Non-Prescription Mevacor ® Merck & Co., Inc. New Drug Application 21-213 Nonprescription Drugs and...
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Transcript of Non-Prescription Mevacor ® Merck & Co., Inc. New Drug Application 21-213 Nonprescription Drugs and...
Non-Prescription MevacorNon-Prescription Mevacor®®
Merck & Co., Inc.Merck & Co., Inc.New Drug Application 21-213New Drug Application 21-213
Non-Prescription MevacorNon-Prescription Mevacor®®
Merck & Co., Inc.Merck & Co., Inc.New Drug Application 21-213New Drug Application 21-213
Nonprescription Drugs and Endocrinologic and Nonprescription Drugs and Endocrinologic and Metabolic Drugs Advisory Committee MeetingMetabolic Drugs Advisory Committee Meeting
Silver Spring, MarylandSilver Spring, MarylandDecember 13, 2007December 13, 2007
Eric Colman, MDEric Colman, MDDivision of Metabolism and Endocrinology ProductsDivision of Metabolism and Endocrinology Products
Nonprescription Drugs and Endocrinologic and Nonprescription Drugs and Endocrinologic and Metabolic Drugs Advisory Committee MeetingMetabolic Drugs Advisory Committee Meeting
Silver Spring, MarylandSilver Spring, MarylandDecember 13, 2007December 13, 2007
Eric Colman, MDEric Colman, MDDivision of Metabolism and Endocrinology ProductsDivision of Metabolism and Endocrinology Products
Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research
2FDA Advisory Committee MeetingFDA Advisory Committee MeetingDecember 13, 2007December 13, 2007
ObjectiveObjectiveObjectiveObjective
• To discuss FDA’s evaluation of data mining signals for amyotrophic lateral sclerosis (ALS) with statins
BackgroundALSWhat is data mining?FDA data mining signal scores for ALS with
statinsFDA’s evaluation of the data mining signalsNext steps
• To discuss FDA’s evaluation of data mining signals for amyotrophic lateral sclerosis (ALS) with statins
BackgroundALSWhat is data mining?FDA data mining signal scores for ALS with
statinsFDA’s evaluation of the data mining signalsNext steps
3FDA Advisory Committee MeetingFDA Advisory Committee MeetingDecember 13, 2007December 13, 2007
FDA Observes Data Mining Signal FDA Observes Data Mining Signal for ALS with Statinsfor ALS with Statins
FDA Observes Data Mining Signal FDA Observes Data Mining Signal for ALS with Statinsfor 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
4FDA Advisory Committee MeetingFDA Advisory Committee MeetingDecember 13, 2007December 13, 2007
Edwards, et al.Edwards, et al.Drug SafetyDrug Safety June, 2007 June, 2007
Edwards, et al.Edwards, et al.Drug SafetyDrug Safety June, 2007 June, 2007
5FDA Advisory Committee MeetingFDA Advisory Committee MeetingDecember 13, 2007December 13, 2007
Edwards, et al.Edwards, et al.Edwards, et al.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.”
