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Combining Drug Delivery and Device Technologies: Challenges and Opportunities Jayne E. Hastedt, PhD ALZA Corporation 1 Outline Regulatory Considerations Definitions Review Process Regulatory Review teams Combination Product Development Technical Challenges Product Development Teams A History Lesson Industry Challenges and Opportunities Current Pharma Challenges From “smart delivery” to “smart medicine” Case Study: Insulin Drug Delivery Challenges and Successes 2 Observations and Opportunities Combination Product FDA Definitions: A Combination Product is a product comprised of any combination of a drug and a device; a device and a biological product; a biological product and a drug; or a drug, a device, and a biological product. Single-entity Kits Cross-labeled products Primary Mode of Action: The single mode of action of a combination product that provides the most important therapeutic action of the combination product. 21 CFR 3.2(e) 3 Drug Delivery and Convergence Drug Delivery Devices are specialized tools for the delivery of a drug or therapeutic agent via a specific route of administration. Such devices are used as part of one or more medical treatments. Technological Convergence refers to a trend where some technologies having distinct functionalities evolve to technologies that overlap, i.e. multiple products come together to form one product, with the advantages of each initial component. 4 Wikipedia: http://en.wikipedia.org/wiki/Main_Page accessed 13Sept2008 Examples of Combination Product Components Technologies 5 Drug eluting stents and catheters Pre-filled syringes Dry powder inhalers Auto-injectors Active and Passive Transdermal patches Metered dose inhalers Infusion pumps Jet/Needle-free injectors Molecular Entities Macromolecules Small molecules Antivirals PEGylated or Glycosylated molecules FDA Division Designation and Drug/Device Approval FDA Review will be performed by a combination of Divisions; however, one will be designated as the primary jurisdiction. Decision based on primary mode of action (PMOA) and Request for Designation (RFD) CDRH: CDRH: regulated regulated as as aa Device Device CDER: CDER: regulated regulated as as aa Drug Drug CBER: CBER: regulated regulated as as aa Biologic Biologic Approved Drug Investigational Drug 6 Approved Device Investigational Device + ++ +++ ++++ + → +++ indicates increasing difficulty of approval process Example of FDA Combination Product Review Team Structure CDRH Review Team CDER Review Team Lead Reviewer CDER Project Manager Clinical Reviewer Engineering Review Team Clinical Reviewer Drug Review Team Mechanical Electrical/Software Biocompatibility / Sterility / Shelf Life Branch Chief Deputy Division Director Other Division Senior Management 7 Chemistry Pharmacology Toxicology Supervisory Chemist Supervisory Pharmacologist Other Division Senior Management S. Portnoy, S.Koepke, PharmNet Consulting Group, 2005. http://www.pharmanet.com/pdf/whitepapers/Combo_Products.pdf Combination Product Development 8 Common Technical Challenges Time Quality 9 Cost Materials/Components Compatibility Device Design and Development Formulation Development Manufacturing Capability Specifications/Content Uniformity/Drug Release Stability/Shelf Life/Sterility Patient interface - Biology Risk Assessment and Management Project Management Multi-Functional Product Development Team Clinical • Project Planning • Finance • Clinical Research • Biostats • Clinical Pharmacology • Safety CM&C • Analytical • Engineering • Formulation • Manufacturing • Supply Chain • Process Chemistry • Preformulation • Quality Nonclinical 10 • Toxicology • Biology • Pharmacology Product Development Team Regulatory • Operations • Device • Drug Marketing • Market Research • NPP • Reimbursement Product Development CM&C Teams for Combination Products Chemistry Drug Discovery Chemists Process Chemists Formulation Pharmaceutical Scientists Analytical Chemists Material Scientists Preformulation