1. Non-Prescription Mevacor ® Merck & Co., Inc. New Drug Application 21-213 Nonprescription Drugs and Endocrinologic and Metabolic Drugs Advisory Committee Meeting Silver Spring, Maryland December 13, 2007 Eric Colman, MD Division of Metabolism and Endocrinology Products Nonprescription Drugs and Endocrinologic and Metabolic Drugs Advisory Committee Meeting Silver Spring, Maryland December 13, 2007 Eric Colman, MD Division of Metabolism and Endocrinology Products Center for Drug Evaluation and Research

2. FDA Advisory Committee Meeting December 13, 2007 2 ObjectiveObjective To discuss FDA’s evaluation of data mining signals for amyotrophic lateral sclerosis (ALS) with statins Background ALS What is data mining? FDA data mining signal scores for ALS with statins FDA’s evaluation of the data mining signals Next steps To discuss FDA’s evaluation of data mining signals for amyotrophic lateral sclerosis (ALS) with statins Background ALS What is data mining? FDA data mining signal scores for ALS with statins FDA’s evaluation of the data mining signals Next steps

3. FDA Advisory Committee Meeting December 13, 2007 3 FDA Observes Data Mining Signal for ALS with Statins Earlier this year members from numerous offices and divisions within the Center for Drug Evaluation and Research met to discuss data mining signals for ALS and statins observed in FDA’s Adverse Event Reporting System (AERS) Available data did not justify regulatory action Make evaluation publicly available –Manuscript in progress Earlier this year members from numerous offices and divisions within the Center for Drug Evaluation and Research met to discuss data mining signals for ALS and statins observed in FDA’s Adverse Event Reporting System (AERS) Available data did not justify regulatory action Make evaluation publicly available –Manuscript in progress

4. FDA Advisory Committee Meeting December 13, 2007 4 Edwards, et al. Drug Safety June, 2007

5. FDA Advisory Committee Meeting December 13, 2007 5 Edwards, et al. “…….we hope that this signal [for an ALS-like syndrome with statins] will be accepted not as anything more than a hypothesis that needs to be followed up to ensure the safer use of an important group of medicines.”

6. FDA Advisory Committee Meeting December 13, 2007 6 Wall Street Journal July, 2007

7. FDA Advisory Committee Meeting December 13, 2007 7 Amyotrophic Lateral Sclerosis Progressive destruction of motor neurons with retraction of axons from neuromuscular junction Often presents with muscle weakness Annual incidence 1.5 to 2 cases per 100,000 Incidence increases with age Males > females Etiology unknown Progressive destruction of motor neurons with retraction of axons from neuromuscular junction Often presents with muscle weakness Annual incidence 1.5 to 2 cases per 100,000 Incidence increases with age Males > females Etiology unknown

8. FDA Advisory Committee Meeting December 13, 2007 8 Drug Safety Data Mining Definition: the use of computer algorithms to analyze adverse event data in a large, complex database –FDA’s Adverse Event Reporting System (AERS) –Spontaneously-submitted adverse events from healthcare professionals, consumers, and drug companies Goal: to identify reporting relationships that could signal possible adverse drug reactions Data mining CAN: generate hypotheses regarding adverse drug reactions Data mining CANNOT: prove or refute causal associations between drugs and adverse reactions Definition: the use of computer algorithms to analyze adverse event data in a large, complex database –FDA’s Adverse Event Reporting System (AERS) –Spontaneously-submitted adverse events from healthcare professionals, consumers, and drug companies Goal: to identify reporting relationships that could signal possible adverse drug reactions Data mining CAN: generate hypotheses regarding adverse drug reactions Data mining CANNOT: prove or refute causal associations between drugs and adverse reactions

9. FDA Advisory Committee Meeting December 13, 2007 9 Proportional Reporting Ratios Observed/Expected a/(a+b)/c/(c+d) Reports With Adverse Event Y Reports Without Adverse Event Y Drug Xaba+b All Other Drugscdc+d a+cb+dtotal

10. FDA Advisory Committee Meeting December 13, 2007 10ExampleExample Reports With Pancreatitis Reports Without Pancreatitis Lipovent1020010/10+200 All Other Drugs In AERS 320003/3+2000 Observed ratio of pancreatitis reports for Lipovent: 10/10 + 200 = 0.048 Expected ratio of pancreatitis reports for Lipovent: 3/3 + 2000 = 0.001 Proportional reporting ratio = 0.048/0.001 = 48

11. FDA Advisory Committee Meeting December 13, 2007 11 Data Mining Terminology EBGM is the Empirical Bayes Geometric Mean - an adjusted estimate of the mean proportional reporting ratio that addresses small cell counts –EB05 = lower bound of confidence interval –EB95 = upper bound of confidence interval EBGM is the Empirical Bayes Geometric Mean - an adjusted estimate of the mean proportional reporting ratio that addresses small cell counts –EB05 = lower bound of confidence interval –EB95 = upper bound of confidence interval

12. FDA Advisory Committee Meeting December 13, 2007 12 What Constitutes a Data Mining Signal? Criteria not written in stone EB05 > 2 EBGM > 2 Consider the whole range of scores for new drugs or very serious outcomes Criteria not written in stone EB05 > 2 EBGM > 2 Consider the whole range of scores for new drugs or very serious outcomes

13. FDA Advisory Committee Meeting December 13, 2007 13 FDA Data Mining Signal Scores for Statins and ALS IngredientEBGMEB05EB95 Pravastatin2.71.45.0 Fluvastatin1.60.54.1 Atorvastatin9.37.012.1 Cerivastatin3.82.55.7 Lovastatin2.51.05.7 Simvastatin4.43.06.4 Rosuvastatin2.41.24.4 EBGM is not an odds ratio or a measure of relative or absolute risk EBGM is not a causality score

