Санкт-Петербургский МеждународныйФорум 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 GroupOffice of the Chief Medical Officer

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

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 futuremedical 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

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

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.

Multiple Factors Drive Today’s Healthcare Agenda …

PRICINGPRESSURES

WHO PAYS? INDUSTRY vs. GOVT

Health CareDynamics

AGING OF POPULATIONS

RISING ALLOCATION OF GDP TO HEALTH

CARE

EconomicCrisis

CREDITTIGHTENING

EQUITY VALUES DOWN

IPO MARKETCLOSED

GOVTS FACINGBIGGER DEFICITS,

SPENDING

Global (BRIC)Mega-trends

REGIONALECONOMIC GROWTH

DIFFERENCES

EMERGENCE OF

PUBLIC/PRIVATESYSTEMS

I/P RECOGNITIONCHALLENGES

DEVELOPMENT COSTS/REQUIREMENTS

SURGINGEVOLVING

COMMERCIAL MODELS

R&D PRODUCTIVITYPATENTEXPIRATIONS

PIPELINESLESS CERTAIN

SHIFTING STAKEHOLDERROLES

BioPharmaChallenges

REENGINEERING OFCOST STRUCTURES

The BioPharmaIndustry

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.

What is Changing in the World of Clinical Research and Drug Development? – An Industry Perspective

Deteriorating Capacityfor Clinical Trial Execution

EvolvingResearch Partnerships

& Regulatory Environment

Ballooning Costs of Research &

Development

A Difficult Process Turns More

Challenging

Productivity Trends BioPharma R&D Spend v. FDA Approvals

37 37

29 29

2427

36

2022

18

24

0

10

20

30

40

50

60

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Year

R&

D S

pend

($ b

illio

ns)

0

10

20

30

40

50

60

# of

NC

Es

R&D Spend FDA Approvals

Source:  PhRMA, FDA

Notes:

1) R&D spend data for PhRMA members

2) FDA approvals reflect new molecular entities and biologics

The New Reality: R&D Costs Continue to Rise While Output Falls

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.

“…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 SummersFinancial Times, January 2007*

“…If you think research is expensive, try disease.”

- Mary Lasker, Health Activist andPhilanthropist (1901-94)*

Academia/Government and Industry Roles in R&D: Complementarity

Private Sector – $65.2B

Clinical Research

Basic Research

TranslationalResearch

Clinical Research

Basic Research

Translational Research

NIH3 – $29.4B total– $20.1B research

There is an ecosystem of science and biotechnology. Public organizations, patient organizations, universities, Congress, FDA, all of this is an ecosystem that is envied in the rest of the world.

– E. Zerhouni, Director of NIH

““

Private sector outspends NIH 2:1

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

New Medicines Increase Longevity

They account for 40% of increase in life expectancy.

0.120.23 0.30

0.570.45

0.76

0.56

1.07

0.62

1.37

0.70

1.65

0.79

1.96

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0.5

1.0

1.5

2.0

2.5

Num

ber o

f Yea

rs In

crea

sed

Long

evity

1988 1990 1992 1994 1996 1998 2000

0.120.30

0.450.56 0.62

0.70

Increase in Longevity Due to New Drug Launches

Total Increase in Longevity

Data source: Lichtenberg8

11

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

Medicines Prevent Cancer Recurrence

New breast cancer drug greatly reduces recurrence and death (5 to 10 Years After diagnosis in postmenopausal women).

Perc

ent o

f Pat

ients

Pro

jecte

d Ov

er 4

Year

s

Breast Cancer Recurrence or Death

Note: Study halted early in order to provide the drug to all participants.

13%

7%

0%

2%

4%

6%

8%

10%

12%

14%

Placebo New Drug

13%

7%

0%

2%

4%

6%

8%

10%

12%

14%

Placebo New Drug

13%

7%

0%

2%

4%

6%

8%

10%

12%

14%

Placebo New Drug

Perc

ent o

f Pat

ients

Deaths Due to Breast Cancer

Death Rate Almost Halved

6.6%

3.5%

0%

1%

2%

3%

4%

5%

6%

7%

Placebo New Drug

Data source: Goss et al.15

13

U.S. AIDS Deaths Drop Dramatically with Introduction of New Medicines

(HAART treatment approved)

16.2

5.3 4.9

0

2

4

6

8

10

12

14

16

18

1995 1999 2002

Deat

hs P

er 10

0,000

Peo

ple

Data source: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics14

12

Response: Increased Allocation of Development Spending and Patient Accrual in ex-US Regions

Source:  Jefferies, CRO Survey, March 2007

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

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

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 industryCommunicate that optimizing patient benefits is the result of collaboration between academia and pharmaProvide an example of meaningful objective collaboration that can make a difference.

