for Indu trial Pharmacy & Contract Manufacturing Dr. Da i 'r arch int re t in lu drug li r t th lung nd drug ab rpti n. H wa in trumental in the developn1ent f pharmaceuti al u d in th tre tm nt f R pirat ry i tre yndr me and AI

Francois Ferre, Ph.D., Co-Founder, Co-President/CEO, Althea Technologies, Inc. Dr. Ferre is an internationally recognized expert in the u e f gene quantificati n te ting for the di covery and development of biopharmaceuticals and diagno tics. In 1994 he was the co-editor of a book entitled "The Polymerase Chain Reaction" with K. Mulli and R. Gibb , which went on to become an all time be t eller for Birkhauser Publishing.

Dan Peterson, Vice President, Industry & Government Affairs, Cook Group, Inc. Mr Peterson has had management and executive level responsibilities in the areas of operations, finance/accounting, human resources, and benefits since joining Cook in 1989. His current responsibilities are in industry relations and government and external affairs.

14


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15


Panel4

Delivering innovation in a global economy: The place of partnerships in a product life cycle

• Wh t are th key char t ri ti and mp t nci f Big harma/Bio today?

• What doe it t ke £ r a ompany t 1 unch pr duct in tod y gl bal conomy?

• Will the curr nt merg r and qui iti n tr nd ontinu ?

• How will targ ted therapeuti and p r naliz d medicine tran form the commercialization proces ?

• Will the Big Pharma/Bio indu try end up with characteri tic of the defen e indu try - that is, large companies, few customer (one?), and a c t + bu ine m d 1?

16


Panelists Delivering innovation in a global economy: The place of partnerships in a product lifecycle

Moderator - Steve Burrill, CEO, Burrill & Company Mr. Burrill has been involved in the growth and prosperity of the biotechnology industry for over 40 years. Prior to founding Burrill & Company in 1994, he spent 28 years with Ernst & Young, directing and coordinating the firm's service to clients in the biotechnology/life sciences/high technology/manufacturing industries worldwide. In 2002, Mr. Burrill wa recognized as the biotech investment visionary by the prestigious Scientific American magazine (The Scientific American 50).

Jack Bailey, Vice President - Business to Business Division, Eli Lilly & Company Mr. Bailey has led Business-to-Business since early 2001, and is responsible for all payer segments. During his broad career, Mr. Bailey has served in the areas of business development, brand management, area sales management, and general management in South and Sub-Saharan Africa. Mr. Bailey received a Bachelor of Science degree with a concentration in Genetics from Hobart College in Geneva, New York, and an MBA from the University of North Carolina at Chapel Hill.

Lynn Kippenhan, Global Vice President - Sales Marketing & Commercial Development, Covance Central Laboratory Services Lynn Kippenhan is Vice President, Global Sales and Marketing, for Covance Central Laboratory Services. Ms. Kippenhan i responsible for all commercial activities within the Central Laboratory division. She has been with Covance in this capacity for four and 1/2 years.

John Lally, Regional Manager, Customer Business Unit, Pfizer, Inc. Mr. Lalley has held various field and management level position during Pfizer's explosive growth over the past twentythree year . During thi period, he helped create new sales teams and shape the numerous merger and acquisition at the field level. He is currently responsible for providing consumer access to Pfizer' medicines through restricted Managed Care channels of business (i.e., Medicare, Medicaid, HMOs, Medical Groups, Pharmacy Benefit Managers, etc.) for Pfizer's broad portfolio.

17


.............. """""" :--- - ::;...--

Bj~L~ BIOMED REALTY TRUST, INC~

is pleased to sponsor the · panel on

Delivering innovation in a global economy: The place of partnerships in a product life cycle

18

Notes

19

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Science and society

Drug discovery in jeopardy Pedro Cuatrecasas

Departments of Pharmacology and Medicine, University of California San Diego, San Diego, California, USA.

Despite striking advances in the b iomedical sciences, the flow of new drugs has slowed to a trickle, impairing therapeutic advances as well as the commercial success of drug com panies. Redu ced productivity in the drug industry is caused mainly by corporate policies that discourage innovation. This is compounded by various consequences of mega-mergers, the obsession for blockbuster drugs, the shift of control of research from scientists to marketers, the need for fast sales growth, and the discontinuation of development compounds for nontechnical reasons. Lessons from the past indicate

that these problem s can be overcome, and herein, new and improved directions for drug discovery are suggested.