6FDA Advisory Committee MeetingFDA Advisory Committee MeetingDecember 13, 2007December 13, 2007
Wall Street Journal Wall Street Journal July, 2007July, 2007
Wall Street Journal Wall Street Journal July, 2007July, 2007
7FDA Advisory Committee MeetingFDA Advisory Committee MeetingDecember 13, 2007December 13, 2007
Amyotrophic Lateral SclerosisAmyotrophic Lateral SclerosisAmyotrophic Lateral SclerosisAmyotrophic 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
8FDA Advisory Committee MeetingFDA Advisory Committee MeetingDecember 13, 2007December 13, 2007
Drug Safety Data MiningDrug Safety Data MiningDrug Safety Data MiningDrug 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
9FDA Advisory Committee MeetingFDA Advisory Committee MeetingDecember 13, 2007December 13, 2007
Proportional Reporting RatiosProportional Reporting RatiosProportional Reporting RatiosProportional Reporting Ratios
Observed/Expected
a/(a+b)/c/(c+d)Observed/Expected
a/(a+b)/c/(c+d)
Reports With
Adverse Event Y
Reports Without Adverse Event Y
Drug X a b a+b
All Other Drugs c d c+d
a+c b+d total
10FDA Advisory Committee MeetingFDA Advisory Committee MeetingDecember 13, 2007December 13, 2007
ExampleExampleExampleExampleReports
With Pancreatitis
Reports Without
Pancreatitis
Lipovent 10 200 10/10+200
All Other DrugsIn AERS
3 2000 3/3+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
11FDA Advisory Committee MeetingFDA Advisory Committee MeetingDecember 13, 2007December 13, 2007
Data Mining TerminologyData Mining TerminologyData Mining TerminologyData 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
12FDA Advisory Committee MeetingFDA Advisory Committee MeetingDecember 13, 2007December 13, 2007
What Constitutes a Data Mining Signal?What Constitutes a Data Mining Signal?What Constitutes a Data Mining Signal?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
13FDA Advisory Committee MeetingFDA Advisory Committee MeetingDecember 13, 2007December 13, 2007
FDA Data Mining Signal Scores FDA Data Mining Signal Scores for Statins and ALSfor Statins and ALS
FDA Data Mining Signal Scores FDA Data Mining Signal Scores for Statins and ALSfor Statins and ALS
Ingredient EBGM EB05 EB95
Pravastatin 2.7 1.4 5.0
Fluvastatin 1.6 0.5 4.1
Atorvastatin 9.3 7.0 12.1
Cerivastatin 3.8 2.5 5.7
Lovastatin 2.5 1.0 5.7
Simvastatin 4.4 3.0 6.4
Rosuvastatin 2.4 1.2 4.4
EBGM is not an odds ratio or a measure of relative or absolute risk
EBGM is not a causality score
14FDA Advisory Committee MeetingFDA Advisory Committee MeetingDecember 13, 2007December 13, 2007
What Did FDA Do In Response to the Data What Did FDA Do In Response to the Data Mining Signals for ALS and Statins?Mining Signals for ALS and Statins?
What Did FDA Do In Response to the Data What Did FDA Do In Response to the Data Mining Signals for ALS and Statins?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
15FDA Advisory Committee MeetingFDA Advisory Committee MeetingDecember 13, 2007December 13, 2007
Review of AERS Reports of ALSReview of AERS Reports of ALSReview of AERS Reports of ALSReview 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
16FDA Advisory Committee MeetingFDA Advisory Committee MeetingDecember 13, 2007December 13, 2007
Retrospective Analyses of Statin Retrospective Analyses of Statin Clinical TrialsClinical Trials
Retrospective Analyses of Statin Retrospective Analyses of Statin Clinical TrialsClinical 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
17FDA Advisory Committee MeetingFDA Advisory Committee MeetingDecember 13, 2007December 13, 2007
Statin Use – ALS IncidenceStatin Use – ALS IncidenceStatin Use – ALS IncidenceStatin 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.
• 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.
0
20
40
60
80
100
120
140
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
Year
# of
Pre
scrip
tions
(mill
ions
)
Atorvastatin
Simvastatin
Lovastatin
Rosuvastatin
Pravastatin
Fluvastatin
Cerivastatin
Total (all statins)
Dispensed prescriptions by US retail pharmacies. Verispan Vector One; National, Years 1991-2006, Extracted October 2007
18FDA Advisory Committee MeetingFDA Advisory Committee MeetingDecember 13, 2007December 13, 2007
What Should We Make of the Data What Should We Make of the Data Mining Signals?Mining Signals?
What Should We Make of the Data What Should We Make of the Data Mining Signals?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?
19FDA Advisory Committee MeetingFDA Advisory Committee MeetingDecember 13, 2007December 13, 2007
Reporting BiasesReporting BiasesReporting BiasesReporting 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
20FDA Advisory Committee MeetingFDA Advisory Committee MeetingDecember 13, 2007December 13, 2007
Next StepsNext StepsNext StepsNext 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
21FDA Advisory Committee MeetingFDA Advisory Committee MeetingDecember 13, 2007December 13, 2007
ColleaguesColleaguesColleaguesColleagues
• 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