2013 màster upf josep m. badenas

Facts and Trends in Clinical
Development 2013
Josep M. Badenas
Senior Medical Director, Neuroscience
Covance
Cell: +34 629 52 73 84
18182jbp@comb.cat
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 Fabra
Barcelona, Spain
27 April 2013

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.
2
Pharmaceutical Research and Manufacturers of America,
PhRMA Annual Membership Survey (Washington, D.C.: PhRMA, 2012)

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.
3
Alzheimer’s Association, “2012 Alzheimer’s
Disease Facts and Figures” (2012)

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
4

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 (**)
5
* 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.

6
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?
9

Quick win, fast fail drug development paradigm
Translational Medicine

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

Annual and cumulative new drug approvals by the
FDA’s CDER, including both NMEs and BLAs
12
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
Source: Rodney Zemmel, PhD., McKinsey & Company, Bernstein Pharmaceuticals Longview Conference, May 5, 2010

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

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

Innovation - Pipeline
• Total numbers of
medicines in
development, by
therapeutic area
18
PhRMA Report: The Biopharmaceutical Pipeline: Evolving Science, Hope for Patients Analysis
Group, Innovation in the Biopharmaceutical Pipeline: A Multi-Dimensional View, 2013

• Potential first-in-class medicines introduce a new
mechanism of action or pharmacological class for attacking a
given disease or condition.
19
PhRMA Report: The Biopharmaceutical Pipeline: Evolving Science, Hope for Patients
Analysis Group, Innovation in the Biopharmaceutical Pipeline: A Multi-Dimensional View, 2013

20
Innovation in the Biopharmaceutical Pipeline: A Multidimensional View. Long G,
Works J. Analysis Group, Inc., Boston, Massachusetts, January 2013

• Medicines targeting rare orphan diseases affecting 200,000
or fewer patients in the U.S.
21

• Medicines targeting
rare orphan diseases
affecting 200,000 or
fewer patients in the
U.S.
22

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

• Medicines targeting diseases for which there have been no
recently approved therapies
24

• Medicines that
incorporate a
personalized medicine
approach, tailored to
specific subpopulations
of patients based on
molecular or genetic
characteristics.
25

26
Personalized medicines are a growing proportion of the 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).
27
ABPI, www.abpi.org.uk

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.
28

29

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
30

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

32
Gene 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

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)
33
(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).

• 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)
34
(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.)

• Enhance communication between FDA and sponsors during
drug development
35
Chart from Vikram Sinha, PhD, Director
Division of Pharmacometrics
Office of Clinical Pharmacology
OTS, CDER, FDA
A SCPT Annual Meeting Open Forum, March 6, 2013
Model-Informed Drug Development and Regulatory Review

• Clinical trial design: Adaptive Study Design
36

• 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
37
Learning Versus Confirming in Clinical Drug Development. Sheiner, LB,
Clin. Pharm Ther 1997; 61:275-291

38

• 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
39

• 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
40

41

42
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

43
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

44

• 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
45
(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

• 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
46
FDA, Guidance for Industry, Enrichment Strategies for Clinical Trials to
Support Approval of Human Drugs and Biological Products, December 2012

• 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.
47
FDA, Guidance for Industry, Enrichment Strategies for Clinical Trials to
Support Approval of Human Drugs and Biological Products, December 2012

• 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?)
48
FDA, Guidance for Industry, Enrichment Strategies for Clinical Trials to Support Approval of Human
Drugs and Biological Products, December 2012

• 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.
49

Biomarker Study Design 1: Upfront stratification
• Produces data on all patients
• Completely prospective
50
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.
51
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
52
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)
54
(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

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

• Adaptive Licensing – Balancing Evidence and Access
57
Eichler 2012. PMID: 22336591

• Adaptive Licensing – Balancing Evidence and Access
58
Exploratory
(Learn)
Confirmatory
(Confirm)
Monitored
release
Full release
Biomarker Development
Model and Simulation
Targeted Approval Full Approval

Conclusions
1. Cost per NME/NBE will grow at annual rates above 13%
2. Cost estimate for developing a new drug between $ 1.2-3.9 billion
3. 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 back
5. It is time for innovation: this is a one way street with no return
6. 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)
59

Abbreviations (1)
1. ABPI: Association of the British Pharmaceutical Industry
2. ADMET: Absorption, Distribution, Metabolism, Excretion and Toxicity
3. BLA: Biologic License Entity
4. CBER: Center for Biologic Evaluation and Research
5. CCLS: Covance Central Laboratory Services
6. CDER: Center for Drug Evaluation and Research
7. CDS: Clinical Development Services
8. CLS: Central Laboratory Services
9. CMC: Chemistry Manufacturing and Control
10. CPP: Certificate of Pharmaceutical Product (Taiwan)
11. CRO: Contract (also Clinical) Research Organization
12. CSDD: Tufts Center for the Study of Drug Development
13. CT: Clinical Trial
14. CTA: Clinical Trial Application
15. CTD: Clinical Trial Directive
16. 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 India
19. DOH: Taiwan Department of Health
20. DSMC: Data Safety Monitoring Committee
21. EC: European Commission
22. EC: Ethics Committee
23. EMA: European Medicines Agency
24. EMEA: Europe, Middle East & Africa
25. EMRC: European Medical Research Councils
26. ESF: European Science Foundation
27. FD&C Act: Federal Food Drug and Cosmetic Act
28. FDA: Food & Drug Administration
29. FDAMA: Food and Drug Administration Modernization Act 1997
30. FDASIA:Food and Drug Administration Safety and Innovation Act
31. FSC: Free Sales Certificate (Taiwan)
32. GCP: Good Clinical Practice
33. GMP: Good Manufacturing Practice
34. GRS: Global Regulatory Submissions
35. GSS: Global Site Services
36. GSF: Global Science Forum
37. 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 Harmonisation
33. IDCT: Investigator-Driven Clinical Trials
34. IFPMA: International Federation of Pharmaceutical Manufacturers and Associations
35. IMPD: Investigational Medicinal Product Dossier
36. IND: Investigational New Drug Application
37. IRB: Institutional Review Board
38. IRR: Internal Rate of Return
39. LO: Lead Optimization
40. MHRA: Medicines and Healthcare products Regulatory Agency (UK)
41. NBC: Italy’s National Bioethics Committee
42. NBE: New Biologic Entity
43. NCE: New Chemical Entity (Taiwan)
44. NDA: New Drug Application
45. NME: New Molecular Entity
46. NPV: Net Present Value
47. OECD: Organisation for Economic Co-operation and Development
48. PASS: Post-authorization safety studies
49. PDUFA: Prescription Drug User Fee Act
50. PhRMA: Pharmaceutical Research and Manufacturers of America
51. PHS Act: Public Health Service Act
52. POC (or PoC): Proof-of-Concept
53. POS: Probability of Success
54. R&D: Research & Development
55. RA: Regulatory Authority
56. RAC: Re-Combinant Advisory Committee
57. REMS: Risk Evaluation and Mitigation Strategies
58. ROIC: Return On Invested Capital
59. SCRS: Society for Clinical Research Sites (US)
60. SFDA: State Food & Drug Administration of China
61. TFDA: Taiwan Food and Drug Administration

62
Moltes gràcies
Muchas gracias
Thank you
Josep M. Badenas
Senior Medical Director, Neuroscience
Covance
Cell: +34 629 52 73 84
18182jbp@comb.cat

2013 màster upf josep m. badenas

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