Scientists Device Engineers Device Design Engineers Device Development Engineers Product Process Engineers Process Scale-up Engineers Packaging Engineers Validation Engineers Requires Cross-Functional and Diverse Development AND 11Regulatory Review Teams – Collaboration is Critical! Physical Pharmacy Meets Drug Delivery Father of Physical Pharmacy Tak Higuchi 12 Father of Drug Delivery Alejandro Zaffaroni ALZA Drug Delivery Technologies D-TRANS® Transdermal 13 OROS® Oral E-TRANS® Electrotransport DUROS® Implant Macroflux® Transdermal STEALTH® Liposomal ALZAMER® Depot Drug Delivery Successes Delivery Mechanisms Diffusion (ALZA) Osmosis (ALZA) 1970s 1980s 1990s 2000s 2010s Ocusert® (1974) Progestasert® (1976) D-TRANS™(1981) Alzet® (1977) OROS® (1983) RUTS® (1989) DUROS™(2000) Electrokinetics (ALZA) 14 E-TRANS™ (2006) Drug Delivery Successes Delivery Mechanisms Erosion (Astra Zeneca) (Tap Pharmaceuticals) PEGylation (ENZON) Liposomes (Sequus) Drug Eluting Stents (Cordis) (Boston Scientific) (Medtronic) (Abbott) Pulmonary Inhalation – 15 systemic delivery (Nektar) 1980s 1990s 2000s 2010s ZOLADEX® (1989) Lupron® (1995) ADAGEN (1990) Doxil (1995) OCP Established Cypher® (2003) Taxus® (2004) Endeavor® (2008) Xience® (2008) Exubera (2006) New Drug Delivery Technology Advances Are Not Short Term Efforts OROS®® Systems ~ 15 Years Transdermal Systems ~ 9 Years Electrotransport Patches ~ 21 Years Pulmonary Systemic Delivery ~ 15 Years Average cost for development of a new biotechnology product is now $1.2B 16 Tufts CSDD, 2006 Key Learning: To Develop the Technology - Understand the Science of Drug Delivery Dosage Form Design (Basic Pharmaceutics and Engineering) Mechanism of Delivery Route of Administration Dosage Form and Device Construction API API selection, selection, prototype prototype testing, testing, scale scale up, up, manufacturing manufacturing Product Product performance, performance, quality, quality, stability, stability, specifications specifications DOE, DOE, PAR, PAR, Validation, Validation, FMEA, FMEA, Risk Risk Assessment Assessment Dosage Form – Body Interface Biopharmaceutics preclinical/clinical Risk/Benefit, RMP, REMs, etc. Delivery Rate Selection and Clinical Pharmacology Zero Order Pharmacology Rate of Rise Dependent Pharmacology Circadian Pharmacology Site Specific Pharmacology 17 Serum Concentration (ng/ml) E-TRANS™ Technology for the Pulsatile Delivery of Fentanyl 25 20 n=6 males Baseline + bolus ( ) delivery System off 15 System on Observed Simulated 10 05 0 0 12 24 36 Time (h) 18 48 60 72 E-TRANS™ Electrotransport Device Technology 19 Revenue from Drug Delivery Products Peak Sales: $1.0BN2 Peak Sales: $300MM1 Peak Sales: $300MM2 Peak Sales: $2.1BN2 Peak Sales: $1.4BN2 20 1) 2) Peak sales estimate based on research reports. Estimate of peak sales based on publicly available information and company reports. Big Pharma Challenges: Productivity & Innovation 21 Declining Productivity: R&D Spend Increases as FDA Approvals Decrease 22 Source: PhRMA Pharmaceutical Industry Profile 2007, FDA Big Pharma’s Year of Lay Offs Abbott Schering Plough 700 1,100 Eli Lilly 700 Amgen Pfizer 2,400 J&J 10,000 4,800 BayerSchering 2007: Pink is the New Black 6,100 7,600 7,000 23 Merck & Co IN VIVO: The Business Medicine Report (Sept 2007) AstraZeneca SOURCE Company Reports, Windhover estimates Biotech Business Trends Big pharma R&D Biotech new product approvals Big pharma new product approvals $70 35 $60 30 $50 25 $40 20 $30 15 $20 10 $10 5 $0 0 2000 2001 2002 2003 Source: Ernst & Young Global Biotechnology Report 2007. 