non-prescription mevacor ® merck & co., inc. new drug application 21-213 nonprescription drugs...

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


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


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


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.”


Wall Street Journal Wall Street Journal July, 2007July, 2007

Wall Street Journal Wall Street Journal July, 2007July, 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


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


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


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


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


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


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


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


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


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


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


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?


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


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


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

non-prescription mevacor ® merck & co., inc. new drug application 21-213 nonprescription drugs...

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