? OTC LOVASTATIN

1. ? OTC LOVASTATIN • Jesse M. Polansky M.D., M.P.H. jmpqz@yahoo.com • Representing self

2. ? EFFICACY PRIMARY PREVENTION • FDA Statistical Review: • Uncertainty in post-hoc AFSCAPs analysis (low HDL population vs OTC population) • Absolute vs. Relative Risk Reduction • ? “Lower is Better” in moderate and low risk populations

3. ? EMERGING SAFETY CONCERNS STATINS • Hemorrhagic Stroke - FDA label change atorvastatin based on post-hoc analysis SPARCL (4D/atorvastatin in diabetics on dialysis had a reported stroke finding also) • GI and Prostate Cancer Clinical Trial Findings (pravastatin and rosuvastatin respectively) • Cognitive, Behavioral (including suicide, sleep disturbances), and Gross Underreporting of Statin Side Effects (UCSD Statin Study) • ALS (WHO)

4. Balancing Risks & Benefits: NCEP ATP-III • 2003 NCEP Update : drug therapy only for Moderate Risk patients with LDL>160 Moderate Risk = 2 RF (includes Family Hx) and <10% Framingham Risk Score • The NCEP Moderate Risk category includes approx 13 million Americans who according to the guidelines only require Total Lifestyle Change (TLC) (?impact of self-rx)

5. NCEP Risk Categories Therapeutic Lifestyle Changes (TLC) Drug CHD and CHD Risk Equivalents 10-year risk >20% 24.1 20.7 2+ Risk Factors 10-year risk 10-20% 10.9 8.3 SUBTOTAL 35 29 2+ Risk Factors 10-year risk <10% 14.6 million 2.8 0-1 Risk Factor 15.6 million 4.7 SUBTOTAL 30.2 37.5 TOTAL 65.3M 36.5M

6. Balancing Risks & Benefits: The UK Experience • 11/2003 simvastatin approved for Behind the Counter use for “Moderate Risk” patients • In the UK “Moderate Risk” = 10%-15% 10 year risk of a first major coronary event (note NCEP Moderate Risk is defined as <10%) • Controversy Continues • ? Update

7. ? Balancing Risks & Benefits: The Underserved • Under treatment for patients with favorable risk/benefit profiles • Marginalizing the Total Lifestyle Change Imperative

8. Customer Use Study • Although the investigators collected data necessary to evaluate self-rx decision vs. NCEP guidelines the data was not presented and could not be extracted from publically available data. • In addition, the Mrk presentations to the OTC Committee inappropriately collapsed the NCEP Moderate and Moderately High Risk categories they renamed the “Moderate Risk Group”.

9. ? Thoughts The lovastatin OTC request should be denied • The risks of lovastatin OTC are not insignificant and magnified in an unmanaged OTC population • The benefits of lovastatin OTC are uncertain and limited at best • OTC lovastatin is an uncontrolled and ill-begotten public health experiment of unprecedented scale • Approval would be a substantial failure of FDA’s obligation to be an advocate for patient safety

10. Background I Statin Safety • FDA Atorvastatin label change: Addition of Precaution for patients with recent stroke or TIA • NEJM: Atorvastatin in Patients with Type 2 Diabetes Mellitus Undergoing Hemodialysis • Drug Safety: Physician Response to Patient Reports of Adverse Drug Effects: Implications For Patient-Targeted Adverse Effect Surveillance. <note: Statin Case Study> • Drug Safety: Statins, Neuromuscular Degenerative Disease and an Amyotrophic Lateral Sclerosis-Like Syndrome An Analysis of Individual Case Safety Reports from Vigibase • JACC: Effect of the Magnitude of Lipid Lowering on Risk of Elevated Liver Enzymes, Rhabdomyolysis, and Cancer • Journal of Clinical Oncology: Statins and Cancer Risk: A Literature-Based Meta-Analysis and Meta-Regression Analysis of 35 Randomized Controlled Trials • NEJM: Use of Statins and Outcome of BCG Treatment for Bladder Cancer • NEJM Statins for Atherosclerosis — As Good as It Gets? <Note: Immunologic considerations> • Clinical P&T: Benefit/Risk Ratio of Statins in Primary Prevention • AJCard: Effect of Atorvastatin on Left Ventricular Diastolic Function and Ability of Coenzyme Q10 to Reverse That Dysfunction • BMJ: Controversy: Should we lower cholesterol as much as possible?

11. Background II Eficacy Considerations • JACC: Low and Lowered Cholesterol and Total Mortality • Annals IM: Narrative Review: Lack of Evidence for Recommended Low-Density Lipoprotein Treatment Targets: A Solvable Problem • PLOS: Factors Associated with Findings of Published Trials of Drug–Drug Comparisons: Why Some Statins Appear More Efficacious than Others • FDA Memos; Statistical Review AFCAPS/TEXCAPS and Clinical Review Excerpt • Center for Science in the Public Interest: Petition to the National Institutes of Health Seeking an Independent Review Panel to Re-Evaluate the NCEP Guidelines III OTC Statins • NEJM: Statins and Over-the-Counter Availability IV NCEP Data • Distribution of Patients by NCEP Risk Category