2013 màster upf josep m. badenas

Facts and Trends in Clinical Development 2013

Josep M. BadenasSenior Medical Director, Neuroscience

CovanceCell: +34 629 52 73 84

[email protected]

Máster Universitario en Liderazgo y Gestión de la Ciencia y la Innovación / Màster Universitari en Lideratge i Gestió de la Ciència i la Innovació / Management and Leadership in Science and Innovation

Universitat Pompeu FabraBarcelona, Spain27 April 2013

mailto:[email protected]

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Investment

• Invested almost $50 billion in 2011 in discovering and developing new medicines, representing the majority of all biopharmaceutical research and development (R&D) spending in the U.S.

Pharmaceutical Research and Manufacturers of America, PhRMA Annual Membership Survey (Washington, D.C.: PhRMA, 2012)

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Need for continued development of new treatments• Direct costs to all payers of

caring for those with Alzheimer’s disease, including out-of-pocket costs to patients and their families, is estimated to increase five-fold, from $172 billion in 2010 to $1.1 trillion in 2050, unless new treatments are found that delay its onset or slow its progression. Alzheimer’s Association, “2012 Alzheimer’s Disease Facts and Figures” (2012)

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DISCOVERY

Toxicology and Safety Pharmacology

Biomarkers/Genomics

DEVELOPMENT COMMERCIALIZATION

PHASE IVRESEARCH PRE-CLINICAL PHASE I PHASE II PHASE III

Clinical Pharmacology

Clinical Development

Market Access

Central Laboratories

Drug development at Covance

Bioanalytical Small & Large Molecule, Biopharmaceutical, Drug Metabolism & Pharmacokinetics,Immunology & Vaccines; CMC Pharmaceutical Development Services, Environmental Sciences

Antibody Products &Research Models

Discovery Pathology, Discovery Toxicology, In Vivo Pharmacology

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The drug discovery and development process

• Long and complex, risk of failure at each step• Average cost to yield a single FDA-approved drug is

approximately $1.2 billion (including the cost of development failures) (*)

• Entire research and development and FDA approval process time: 10 and 15 years (**)

* In 2005 dollars, when capitalized using an 11.5% discount rate, and including the cost of development failures. J.A. DiMasi and H.G. Grabowski, “The Cost of Biopharmaceutical R&D: Is Biotech Different?” Managerial & Decision Economics (2007) 28:469–479.

** Dickson and J.P. Gagnon, “Key Factors in the Rising Cost of New Drug Discovery and Development, ”Nature Reviews Drug Discovery 3 (May 2004): 417–429; J.A. DiMasi, R.W. Hansen, and H.G. Grabowski, “The Price of Innovation: New Estimates of Drug Development Costs,” Journal of Health Economics 22 (2003): 151–185.

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Probability of success model

Source: Jim Grace, Ph.D., Lilly Research Labs

Cost per NME has grown exponentially over the past 60 years• Costs per NME have been growing at an annual rate of 13.4%

for 5 decades.• An update by DiMassi 2000 estimate yields $3.9 billion• Only 27% of companies have NME costs smaller than $1 bn• All big pharmas have NME costs greater than $4 bn• PhRMA members’ R&D budgets have only grown at an annual

rate of 12.3%• Drug companies are getting more efficient, but less productive

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

The cost of clinical trials

The total cost can reach $300−600 million to implement, conduct, and monitor a large, multicenter trial to completion.

Source: Transforming Clinical Research in the United States: Challenges and Opportunities: Workshop Series http://www.nap.edu/catalog/12900.html

Success rates 2006 Are we doing better?

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Quick win, fast fail drug development paradigm

Translational Medicine

Growth in talk of "New Pharmaceutical Research Paradigms" inversely correlated with NME approvals

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Annual and cumulative new drug approvals by the FDA’s CDER, including both NMEs and BLAs

Innovation in the Biopharmaceutical Pipeline: A Multidimensional View. Long G, Works J. Analysis Group, Inc., Boston, Massachusetts, January 2013

Exponential growth in inputs with no numerical increase in outputs


R&D productivity has stagnated despite technological advances

We produce no more new drugs than 50 years ago.Over 4300 companies engaged in drug innovation

Only 261 (6%) have ever registered a drug with FDA.Only 30 (11%) have existed for the entire 60 years.89% have failed, merged, or were created by M&A.