The decreasing output of new drugs and the drying up of industry pipelines are well established (1-4). To maintain profitability the pharmaceutical industry has resorted to practices that have drawn public cricicism including markedly increasing drug prices, increasing spending on advertising and promotion, direct-to-consumer advertising, ineffeccively conducting postmarketing surveillance, and limiting comparative efficacy/ safety studies with alternacive drugs. However attencion should be directed more to the root of these problems - the inefficiencies of drug discovery and development (D&D) which result from the management policies and corporate cultures of the institutions (corporations) that undertake the research and development (R&D). These conditions are so entrenched that we must ponder whether the current system can recover.

What is really wrong? Low productivity. The low productivity (1 - 4) of drug D&D is certainly not related to available budgets which have increased 30-fold since 1970. Many Pharmas devote more than $5 billion/ year to R&D, with over $30 billion/ year of cumulative spending, greater that the total NIH budget of $28 billion. The falling productivity has been ascribed commonly to a number of well-discussed factors such as regulatory hurdles and high attrition of drug candidates (1 - 4). Most of these issues are contributory rather than fundamental· at the heart of the problem are the more profound underlying dynamics that drive R&D.

The FDA oversees drug development and approval of new drug applications (NDAs). While the regulatory requirements are well warranted, grossly inadequate resources (5) have resulted in an antiquated process ofNDA review that is slow, sometimes of poor quality, and at times subject to political influence. Other issues include the retraction of agreed-upon requirements for approval, the current crisis of FDA leadership (e.g. absence of a permanent commissioner) and the inappropriate role of ideology in decisionmaking (e.g., the case of approval for the "morning-after ' pill) . Other critiques can be found elsewhere (e.g., in refs . 1- 4 and 5- 8) . Although significant reforms are in order the FDA or regulatory issues are not fundamental barriers and contribute only marginally to the decline in drug productivity.

Nonstandard abbreviations used: CEO, chief executive o fficer; D&D, dis overy and developm nt· NDA, new drug application; R&D, research and development.

Conflict of interest: The author is a consultant ro Dai ichi Sankyo Research lnsrirure and a member of d1e board of direcror of Alliance Pharmaceutical orp.

Citation for this article:]. lin. Invest. 116:2837- 2842 (2006). doi:l0.1172/J 129999.

Likewise we cannot blame the current state of scientific advances, which in the last 20 years have been revolutionary. These advances offer mind-staggering new opportunities in innovative drug discovery and development. It is also fallacious to suggest that the decrease in new drugs is due to our already having conquered the "easy' diseases, a rationalization repeatedly expressed for 3 decades.

The complex, lengthy, and unpredictable nature of drug R&D certainly contributes significantly to high costs and inefficiencies. For example, only 1 or 2 of every 10 compounds entering the phase ofhuman clinical trial ever reaches the market. However, this high rate ofloss of drug candidates during development (i.e., attrition) is not greater today than in past decades. As will be elaborated, the current problem oflow productivity relates instead primarily to the pervasive mismanagement of the already difficult R&D process.

Changes in the approach to management. Foremost among the issues that cripple drug R&D is that while utmost creativity and innovation are required, the R&D is conducted in traditional for-profit corporations that are virtually indistinguishable operationally from those that conduct little or no R&D . Most corporations' top management does not understand the complexities of science its mode of conduct or objectives and runs the companies in ways that stifle creativity and innovation (9 , 10). Prior to 1980 most drug companies functioned differently. They were smaller than todays companies and the nontechnical executives knew and were proud of their scientists and were more likely to allow R&D staff to pursue objectives with little interference. Informal systems dominated behavior. Each company had its unique ways, history character, and culture. Most appreciated that their existence and fortunes were ba ed on a combination of need and economic benefit, such that profitability was balanced with public responsibility. This tended to minimize the overpricing of drugs. A corporate identity of (and pride in) uniqueness of purpose were evident. Employees felt they were contributing to the improvement of human health .

In the 1970s things began to change. Modern managers entered as chief e cutive officers (CEOs) and other high-level executiv s mostly with little or no technical experience. Many had legal or business school training or came from non-drug indu tries that functioned with greater organizational discipline. Those promoted internally were often from legal or finance departments with littl or no experi nee in research, manufacturing or ngineering. Mo t were unacquainted with research and were uncomfortable with seemingly ((unfocused" re earch organizations that they p r-

The Journal of CLinical Investigation hrrp://www.jci .org Volume 11 6 Nu mber 11 November 2006 2837

science and society

ceived to operate in a freewheeling, independent style. These executives found comfort in outside management consulting firms that were called upon to suggest structural reshapings and behavioral changes. Corporate management had an instrument by which to introduce order into the research e tablishments (10) .

Unfortunately while consulting firms had experience in advising non- technology-based corporations few were familiar with drug companies or complex professional-based matrix organizations. Their recommendations to change organizational structures procedures, and even program and project portfolios were patterned after companies with which they were familiar, such as General Electric and other so-called well-managed companies.

