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Validating Imaging Readouts in the Validating Imaging Readouts in the Drug Development ProcessDrug Development Process

Andreas SchmidtClinical Development & Medical Affairs

Novartis Pharma AG, Basel - Switzerland

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Overview

• Pharma value proposition• Novartis positioning• Health care environment• FDA’s Critical Path Initiative and Novartis strategies• Biomarker – Definitions, need and future role• Examples from clinical imaging studies• Outlook• Novartis and Public Private Partnerships

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Pharma Industry’s Value Proposition is Strong

Mortality improvement

Mortality improvement • Saving lives

Morbidity reduction

Morbidity reduction

Improved quality of lifeImproved

quality of life

Positive economic

impact

Positive economic

impact

• Innovative treatments• Shortened duration of disease

• Decrease in chronic disability• Improved efficacy / side effect profiles

• Reduction in overall healthcare costs• Improvement in worker’s productivity

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-80%

-75%

-68%

-67%

-61%

-41%

-31%

Early infancy diseases

Rheumatic fever and rheumatic heart disease

Atherosclerosis

Hypertensive heart disease

Ulcer of stomach and duodenum

Ischemic heart disease

Emphysema

Drop in death rate for diseases treated with pharmaceuticals 1965–1999

Major Achievements of Innovative Drug Therapy

Source: EFPIA 1999 – 2002

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65

70

75

80

85

1950 1960 1970 1980 1990 2000 2010 2020 2030 2040 2050

Dramatic Increases in Life Expectancy

Example – US life expectancy at birth

77.2

83.9

1 Average gain of 2 years between 1986 and 2000 in the 52 countries studied (PhRMA 2004)Source: National Vital Statistics Reports 2004; U.S. Bureau of the Census, International Data Base 2004

New medicines generated 40% of the gain in life

expectancy1 achieved in 52 countries between

1986 and 2000

Years

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Average Health of Elderly Population is Improving

26.2%

19.7%

1982 1999

Prevalence of disability in US seniors

25% decrease between 1982 and 1999:

We are not only living longer but also

healthier!

Source: Manton KG, Gu X. Changes in the prevalence of chronic disability in the United States black and non-black population above age 65 from 1982 to 1999. Proc Natl Acad Sci U S A. 2001 May 22;98(11):6354-9

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Despite Excellent Novartis Development Track Record…

• 75 projects in clinical development

• Third most valuable pipeline in industry 1

• Among best late phase success rates 2

• Amongst most innovative pipelines 3

• Leads industry in replacement power 4

1 Lehman Brothers Pharma Pipelines 2004

2 CMR 2004

3 R&D Directions 2004

4 Goldman Sachs, November 2004

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5

An R&D Pipeline with Key Innovative Products …

6

10

0

10

20

30

40

50

60

70

80

90

1977-78 1981-84 1985-88 1989-92 1994-95 1998-2001

There are Challenging Business Trends in the Industry

Ave

rage

clin

ical

tria

ls p

er N

DA A

verage patients per ND

A

6000

5000

4000

3000

2000

1000

clinical trials patients

Source: SkyePharma, Parexel 2003/ 4

30 30 36 60 68 82

1576 1321

3233

3567

4237

5303More Patients and Trials required per NDA…

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With more Development Time needed…

Source: CMR

Development Times of Top Pharma

12

318

1100

1700

0

400

800

1200

1600

2000

19871995-20002000-2002

And Development Costs rising rapidly.

Investment required for One Successful Drug Launch

Sources: DiMasi et al, PhRMA 2003; Windhover’s In Vivo: The Business & Medicine Report, Bain drug economics model, 2003

$ (MM)

Source: CMR Source: SkyePharma, Parexel 2003/4

Sources: DiMasi et al, PhRMA 2003; Windhover’s In Vivo: The Business & Medicine Report, Bain drug economics model, 2003

4

7

13

564 752

775

1 136 376

386

1999 2003

Phase IIIPhase IIPhase I

In a nutshell, a rich Pharma Pipeline …

Source: Pharmaprojects (all Pharma and Biotech companies, includes NMEs, LCMs and Biological products)

1 715

2 274Development Projects by Phase

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Does not translate into corresponding Drug Approvals...