The fact that 30 companies have existed for the entire period shows sustainability is possible but hard.The fact that 23 (out of 30) are small firms suggests there are ways to thrive despite small size.


Life cycle of small molecule drugs versus biologics

• Slower rate of decay with biologics

• Average sales levels of biologics has surpassed average sales of small molecule drugs.

• Assumption: biologics will start to face generic competition downstream of 2015

R&D productivity

• Merck, Eli Lilly, and Roche have the best 60-year track records

• Have produced innovation at constant rates for 60 years: slightly short of 1 NME/year (industry average is 1 NME every 6 years)

• Nothing drug firms have done in the last 60 years has changed these dynamics

• Probability of producing 2 to 3 NMEs per year: 0.06% - 0.003%

Pharma still a source of value creation

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Innovation - Pipeline

• Total numbers of medicines in development, by therapeutic area

PhRMA Report: The Biopharmaceutical Pipeline: Evolving Science, Hope for Patients Analysis Group, Innovation in the Biopharmaceutical Pipeline: A Multi-Dimensional View, 2013

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Innovation - Pipeline• Potential first-in-class medicines introduce a new

mechanism of action or pharmacological class for attacking a given disease or condition.


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Innovation in the Biopharmaceutical Pipeline: A Multidimensional View. Long G, Works J. Analysis Group, Inc., Boston, Massachusetts, January 2013

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Innovation - Pipeline• Medicines targeting rare orphan diseases affecting 200,000

or fewer patients in the U.S.


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• Medicines targeting rare orphan diseases affecting 200,000 or fewer patients in the U.S.

Innovation – Pipeline

Orphan Medicinal Products - Europe• Objective criteria for designation based on the prevalence of

the condition for which diagnosis, prevention or treatment is sought:– Prevalence Threshold: not more than 5 affected persons per 10,000– Medicinal products intended for a life-threatening, seriously

debilitating or serious and chronic condition should be eligible even when the prevalence is higher than 5 per 10,000

REGULATION (EC) No 141/2000 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 December 1999 on orphan medicinal products

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Innovation - Pipeline• Medicines targeting diseases for which there have been no

recently approved therapies


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• Medicines that incorporate a personalized medicine approach, tailored to specific subpopulations of patients based on molecular or genetic characteristics.


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Personalized medicines are a growing proportion of the pipeline

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Innovation - Pipeline• Medicines that are among the first to apply new scientific strategies to

address disease and that may hold promise in enabling other future therapies previously impossible with existing technologies (e.g., gene therapy, therapeutic vaccines for cancer).


ABPI, www.abpi.org.uk

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Novel Scientific Strategies • 245 projects using cell therapy.• 127 projects using antisense RNA interference therapy (an approach that

targets RNA, which carries genetic information that creates proteins, rather than proteins themselves).

• 102 projects using monoclonal antibodies joined to cytotoxic agents to target and kill tumors while sparing nearby healthy cells.

• 99 projects using gene therapy.


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Gene Transfer Designs • NIH Re-Combinant Advisory Committee (RAC)• RAC reviews new gene transfer trials• Mostly very early phase studies• Designs often not appropriate

– No objectives clearly stated– Borrowed from other settings that are not relevant

• Design guidelines need further development

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Gene Therapy Submissions • 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

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Innovation – PipelineGene Therapy in Parkinson’s Disease• Intraputaminal delivery of CERE-120 (adeno-associated virus

serotype 2–neurturin) to patients with idiopathic Parkinson’s disease

• 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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Methods in order to improve R&D efficiency

• Computer-based models:– Predict how a candidate drug is absorbed, distributed, and eliminated

from the body

• Better predictive models: – Narrowing the patient population where the drug has the best chance

of success– Eliminating candidate drugs before risky and costly clinical trials begin

• Simplify Clinical Trials: – 2004-2007: increase of 49% in median procedures per clinical trial as

compared to 2000-2003 (1)– Decrease of 21% patient enrollment rates as a result of more

demanding eligibility criteria (1)

(1) Tufts Center for the Study of Drug Development, “Rising Protocol Complexity, Execution Burden Varies Widely by Phase and TA,” Impact Report 12, no. 3 (May/June 2010).

