Globalization of Clinical Trials

Josep M. Badenas

Mobile: +34 629 52 73 84

E-mail: 18182jbp@comb.cat

E-mail: josepmaria.badenas@gmail.com

Globalization

• Global trials bring drug to market more quickly.

• 96% of R&D dollars spent in developed countries (US: 49% & Western EU:

37%).

• Vast majority of trials still in US and EU* but US & EU lost 4.3% sites to

RoW (6,500 sites)*

• Need to identify strategies for enhancing the effectiveness and efficiency

of clinical trials.

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* Value of Insight Consulting Report, 21 July 2009

Trial Density 2007

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Density is in per country inhabitant (in millions; based on 2005 population censuses); darker orange/red denotes a higher density. The trial density and average relative annual growth rate in percent is shown for selected countries. The countries in grey had no actively recruiting biopharmaceutical clinical trial sites as of 12 April 2007.

Ref: Trends in the globalization of clinical trials, Fabio A. Thiers, Anthony J. Sinskey & Ernst R. BerndtNature Reviews Drug Discovery 7, 13-14 (January 2008)

Globalization

Emerging Countries

– Play a vital role in global clinical development

– Governments develop clinical research infrastructure

– Improving the health systems and economies in emerging markets

– Trials in emerging countries conducted to global standards

– Regulations in emerging countries often more strict (all participants be equally

protected)

– FDA & EMEA resources for increased inspections

5Global Development R&D Spend ($M) Source: PhRMA

India• Very cost effective

• Huge population, good enrollment

• Longer regulatory lead times

• General use

Central Drugs Standard Control OrganizationDirectorate General of Health Services, Ministry of Health and Family Welfare, Government of India

www.cdsco.nic.in

India - Proposed CTA Categories

Category A

• Clinical Trial already approved in the

following reference countries: USA, UK,

Switzerland, Australia, Canada, Germany,

South Africa, Japan, EMEA

• Assumption: Same Protocol

• Proposed Review Timeframe: 2 – 4 weeks

Category B

• All applications NOT categorized under

category A

• Note: ‘Switching’ to Category A is not

allowed once filed as Category B

• Proposed Review Timeframe: 8 – 12

weeks

CTA: Clinical Trial Application

China• Huge patient population, but dissimilar to the U.S.

• Public and private hospitals

• Most public hospitals are linked to a university

• % of patients with health insurance is increasing, especially in big cities

• Patients select their own doctors

• No appointments are necessary

• Fee for a consultation at outpatient clinic around 10 yuan (1€)

• Medication is provided by hospital pharmacies

• Doctors make a provit from the medication they prescribe

• Special treatment for VIPs

• In general, diagnosis and treatment very similar to Western world

China – Clinical Trials• Long regulatory lead times

• Mandatory for Chinese registration

• A program conducted in the U.S. will require new studies for China

• Clinical Trials must be approved by SFDA prior to ethics committee approval

• Trials must be conducted by designated hospitals

• Designated hospitals are pre-selected and accredited by SFDA and MOH, as Clinical Bases

• GCP works as guideline

• Large part trials for generics

• Only public hospitals are certified by the SFDA for clinical research

Cost per Patient– In ECE (United Nations Economic

Commission for Europe), Latin America, and

parts of Asia, clinical trials can be cost

effective relative to the U.S.

– A center in India will charge $1500 to 2000

per patient, 1/10 the comparable rate in the

U.S.1

– NDAs will have thousands of patients (the

cost advantage can add up)

– An exception to this rule is Japan

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1Garnier JP. Rebuilding the R&D engine in big pharma. Harvard Business Reviews 2008; 86:68-76

Relative Costs by Region

Global Research CostsRelative Cost Indexes of Payments to Clinical Trial Sites

Challenges

– Cross-cultural differences

– Genetic polymorphism

– Different regulations

– IRB/EC roles and organizations

– Reputation: well publicized “ghosts”

from the past

– Patient access and availability of

patients

– Ethics

– Placebo

– Quality

– Cost

– Disease incidence

– Medical practice, treatment

differences

– Rating scales

– Statistical considerations

– Data generation and acceptability

– Other

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Patient Access and Availability of Patients