3026 25

22

28

53

39

3035

2724

1722

28

0

10

20

30

40

50

60

91 92 93 94 95 96 97 98 99 00 01 02 03 04E

Source: FDA CDER & CBER; Evaluate

# NMEs approved by FDA

Source:Pharmaprojects (all Pharma and Biotech companies, includes NMEs, LCMs and Biological products)

8

10%

15%

20%

25%

30%

35%

15

23

29

34

17

2022

31

Europe

1617

19

26

NorthAmerica

Japan

1990 2000 2010 2030

But the need for new pharmaceuticals will sub-stantially increase with changes in demographics.

Source: USA Census Bureau 2001, World Bank, Natwest Securities

Population Growth (billions)

3.7

6.1

8.1

0

2

4

6

8

10

1970 2000 2030

+65%

+33%

Percentage of > 60

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Setting new standards for Development…

“Its mission is to advance and protect public health……by helping to speed innovations that make medicines more effective, safer and more affordable.”

Dr. Mark McClellan, FDA Commissioner in “Improving Innovation in Medical Technology: Beyond 2002” and reported in the Pink Sheet, February 3, 2003

FDA launched the Critical Path Initiative

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Creating innovative and validated methods …

Opportunity: Imaging technologies, such as molecular imaging

tools in neuropsychiatric diseases or as measures of drug absorption

and distribution, may provide powerful insights into the distribution,

binding, and other biological effects of pharmaceuticals, but

their predictive value needs further study and evaluation. New imagingtechnologies will ultimately contribute important biomarkersand surrogate endpoints, but how soon these new tools will be available

for use will depend on the effort invested in developing them

specifically for this purpose.Source: Challenge and Opportunity on the Critical Path in New Medical Products. FDA, March 2004

“A new product development toolkit (...) is urgently needed to improve predictability and efficiency along the critical path”

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Our Goal for Regulatory Innovation: To shape HA and industry efforts towards the integration of new scientific technologies in drug development as the basis for regulatory decision making.

Objectives:• To position Novartis as a partner and leader in the Critical Path

Initiative• Identify opportunities to work directly with Health Authorities e.g., to

validate new technologies• Monitor and actively participate in external Critical Path-related

activities (eg. PhRMA, possible Pharma consortiums) and any parallel EU initiatives.

Novartis launched Key Strategic Initiatives

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Aligned with our 5 years Clinical Strategy

• Charter: Explore innovations that will revolutionize drug development and enhance regulatory decision making• Shaping the external development landscape by expanding our partnerships with leading institutions• Utilize technologies to increase the quality and efficiency of clinical development:

− Educate the organization on the value and focused use ofbiomarkers/surrogate endpoints, innovative study designs, modeling and simulation

− Develop efficient organizational structure to integrate all innovative technologies into the drug development process.

(extract)

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Definitions

Biomarker

• A characteristic that is objectively measured as an indicator of normal biological processes, pathogenic processes, or a pharmacological response to a therapeutic intervention

Biomarkers can be either readily observable characteristics or quantifiable changes at the protein, mRNA or DNA level

Examples include: blood pressure, β-Amyloid, PSA, bcr-abl translocation

Surrogate Marker/Endpoint

• A biomarker that is intended to substitute for a clinical endpoint. A surrogate endpoint is recognized as being able to predict clinical benefit (or harm or lack of benefit/harm) based on epidemiologic, therapeutic, pathophysiologic or other scientific evidence.