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• If we:– Decrease amount of variables, Decrease amount procedures, Keep it

focused and simple (“Less is more”)

• We will see immediate positive consequences: – Less cost, less total clinical staff time, better enrollment and retention

of patients, increase reliability of assessments

• If not offset:– These developments may lead to future increases in the expense and

time required to successfully develop new drugs (1)

(1) Tufts Center for the Study of Drug Development, “Rising Protocol Complexity, Execution Burden Varies Widely by Phase and TA,” Impact Report 12, no. 3 (May/June 2010).

Simplify Clinical Trials (Cont.)

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• Enhance communication between FDA and sponsors during drug development

Chart from Vikram Sinha, PhD, DirectorDivision of PharmacometricsOffice of Clinical PharmacologyOTS, CDER, FDAA SCPT Annual Meeting Open Forum, March 6, 2013Model-Informed Drug Development and Regulatory Review

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Methods in order to improve R&D efficiency• Clinical trial design: Adaptive Study Design

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• Objectives of Learn: Disease-based Learning; Identify and recommend most attractive molecules; Identify and recommend the best ways to use the molecule for therapeutic purposes (dosage, delivery) before going to Confirm

• Improve POS

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

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• Development of biomarkers and pharmacogenomics, use of enrichment strategies• 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• Genomic biomarkers are the foundation of personalized medicine

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• Development of biomarkers and pharmacogenomics, use of enrichment strategies• Diagnostic • Prognostic: outcome related to disease, but not necessarily to drug

therapy• Predictive: outcome necessarily related to therapeutic intervention• Validated• Clinical trial vs. Clinical utility• Study design: Enrichment or a stratification strategy implementation

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Putative Biomarkers for the Alzheimer Disease Pathophysiological Process Currently Being Used

1. Markers of amyloid-beta (Ab) protein deposition in the brain

a. Low cerebrospinal fluid Ab42

b. Positive PET amyloid imaging

2. Markers of downstream neurodegeneration

a. Elevated cerebrospinal fluid tau (total and phosphorylated)

b. Decreased metabolism in temporal and parietal cortex on 18flurodeoxyglucose positron emission tomography

c. Atrophy on magnetic resonance imaging in temporal (medial, basal, and lateral) and medial parietal cortex

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Criteria for Dementia Unlikely to be Due to Alzheimer Disease (AD)

(1) Does not meet clinical criteria for AD dementia

(2) Regardless of meeting clinical criteria for probable or possible AD dementia

a. There is sufficient evidence for an alternative diagnosis such as

HIV dementia, dementia of Huntington disease, or others that rarely overlap with AD

b. Biomarkers for both amyloid b and neuronal degeneration are negative


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Methods in order to improve R&D efficiency• Use of enrichment strategies

– Prospective use of any patient characteristic to select a study population in which detection of a drug effect (if one is in fact present) is more likely than it would be in an unselected population.

– 3 enrichment strategies: • Practical enrichment: Decrease heterogeneity and “noise” (1)• Prognostic: Identifying high risk patients‐• Predictive enrichment: Choosing patients likely to respond to

treatment

(1) Noise reduction is one of the variety of ways researchers try to include people who can be measured precisely and correctly, so if they have a drug effect it can be detected.

