Презентация доклада в рамках Санкт-Петербургского Международного Форума по фармацевтике и биотехнологиям IPhEB "Опыт применения образовательной программы Йельского университета"

1. Санкт-Петербургский Международный
Форум по Фармацевтике и Биотехнологиям
Knowledge Sharing on Drug Development
- the Merck/Yale Initiative
Marcelo E. Bigal, M.D., Ph.D.
Head of the Merck Investigator Studies Program and
Scientific Education Group
Office of the Chief Medical Officer

2. Overview
Medical Education and Industry
Challenges Facing Industry and Countries
Principles of Drug Development
The Drug Development Course – the Yale/Merck Initiative.
The St. Petersburg Initiative

3. Background
Regardless of their career path, M.D.’s will be exposed on a daily basis
to issues around pharmacology and drug development, yet they have
little practical knowledge.
Although academic institutions are charged with educating future
medical professionals, expertise in drug development largely resides in
industry (pharmaceutical).
In order to bridge this gap, an ethical and transparent partnership
between academia and industry is critical.
– Serves the public interest
– Students become educated on the complexities of the drug development process
– Patients benefit from sharing of expertise and resources

4. Examples of Physician-Scientist Roles in Industry
Basic and clinical research roles
Outcomes research
Policy
Integrative roles
Externally facing roles
Internal support roles
Senior leadership roles

5. Challenges Facing Industry
Drug development, already an unpredictable and expensive
undertaking, has taken on greater uncertainty.
There are significant implications resulting from the difficulty to
efficiently execute drug development in the United States.
Innovation and advances in therapeutics, which critically
depend on clinical research, are threatened.

6. Multiple Factors Drive Today’s Healthcare
Agenda …
AGING OF RISING PRICING WHO PAYS?
POPULATIONS ALLOCATION OF PRESSURES INDUSTRY vs. GOVT
GDP TO HEALTH
CARE
Health Care
Dynamics REGIONAL
ECONOMIC GROWTH
CREDIT DIFFERENCES
TIGHTENING
EQUITY VALUES
DOWN The BioPharma EMERGENCE
Economic OF
IPO MARKET Crisis Industry Global (BRIC)
Mega-trends
PUBLIC/
PRIVATE
CLOSED SYSTEMS
GOVTS FACING
BIGGER DEFICITS, I/P RECOGNITION
SPENDING BioPharma CHALLENGES
Challenges
PATENT R&D PRODUCTIVITY PIPELINES SHIFTING STAKEHOLDER
EXPIRATIONS LESS CERTAIN ROLES
DEVELOPMENT COSTS/
REQUIREMENTS EVOLVING REENGINEERING OF
SURGING COMMERCIAL MODELS COST STRUCTURES

7. Drug Discovery & Development Is High Risk1,2
1. Lilly Clinical Trial Registry Web Site. http://www.lillytrials.com/docs/education.html. Accessed February 3, 2010.
2. Eye on FDA Web site. http://www.eyeonfda.com/downloads/FDADrugApprovalCommunications.pdf. Accessed February 3, 2010.
3. Watkins KJ. Chem Eng News. 2002;80:27-33.
4. DiMasia JA et al. Manage Decis Econ. 2007;28:469-479.

8. What is Changing in the World of Clinical Research
and Drug Development? – An Industry Perspective
Ballooning Costs of
Research &
Development
Evolving
Deteriorating Capacity Research Partnerships
for Clinical Trial Execution & Regulatory Environment
A Difficult Process
Turns More
Challenging

9. The New Reality: R&D Costs Continue to Rise While
Output Falls
Productivity Trends
BioPharma R&D Spend v. FDA Approvals
60 60
R&D Spend FDA Approvals
50 50
R&D Spend ($ billions)
40 40
37 37 36
# of NCEs
30 30
29 29
27
24 24
22
20 20 20
18
10 10
0 0
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Source: PhRMA, FDA Year
Notes:
1) R&D spend data for PhRMA members
2) FDA approvals reflect new molecular entities and biologics

10. Probability of Success for Investigational Drugs is Small
20% of self-originated new drugs that enter clinical testing will be
FDA-approved.
Clinical Approval Success Rates by Therapeutic Class1
Source: 1Tufts Center for the Study of Drug Development, “New drugs entering clinical testing in top 10 firms jumped 52% in 2003-05,” Impact
Report, 2006.

