Форум IPhEB - Марсело Э. Бигаль, компания Merck
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Transcript of Форум IPhEB - Марсело Э. Бигаль, компания Merck
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
0.0
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
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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
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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