FDA, Guidance for Industry, Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products, December 2012

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Methods in order to improve R&D efficiency• 5 Predictive Enrichment Categories:

– Empiric strategies• Open Trial Followed by Randomization• An Individual’s History of Response to a Treatment Class• Factors Identified in Results from Previous Studies

– Pathophysiologic strategies• Metabolism of the Test Drug • Effect on Tumor Metabolism • Proteomic Markers and Genetic Markers Linked to a Proteomic Marker

– Genomic strategies– Randomized withdrawal studies– Studies in non-responders or patients intolerant to other therapy


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Methods in order to improve R&D efficiency• Randomized withdrawal studies: In a randomized withdrawal study,

patients who have an apparent response to treatment in an open label period or in the treatment arm of a randomized trial are randomized to continued drug treatment or placebo.


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Methods in order to improve R&D efficiency• Use of enrichment strategies

– The increased study power facilitates “proof of principle” (there is a clinical effect in some population) but it leaves open:

• The question of generalizability of the result• How much data are needed before or after approval in the “non‐

selected” group. (Do these patients benefit at all? Are they harmed?)


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Methods in order to improve R&D efficiency• Enriching Trials for Early Responders:

– 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.

– Genentech’s trastuzumab (Herceptin®) was studied only in people expressing the Her2 protein, which represents roughly 1/3 of the population.

– If an unselected population had been studied, a two-month improvement on survival would probably have been seen rather than a six-month improvement on survival.

Biomarker Study Design 1: Upfront stratification

• Produces data on all patients• Completely prospective

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Test

M+, randomize

M-, randomize

Treatment A

Treatment B

Treatment A

Treatment B

Biomarker Study Design 2: Biomarker-based strategy

• May not produce data for all patients (although it can)• Can include retrospective design aspects.

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Randomize

Marker-based

Non-marker based

Treatment A

Treatment B

Treatment A

Treatment B

Test

Randomize

Biomarker Study Design 3: Biomarker-based strategy

• May not produce data for all patients (although it can).• Dose selection

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Randomize

Marker-based

Non-marker based

M+ Dose 1

M- Dose 2

Test

Standard Dose

Targeted therapy is not a new concept

ASCPT Annual Meeting March 6, 2013 Open Forum, Contemporary Issues in Clinical Pharmacology: Development and Regulatory Evaluation of Targeted Therapies, Mike Pacanowski, PharmD, MPH, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration

Personalized Medicine• Development of biomarkers and pharmacogenomics. Genomic

biomarkers are the foundation of personalized medicine • 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 (1)

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(1) 2009 Report on Status of Regulatory Science at FDA: Progress, Plans and Challenges. Office of the Chief Scientist and Principal Deputy Commissioner. US Food and Drug Administration. Frank M. Torti, M.D., M.P.H. FDA’s overarching scientific priority

Personalized Medicine

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Our future: targeting the molecular basis of disease

ASCPT Annual Meeting March 6, 2013 Open Forum, Contemporary Issues in Clinical Pharmacology: Development and Regulatory Evaluation of Targeted Therapies, Mike Pacanowski, PharmD, MPH, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration

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Methods in order to improve R&D efficiency• Adaptive Licensing – Balancing Evidence and Access

Eichler 2012. PMID: 22336591

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• Adaptive Licensing – Balancing Evidence and Access

Exploratory(Learn)

Confirmatory(Confirm)

Monitored release Full release

Biomarker Development

Model and Simulation

Targeted Approval Full Approval

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Conclusions1. Cost per NME/NBE will grow at annual rates above 13%2. Cost estimate for developing a new drug between $ 1.2-3.9 billion3. Pharmaceutical industry will continue to be a source of value (20-year ROIC of

30% that beats most other industries (average of 9%)4. Time for “me too” drugs, “enantiomers”, is over, no way back5. It is time for innovation: this is a one way street with no return6. Innovation leads to an increase of translational medicine activities and the

number of POC studies (“learn and confirm”, “quick win, fast fail” drug development paradigm)

7. Innovation focused on: a) pipeline, b) study designs and analysis, c) development of biomarkers, d) orphan drugs, e) pharmacogenomics and personalized medicine, f) adaptive licensing