J Clin Pharmacol Therpeut 2001;69:89-95

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Biomarkers must be validated in clinical trials and the significance of the results clear before they are

recognized by regulatory authorities as valid clinical endpoints or surrogate markers

Examples of biomarkers that have been accepted by regulatory agencies as surrogate endpoints include;• HbA1c for complications of diabetes mellitus• Blood pressure for prevention of stroke and renal failure• CD4 lymphocyte count for progression of AIDS• LDL-cholesterol for prevention of first and second myocardial infarctions

Transition from Biomarker to Surrogate Endpoint

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Bringing proof of concept studies to life through biomarkers

Biomarkers may correlate with• Disease pathways• Pathology, Pharmacology• Mode of action of drug

candidate• Clinical Effect (“surrogate

markers”)Validated Biomarkers can be used• To define patient populations

likely to benefit from new treatment

• Serve as trial endpoint in clinical trials (e.g. proof of concept)

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The Role of Biomarkers in the future?

Diseaseunderstanding

Continuous sharing of information with Regulatory Authority

Biomarkers for efficacy & safety & identification responders

Modeling & Simulation

Provisional Approval

FullApproval

Exploratory Confirmatory Provisional approval

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Clinical Imaging at Novartis

Optimize current imaging technologies (X-rays, MRI, PET, ultrasound, etc.) and develop/leverage novel tracers to increase the predictive power of these technologies and develop novel imaging biomarkers Operations & Sample Management

IntegrativeExpression

Profiling

Clinical PharmacoGenetics

Clinical ImagingClinical Imaging

MarkerLocalization& Assays

BioMarker Development

Develop imaging techniques able to accurately stratify patients according to disease stage as well as monitor disease progression

Develop imaging modalities able to provide real-time evidence of disease modification in response to therapy

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Studying Treatment Effects of Gleevec on GIST through FDG (flurodeoxyglucose) PET Imaging

GIST: gastrointestinal stromal tumor

Gleevec was first developed for chronic myeloid leukemia (CML)

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Low dose versus Placebo in Healthy Volunteers

High dose versus Placeboin Healthy Volunteers

Studying (pharmacodynamic) Dosing Effects of a new CNS Drug on Brain Activity (regional cerebral glucose metabolism)

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Facing Multiple Priorities

• The need to develop additional imaging methods (new drug targets, new drugs, and new therapeutic endpoints)

− Validation of new assays (radiotracer, contrast agents) compliant with GMP standards

− Verifying disease or drug compound specific claims− Reliability in detecting treatment effects− Predictive value for the patient's clinical long-term outcome.

• The need for standardization of existing methods for image acquisition, processing and analysis (Pharma research require image data analysis from subject groups rather than from individuals)

• Development of standards relative to image header information, data transfer, data audit trail etc compliant with GCP, regulatory requirements, patient privacy (HIPAA - Medical Privacy - National Standards to Protect the Privacy of Personal Health Information) etc.

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FDA Guidance for Industry: Pharmacogenomic Data Submissions (March 2005)

The following definitions are for use in the processes outlined in this guidance (…).

Biological marker (biomarker) : A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, orpharmacologic responses to a therapeutic intervention. *

Valid biomarker: A biomarker that is measured in an analytical test system withwell established performance characteristics and for which there is an established scientific framework or body of evidence that elucidates the physiologic, toxicologic, pharmacologic, or clinical significance of the test results. The classification of biomarkers is context specific. Likewise, validation of a biomarker is context-specific and the criteria for validation will vary with the intended use of the biomarker. The clinical utility (e.g., predict toxicity, effectiveness or dosing) and use of epidemiology/population data (e.g., strength of genotype-phenotype associations) are examples of approaches that can be used to determine the specific context and the necessary criteria for validation.

* Biomarkers Definitions Working Group, "Biomarkers and Surrogate Endpoints: Preferred Definitions and Conceptual Framework," Clinical Pharm. & Therapeutics, vol. 69, N. 3, March 2001.

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FDA Guidance for Industry: Pharmacogenomic Data Submissions (March 2005) cont.

The following definitions are for use in the processes outlined in this guidance (…).