Shareholders, investment bankers, and analysts, who know little about drug discovery, place intense pressures on CEOs and their boards tor quick returns.

Use of these consulting firms became so fashionable that virtually every Pharma underwent similar externally driven reshaping in an effort to manage and control its scientific enterprise. Further, by popularizing ((benchmarking," a process in which companies review their activities against what others are doing rather than exploiting their own unique skills and experience, drug companies began to all look alike (10).

Conformism. With such restructuring drug companies now felt more confident that they could manage and mandate results with discipline, order, formality, and efficiency. Unfortunately, many of these qualities are ones that suffocate creativity and innovation. Freedom, spontaneity, flexibility nimbleness, tolerance, compassion, humor, and diversity were replaced by bulky and inflexible organizational structures characterized by regimentation, control, conformity and excessive bureaucracy. Managers often overfocused and employed top-down decision-making (10). The objective outcomes resulted in more mediocre, not novel, products, and there was no evidence of improved long-term profitability. Ironically, great-sounding slogans were used to achieve conformity while proclaiming the importance of innovation empowerment, diversity and compassion.

Managers) not leaders. It is understandable that most corporate human resources departments are unaware of some of these issues. However, top research managers can unfortunately be similarly uninformed. Most rise through the ranks by satisfying superiors and are selected by nontechnical management (and human resources programs) as ccgood company players." While outstanding scientists are often recruited for high leadership roles in research, the cclearn about industri' education process and lure of power can ultimately result in an intellectual shortsightedness regarding science. For some the financial incentives are important. Of course, many of the best-qualified who cannot adjust depart quietly while others find ways to quixotically manage the system and foster creative environments and research programs. There are still companies that try to focus on excellent science and that attract first-rate scientists. These are, however, exceptional situations.

Drug R&D thrives in a creative, flexible, and nonautocratic environment (9) . Success depends on individual freedom and inspiration rather than dogmatic leadership. Instead, in 'well-run" corporations today scientists must contend with ((management by

objectives," hierarchical and autocratic organizations, mandates from strategic planning groups, detailed and rigid scheduling constant reporting, and achievement driven by milestones and flowcharts. Normally, rewards are based on quantitative output (number and weight of reports or numbers of compounds or tests) and extrinsic incentives such as money, promotion, power, and visibility. Is it any wonder that true innovation cannot thrive?

Pressures from shareholders. The ownership of public companies consists mainly of shareholders who expect rapid (and substantive) returns on their investments. This contrasts (and often conflicts) with the nature of the business objectives, which must be based on long-term investments in science and technology. This dilemma is illustrated by the requirements for quarterly reporting of earnings versus the 10- to 20-year cycles ofbusiness operations (product projects). Companies have managed to navigate through this quandary, but it is becoming increasingly difficult.

Shareholders, investment bankers, and analysts, who know little about drug discovery, place intense pressures on CEOs and their boards for quick returns. Boards of directors, although often understanding of the CEOs' dilemma, are nevertheless forced (by their primary role of representing the interests of shareholders) to push CEOs by setting stringent, short-term financial performance outcomes for determining annual compensation. CEOs are thus under even more pressure to achieve quick results through cost-cutting, low-risk projects, and acquisitions. All too rarely, an enlightened CEO undertakes energetic efforts to educate boards and analysts regarding the nature of their business and to insist that responsibility and accountability to the public are paramount concerns that demand a long-term view and, perhaps, profit expectations more in line with those of other industries.

Merger mania. The decreasing earnings of Pharmas have stimulated mergers and acquisitions, driven by the desire to acquire existing sales (products) while decreasing costs via layoffs. This has created conditions that catalyze further inefficiencies and suffocation of innovation. The merged megacompanies' research organizations must be integrated rapidly and redundancies eliminated, oftentimes in haste. Decisions regarding people and programs are made arbitrarily, by people far removed from the science and labs . Good programs are eliminated in attempts to consolidate, and knowledge, training, and expertise, often cultivated over many years are often lost. Active scientists can be transferred to administrative, nonscientific tasks such as project management, licensing, and planning. While these posts often appear glamorous, such appointments can remove the individual from the scientific arena and result in the loss of valuable expertise to the company.

With rapid growth and huge size come changes in bureaucratic procedures and organizational hierarchies that may be confusing or meaningless to individuals (9) . Communication so important in complex scientific undertakings dependent on teams and matrix interactions, becomes burdensome. The dispersion of personnel and projects over geographic regions or buildings is also disruptive.

