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Advisory Committee Industry Briefing Document Testosterone Replacement Therapy Testosterone Replacement Therapy Advisory Committee Briefing Document Advisory Committee Industry Briefing Document Testosterone Replacement Therapy Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting on September 17, 2014 Advisory Committee Briefing Materials: Available for Public Release Testosterone Replacement Therapy Advisory Committee Briefing Document Table of Contents 1.0 Executive Summary.................................................................8 2.0 Testosterone Replacement Therapy: Regulatory History ....................................................................................11 2.1 Approval History in the United States .....................................................11 2.2 Requirements for Regulatory Approval...................................................12 2.3 Indication .................................................................................................13 2.4 Safety Labeling ........................................................................................14 2.5 Current Regulatory Activities..................................................................15 3.0 Testosterone, Hypogonadism, Guidelines, and Testosterone Replacement Therapy Benefits .....................16 3.1 Testosterone .............................................................................................16 3.2 Hypogonadism .........................................................................................19 3.2.1 Classification, Signs, and Symptoms of Hypogonadism.........................19 3.2.2 Prevalence of Hypogonadism ..................................................................22 3.2.3 Comorbid Conditions...............................................................................26 3.2.4 Endocrine Society Guidelines..................................................................26 3.3 Testosterone Replacement Therapy.........................................................28 3.3.1 Introduction..............................................................................................28 3.3.2 Limitations of Literature Evaluating Benefits of Testosterone Replacement Therapy ..............................................................................28 3.4 Effects of Testosterone Replacement in Hypogonadal Men....................29 3.4.1 Benefits Related to Lean Mass, Muscle Strength, and Fat Mass.............30 3.4.2 Benefits Related to Bone Mineral Density and Bone Architecture .........33 3.4.3 Benefits Related to Sexual Function........................................................36 3.4.4 Benefits Related to Fatigue......................................................................38 3.4.5 Benefits Related to Mood and Cognition.................................................40 3.4.6 Benefits Related to Special Populations ..................................................42 3.4.6.1 Metabolic Syndrome and Type 2 Diabetes Mellitus................................42 3.4.6.2 Human Immunodeficiency Virus.............................................................45 3.4.6.3 Additional Special Populations................................................................46 3.5 Limitations and Uncertainties for the Evidence of Benefit......................46 Advisory Committee Briefing Materials: Available for Public Release 1 Testosterone Replacement Therapy Advisory Committee Briefing Document 3.5.1 Late Onset Hypogonadism (Androgen Deficiency of the Aging Male) ........................................................................................................46 3.6 Ongoing Studies.......................................................................................47 3.7 Summary: Hypogonadism, Guidelines, and Benefits of Testosterone Replacement Therapy.........................................................48 4.0 Cardiovascular Risk in Hypogonadal Men.........................50 4.1 Cardiovascular Risk Introduction ............................................................50 4.2 Cardiovascular Background.....................................................................52 4.3 Incidence and Prevalence of Cardiovascular Events ...............................54 4.3.1 Cardiovascular Events in the Hypogonadal Male Population .................56 4.4 Risk Factors for Cardiovascular Events...................................................59 4.5 Associations Between Hypogonadism and Cardiovascular Events.........59 4.5.1 Type 2 Diabetes Mellitus, Obesity and Metabolic Syndrome, Hypertension, and Hyperlipidemia ..........................................................59 4.5.2 Coronary Artery Disease..........................................................................60 4.5.3 Cardiovascular and All-Cause Mortality .................................................62 4.6 Evaluation of Testosterone Replacement Therapy and Cardiovascular-Related Events................................................................65 4.6.1 Placebo-Controlled Studies......................................................................65 4.6.2 Meta-Analyses of Testosterone Replacement Therapy and Cardiovascular Events or Cardiovascular Risk Factors...........................67 4.6.2.1 Meta-Analyses of Testosterone Replacement Therapy and Cardiovascular Events .............................................................................70 4.6.2.2 Meta-Analyses of Testosterone Replacement Therapy and Cardiovascular Risk Factors ....................................................................74 4.6.3 Observational Studies ..............................................................................75 4.7 Evaluation of Testosterone Replacement Therapy and Cardiovascular Risk Factors ....................................................................84 4.8 Summary..................................................................................................90 5.0 Drug Utilization .....................................................................92 5.1 Drug Utilization Introduction ..................................................................92 5.2 Background: Prevalence of Hypogonadism and Common Comorbid Conditions...............................................................................93 5.3 Prescription Trends over Time for Testosterone Products ......................93 Advisory Committee Briefing Materials: Available for Public Release 2 Testosterone Replacement Therapy Advisory Committee Briefing Document 5.4 Prescribing Patterns by Physician Specialty............................................96 5.5 Age Distribution of Patients Receiving Testosterone Replacement Therapy ....................................................................................................98 5.6 Characteristics of Patients Receiving Testosterone Replacement Therapy ..................................................................................................100 5.7 Reported Diagnostic Codes for Patients Who Receive Testosterone Replacement Therapy.......................................................101 5.8 Presence of Testosterone Values Prior to Starting Testosterone Replacement Therapy ............................................................................103 5.9 Persistence of Testosterone Replacement Therapy Use ........................105 5.10 Summary of Utilization Data .................................................................105 6.0 Conclusions...........................................................................107 7.0 References.............................................................................110 List of Tables Table 1. FDA-Approved Branded Testosterone Products Currently Marketed in the United States..................................................................12 Table 2. Classification of Male Hypogonadism.....................................................21 Table 3. Estimation of Prevalence of Testosterone Deficiency.............................24 Table 4. Strengths and Limitations of Changes in Fat Mass, Lean Mass, and Muscle Strength ................................................................................32 Table 5. Strengths and Limitations of Changes in Bone Mineral Density.............36 Table 6. Mean ± SD Difference on Total and Domain Score of the International Index of Erectile Function (IIEF-15) Between the Testosterone and Placebo Groups............................................................37 Table 7. Strengths and Limitations of Changes in Sexual Function......................38 Table 8. Strengths and Limitations of Changes in Fatigue ....................................40 Table 9. Strengths and Limitations of Changes in Mood and Cognition...............42 Table 10. Strengths and Limitations of Improvements in Glycemic Control in Metabolic Syndrome and Type 2 Diabetes Mellitus ...........................45 Table 11. Strengths and Limitations of Testosterone Replacement Therapy in HIV-Infected Males .............................................................................46 Table 12. Annual Rates of Heart Failure per 1,000 Population in 2006..................55 Advisory Committee Briefing Materials: Available for Public Release 3 Testosterone Replacement Therapy Advisory Committee Briefing Document Table 13. Cardiovascular Events in the Hypogonadal Male Population .................57 Table 14. Summary of Studies Reporting on Low Testosterone and Coronary Artery Disease..........................................................................61
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