24 2004 2005 2006 Number of new product approvals by the FDA R&D expenditures ($b) Biotech R&D Biotech is Viewed as a Large and Growing Market Biotech is on track to become a US$100 billion industry by the end of the decade US$b 100 50 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 0 Source: Ernst & Young Global Biotechnology Report 2007. Forecast assumes 14 percent annual growth rate and no major acquisitions of 25 biotech companies. Pharma Increasingly Dependent on Delivery, Biotech, and Specialty Players for Product Innovation Nearly 50% of respondents attributed at least 20% of revenue to alliances… …and an overwhelming majority expect the frequency of alliances to increase Estimated percent of revenue from Alliances percent of respondents Expected frequency of alliances over next 5 years percent of respondents "Decrease" “Increase “Stay the 7 Dramatically” 7 22 Same” 29 >50% 20-30% 24 0-10% 10-20% “Increase moderately” 64 26 Source: McKinsey Pharmaceutical and Biotechnology Alliances Survey Reducing Non-Compliance Rates Could Dramatically Increase Sales for Some Drugs Non-compliance is a major problem in people with minor and serious illnesses alike. 27 Source: Manhattan Research, 2004; as shown in Pharma 2020: The Vision, 2007. The Future: Marketing Focus Is Changing – Enter “The Payer” 28 Evolution: From Drug Delivery to “Smart Medicine” Payer Provider Professional Patient This is Smart Drug Delivery Therapeutic Effect API Doctor Nurse Pharmacist Hospital Clinic Nursing Home CONCERTA: Ascending PK profile Improved duration Enhanced enhances of action Reduced Care Efficiency Cost DURAGESIC: Extends control of chronic pain CONSTA: Improves patient compliance better outcome Drugfor Delivery System Drug Delivery System 29 Insurance Medicare Employer This is Smart Medicine The Quest for Smart Medicine: A Case Study: Diabetes and Insulin Drug Delivery 30 30 A Worldwide Type 2 Diabetes Epidemic 72% Growth Anticipated (189MM to 324MM) 38.2 44.2 +16% 25.0 39.7 +59% Key: 2003 Prev 2025 Prev % Growth 31 Source: Source: WHO WHO 2003 2003 10.4 19.7 +88% 13.6 26.9 98% 18.2 35.9 +97% 81.8 156.1 +91% 1.1 1.7 +59% Diabetes Treatment: Insulin Pancreas origin of diabetes: 1889 Successful extraction: 1921 Mass production of naturally sourced insulin by Eli Lilly: 1923 Sourced from Pigs/Cows/Sheep Genentech/Eli Lilly introduced recombinant source of Insulin: 1982 32 Charles Best and Dr. Frederick Banting Insulin Drug Delivery: Basal/Bolus Delivery Pattern 33 Insulin Drug Delivery Platforms Pens Pumps Needle Free Injectors Syringes 34 Pulmonary DPI Transdermal Key Learnings: Insulin Drug Delivery 86 years - large advances made in insulin engineering and delivery In 2000, 4 million years of life still lost to Type I diabetes Much learned about pulmonary delivery of biomolecules Market always driving toward more patient friendly compliant dosage forms Closed loop delivery system is almost a reality 35 Observations and Opportunities What have we learned from combining drug delivery and device technologies? 36 Drug Delivery and Devices: Some Observations Technology differentiated products provide new solutions and create high value Taxus and Cypher drug eluting stents Significantly improved clinical outcomes Revolutionized interventional cardiology market Duragesic Injectable transformed into a transdermal product New indication for old drug Exubera 37 Revolutionary needle-free pulmonary delivery for insulin Approved by FDA, but no longer marketed Opportunities Drug delivery is always evolving Cross-functional collaborations are critical Don’t underestimate biological complexity Utilize combined pharma and device skills to continue to bring products to the market and advancing patient care – don’t work in silos! Be aware of stakeholders beyond the regulator and the patient The health care professional The health care provider The health care payer Combination drug delivery and device products, though currently complex, provide new treatment opportunities 38 Continued collaboration and expansion of scientific understanding will reduce complexity Acknowledgements John Patton, Nektar Brad Phipps, ALZA Corporation Felix Theuwees, Durect Gene McNally, Pharma Dev Concepts The Organizing Committee for BioInterface 2008 39 “Building truly convergent technologies represents multifactorial complexity in no small part because it requires the coordination of a multidisciplinary team of experts, each of whom has a very different