Blockbuster mania. Pharmas have become much less interested in developing drugs that will sell less than $1 billion a year. Without these ((blockbusters" they cannot maintain the traditionally high profits . The loss of major drugs to patent expiration, the high-gross sales required and the increasing costs ofR&D and of advertising promotion and marketing require sustaining a sizable number of highly profitable new products. The larger the existing sales, the greater the need for blockbusters.

2838 The J oumal of Clinical Investigation h ccp:f j www.jci.o rg Volume 116 Num ber 11 November 2006

T tmuz th n m1 p t n ial f n '"' bl 1t ry that r mark d th rat gr ' th

high po fr nt- nd up wing b n fit i du t rh urr nt al u maximizing pat nt p ri d pr parin fi r mp titi n and th inh r nt pr m tional alu f

wth it lf Thi i important that man orp ra-n d lib rat 1 d la N s or mark ring it lf until

as impr s iv apr moti nal packag as pos ibl . tudi that upport oth r clini al indi ati n

and d ag b rm mark ring upp rt and c nomic data n th r b n fit " u ch as D rmularies and r imbur m nt. Thi appro a h c nrrast ith the practic of 20- 0 ears ago.

Th ra ti nal then as to initiate marketing mor quietl with what r as n ces ar t r cei FDA appr al and to pand th franchi e graduall but olidly over en uing ear with follow-up tudi and anal e bas d n perience. The medical c mmunity

'vas p rc i d as being cautious with new medicin s. The drug' lab ling as r ised fr qu ntl o er time to reflect new indications and d ag form side ff; ct v arnings and contraindications. Thi approach also helped create longer-lasting brand loyalty er imp rtant in the da b fore automatic gen ric substitution on pat nt piration. The ec nomic alue of n w drugs ' as initially 1 er but it increased and was spread over many years.

danger of coda s exceeding! aggressive introduction of new d rugs into the marketplace is that it is virtually impossible to

brain postmarketing data from pharmacovigilance programs. Thus it is more likely that unexpected serious adverse events will b disco ered only after millions of drug exposures. In recent ears man drugs have been ,;~.,ithdrawn suddenly from the market

und r duress due to such unexpected and serious side effects. Infrequent but s rious adv rse events can arouse significant

public attention and turmoil. There is little time to scientifically e aluate possible contributing factors. The medias quest for senationalism helps create a frenzy of emotion misinformation and

accusations. It is nearly impossible to rationally resolve complex cientific issues under this type of public scrutiny. Thus in many

cases the onl alternative is to take the drug off the market. This can be calamitous for the company as well as those patients who ha e suffered or who received major benefits from the drug. Many

Pharmas have become much less interested in developing drugs that will sell less than $1 billion a year.

of the ad erse events reported are clearly causally related but attribution in other cases rna be questionable. In most cases the stigma of incrimination and market withdrawal is such that no matter what the facts turn out to be marketing cannot be restored.

Another risk of o erzealous development planning for blockbuster status is that une peered clinical or regulatory problems ' that always arise can become sufficiently discouraging to derail the drug altogether- expectations are not met and the blockbuster status is compromised. Clearl to better serve public safety and instill cientifically alid decision-making and improve the long-term interests of corporations and shareholders, better systems of postmarketing sur eillance are needed. But this is probabl not possible without more deliberate and cautious marketing of new drugs .

science and society

Th shift from R& D to mark ting. T h d i i n th a m p n

nn r ur n n n-bl kbu t r d ru ft nl d

ram mp mp und with n 1m chani m

ati n . Th y oft n pu h to di ontinue ( r n t li n gram bas d n un upp rtabl mm rcial xtrap la ti gr at frustration of ci ntist .

Lessons from the past After a career in medicine and research at Washington Uni ersity th NIH andJohns Hopkins University I moved m r lab ratory of mor than 30 workers to Burroughs Wellcome o. as head of its R&D op rations and am mber of its board of dir ctors. Subs quend I became head of R&D and director ofGlaxo Inc. (1985- 1989) th n president of R&D and corporate vice presid nt of Warn r Lambert

o. from 1989 until r tir ment in 1997, and continued as a consultant to the CEO and to R&D until2000. M broad experiences ith the industrial business regulatory and academic communities have helped me to formulate the opinions described here.

