? OTC LOVASTATIN Jesse M. Polansky M.D., M.P.H. Representing self

? 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

? 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)

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)

Therapeutic Lifestyle Changes (TLC) Drug CHD and CHD Risk Equivalents 10-year risk >20% Risk Factors 10-year risk 10-20% SUBTOTAL Risk Factors 10-year risk <10% 14.6 million Risk Factor 15.6 million4.7 SUBTOTAL TOTAL65.3M36.5M NCEP Risk Categories

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

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

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”.

? 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

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.  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?  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?

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