11. “…over the long run, few issues are as important to a nation’s long term
economic security and global standing as being a leader in moving life
sciences forward.”
- Larry Summers
Financial Times, January 2007*
“…If you think research is expensive,
try disease.”
- Mary Lasker, Health Activist and
Philanthropist (1901-94)*

12. Academia/Government and Industry Roles in R&D:
Complementarity
Private Sector – $65.2B Private sector
outspends NIH 2:1
Clinical
Research
Translational
Clinical Research
“ There is an ecosystem of
science and biotechnology.
Public organizations,
patient organizations,
Research universities, Congress,
Translational “
FDA, all of this is an
Research ecosystem that is envied in
the rest of the world.
Basic Basic
Research – E. Zerhouni,
Research Director of NIH
NIH3 – $29.4B total
– $20.1B research
Sources: 1Burrill & Company, analysis for PhRMA, 2005–2009 (Includes PhRMA research associates and nonmembers) in PhRMA, “Profile 2008,
Pharmaceutical Industry;” PhRMA, “PhRMA Annual Membership Survey,” 1996-2009; 2Adapted from E. Zerhouni, Presentation at Transforming
Health: Fulfilling the Promise of Research, 2007; 3NIH Office of the Budget, “FY 2009 President’s Budget Request Tabular Data”,
http://officeofbudget.od.nih.gov/ui/2008/tabular%20data.pdf

13. New Medicines Increase Longevity
They account for 40% of increase in life expectancy.
Increase in Longevity Due to New Drug
2.5 Launches
Total Increase in Longevity 1.96
Number of Years Increased Longevity
2.0
1.65
1.5 1.37
1.07
1.0
0.76 0.79
0.70
0.57 0.62
0.56
0.5 0.45
0.30
0.23
0.12
0.0
1988 1990 1992 1994 1996 1998 2000
Data source: Lichtenberg8
11

14. Deaths in US due to CVD (1900–2007)
Source: NHLBI from NCHS reports. * - CVD does not include congenital.
©2010 American Heart Association, Inc. All rights reserved. Roger VL et al. Published online in Circulation Dec. 15, 2010

15. Medicines Prevent Cancer Recurrence
New breast cancer drug greatly reduces recurrence and death (5 to 10 Years
After diagnosis in postmenopausal women).
Breast Cancer Recurrence or Death Deaths Due to Breast Cancer
14% 13% 7% 6.6%
Percent of Patients Projected Over 4 Years
12% 6% Death
Rate
5% Almost
10%
Percent of Patients
Halved
8% 7% 4% 3.5%
6% 3%
4% 2%
2% 1%
0% 0%
Placebo New Drug Placebo New Drug
Note: Study halted early in order to provide the drug to all participants.
Data source: Goss et al.15
13

16. U.S. AIDS Deaths Drop Dramatically with Introduction
of New Medicines
18
16.2
16
14
Deaths Per 100,000 People
12
10
8
6 5.3 4.9
4
2
0
1995 1999 2002
(HAART treatment approved)
Data source: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics14
12

17. Response: Increased Allocation of Development
Spending and Patient Accrual in ex-US Regions
Source: Jefferies, CRO Survey, March 2007

18. Overview
Medical Education and Industry
Challenges Facing Industry and Countries
Principles of Drug Development
The Drug Development Course – the Yale/Merck Initiative.
The St. Petersburg Initiative

19. Description of Project
The Drug Development Curriculum is a pioneering initiative between
Yale and Merck that bridges this gap by providing valuable insight into
the drug development process
– Scope and objectives defined by Yale faculty
– Content developed by 34 MDs and PhDs from Merck
– Content revised and approved by Yale faculty
– Course administered and assessed by Yale faculty
– Not related to Merck brands

20. Opportunities Offered
Improve and increase relevancy of the medical school curriculum
around the role of the pharmaceutical industry in drug development
and pharma’s relationship with the academic community.
Convey the value brought by pharma to public health policy in
delivering innovative, differentiated treatment options.
Create a forum for the academia to educate trainees on how to
interact with industry
Communicate that optimizing patient benefits is the result of
collaboration between academia and pharma
Provide an example of meaningful objective collaboration that can
make a difference.