Some penonal anecdotes. While in charge of R&D at Burroughs Wellcome Co. from 1975 to 1985 I witn ssed many startling examples of the folly of rendering early marketing (or technical) predictions when dealing with novel compounds or diseases. During the D&D of acyclovir (Zovirax), marketing insisted that there \;1, ere no markets for this compound. Most had hardly heard of genital herpes to say nothing about the common and devastating systemic herpetic infections in immunocompromised patients . But those with knowledge of clinical medicine knew that these were very serious and prevalent conditions for which there were no other therapies. Fortunately at the time, research management had the authority and knowledge to render decisions. Zovirax entered the market, in various dosage forms and indications. At initial marketing in 1982 of the ointment form only the informal estimates of peak sales were about $10 million a year for all forms of the drug, far below the annual sale of well over $1 billion that were ultimately achieved. Marketin~s main job was to distribute and sell what R&D developed and secondarily to provide the research staff' ith information and suggestions. Relations were always amicable and mutually reinforcing, despite differences of opinion. Other examples of compounds developed in that period that became blockbusters despite being considered ccorphan" (rare and nonprofitable) included azidothymidine (AZT Retrovir) for HIV with low predicted markets initially (1981)· bupropion (Wellbutrin) for markets felt to be "well satisfied ' by the tricyclic antidepressants just before the enormous success of fluoxetine (Prozac) disproved this· and colfosceril palmitate (Exosurf) for infant respiratory distress syndrome. At Parke Davis/ Warner Lambert during 1989- 1997 numerous other compounds would never have been marketed had it not been for the strong insistence of research management. These compounds included gabapentin (Neurontin) atorvastatin (Lipitor), troglitazone (Rezulin) fosphenyroin (Cerebyx) and pregabalin (Lyrica).

The major lesson from the stories of the development of all of these drugs which is repeated throughout the histor of drug D&D is that nearl all drugs that have become blockbusters (and therapeutic breakthroughs - these two normally go together) had similar early histories of major disinterest and skepticism from

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the commercial side, usually due to misunderstanding of the marketing potential or medical need. Other examples include the discoveries by Nobel laureate James Black of the first beta-blocker, propranolol (Inderal) and the first H2 antagonist, cimetidine (Tagamet). "Who needs this H2 thing when we have such great antacids?" was heard as a chorus. Squibb & Co. almost did not market captopril (Capo ten) (the first angiotensin-converting enzyme inhibitor), even when it was approved by the FDA because of initially very restrictive labeling. Similar difficulties occurred at Merck with lovastatin (Mevacor) , the fir t tatin, as well as with many breakthroughs by DavidJack Paul Janssen, and Leo Stenback. The extraordinary success of none of these drugs was predicted before marketing. But these lessons are so easily forgotten!

An indispensable success factor, which today has virtually disappeared is the role of champions.}) Every uccessful drug has had at least one individual who in some way b came a strong proponent for its development. This person(s) fo tered understanding, encouragement, enthusiasm patience commitment and assured the necessary resources. Precipitous discontinuations were thus often avoided, and efforts to resolve problems were enhanced. Champions are now rare; people are discouraged by th risk ofbeing "wrong>' (9, 10). The culture that discourages champion also rejects the expression of passion, confusing this with the loss of objectivity.

Predicting commercial success is difficult_, so how to proceed? Clearly, it is exceedingly difficult to predict the technical or commercial outcomes of novel compounds. One needs to focus instead on the novelty and relevance of the science, the technical rationale, basic pathophysiology, predictability of animal models, availability of human disease models, feasibility of development, and the future potential medical need as perceived through knowledge, experience, and instinct of scientists and physician-scientists. One must proceed with conviction that some of the novel compounds in the portfolio, all of which should have sound inherent scientific merit, will overcome the obstacles in development and provide real value despite perceptions of potentially limited sales. If a new drug turns out to be of great medical value but has limited sales, there is nevertheless real value to the corporation in terms of the pride experienced by the company and its employees prestige and respect in the medical community and recruitment of talented employees.

Orphan drugs and drug pricing. In the 1960s through 1990s orphan diseases were simply rare diseases for which drug companies did not wish to initiate discovery programs for commercial reasons. It was understood that prices could not be adjusted out of line with the prevailing standards. Such pricing concerns applied especially to cancers because of the appearance of a lack of compassion. Commercial people were uncomfortable because they felt that they would have to essentially ((give them away. }) Still, when opportunities presented themselves they were not discarded, and the companies became proud of these products, even if they were not commercially rewarding. Thus in the 1960s- 1980s a significant number of effective drugs for leuk mias and lymphoma (especially Hodgkins disease) were introduced.