• Regulatory requirements in Multiple Sclerosis include double-blind, placebo-controlled trials

of two years duration. Most patients in the US will not enroll in a trial of this design

• Most donepezil-naïve patients in Alzheimer-s disease are outside the US and Western Europe

• Lack of adequate medical care drives patients into clinical trials (Eastern Central Europe, Latin

America, Parts of Asia)

• Pain intensity and disease stage requested in diabetic neuropathic pain difficult to find in

Western EU

• Suicidal ideation in India

• Mild Cognitive Impairment (MCI) diagnosis

• Anxiety in Japan

Ethics – Vulnerable Populations• Framework for conducting human subjects research: Core ethical concepts in the

Belmont Report.

• Interpreting and applying them in another cultural setting may be challenging.

• International guidelines for international research ethics outline and interpret changes,

advances and controversies in research ethics outside western countries.

• Researchers need a clear understanding of both the ethical guidelines and government

regulations pertaining to any proposed research, from both the U.S. and host country

governments.

Inuit family, The National Geographic Magazine, Volume 31 (1917), page 564.

Drug Development Scorecard

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Drug approvals and failures: implications for alliances. Czerepak EA, Ryser S.Nature reviews/Drug Discovery. Vol. 7 March 2008

67 (65%)

Segmenting by Innovation Level

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30%

30%

40%

Drug approvals and failures: implications for alliances. Czerepak EA, Ryser S.Nature reviews/Drug Discovery. Vol. 7 March 2008

January 2006 – December 2007

Segmenting by Innovation Level (Jan 06 - Dec 07)

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¾ from Biotech½ from Biotech ½ from Biotech-pharma alliances

and Pharma Companies

Trends in Disease Focus of Drug Development (Oct 05 - Sept 07)

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2/3 of all protocols, 68%2/3 of all sites, 74,1%

Rheumatology: 157.6%, highest relative growth

Cardiology: 74.3%, lowest relative growth

Trends in disease focus of drug development. Johan P. E. Karlberg. Nature Review/Drug Discovery. Vol. 7. August 2008

Volume and Type of Clinical Trials ConductedAugust 16, 2009

The Cost of Clinical Trials

Exponential Growth in Inputs with No Numerical Increase in Outputs

Source: Rodney Zemmel, PhD., McKinsey & Company, BernsteinPharmaceuticals Longview Conference, May 5, 2010

Growth in Talk of "New Pharmaceutical Research Paradigms" Inversely Correlated With NME Approvals

R&D Productivity Has Stagnated Despite Technological Advances

Cost per NME Has Grown Exponentially Over the Past 60 Years

R&D Productivity: (1) Merck, Eli Lilly, & Roche Have The Best 60yr Track Records; (2) Drug Output Across The Industry Seems To Correlate With The Number Of Companies, Which Argues Against

M&A

McKinsey's "Per Drug" Model of Industry Productivity – Small Molecules vsBiologics

Despite Challenges, Pharma Still a Source ofTremendous Value Creation

New waves of innovation are beginning

ABPI, www.abpi.org.uk

Reminder

• Phase I: clinical trials test an experimental drug or treatment for the first time in a small group of people

(20−80) over the course of a few weeks or a month. Their goals are to assess the safety of the drug or

treatment, find a safe dosage range, and identify any side effects.

• Phase II: larger group of people (100−300) receives the experimental drug to determine whether it is

effective and further evaluate its safety. These trials involve subjects with the target disease and usually

last months.

• Phase III: once preliminary evidence from phase II reveals that a treatment is effective, phase III trials are

designed to fully examine the risk/benefit profile of an experimental drug or treatment and test it over a

longer period of time in a broader population (1,000−3,000). Because these trials are the last phase in the

preapproval process, they are often referred to as “pivotal” trials.