14. FDA Advisory Committee Meeting December 13, 2007 14 What Did FDA Do In Response to the Data Mining Signals for ALS and Statins? Reviewed: –AERS reports of ALS –Statin clinical trial data –Population-based ALS incidence data Reviewed: –AERS reports of ALS –Statin clinical trial data –Population-based ALS incidence data

15. FDA Advisory Committee Meeting December 13, 2007 15 Review of AERS Reports of ALS All reports reviewed by a safety evaluator and two neurologists 57 domestic reports Mean age 67 years –39% 70 – 79 years old 53% male Clinical course after statin D/C’d –84% no improvement –2% improved –14% unknown Most reports received by FDA during or after 2000 Initial Reporter Source –53% non-healthcare consumer –33% physician –11% non-physician healthcare provider All reports reviewed by a safety evaluator and two neurologists 57 domestic reports Mean age 67 years –39% 70 – 79 years old 53% male Clinical course after statin D/C’d –84% no improvement –2% improved –14% unknown Most reports received by FDA during or after 2000 Initial Reporter Source –53% non-healthcare consumer –33% physician –11% non-physician healthcare provider

16. FDA Advisory Committee Meeting December 13, 2007 16 Retrospective Analyses of Statin Clinical Trials 42 placebo-controlled trials of all marketed statins 6 months to 5 years in duration Primary and secondary CAD prevention 200,000 person-years statin exposure 200,000 person-years placebo exposure 9 cases of ALS in statin groups 9 cases of ALS in placebo groups –4.3 cases per 100,000 vs. 4.6 cases per 100,000 42 placebo-controlled trials of all marketed statins 6 months to 5 years in duration Primary and secondary CAD prevention 200,000 person-years statin exposure 200,000 person-years placebo exposure 9 cases of ALS in statin groups 9 cases of ALS in placebo groups –4.3 cases per 100,000 vs. 4.6 cases per 100,000

17. FDA Advisory Committee Meeting December 13, 2007 17 Statin Use – ALS Incidence Use of statins has increased steadily since early 1990s Has the incidence of ALS increased? Data from Rochester, MN –Before 1990: 1.5 cases per 100,000 people per year (1.1 to 2.0) –After 1990: 1.9 cases per 100,000 people per year (1.0 to 2.8) Sorenson EJ, et al. Neurology. 2002;59(2):280-282. Dispensed prescriptions by US retail pharmacies. Verispan Vector One; National, Years 1991-2006, Extracted October 2007

18. FDA Advisory Committee Meeting December 13, 2007 18 What Should We Make of the Data Mining Signals? What Should We Make of the Data Mining Signals? No imbalance in ALS from placebo-controlled statin trials No dramatic increase in the incidence of ALS despite dramatic increase in the use of statins Could statins unmask or exacerbate muscle symptoms of ALS? Could the data mining signals be the result of reporting bias? No imbalance in ALS from placebo-controlled statin trials No dramatic increase in the incidence of ALS despite dramatic increase in the use of statins Could statins unmask or exacerbate muscle symptoms of ALS? Could the data mining signals be the result of reporting bias?

19. FDA Advisory Committee Meeting December 13, 2007 19 Reporting Biases A major concern with all spontaneous reporting databases Both statins and ALS associated with muscle symptoms Detected a data mining signal for ALS with fenofibrate, another lipid-altering drug associated with myopathy Detected data mining signals for dermatomyositis and polymyositis with statins A major concern with all spontaneous reporting databases Both statins and ALS associated with muscle symptoms Detected a data mining signal for ALS with fenofibrate, another lipid-altering drug associated with myopathy Detected data mining signals for dermatomyositis and polymyositis with statins

20. FDA Advisory Committee Meeting December 13, 2007 20 Next Steps Ongoing case-control study Kaiser Permanente Northern California Lorene Nelson, PhD, Stanford University School of Medicine is the Principal Investigator Questions addressed: –Does the use of cholesterol-lowering drugs increase the risk of developing ALS? –Is the use of cholesterol-lowering drugs associated with the length of survival after diagnosis among subjects with ALS? –Is there a relationship between cholesterol levels prior to disease onset and the risk of developing ALS, independent of the use of cholesterol lowering agents? Study should be completed in mid-to-late 2008 Ongoing case-control study Kaiser Permanente Northern California Lorene Nelson, PhD, Stanford University School of Medicine is the Principal Investigator Questions addressed: –Does the use of cholesterol-lowering drugs increase the risk of developing ALS? –Is the use of cholesterol-lowering drugs associated with the length of survival after diagnosis among subjects with ALS? –Is there a relationship between cholesterol levels prior to disease onset and the risk of developing ALS, independent of the use of cholesterol lowering agents? Study should be completed in mid-to-late 2008

21. FDA Advisory Committee Meeting December 13, 2007 21 ColleaguesColleagues Ana Szarfman, MD, PhD Andy Mosholder, MD, MPH Devanand Jillapalli, MD Jay Levine, PhD Jo Wyeth, PharmD Mark Avigan, MD, CM Joe Tonning, MD, MPH Rita Ouellet-Hellstrom, PhD, MPH Allen Brinker, MD, MPH Ana Szarfman, MD, PhD Andy Mosholder, MD, MPH Devanand Jillapalli, MD Jay Levine, PhD Jo Wyeth, PharmD Mark Avigan, MD, CM Joe Tonning, MD, MPH Rita Ouellet-Hellstrom, PhD, MPH Allen Brinker, MD, MPH