# Presentation: 189315

## 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**

**Center for Drug Evaluation and Research**** **

## Objective

- 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

## 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

## Edwards, et al.Drug Safety June, 2007

## 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 July, 2007

## 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

## 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

## Proportional Reporting Ratios

- 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 |

## Example

|  | Reports With  Pancreatitis | Reports Without Pancreatitis |  |
| --- | --- | --- | --- |
| Lipovent | 10 | 200 | 10/10+200 |
| All Other Drugs
In 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 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

## 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

## FDA Data Mining Signal Scores for 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 Mining Signals for ALS and Statins?

- Reviewed:
- AERS reports of ALS
- Statin clinical trial data
- Population-based ALS incidence data

## 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

## 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**

## 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

##  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?

## 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

## 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

## Colleagues

- 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