• Phase IV: or postmarketing trials take place after a drug has been approved. They provide additional

evidence on the risks and benefits of the drug or treatment and how it can be used optimally.

Clinical Trials by Phase of ResearchAugust 16, 2009

New Drug Development Remains a Very Risky Venture

Source: Outlook 2010 (Report)

Success Rates

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Improving the Return on Small-molecule R&D

33Pharmaceutical R&D: the road to positive returns. David E. Tramontin T. Zemmel R.Nature Reviews/Drug Discovery. Vol. 8. August 2009.

Change what they are doingReduce cost of drug failure

6-month delay to launch = $ 100 million in NPV or a reduction of 0.5% in IRR

Can cost hundreds of millions of dolars if made too lateCurrent high attrition rate in Phase III: 106 failures 90-07 (45% efficacy vs. placebo, 24% insufficient differentiation vs. standard of care)

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Trust• Harvard University-affiliated hospitals move toward transparency on industry

gifts

• Bloomberg News (4/10, Lauerman) reports, "A group of Harvard Medical School-

affiliated hospitals will adopt new conflict-of-interest guidelines that forbid industry gifts

to eliminate potential bias in patient care research and recommendations.“ etc,…By John

Lauerman, April 10 (Bloomberg)

• Pharma executives seen as lacking scientific expertise

• The Financial Times (4/6, Jack) reports, "Only one large western pharmaceutical

company [Eli Lilly] will be run by a scientist following completion of the current round of

acquisitions, in spite of the growing need for strengthened innovation to develop new

medicines." etc, ….By Andrew Jack in London. Published: April 5 2009 16:58 | Last

updated: April 5 2009 16:58

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Trust• Publication of fragments

• Fraud and misconduct

• Anesthesiologist admits to fabricating data in

pain studies. The New York Times (3/11, A22,

Harris) reports, "In what may be among the

longest-running and widest-ranging cases of

academic fraud, one of the most prolific

researchers in anesthesiology has admitted

that he fabricated much of the data

underlying his research, said a spokeswoman

for the hospital where he works.“ (March 10,

2009)

• Underpowered studies

• “Ghost” writers

• Image manipulation (fine line between

acceptable enhancements and scientific

misconduct)

http://www.nature.com/news/2009/091009/full/news.2009.991.html

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Restoring Trust - Clinical Trials Registries

• FDAMA* 1997 – www.clinicaltrials.gov

• ICMJE** announces policy to require registration as pre-requisite for publication

(Sept 2004)

• PhRMA*** announces voluntary listing of all hypothesis-testing trials by member

(Jan 2005)

• Major benefit – enhances transparency

* Food and Drug Administration Modernization Act** International Committee of Medical Journal Editors*** The Pharmaceutical Research and Manufacturers of America

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FDAMA (Food and Drug Administration Modernization Act) 1997 – www.clinicaltrials.gov

Initiatives - Trends– Improve execution

– Improve decision-making process: Translational medicine (from preclinical

to Proof-of-Concept).

– Biomarkers

– Study designs

– Pharmacogenomics

– Personalized medicine

Trial ExecutionTop Causes of Study Conduct Delays

Source: CenterWatch, N = 612, 2005Ken Getz.. Senior Research Fellow. Tufts Center for the Study of Drug Development. (CSDD), Kenneth.getz@tufts.edu Phone: +1 617-636-3487

Trial ExecutionInvestigators

– Only 1/3 of the investigators in a study meet or exceed enrolment targets

– 30% of investigator sites enrol no subjects

– US and Western Europe are seeing a decline in experienced clinical investigators

– There are over 700,000 practicing physicians in the US, yet there is a shortage of

qualified investigators (1)

• The total number of investigators declined by 6% between 2001 and 2004 (2)

• There is a core population of at most 2,200 principle investigators, and an annual

turnover of about 40% of the rest (2)

• Only 6% of investigators have conducted 4 or more trials,

• 52% only have conducted only one trial

(1) American Medical Association, June 2005(2) Journal of Clinical Research Best Practices, July 2005

Trial ExecutionDistribution of Complaints Received (2006)

Source: FDA Division of Scientific Investigations, CDER Ken Getz. Senior Research Fellow. Tufts Center for the Study of Drug Development. (CSDD), Kenneth.getz@tufts.eduPhone: +1 617-636-3487

The Quick Win, Fast Fail Drug Development Paradigm

Translational Medicine

Translational Medicine

– Transition between basic research and applied pharmaceutical research.