21. Yale Team
James Howe PhD, Course Director of the Pharmacology Course
Department: Pharmacology
Michael DiGiovanna, MD, PhD, Director Pharmacology Curriculum
Department: Cancer Center
Michael L. Schwartz, Associate Prof & Dir Medical Studies Neurobiology
Department: Neurobiology
Gisella Weissbach-Licht, Director of Curriculum Management
Department: Office of Education

22. Course Objective and Theme
The objective of the course is to provide a supplemental program to
existing course work that introduces students to the basic principles of
clinical and translational research, including how such research is
conducted, evaluated, explained to patients, and applied to patient care
Alzheimer’s disease was chosen as a theme to use through the course
– A chemical compound targeting Alzheimer’s was carried through the
phases of drug development to demonstrate an application of the
module’s content (similar to a case study)

23. Course Structure: Modules
Course is divided into 5 modules with 2-5 lessons per module
19 total lessons ~ 9 hours of course time
– Each module introduced by a Merck Senior Subject Matter Expert
(SME)
– Senior SME oversaw the development of each module’s content (34
SMEs contributed to the entire course content)
– A module concludes with a summary by the Senior SME and a
handoff to the Senior SME of the subsequent module.
– Every lesson includes Knowledge Check questions as assessment
of the content

24. Course Structure: Modules (cont’d)
How New Drugs Are Discovered
– 5 Lessons
– Duration: 2 hours 30 minutes
Considerations for Testing a New Drug in Humans
– 3 Lessons
– Duration : 2 hours
How Investigational Drugs Are Tested in Humans
– 4 Lessons
– Duration : 2 hours
Regulatory Review Process for New Drugs
– 5 Lessons
– Duration : 1 hour 30 minutes
Post-Approval Activities
– 2 Lessons
– Duration : 1 hour 15 minutes

25. Module 1: How Are New Drugs Discovered?
Overall module length ~ 2 ½ hours
5 Lessons
1) Target Identification
2) Target Validation
3) Lead Identification
4) Lead Optimization
5) Biologics

26. The Basic Process of Drug Discovery –
Target Identification
Target Target Lead Lead
ID Opt Post -PCC
ID Val
Biomarkers
The high degree of risk in selecting the “right” drug targets demands a
strategy based on high attrition rate.
Target ID
8 weeks to evaluate a target
1000s
of Diseases 1
Medical need? Modern
Strategy? 1000s biology
& 100s Target Validation
10,000s ”-omics”
of biological
molecules Informed
Choice
Informed
Choice

31. PCC Criteria for Approval Into Development
Proof of Efficacy
– In vitro potency
– In vitro selectivity
– Efficacy readout in animals
– Target engagement
– Disease markers
Proof of Safety
– Ancillary pharmacology
– Metabolism data
– Panlab results
– Dose limiting toxicity (DLT) studies
Merck Research Labs, Whitehouse Station, NJ.

32. Module 2: Considerations for Testing a Drug on
Humans
Overall module length ~2 hours
3 Lessons
1) Formulation activities to support drug development activities
up to PhI
2) Drug metabolism and pharmacokinetics
3) Non-clinical safety assessment in vitro & in vivo and
toxicokinetics

33. Why Formulate ?
Provide patient with convenient dosage
form Stability
– Preferably once/day dosing
– Taste masking (e.g. film coat)
Drug
Processability
Stabilize the API (Shelf life target 3 years Absorption
at RT)
Optimize drug absorption in the GI tract PK Profile
Achieve desired PK profile
– Improve therapeutic index
Robust/scaleable manufacturing process