• Known valid biomarker: A biomarker that is measured in an analytical test system with well-established performance characteristics and for which there is widespread agreement in the medical or scientific community about the physiologic, toxicologic, pharmacologic, or clinical significance of the results

• Probable valid biomarker: A biomarker that is measured in an analytical test system with well-established performance characteristics and for which there is ascientific framework or body of evidence that appears to elucidate the physiologic, toxicologic, pharmacologic, or clinical significance of the test results. A probable valid biomarker may not have reached the status of a known valid marker because, for example, of any one of the following reasons:

− The data elucidating its significance may have been generated within a single company and may not be available for public scientific scrutiny.

− The data elucidating its significance, although highly suggestive, may not be conclusive.

− Independent verification of the results may not have occurred.

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Novartis and Public Private Partnerships; examples

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GOALThe Alzheimer's Disease Neuroimaging Initiative (ADNI) is a 5-year public-private partnership to test whether serial magnetic resonance imaging (MRI), positron emission tomography (PET), other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment and early Alzheimer's disease. There are three major goals of ADNI. The first goal is to develop improved methods, that will lead to uniform standards for acquiring longitudinal, multi-site MRI and PET data on patients with Alzheimer's disease, mild cognitive impairment, and elderly controls. The second goal is to create a generally accessible data repository that describes longitudinal changes in brain structure and metabolism while acquiring clinical, cognitive and biomarker data for validation of imaging surrogates. The final goal is to determine those methods, that provide maximum power to determine treatment effects in trials involving these patient groups. It is expected that ADNI will provide extensive new data concerning the natural history of brain changes which occur during the transition from normal aging to MCI to AD that can be used for future design and power of clinical trials and extensive information about the relationship between brain imaging changes and changes in biomarkers obtained from blood and CSF. 25

NIH Osteoarthritis Initiative

Since July 2001, a public-private partnership will bring together new resources and commitment to help find biological markers for the progression of osteoarthritis, a degenerative joint disease that is a major cause of disability in people 65 and older. Over 5-7 years, the Osteoarthritis Initiative (OAI) will collect information and define disease standards on 5,000 people at high risk of having osteoarthritis and at high risk of progressing to severe osteoarthritisduring the course of the study. Currently, new drug development for OA is hindered by the lack of objective and measurable standards for disease progression by which new drugs can be evaluated.

The OAI consortium includes public funding from the National Institutes of Health (NIH) and private funding from several pharmaceutical companies: GlaxoSmithKline, Merck, Novartis Pharmaceuticals Corporation, and Pfizer. The consortium is being facilitated by the Foundation for the National Institutes of Health, Inc. The OAI will provide approximately $8 million yearly for as many as six clinical research centers to establish and maintain a natural history database for osteoarthritis that will include clinical evaluation data and radiological images, and a biospecimen repository. All data and images collected will be available to researchers worldwide to help quicken the pace of scientific studies and biomarker identification.

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NCI Cancer Biomarkers Research Group (CBRG)

Mission• Supporting research for the development and validation of promising early cancer biomarkers for risk prediction and early detection of cancer. • Supporting the development of databases and informatics systems to optimize tracking and assessment of biomarker utility and expression patterns.

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Acknowledgements

Dr Liqun Wang, Dr Mark Schmidt and Dr Gerard Maurer, Biomarker Development, Pharma Development, Novartis Pharma AG, Basel – Switzerland.

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Thank YouThank You

BackBack--up Slidesup Slides

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Major Achievements of Innovative Drug Therapy (2): Strong Decrease of Cancer Death Rate

• >60% survive >5 years1

• Children: 49% drop in cancer mortality within the last 25 years2

• 75–80%3 of children with cancer and 85% of children with leukemia survive their disease4

1 5-year relative survival rates based on follow up of patients through 2000 Source: Surveillance, Epidemiology, and End Results Program, 1975-2000, Division of Cancer Control andPopulation Sciences, National Cancer Institute, 2003

2 Cancer Facts & Figures 2004, American Cancer Society 3 Journal of Pediatric Oncology Nursing, Vol. 21, No. 3, 160-164 (2004)4 Leukemia Research Foundation, December 2003

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Health Care is Complex: Spending on drugs may save money for Health Care Budgets (US)

-80

-60

-40

-20

0

20

40

New drugs Non-drug spending

Diff

eren

ce in

Spe

ndin

g/ p

atie

nt (

US$

)

For every 18 $ spent more on a newer drug, 71 $ were saved in non-drug medical spending

Source: Lichtenberg FR Health Affairs Sep/Oct 2001

18.0

-56.0

-15.1

non-drug medicalspending

hospitalspending

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A focused portfolio in attractive market segments..