– Takes basic research into the first phases of product development and initial

human trials, producing new findings that answer questions about safety and

efficacy.

– May increase scientists’ knowledge about disease.

– Leading to critical Proof-of-Concept (PoC) phase.

Genomic Biomarkers are the Foundation of Personalized Medicine

– We look for variability in drug response for every molecule and the source of

that variability

– Biomarkers are typically in the causal pathway of disease pathology or drug

pharmacology

– Qualification of biomarkers refers to the extent of information needed to

understand its clinical utility

– Qualification is for a specific intended use that informs a regulatory and/or

medical decision

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Biomarkers

– Diagnostic

– Prognostic: outcome related to disease, but not necessarily to drug therapy

– Predictive: outcome necessarily related to therapeutic intervention

– Validation

– Clinical Trial vs. Clinical utility

– Should an enrichment or a stratification strategy be used?

• Upfront stratification

• Biomarker-based strategy

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Biomarkers - FDA

– Development and implementation of new or improved biomarkers, models

and methods to predict safety and efficacy of regulated products including

drugs, biologics, devices and foods

– Among the high priority Critical Path projects:

• Biomarker Qualification: The ability to define useful biomarkers will improve efficacy of

medical products, enhance safety and use in the era of personalized medicine. In June 2008,

the Critical Path Institute, co-founded by FDA, announced the qualification of seven urinary

biomarkers of kidney injury for use in certain regulatory decisions. This was a collaborative

effort with preclinical data provided by Novartis, Merck, Harvard Medical School and FDA.

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Study DesignBiomarkers – Example Upfront stratification

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Test

M+, randomize

M-, randomize

Treatment A

Treatment B

Treatment A

Treatment B

Study DesignSheiner’s Principles – Adaptive Designs

Assignment

Learn: Many regimens, doses

Confirm: Few regimens, doses

Observation

Learn: Many variables, outcomes

Confirm: Few variables, outcomes

Analysis & approach

Learn: Bayesian, iterative, decision-trees

Confirm: Null hypothesis - yes/no

48Learning Versus Confirming in Clinical Drug Development. Sheiner, LB, Clin. Pharm Ther 1997; 61:275-291

Adaptive Design

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Study DesignFrom “phased” to “seamless”

… to Learn and Confirm

Phase RPhase R

Transition Zone

IND NDA SubmissionPOC

ConfirmLearn

… to Learn and Confirm

Phase RPhase R

Transition Zone

IND NDA SubmissionPOC

ConfirmLearn

Phase 2

From today ’ s phased approach …

IND POC NDA Submission

Phase 1 Phase 2 Phase R

Transition time

Phase 3Phase 2

From today’s phased approach……..IND POC NDA Submission

Phase 0/1 Phase 2 Phase R

Transition time

Phase 3

Learning Versus Confirming in Clinical Drug Development. Sheiner, LB, Clin. Pharm Ther 1997; 61:275-291

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Study DesignAdaptive Design: Regulatory Perspective

• FDA has had little experience with adaptive design to date

• No NDAs had been approved based on them yet, but almost every

review division has had between 1 to 3 to review under INDs

• Reality is very likely somewhere in the middle

Clinical Trial Design and Analysis - FDA

• Implementation of clinical trial design and analysis methodologies to more rapidly

and efficiently evaluate safety and efficacy of FDA regulated products.