notion about how to build things and why things work. Finding and managing this disparate pool of talent is one of the most overlooked and misunderstood challenges of developing convergent technologies. It is rare to find the compatibility required.” - John Patton, on Managing Technology Development Teams; from Nature Publishing Group, 2006 40 41 Combination Products Include: 1. A product comprised of two or more regulated components physically, chemically, or otherwise combined or mixed and produced as a single entity 2. Two or more separate products packaged together in a single package or unit 3. change change in in intended intended use, use, dosage dosage form, form, strength, strength, route route of of administration, administration, or or significant significant change change in in dose dose Combination of a separately packaged investigational drug, device, or biological product for use only with another individually specified investigational drug, device, or biological product 42 i.e., i.e., drug drug and and device, device, device device and and biological, biological, or or biological biological and and drug drug Combination of approved individual drug, device, or biological products resulting in a label change of the approved combination product 4. ie., ie., drug/device, drug/device, biologic/device, biologic/device, drug/biologic, drug/biologic, or or drug/device/biologic drug/device/biologic both both are are required required to to achieve achieve the the intended intended use, use, indication, indication, or or effect effect 21 CFR §3.2(e) Diabetes: The Worldwide Epidemic $177 million worldwide (5% of population) Numbers expected to double by 2030 $19 billion – WW estimate of drug and device for treatment $12.5 billion – US only $132 billion (US only) spent on diabetes treatment and complications 5-10% of cases are Type 1, rest are Type 2 43 Insulin Drug Delivery Systems Approved 44 Syringes Insulin Pens Jet/Needle Free Injectors Subcutaneous Infusion Sets Insulin Pumps (external) Insulin Inhalers On The Horizon Transdermal Nasal Buccal Oral Insulin Pumps (implanted) Beta cell replacement (transplantation) Bariatric surgery/gastric bypass Insulin Drug Delivery System Requirements Highly complex natural control of blood glucose levels Fast onset/long-acting Flexible/adjustable Daily variability due to exercise/meal time/food combinations Easy to use, discrete format 45 Insulin Pens 46 Subcutaneous dosing Prefilled /Disposable Alternative to vial and syringe Discreet (pocket/purse) Dial in dosing (1-60 units) Resets to zero during injection Accurate/affordable/easy to use Once in use - stable @ controlled RT for 42 days Junior versions Memory (date/time/amount dosed) Insulin Needle Free Injection Technologies Delivery through skin without use of needle High velocity delivery of liquid/powder though orifice Jet opens and forms hole in skin (fraction of a second) Attributes: 47 Enhanced compliance Improved Safety Not necessarily decreased pain, rather decreased fear Significant ease of self use (some devices) Fixed volume (< 1.5mL) Insulin Pumps OneTouch Ping 48 Combination meter and pump Wireless communication Pump calculates infusion rates and boluses based on meter readings Hands-free insulin delivery; patient must confirm dose Downloads to data management software Not closed loop - requires calibration to blood glucose q 12 hr. Insulin Pulmonary Delivery Highly effective Non-invasive Exubera approved in January 2006 -withdrawn October 2007 49 Long term pulmonary safety concerns Cost effectiveness concerns Dose adjustment (3 (3 units units vs vs 1/20th 1/20th unit unit from from pump) pump) Not a discrete device Daily injection of long acting insulin still required Physician/patient conversion Transdermal Insulin Delivery Valeritas’ V-Go™ 50 Micro-needle based technology Small disposable waterproof device Changed daily - rotate site Delivers continuous basal dose On demand bolus dosing FDA approved device (510(k)) Type II diabetic market