11713Cardiovascular, metabolism

13337Respiratory & dermatology

3201Transplantation

10532Neuroscience

13544Arthritis, bone, GI1, HRT2, UI3

16475Oncology

Total 23 21 31 75

Phase

5410Ophthalmics

I II III & Reg Total

4121Infectious diseases

Business unit / Business franchise

1 Gastrointestinal 2 Hormone replacement therapy 3 Urinary incontinence

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Why do we need Biomarkers ?

1. To treat diseases more effectively:We currently lack predictive biomarkers to stratify patients with similar

diseases as well as accurately measure disease susceptibility, presence and progression

2. To verify the impact of novel drugs on targets/pathways:We currently lack the ability to determine the ability of a novel drug to bind the

desired target and whether this binding actually leads to changes in the desired pathway

2. To avoid drug adverse events:E.g., 1.5 million people are hospitalized each year due to adverse effects of

prescription drugs

2. To increase drug development predictability: Only 1 in 15 drugs entering phase 1 ever reach the market with the great

majority of compounds failing in phase II.

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GOALThe Alzheimer's Disease Neuroimaging Initiative (ADNI) is a 5-year public-private partnership to test whether serial magnetic resonance imaging (MRI), positron emission tomography (PET), other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment and early Alzheimer's disease. There are three major goals of ADNI. The first goal is to develop improved methods, that will lead to uniform standards for acquiring longitudinal, multi-site MRI and PET data on patients with Alzheimer's disease, mild cognitive impairment, and elderly controls. The second goal is to create a generally accessible data repository that describes longitudinal changes in brain structure and metabolism while acquiring clinical, cognitive and biomarker data for validation of imaging surrogates. The final goal is to determine those methods, that provide maximum power to determine treatment effects in trials involving these patient groups. It is expected that ADNI will provide extensive new data concerning the natural history of brain changes which occur during the transition from normal aging to MCI to AD that can be used for future design and power of clinical trials and extensive information about the relationship between brain imaging changes and changes in biomarkers obtained from blood and CSF.

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NIH Osteoarthritis Initiative

Since July 2001, a public-private partnership will bring together new resources and commitment to help find biological markers for the progression of osteoarthritis, a degenerative joint disease that is a major cause of disability in people 65 and older. Over 5-7 years, the Osteoarthritis Initiative (OAI) will collect information and define disease standards on 5,000 people at high risk of having osteoarthritis and at high risk of progressing to severe osteoarthritis during the course of the study. Currently, new drug development for OA is hindered by the lack of objectiveand measurable standards for disease progression by which new drugs can be evaluated.

The OAI consortium includes public funding from the National Institutes of Health (NIH) and private funding from several pharmaceutical companies: GlaxoSmithKline, Merck, Novartis Pharmaceuticals Corporation, and Pfizer. The consortium is being facilitated by the Foundation for the National Institutes of Health, Inc. The OAI will provide approximately $8 million yearly for as many as six clinical research centers to establish and maintain a natural history database for osteoarthritis that will include clinical evaluation data and radiological images, and a biospecimen repository. All data and images collected will be available to researchers worldwide to help quicken the pace of scientific studies and biomarker identification.

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NCI Cancer Biomarkers Research Group (CBRG)

Mission• Supporting research for the development and validation of promising early cancer biomarkers for risk prediction and early detection of cancer. • Supporting the development of databases and informatics systems to optimize tracking and assessment of biomarker utility and expression patterns.