• Among the high priority Critical Path projects:

– Clinical Trials Transformation Initiative: Effective, well designed clinical trials are the basis

for most FDA regulatory decisions. In November 2007, as part of FDA’s Critical Path

Initiatives, FDA in collaboration with Duke University Medical Center announced the

creation of a Public-Private Partnership to improve the quality and efficiency of clinical

trials. In May 2008, a 12 member Executive Board including representatives from

academia, industry, government and patient advocacy was named.

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– Identify individual’s profile of drug response

and predict the best possible treatment

option for this individual.

• e.g. Test detects patients who don't respond to

Plavix

• e.g. Genetic variant may be linked to tamoxifen

response in breast cancer patients

– Shorter timelines (time to achieve endpoint);

smaller number of subjects needed; lower

failure rate; enhanced safety; enhanced

patient loyalty (fewer non-responders)

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Gene ProteinTarget

ChemicalDiversity Screen and

Identify Hits

(compoundlibrary)

Chemical propety andpotency evaluation

Leadidentification

Leadoptimization

Pre-clinical development(safety and efficacy)

Phase I

Safety and dosagePhase IIA Phase IIB

Phase III

Comparative safety and efficacy: randomized and controlled

Pharmacogernetic screen

Phase I Phase IIA Phase IIB Phase III Phase III

Product licensing

Product licensing

Placebo

Placebo

Larger safety,efficacy and dose-

ranging studies

Small efficacy andsafety studies

a

b

c

Roses AD. Nat Rev Gen 2004;5:645-56

Pharmacogenomics in the R&D Process

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Application of Pharmacogenomics to Patient’s Care

• Find new uses for existing drugs

• Enhance efficacy or safety with a diagnostic test

• To predict dosage requirement

• To help select a drug regimen

• To optimize a patient’s response to their medication

• To prevent ADE’s

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Pharmacogenomics - Drugs and Tests

• Development of drugs with tests that help to make better decisions about how to use the

drug in question. There are two types of such tests:

– Tests that are being developed in conjunction with the drug and are “required” for drug use (e.g.

Her2/neu measurement for trastuzumab (Herceptin®) therapy.

– Tests that have been developed after a drug has come to market, e.g. CYP2C9 and VKORC1 for better

determining the starting dose for warfarin; azathioprine and MTPT.

An advertisment from a Farm Magazine 1958 European Atrial Fibrillation Trial Study Group. N Engl J Med 1995; 333:5-10

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Gene Therapy in Parkinson’s Disease

– Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus

serotype 2–neurturin) to patients with idiopathic Parkinson’s disease: an open-label, phase I

trial

– Most experts acknowledge that if these goals could be achieved…it would revolutionize the

treatment of PD

Lancet Neurol 2008; 7: 400–08

Stereotactic neurosurgery for Parkinson’s disease gene therapy

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AAV-NTN: opportunity for innovative therapy for Parkinson’s disease

– Target dopamine nigrostriatal neurons: degeneration implicated as key

pathogenic event in disease

• Provide constant supply of neurotrophic factor

• Enhancing condition and function of neurons

• Strengthening their ability to withstand degeneration

Lancet Neurol 2008; 7: 400–08

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Key Registration Authority Committee review points

– Questions regarding efficacy of CERE-120

– Kinetics and accumulation of NTN in brain

– ‘Multiple brain regions’ targeted and spread of protein to non-targeted brain

regions

– The use of non-regulatable vector

– Question of ‘rescue strategy’

– Cerebellar toxicity reported in select, GDNF protein-treated monkeys

– Rationale for dosing schedule in humans

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Gene Therapy in Parkinson’s Disease

– Extensive safety monitoring in all patients revealed no clinically significant

adverse events at 1 year.