In 1983 the U.S. Congress passed the Orphan Drug Act to provide tax, funding, and exclusivity incentives to cornpanies developing drugs for low-prevalence diseases (defined as fewer than 200,000 cas ) that wer not expected to provide investment returns. Indu -try embraced and used the provision of the ace for years. However this situation ha changed drastically in recent years especially regarding lethal cancers and other rare genetic diseases. Good drugs have been intr du ed recently for orne of these disorders, but the

pricing practices could be considered scandalous (11). Prices do not relate to the costs of R&D for these drugs, or to the costs of goods. Some companies now apparently feel that desperate patients (and society) will pay whatever is charged. Some examples ( 11) include Rituxan (for lymphoma; which costs about $13,000- $25 000 per cycle) Herceptin (breast cancer; about $3,200 per month), Avastin (colorectal cancer; about $14 400 per month), Revlimid (multiple myeloma; about $60,000 per year), Erbitux (head and neck cancer; about $110,000 a year) , and Cerezyme (Gaucher disease; between $200,000 [children] and $600,000 [adults] per year). The ability to commercially exploit small sectors in the cancer field (e.g. 5,000 patients) by pricing and high profits has stimulated spectacular success in discovery research and rapid development (12), demonstrating, cynically the current technical capacity of major companies to apply m.odern science to many diseases.

Nearly all drugs that have become blockbusters had early histories of major disinterest and skepticism.

Reasons for loss of compounds during development are changing. As mentioned earlier, the majority (80%- 90%) of compounds entering clinical testing do not make it to the market. This very high attrition rate is nearly always blamed on technical problems. In my experience, however, in at least a fourth of cases today, drugs are discarded during development for reasons that are not technical or scientific in nature.

The major nontechnical reasons for discontinuations are the result of marketing reassessments or management discontent. Most occur before sufficient data are available to make informed judgments. Often a project simply becomes low priority. Since "resources are scarce " something has to go. Formal prioritization is today a managem.ent obsession, intended to remove appearances of doubt in decision-making. Priority lists are sacrosanct, infrequently revised, and followed religiously. It is not important whether or not two or more compounds are competing for the same resource in a rate-limiting way. This can lead to bad decisions. It is easier to check lists and make decisions with minimal thinking, agonizing, weighing things and making judgments on an ongoing basis.

New management often has different interests and perceptions, or people just get tired or discouraged and nobody is beating the drums for the project. A 10-year development period is an exceedingly long time for sustaining enthusiasm focus , and nurturing and maintaining continuity of leadership/management. Such factors , although understandable are subjective and arbitrary and not scientifically based. The same reasons that lead to project disconcinuations also discourage the resolve to work out a n ew technical problem which then serves a a convenient excuse for cutting a project for which management has lost interest. Amazingly, Pharmas will eldom out-license rejected compounds v n with generous buy-back provisions. The major reasons are fear of ernbarrassment (i .e. the appearance of having "bad judgment") should the compound become a success and the fear that impo rtant trade secret may be passed on inadvertently.

Since the overall rate of attrition today is similar to that of pr ious decade when los of projects for nontechnical reasons was rare it follows that the ability to predict technical uccess in development is actually b tter that in earlier eras - contrary to prevailing view .

2840 The Journal of Clinical Investigation http://\ vw.j i.org Volume L 16 Number 11 November 2006

Planning departrn nt are now in control of most of the develpment proc s based on th b lief that good planning assur s

a compli hm nt. Plann r are enamored with theoretical and cooki -cutter program e aluation and review technique (PERT) charts, mil scones and ' d cision tree .' In this atmospher it is difficult t proce d thoughtfully based on the growing body of data - co go with th science' (10). Deci ion-making is managed impli ti

cally b following preestablished expected outcomes at o-called 'go- no-go' decision points. It is black and white; the mentality is that th re is no need co agonize over decisions. Avoiding the thinking process does not serve research well. Similarly, nontechnical managem nt often concludes that research people always have "coo many projects" and that they are unable co discontinue their pet projects so it is done for them. Managers thus can make illogical discontinuations co please their bosses. How many scientists enjoy working on a poor idea or an unsuccessful progran1.?

Every single drug discussed above (AZT, acyclovir, bupropion gabapentin troglitazone fluoxetine captopril, cimetidine, propranolollovastatin etc.), as well as virtually all other breakthrough drugs ever marketed encountered serious technical problems that j opardized development. Most problems were so severe that the compounds would have been discarded under our current wellmanaged and efficient go- no-go systems. The problems faced by ach of these drugs were different and difficult to solve. Separation of reseaTch from development. The process of drug D&D

is a continuum without clear, categorical separations. Today this is not understood, as illustrated by the fact that most Pharmas have

parated their D&D divisions organizationally, operationally, and often geographically. This reduces communication, cross-fertilization cooperation, and teamwork. It diminishes the potential for basic researchers to solve problems arising during development. The "hands-off' mentality (i.e., give us the compound, we'll take it from here) results from the unrealistic presumption that development can be predictably managed.