35. “Ideal” Drug Candidate – DMPK Point of View
Good aqueous solubility for IV formulation and oral absorption
High bioavailability and acceptable PK characteristics for intended route
Small “first-pass” effect (liver/gut wall)
“Balanced” clearance:
– Renal excretion of intact drug
– Biliary elimination of intact drug
– Metabolism to limited number of products
No pharmacologically active metabolites (unless prodrug)
No chemically reactive metabolites (toxicity issues)
Minimal CYP induction (drug interaction liability)
Minimal CYP inhibitory potential (especially mechanism based)
Metabolism should be catalyzed by multiple CYP enzymes
– e.g., CYP3A4, 2C9, 1A2
Metabolism should not depend largely on a polymorphically expressed enzyme
– e.g., CYP2D6, 2C19
Minimal Pgp activity (central nervous system programs)
DMPK = drug metabolic and pharmacokinetic; IV = intravenous; PK = pharmacokinetic; CYP = cytochrome P450; Pgp = P-Glycoprotein.
Merck Research Labs, Whitehouse Station, NJ.

36. Non-mechanism-based Toxicity
Occurs when the compound, or one of its metabolites, interacts with a molecule other than the
intended target
Common problems
– Ion channels
– Protein modifications
– Uptake inhibition
– Metabolic clearance pathways: inhibition or activation
– Mutagenicity, genotoxicity
Idiosyncratic problems: can be anything
Tools
– Experience, institutional memory
– Identify off-target hits early: Panlabs
– Modeling for common problems
– Animal models
– Expression profiling
Merck Research Labs, Whitehouse Station, NJ.

37. Ancillary Pharmacology and Special Safety
Assessment Studies
Ancillary Pharmacology; full panel consists of1:
– Cardiovascular dog study
– Respiratory dog study
– Renal dog study
– Central nervous system (CNS) mouse study
– Gastrointestinal mouse study2
The following are required for all preclinical candidates3:
– Cardiovascular dog study
– Central nervous system mouse study
– Dose limiting toxicity (DLT)
Additional studies to address compound- or program-specific issues may be required prior to
preclinical candidate approval. These may include4,5:
– Genetic toxicity
– Repeat dose toxicity assessment
1. Berkowitz BA et al. Basic & Clinical Pharmacology. 5th ed. Norwalk, CT: Appelton & Lange; 1992:60-68.
2. Calvert Labs, Safety Pharmacology Web site. https://www.calvertlabs.com/services/safety-pharmacology/. Accessed May 20, 2010.
3. Bass A et al. J Pharmacol Toxicol Methods. 2004;49:145-151.
4. International Conference on Harmonisation Web site. http://www.ich.org/LOB/media/MEDIA4474.pdf. Accessed February 3, 2010.
5. International Conference on Harmonisation Web site. http://www.ich.org/LOB/media/MEDIA5544.pdf. Accessed February 3, 2010.

38. Pharmacokinetics vs. Pharmacodynamics
PK is a measure of compound level as a function of time
PD is a measure of target engagement as a function of time
PK and PD can differ dramatically
– Compound present but not available to target: PK > PD
– Compound has very slow off-rate, target slow turnover: PD > PK
– Active metabolite: PD > PK
PD assays
– Often used to drive preclinical development
– Important for establishing dosing in clinic and interpreting clinical results
PK = pharmacokinetic; PD = pharmacodynamic.
Ng R. Drugs: From Discovery to Approval. Wiley-LISS; 2004.

39. Module 3: How are Investigational Drugs Tested in
H
Humans?
Overall module length ~2 hours
4 Lessons
1) Clinical Development Plan
2) Phase I Trials
3) Phase II Trials
4) Phase III Trials

41. Objectives of Phase I Trials
Phase I provides initial assessment of clinical safety and tolerability.
– Attention focuses on preclinical toxicology
– Identify common adverse experiences and target organ(s) of toxicity
Detailed understanding of the pharmacokinetics (“what the body does
to the drug”)
– Pharmacokinetics: the study and characterization of the time course of
drug absorption, distribution, metabolism and excretion.
Preliminary understanding of the pharmacodynamics of the drug using
relevant biomarkers (“what the drug does to the body”)
– Pharmacodynamics: the study of the relationship between dose, or
concentration of drug at the site(s) of action, and the magnitude of the
effect(s) produced.
Ultimate goal is to identify dose range and regimen for Phase II studies
based on PK and/or PD data.