8. Communication with regulatory agencies should be a two way street. Ask for early advice. Work closely with agencies.

9. Outsourcing (from discovery to late phase) will continue to increase (outsourcing rate increased from 35% in 2010 to 41% in 2012, Source: Health Care Distribution & Services. Baird Equity Research. April 2, 2013)

Abbreviations (1)1. ABPI: Association of the British Pharmaceutical Industry 2. ADMET: Absorption, Distribution, Metabolism, Excretion and Toxicity3. BLA: Biologic License Entity4. CBER: Center for Biologic Evaluation and Research5. CCLS: Covance Central Laboratory Services6. CDER: Center for Drug Evaluation and Research7. CDS: Clinical Development Services8. CLS: Central Laboratory Services9. CMC: Chemistry Manufacturing and Control10. CPP: Certificate of Pharmaceutical Product (Taiwan)11. CRO: Contract (also Clinical) Research Organization12. CSDD: Tufts Center for the Study of Drug Development 13. CT: Clinical Trial14. CTA: Clinical Trial Application15. CTD: Clinical Trial Directive16. CTTI: Clinical Trials Transformation Initiative (US)17. DCG: Drug Controller General (India)18. DCGI: Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India19. DOH: Taiwan Department of Health20. DSMC: Data Safety Monitoring Committee21. EC: European Commission22. EC: Ethics Committee23. EMA: European Medicines Agency24. EMEA: Europe, Middle East & Africa25. EMRC: European Medical Research Councils26. ESF: European Science Foundation27. FD&C Act: Federal Food Drug and Cosmetic Act 28. FDA: Food & Drug Administration29. FDAMA: Food and Drug Administration Modernization Act 199730. FDASIA: Food and Drug Administration Safety and Innovation Act 31. FSC: Free Sales Certificate (Taiwan)32. GCP: Good Clinical Practice33. GMP: Good Manufacturing Practice34. GRS: Global Regulatory Submissions35. GSS: Global Site Services36. GSF: Global Science Forum37. GT: Gene Transfer

Abbreviations (2)28. GTAC: Gene Therapy Advisory Committee (UK) 29. HTA: Human Tissue Authority (UK)30. HTS: High Throughput Screening 31. HSE: Health and Safety Executive (UK)32. ICH: International Conference of Harmonisation33. IDCT: Investigator-Driven Clinical Trials34. IFPMA: International Federation of Pharmaceutical Manufacturers and Associations35. IMPD: Investigational Medicinal Product Dossier36. IND: Investigational New Drug Application37. IRB: Institutional Review Board38. IRR: Internal Rate of Return39. LO: Lead Optimization 40. MHRA: Medicines and Healthcare products Regulatory Agency (UK)41. NBC: Italy’s National Bioethics Committee42. NBE: New Biologic Entity43. NCE: New Chemical Entity (Taiwan)44. NDA: New Drug Application 45. NME: New Molecular Entity46. NPV: Net Present Value47. OECD: Organisation for Economic Co-operation and Development48. PASS: Post-authorization safety studies49. PDUFA: Prescription Drug User Fee Act50. PhRMA: Pharmaceutical Research and Manufacturers of America51. PHS Act: Public Health Service Act52. POC (or PoC): Proof-of-Concept53. POS: Probability of Success54. R&D: Research & Development55. RA: Regulatory Authority56. RAC: Re-Combinant Advisory Committee57. REMS: Risk Evaluation and Mitigation Strategies58. ROIC: Return On Invested Capital 59. SCRS: Society for Clinical Research Sites (US)60. SFDA: State Food & Drug Administration of China61. TFDA: Taiwan Food and Drug Administration

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Moltes gràcies

Muchas gracias

Thank you

Josep M. BadenasSenior Medical Director, Neuroscience

CovanceCell: +34 629 52 73 84

[email protected]

mailto:[email protected]

2013 màster upf josep m. badenas

Documents

cost of development

cost of biopharmaceutical

development process

drug companies

years costs

nme costs greater

nme costs smaller

cost ofdevelopment failures