Disinterest in new technologies. There are exciting opportunities for advancing the therapeutic value of drugs through pharmacogenomics (identifying subpopulations of patients based on response, side effects, or metabolism). Genetic techniques can uncover the molecular basis of subclasses of diseases or diseases of unknown etiology, which could provide new therapeutic targets. But these opportunities are often ignored by the industry, which focuses rather on "one pill for all " despite the fact that only a certain proportion of patients may benefit. Why develop and market a drug that treats only 10%-20% of patients, with a requirement to identify these before treatment starts?

Even in clinical trial design, there has been little exploration of new paradigms based on modern science. Current practices hav changed little in 3 decades. Stati tical theory and regulations drive trial design under the fundamentally faulty assumption that human populations are homogeneous. As a result, an unnecessary number of very large, costly, and low-sensitivity trials are conducted or required by the FDA.

The future of pharma: a change in focus? Perhap Pharmas should shift their R&D focus away from novel discovery and toward development areas in which they excel. These includ improved formulations compounds with superior pharmacokinetics and analog of knovvn drugs with significant benefit . Incremental improvements have historically been among the most important approaches co advance in therapeutic agent .

science and society

Enhancing potency· r clueing or eliminating a side f[l ct; limiting dosage to once-daily (leading to improved complian e) · nhan -ing bioavailability (resulting in less ariation in th blood 1 1 of a drug)· decrea ing pill iz (making th m ea i r to swall w, increasing compliance)· and ov rcoming drug r si tance (in th case of antibiotics antivirals, anticancer drugs) are changes that can re ult in valuable th rap utic contributions (n t simply "m -too" drugs). These may not be as lucrative as new and possibly blockbu ter drugs, but the co t and risk in their D& will be drastically decreased. Also, these kinds of products ar more rational than some recent ones that are counterscientific and designed to achi ve big sales rather than meet medical need . Examples are fixed-dose combinations of drugs to treat 2 or more unrelated conditions simply because they happen to coexist in many individuals (e.g., hypertension dyslipidemias, arthritis diabetes, etc.) . Genomic sciences increasingly point to the logic of doing just the opposite, the individualization of therapeutics.

Can small biotech companies contribute more? Because of their small size, such companies may offer attractive alternatives. However, these companies have funding constraints that dictate a narrow technical focus. The overriding objectives of those controlling the purse strings (venture capitalists) are short-term and financial . In most sooner or later, unreasonable and disruptive demands are made on scientific operations. Venture capitalists are often disinterested in vanguard science and want only advanced compounds that appear "safe.' Collaborations with major funding from pharma have lost appeal. Deals are often terminated suddenly, capriciously, or because pharma no longer perceives the potential for a blockbuster. Termination stalls the progra1n and may cause it to languish or die. This industry has a role but it is not one of replacing the primary existing systems. A few of these companies do succeed, but rar ly, and in totality, like pharma, this industry is not very productive.

A larger role for nonprofit institutions? An attractive alternative to the current, nearly exclusive role played by industry is to enhance the drug R&D efforts in nonprofit biomedical research institutions, mainly universities, private research institutes, and government laboratories. These institutions have the appropriate climate for creative and innovative science. They understand the value of individual freedom intellectual diversity flexibility, and originality. Their science is not dictated by marketing or commercial objectives. Scientific collaborations are based on equality and contribution, not authoritative commands. These are places where cutting-edge science is done, and they attract the sharpest minds and bright young people. They have experti e in many disciplines in the biological, medical, chemical, computational engineering, and mathematical sciences. The notion that academics normally engag in basic re arch while industry focu -es on "applied research" is a myth based on misunderstanding of the nature of scientific res arch (13) . Further nonprofit biomedical research today is big-tim , totally modernized, and unlike the caricatures of a sleepy environm nt for detached academic and scholars. The private ector could readily furth r mobilize to enhance its efforts in drug discovery as well as development. The maturation of the contracc research organization ( RO) industry has been extensi e and provide a source for competencie for regulatOry-driven activiti sin developm nt that anyone can utilize a demonstrated b th ucc s s of some biot ch companies.

Ther are many activities nm.v unfolding that are boldly e tending research co th area of drug D&D. S m of the cientific rati -

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nale for this has recently been discussed by Duyk (14). The field of translational medicine which generally refers to efforts by nonindustry scientists to bring basic discoveries to the clinic, has been exploding (15). Universities and research institutes have created departments or units of drug discovery or of translational m edicin e. The NIH has vigorously undertaken important new efforts in drug discovery. Although individual institutes have had drug discovery programs for decades (e.g. , in epilepsy cancer, HIV) a new approach has been initiated that involves an amalgamated NIH (16) . The multiyear program has already established a 10-center network (1 intramural 9 others outside of NIH) to screen potential drug targets. They have initiated dozens of other funding opportunities such as soliciting s tudies ofhigh-throughput screening of molecular libraries and establishing Exploratory Centers for Cheminformatics Research (1 7).