42. Question 1: Determining Dosing Frequency
Once daily feasible if high levels are well tolerated, or
need to use twice daily (BID) dosing
or use controlled release (CR)
Drug Concentration
Q day dosing at 2x dose
Bid Dosing at 1x dose
Minimal effective level
by PD marker
12h 24h

43. Question 2: Food Effect
In order for drug A to be effective, it needs to achieve an AUC
of xx nM-hr. When peak concentrations are above yy nM,
subjects complain of nausea and vomiting. Here are the PK
data from Phase I including a comparison of the xx mg dose
when given fed and fasted.
How would you recommend administering the drug (what
dose, with or without food)?
What issues would concern you?

44. Question 3: Whether to Discontinue a Drug?
Reasons to kill a drug in Phase I :
Excessive toxicity
No pharmacodynamic effect
No sufficient exposure to test hypothesis

45. Common Trial Designs
Parallel Treatment A
Randomization
– Better for comparing efficacy and
Safety
Treatment B
– Shorter trial
Cross Over Treatment A Treatment B
– More power, less costly, but longer Randomization
trial
Treatment B Wash Treatment A
– Need to watch for control cross over out
effect
Adaptive

46. Phase IIa: Establishing Proof of Concept
What is proof of concept?
– Proof of pharmacology
– Role of mechanism
– Proof of clinical efficacy
– Commercial proof of concept

47. PHASE III
Phase III trials represent an enormous investment of resources.
There are a number of questions you should be confident in
answering before you make this investment.
– Have you learned enough about the drug in your Phase I and II
studies?
– Do you have agreement with the regulatory authorities on
whether your clinical program will lead to approval of the drug?
– Does the clinical program provide enough information to
adequately inform physicians

48. What are Goals of Phase III Trials?
Confirm the risk/benefit profile of the drug in large population and
specialized populations
– Is the treatment effect generalizable to larger population, subgroups?
– Is it clinically meaningful? How does it impact patients’ health, function, life-
span?
– Safety and tolerability in larger population
– How does it compare with what is currently available? Does this drug fulfill
some unmet medical need?
– Initial cost/benefit data
Provide the information needed for product labeling

49. What Does a Phase III Trial Not Answer?
Rare adverse experiences may not be detected
The effects of a drug in the real world, where its administration is not
as carefully monitored as it is in the clinical trial
Effects of concomitant medications (excluded from the Phase III trial)
Differing drug effects in subgroups of individuals (who differ by age,
gender, race, genetic background and concomitant medical
conditions...)

50. Module 4: Regulatory Review Process for New Drugs
Overall module length ~1 ½ hours
5 Lessons
1) Lesson 1: Who Regulates?
2) Lesson 2: Product Drug Labeling
3) Lesson 3: Global Regulatory Strategy
4) Lesson 4: The NDA
5) Lesson 5: FDA Review and Approval Process

52. Major Regulatory Agencies
United States Food and Drug Administration (FDA)
– Extremely important agency
– Regulates the world's largest pharmaceutical market
– Very well-respected around the world; ex-US agencies are influenced by FDA decisions
European Medicines Agency (EMA)
– Pan-European regulatory agency for new drug approvals (27 nations)
– Committee for Human Medicinal Products (CHMP) provides scientific and medical
opinions for the EMA, which is the operational part of the regulatory agency
PMDA
– Japanese regulatory agency

53. Lesson 2: Product Drug Labeling
Includes all written, printed, or graphic matter accompanying an article at any time
while such article is in interstate commerce or held for sale after shipment or
delivery in interstate commerce. (i.e., paper inside the packaging) [21CFR 1.3(a)]
Prescription drug labeling is commonly called:
• Prescribing information
• Package insert
• Package leaflet
• Package circular
• Physician circular
Defined as any display of written, printed, or graphic matter on the immediate
container of any article, or any such matter affixed to a consumer commodity or
affixed to or appearing upon a package containing any consumer commodity.
[21CFR 1.3(b)]

