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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 Group Office 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 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
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 HealthcareAgenda … 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
Drug Discovery & Development Is High Risk1,21. 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 Researchand Drug Development? – An Industry Perspective Ballooning Costs of Research & Development Evolving Deteriorating Capacity Research Partnershipsfor Clinical Trial Execution & Regulatory Environment A Difficult Process Turns More Challenging
The New Reality: R&D Costs Continue to Rise WhileOutput 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
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 termeconomic security and global standing as being a leader in moving lifesciences forward.” - Larry Summers Financial Times, January 2007* “…If you think research is expensive, try disease.” - Mary Lasker, Health Activist and Philanthropist (1901-94)*
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
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
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
U.S. AIDS Deaths Drop Dramatically with Introductionof 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
Response: Increased Allocation of DevelopmentSpending and Patient Accrual in ex-US RegionsSource: 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 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.
Yale TeamJames Howe PhD, Course Director of the Pharmacology CourseDepartment: PharmacologyMichael DiGiovanna, MD, PhD, Director Pharmacology CurriculumDepartment: Cancer CenterMichael L. Schwartz, Associate Prof & Dir Medical Studies NeurobiologyDepartment: NeurobiologyGisella Weissbach-Licht, Director of Curriculum ManagementDepartment: 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 Lessons 1) Target Identification 2) Target Validation 3) Lead Identification 4) Lead Optimization 5) Biologics
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
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) studiesMerck Research Labs, Whitehouse Station, NJ.
Module 2: Considerations for Testing a Drug onHumans 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
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
“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.
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 profilingMerck 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 assessment1. 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 resultsPK = pharmacokinetic; PD = pharmacodynamic.Ng R. Drugs: From Discovery to Approval. Wiley-LISS; 2004.
Module 3: How are Investigational Drugs Tested in HHumans? Overall module length ~2 hours 4 Lessons 1) 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 studies based on PK and/or PD data.
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
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 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
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 andspecialized 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 dataProvide 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 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
Major Regulatory Agencies United States Food and Drug Administration (FDA) – Extremely important agency – Regulates the worlds 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 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.
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 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)
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
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 InitiativeCurriculum 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 Group Office 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 ProjectCourse 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