These efforts are important for encouraging nonprofit institutions to initiate or increase research in drug discovery. However this does not mean that the perpetuation and expansion of such programs should remain under the direction of the NIH or in competition with the NIH for funding. Such a role could lamentably end up redirecting the primary focus of the NIH, squeezing its budgets away from funding fundamental research (18) . Current NIH budgets are in serious crisis (18 19), as are those of the FDA (5) and other scientific agencies.

352:1063- 1066.

Market forces would dictate future changes in industry Major success in discovery research in the nonprofit sector would likely encourage corporate management and shareholders to abandon discovery research for economic reasons . How much and what kind of development drug companies would perform would depend on how they fare with the competition, particularly with regard to public institutions working in concert with CROs. However, one would expect that Pharmas' unique strengths would lead them to focus on efforts to develop new formulations and dosage forms of existing drugs, improvements in the methods to scale-up organic synthesis and analogs with improved properties, as well as manufacturing, distribution, marketing, and selling of virtually all products.

Acknowledgments The author is grateful to Alan R. Saltiel, Stephen Weiss Robert E. Davis, Wendell Wierenga Jerrold M . Olefsky,Joe Graedon, and Teresa Graedon for their critical review of the manuscript and for excellent suggestions.

Address correspondence to: Pedro Cuatrecasas, Departments of Pharmacology and Medicine, University of California, PO Box 2249, Rancho Santa Fe, California 92067, USA Phone: (858) 756-0908; Fax: (858) 759-80 11 · E-mail: [email protected].

1. Booth, B. and Zemmel, R. 2004. Prospects for productivity. Nat. Rev. DmgDiscov. 3:45 1- 456.

2. Francz, S. 2004. FDA publishes analys is of rhe pipeline problem. Nat. Rev. DrugDiscov. 3:279.

3. Mervis,]. 2005. Productivity counts - bur rhe definition is key. Science. 309:726- 727.

9. Cuarrecasas, P. 1995. Co rporate America: creativity held hostage. In Creative action in organizations. C.M. Ford and D.A. Gioia, editors. Sage Publications. Thousand Oaks, Califo rni a, USA. 201- 205.

ances in biomedical research . ]. Clin. Pharmacal. 32:100- 106.

14. Duyk, G. 2003. Attrition and translation. Science. 302:603- 605 .

15. Kaiser, ]. 2006 . A cure for medicine's ailments?

4. Wood, A.].]. 2006. A proposal for radical changes in th e drug-approval process. N. Engl.]. Med. 355:618- 623.

5. Kenn edy, D. 2006. FDA centennial [edi to ri al] . Science. 312:19.

6. Miller, H .I. 2005 . September 2. Improving rhe drug ap proval process [editorial]. The San Diego Union -Tribtm e.

7. Avorn,J. 2005. FDA standards- good enough for government work? N. Engl.]. Med. 353:969- 972.

8. Okie, S. 2005. What ai ls the FDA? N. Engl.]. Med.

10. Cuarrecasas, P. 1991. Devising the portfolio. In Creating the right environment for drug discove1)'· S.R. Walker editor. Quay Publishing. London, Uni ted Kingdom. 51- 65 .

11. Graedon, ]. , and Graedon, T. 2005. Orphan drugs have beco me big business. The People's Pbannacy. hrrp:/ / >vww.peoplespharmacy.org/archives/ edirorial/ orphan_drugs_have_become_big_business.asp.

12. Druker, B.J. 2006. Circumve nting resis tan ce to kinase-in h ibitor th erapy. N. Engl. ]. Med. 354:2594- 2596.

13 . Cua rrecasas, P. 1992. Industry-universi ty alli -

Science. 311:1852- 1854. 16. Co uzin , ]. 2003. NIH dives into drug discovery.

Science. 302:2 18- 222. 17. Office of Portfolio Analysis and Strategic Initia

tives. 2006. Molecular libraries and imaging: NIH Roadmap for medical research. hrrp:f/nihroadmap. nih.govj molecularlibraries/ fundedresearch.asp.

18. Marks, R.M. 2006. Rescuing rhe NIH before it is roo lace [editorial).]. Clin. Invest. 116:844. doi:10.1172/ JCI28364.

19. Loscalzo,]. 2006. The NIH budget and the furure of biomedical research. N. Engl.]. Med. 354:1665- 1667.

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