– Several secondary measures of motor function showed improvement at 1

year

Lancet Neurol 2008; 7: 400–08

Gene Therapy Submissions – Western Europe

– Many health authorities have a specific division for Gene Therapy

– All follow the recommendations of the EU Directive

– Mean time for approval in the countries is 6 months

– Some of the ECs in these countries are specific to gene therapy e.g. GTAC in the UK

– Roll of the investigator is critical

Personalized Medicine - Rational

– Variability in drug response, adverse events and absence of benefit

• “If it were not for the great variability among individuals, medicine might have well been

a science and not an art”. Sir William Osler (1849 – 1919) The Father of Modern

Medicine

• “One important characteristic of biology is its diversity, its variation. It’s why

personalized medicine is so important” Dr. Andy Kessler (1958 -) Author and Hedge Fund

Manager

Categories of Personalized Medicine

– Diagnostic test used to select (potential for benefit) or avoid (potential for harm) a

drug

– Diagnostic test used to select an optimal initial and/or maintenance dose of drug

– Biomarker discovered during drug development to inform subsequent clinical trial

design

– Rigorous qualification and regulatory oversight is mandatory in the first two

categories, and highly desirable in the third category; implications of false + and

false

The Path to Personalized Medicine

Personalized Medicine and Nutrition - FDA

• Development of individualized approaches to therapeutics and nutrition, such as

toxicogenomics, pharmacoselection, and complex prognostic and predictive devices, and the

use of these techniques to accelerate product development and provide enhanced product

and food safety.

• Among the high priority Critical Path projects:

• Genomics coordination:

– In June 2008, FDA held a symposium to assess “omics” (including genomics, proteomics and

metabolomics) needs across the Agency and to develop recommendations for use of and

development of “omics” data at FDA. One of the recommendations of this symposium reiterated the

need for formal coordination of “omics” across the Agency as identified in the Science Board Report.

An Agency-wide Genomics Coordinator has been recruited as of February 1, 2009, to integrate

“omics” across the Agency. This person will facilitate “omics’ efforts and will establish a core group

including at least 3 bioinformatics experts to provide cross-center expertise in large data set

analyses.

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FDA Cannot do it Alone

• Centers of Excellence with Academia:

– Within academic medical centers there is expertise in scientific areas that form the foundation of

FDA regulatory science. Partnering with these centers is an important approach to developing the

datasets that form the foundation of FDA regulatory decisions. FDA will identify through a

competitive process academic centers that have depth and breadth of scientific expertise in areas

critical to FDA’s public health mission. Centers would be recipients of specific funding from the FDA

to tackle FDA mission-critical scientific issues.

• Resource Networks with Biotechnology Firms:

– Small biotechnology firms represent a flexible resource. They are operationally and scientifically

nimble and often have the capability to devote a large proportion of human capital to a single

project. Biotech firms that have an interest in partnering to resolve mission-critical FDA questions

will be identified and engaged through contracts and other funding mechanisms.

• Partnerships with industries in the “pre-competitive” space:

– We will explore how FDA can harness the extensive expertise of regulated industries in areas that are

of mutual benefit, such as drug-induced liver toxicity [see II (f)]. Such partnerships with industry

already exist in the area of safety assessment of kidney toxicity and the Sentinel initiative [see II (e)].

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Conclusions• The pharmaceutical industry continues to face substantial challenges at multiple levels.

• Confluence of major patent expiries and low pipeline productivity will force significant change over a multi-year period for the average company.

• What lies ahead is a period of inevitable contraction (tied to patent expiries) that could one day lead to a new and smaller base off of which growth might ultimately be achieved.

• Ongoing efforts to revamp R&D are at least partially successful.

• When will this potential rebound occur? Not for several years to come. For certain names, the "patent cliff" appears to extend even beyond 2015, yet for a lucky few the impact will likely be much more modest.

• Clinical trial experts from academic research centers, pharmaceutical companies, contract research organizations, government, nonprofit research networks, and patient advocacy groups should come together to discuss their clinical trial successes and failures, the challenges they face in conducting clinical research, and strategies for improving the efficiency of clinical trials while maintaining the highest standards for the data generated.

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Moltes gràcies

Muchas gracias

Thank you