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 NeurobiologyDepartment: Neurobiology

Gisella Weissbach-Licht, Director of Curriculum Management

Department: Office of Education

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)

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

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

Module 1: How Are New Drugs Discovered?

Overall module length ~ 2 ½ hours

5 Lessons1) Target Identification

2) Target Validation

3) Lead Identification

4) Lead Optimization

5) Biologics

The Basic Process of Drug Discovery –Target Identification

The high degree of risk in selecting the “right” drug targets demands a strategy based on high attrition rate.

Target ID

TargetVal

LeadOpt Post -PCC

LeadID

TargetID

Biomarkers

TargetVal

TargetVal

LeadOpt Post -PCC

LeadID

TargetID

Biomarkers

1000s

1000sof Diseases

100sMedical need?

Strategy?

Modernbiology

&”-omics”

Informed Choice

Informed Choice

Target Validation

10,000sof biological

molecules

1

8 weeks to evaluate a target

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.

Module 2: Considerations for Testing a Drug on Humans

Overall module length ~2 hours

3 Lessons1) 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

Why Formulate ?

Stability

Drug Absorption Processability

Provide patient with convenient dosage form

– Preferably once/day dosing

– Taste masking (e.g. film coat)

Stabilize the API (Shelf life target 3 years at RT)

Optimize drug absorption in the GI tract PK Profile

Achieve desired PK profile

– Improve therapeutic index

Robust/scaleable manufacturing process

“Ideal” Drug Candidate – DMPK Point of ViewGood aqueous solubility for IV formulation and oral absorptionHigh bioavailability and acceptable PK characteristics for intended routeSmall “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, 1A2Metabolism should not depend largely on a polymorphically expressed enzyme

– e.g., CYP2D6, 2C19Minimal 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.

Non-mechanism-based ToxicityOccurs 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.

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.

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.

Module 3: H: How are Investigational Drugs Tested in Humans?

Overall module length ~2 hours

4 Lessons1) Clinical Development Plan

2) Phase I Trials

3) Phase II Trials

4) Phase III Trials

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 studiesbased on PK and/or PD data.

Question 1: Determining Dosing Frequency

Once daily feasible if high levels are well tolerated, orneed to use twice daily (BID) dosing or use controlled release (CR)

Drug

Con

cent

ratio

n

Q day dosing at 2x dose

Bid Dosing at 1x dose

Minimal effective levelby PD marker

12h 24h

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?

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

Common Trial Designs

Parallel

– Better for comparing efficacy and Safety

– Shorter trial

Cross Over

– More power, less costly, but longer trial

– Need to watch for control cross over effect

Adaptive

Randomization

Treatment A

Treatment B

Treatment B

Treatment AWashout

Randomization

Treatment A

Treatment B

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

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

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

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...)

Module 4: Regulatory Review Process for New Drugs

Overall module length ~1 ½ hours

5 Lessons1) 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

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

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)]

Lesson 3: Global Regulatory Strategy

Regulatory agencies are responsible for protecting and promotingtheir 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.

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

Phase IIIb & IV Post-Marketing Studies

New clinical indicationsLong-term safety: including rare adverse drug reactionsSpecial populationsThe purpose is frequently to support the marketing campaign (e.g. a head-to-head study to demonstrate advantages, efficacy or otherwise)

Hierarchy of Strength of Study Designs(with Respect to Internal Validity)

Randomized experiment*

Cohort (prospective or retrospective)

Case-control

Cross-sectional / “ecologic” studies

Case series

Case reports

Stronger Design

* Some place meta-analyses of clinical trials at the top of the hierarchy

Observational Research

WeakerDesign

58

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

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

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)

Curriculum on Clinical Protocol Design

Marcelo E. Bigal, M.D., Ph.D.Head of the Merck Investigator Studies Program and

Scientific Education GroupOffice of the Chief Medical Officer

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

Description of Project

Course objective: To provide an overview of non-interventional and interventional clinical studies with a focus on protocol design

Four proposed modules1) 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