Chapter 1. Introduction
1.1. Scope of Report
1.2. Overview of Combination Products
1.3. Rationale for Combination Products (Drug-Drug)
Increased Compliance and Efficacy
Product Life Extensions
-Patent Extensions
-Exclusivity
1.4. Rationale for Drug-Device or Biological-Device Combinations
Chapter 2. FDA’s Guidelines on Combination Products
2.1. Single Entity Products Regulations
Center for Drug Evaluation and Research
Center for Devices and Radiological Health
Center for Biologics Evaluation and Research
2.2. Combination Products Regulations
Drug-Drug Combinations
-Two Previously Approved Drug Components
-One Previously Approved and One New Molecular Entity
-Two New Molecular Entities
Drug-Device, Drug-Biological, Device-Biological, or Drug-Device-Biological Combinations
-The Office of Combination Products
-Primary Mode of Action
Chapter 3. Combination Therapies Product Development
3.1. Fixed-Dose Combinations Product Development
Chemistry, Manufacturing, and Controls
-Techniques to Create Fixed-Dose Combination Products
Preclinical Studies
Clinical Studies
-Factorial Studies
Examples of Fixed-Dose Combination Product Studies
-Hyzaar (losartan and hydrochlorothiazide)
-Prevacid NapraPAC (lansoprazole/naproxen)
--Clinical Studies: Risk Reduction of NSAID-Associated Gastric Ulcer
3.2. Drug/Device/Biological Combinations Product Development
Chemistry, Manufacturing, and Controls
Preclinical Studies
Clinical Studies
FDA Review
Chapter 4. Business Issues of Combination Products
4.1. Patents and Exclusivity
The Pharmaceutical Company’s View
Combining Therapies to Extend Patent Life
4.2. Partnering Issues
Vytorin
Sustiva Plus Truvada
Artesunate Plus Amodiaquine
Chapter 5. Marketplace Issues
5.1. Pricing
5.2. Reimbursement Issues
5.3. Development Issues
5.4. Personalized Medicine: Implications of a Race-Based Combination Treatment
Chapter 6. Examples of Combination Therapies
6.1. Fixed-Dose Combinations
Cardiovascular Agents Including Dyslipidemia Combinations
-Antihypertensive Combinations
-Antihypertensive/Lipid-Lowering Combinations
-Lipid-Lowering Combinations
HIV/AIDS
-Guidance for Industry: Fixed-Dose Combination and Co-Packaged Drug Products for Treatment of HIV
-HIV Medications
--Reverse Transcriptase Inhibitors
--Protease Inhibitors
Inflammation
-Arthrotec
--Costs
-Prevacid NapraPAC
Anti-Infective Combination Therapies
Oral Contraceptives
Biological-Biological Combination Products
-Vaccines
6.2. Drug/Biologic-Device Combination Products
Drug-Device Combination Products
-Coronary Drug-Eluting Stents
-American Heart Association’s Heart Disease and Stroke Statistics - 2004 Update
-PTCA/Balloon Angioplasty
-Stent Procedure
-In-Stent Restenosis
-New Techniques to Prevent Restenosis: Drug-Eluting Stents
-Stent Technology
Antibiotic Bone Cement
Halogen-Light Source Combination
Diagnostic Combination Products
-Helicobacter pylori Detection Test
Drug-Delivery Device Combinations
-Asthma Inhalers
-LidoSite
Device-Biological Combination Products
-Interactive Wound-Care
-Absorbable Collagen Sponge With Genetically Engineered Human Protein
Drug-Biological Combination Products
-Interferon-Ribavirin Combination
-Antibody-Drug Conjugates
Chapter 7. Company Profile: CombinatoRx, Inc.
7.1. Overview: CombinatoRx, Inc.
Technology
Oncology
Immuno-Inflammatory Program
Partnerships
Chapter 8. Conclusions
References
Index
List of Tables
Table 1.1. Number of NDAs for Combination Products (Years 2001-2005)
Table 1.2. Examples of Top-Selling Drugs in 2003 with Patent Expiration Years and 2003 US Sales (Billions of Dollars)
Table 3.1. Studies of Losartan and Hydrochlorothiazide Examining Effects on Blood Pressure
Table 3.2. NSAID-Associated Gastric Ulcer Risk-Reduction Rates
Table 3.3. Gastric Ulcer Risk-Reduction Rates in Patients Whose NSAID was Naproxen Only or Naproxen and Aspirin Only
Table 5.1. Examples of Prices of Combination Products Compared to the Individual Components Added Together
Table 6.1. Examples of Fixed-Dose Combination Products From Various Therapeutic Areas
Table 6.2. Classification and Management of Blood Pressure for Adults
Table 6.3. Oral Antihypertensive Medication Combinations
Table 6.4. Antiretroviral Agents Approved for the Treatment of HIV Infection
Table 6.5. Price Comparison of Arthrotec 75 in Comparison to the Individual Components
Table 6.6. Combination Antibiotics According to Class
Table 6.7. Ratio of Male and Female Medical, Law, Dental, and Business Students From 1960-2000
Table 6.8. Low-Dose Oral Contraceptives Currently Available in the United States
Table 6.9. Licensed Vaccines in Combination
Table 6.10. Drug-Eluting Coronary Stents Currently Available
Table 6.11. Drug-Eluting Coronary Stents in Clinical Trials
Table 6.12. Currently Available Helicobacter pylori Detection Tests
Table 6.13. Wound-Care Combination Products Currently Available
Table 6.14. Monoclonal Antibodies (Monotherapy) Currently Available
Table 8.1. Value Proposition and Opportunities of Different Types of Combination Products
List of Figures
Figure 1.1. Patent Issues Throughout the Product Lifecycle Stages
Figure 1.2. Development Process Regarding Timelines and Regulatory Procedures
Figure 2.1. Combinations of Previously Marketed Drugs: Recommended General Procedure
Figure 2.2. Combinations of Previously Marketed Drugs with NMEs: Recommended General Procedure
Figure 2.3. Combinations of NMEs with NMEs: Recommended General Procedure
Figure 3.1. Hypothetical Factorial Study Design for Combination Antihypertensives
Figure 3.2. Hypothetical Factorial Study Design for Combination Cholesterol-Lowering Drugs
Figure 4.1. Comparison of Number of Submissions to FDA Versus Cost of Pharmaceutical Research
Figure 4.2. Pfizer’s Revenue From Lipitor Sales, 1999-2005
Figure 5.1. Increased Development Efforts Required When Combining Two Already-Released Drugs in a Fixed-Dose Combination Product
Figure 5.2. Increased Development Efforts Required When Combining a NBE and a Released Drug in a Fixed-Dose Combination
Figure 6.1. The Stent Procedure
Figure 6.2. Principles of PDT After Application of Metvix
Figure 6.3. LidoSite Patch and Dose Controller Combining a Transdermal Delivery System and Topical Anesthesia
Figure 7.1. CombinatoRx’s Approach to Drug Discovery in Comparison to Traditional Methods
Figure 7.2. CombinatoRx Compounds in Clinical Trials by Phase and Disease Area