54. Lesson 3: Global Regulatory Strategy
Regulatory agencies are responsible for protecting and promoting
their nation’s public health.
They do so by developing regulations that set a minimum
standard for the three key characteristics for evaluating a drug
• Efficacy
• Safety
• Quality - this has to do with the chemical properties, process and controls
of the manufactured product
While many country’s drug regulations are similar, there are
significant differences. These similarities and differences are the
basis of having a global regulatory strategy that strategically
encompasses the needs of all regions.

55. Module 5: Post-Approval Activities
Overall module length ~1 ¼ hours
2 Lessons
1) Lesson 1: Phases IIIb and IV
2) Lesson 2: Post Market Regulatory Activities

56. Phase IIIb & IV Post-Marketing Studies
New clinical indications
Long-term safety: including rare adverse drug reactions
Special populations
The purpose is frequently to support the marketing campaign (e.g. a
head-to-head study to demonstrate advantages, efficacy or otherwise)

58. Hierarchy of Strength of Study Designs
(with Respect to Internal Validity)
Stronger
Design
Randomized experiment*
Cohort (prospective or retrospective)
Observational Research
Case-control
Cross-sectional / “ecologic” studies
Case series
Case reports
* Some place meta-analyses of clinical trials at
Weaker the top of the hierarchy
Design
58

59. REMS
Risk Evaluation and Mitigation Strategies (REMS)
– U.S. FDA specific regulation that describes the use of risk
minimization actions for drugs in the U.S.
– FDA will require a REMS when one would be necessary to
ensure that the benefits of the drug outweigh its risks
– REMS may include a range of measures
59

60. Drug Development Curriculum Implementation:
MSD-Yale-SPbSU
E-learning course The Drug Development Curriculum
(DDC):
• a pioneering initiative between Yale and Merck is planned to
be implemented in SPb State University, one of the oldest
universities in Russia
Project status
• December 2010: MSD/SPbSU joint working group started functioning
• 27-Jan-2011: the agreement is signed between MSD & SPbSU
• Mar 2011: DDC Implementation Lead & IT staff were allocated
• Mar-Apr 2011: Russian Regulatory module has been developed and incorporated into the DDC
• 25-Mar-2011 educational seminar on Drug Development process "Discovery of Gardasil" (delivered by
Dr. Eliav Barr)
• Q3-4 2011: pilot course of DDC is planned to be initiated in SPbSU; MRL tutors are desirable for
successful DDC introduction
• Sep-Oct-2011: Joined Research Day is planned to be conducted in SPbSU

61. Education Initiative
Curriculum on Drug Development (Yale pilot) being rolled out globally
Russia: St. Petersburg University (English)
• Agreement has been signed
• Separate module on Russian regulatory process being developed
China: Fuwai University Hospital (translated)
Brazil: Sao Paulo University (under discussion)
Turkey & Latin America (initial discussions)

62. Curriculum on Clinical Protocol Design
Marcelo E. Bigal, M.D., Ph.D.
Head of the Merck Investigator Studies Program and
Scientific Education Group
Office of the Chief Medical Officer

63. Opportunities Offered
Course is perfectly fit to the Yale course
• Capability transfer/education
• Plans for English and localized versions for Key Countries
Course will also support NIH task force recommendations on
pharmaceutical industry/academic center collaborations and
sharing of knowledge
Plans to roll out to key academic/medical schools

64. Description of Project
Course objective: To provide an overview of non-interventional and
interventional clinical studies with a focus on protocol design
Four proposed modules
1) Overall Principles of Clinical Research
2) Randomized Clinical Trials
3) Epidemiology Studies
4) Health Economics/Outcomes Research Studies
Content to be developed by e-learning vendor and refined by MRL
SMEs in conjunction with CMO Scientific Education Group and Merck
Polytechnic Institute