# Presentation: 399616

## MevacorTM Daily (lovastatin)Tablets, 20 mgMerck & Co., Inc.

**Joint Meeting of the Nonprescription Drugs and**
**Endocrinologic and Metabolic Drugs Advisory Committees **
**Silver Spring, Maryland**
**December 13, 2007**
**Shewit Bezabeh MD, MPH**
**Division of Drug Risk Evaluation, **
**Office of Surveillance and Epidemiology **

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

## Introduction/Background  

**Regulatory background**
**January, 2005 AC meeting, the NDA was ****non-approvable**** due to several deficiencies**
**One deficiency - lack of adequate safety data of lovastatin   in patients with asymptomatic liver disease**
**Applicant submitted  “****A study of potential hepatotoxicity of Lovastatin in  Kaiser Permanente Northern California (KPNC) liver disease population”**

**Notes:**
Good morning members of the committee, my name is shewit bezabeh , I’m a medical epidemiologist with the office of surviellance and epidemiology, Division of Drug Risk Evalaution. This morining I will be discussing FDA’s review of a pharmacoepidemiology study submitted by the applicant. Durging the last AC meeting held on January, 2005, the NDA was non-approvable due to  a number deficiencies sited. 
Among the deficiency were that at the time of the NDA review, there were lack of adequate safety data of Lovastatin use in patients with asymtomatic or pre-existing liver disease. 
Since, the AC meeting, the applicant had a submitted a pharmacoepidemiology study titled “ a study of potential hepatotoxicity of lovastatin in Kaiser Permanente Northern California liver disease population. 

## Introduction/Background

**Objective of presentation**
** **
**Review of the submitted population study**
**Discuss the study’s strengths **
**Major limitations:**
**Channeling  bias  **
**Heterogeneity of baseline liver “disease”**
**Surveillance bias**
**Study results**
**FDA’s Review and Conclusions**** **
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**       **

**Notes:**
The objective presentation today is 
 to review and critic the population study. 
I will discuss the strength of the study as well the major limiations. 
With regard to the limitations of the study, I will focus on three major which include
1.Channeling bias also referred as confounding by contraindication ( a bias where lovastatin is channeled to patients at low risk and /or where high risk subjects are not treated)
2. The composition of the cohort, where disparate clinical entities and hetergenous baseline liver disease based on author’s definition were included
3. Surveillance bias ( tendency to monitor liver enzyme tests in patients with liver disease and the tendency to discontinue lovastatin after a positive test
And Finally, I will discuss the study results, FDA’s review and final conclusion.

## KPNC study

**A ****retrospective cohort**** observational study**
**KPNC is an integrated health plan with  > 3.2 million members and an electronic information system**

## KPNC study

**Population****: HMO members with liver disease or evidence of hepatic dysfunction**
**Study Period****:  January 1, 1995 to June 30, 2004**

**Notes:**
The population as mentioned above consisted HMO members with liver disease or some evidence of hepatic dysfunction
Exposure is Lovastatin prescription for 1 year prior to enrollment into study. 
The study period was from January 1, 1995 to June 30, 2004.

## KPNC study

**Inception Cohort:**** **
** ****Adults with evidence of liver disease at baseline ****or **
** ****High risk for liver disease due to either elevated liver test or presence of a selected diagnosis**
**13 months of continuous membership**
**No statin exposure 1 yr prior to study entry**

**Notes:**
The cohort of the study included adult patients with evidence of liver at baseline or who were felt to be a high risk to develop liver disease due to either the presence of elevated liver enzyme tests or a presence of a diagnosis
Inaddition, study subjects had at least 13 months of continuous membership in the HMO and No Statin Exposure one year prior to study enrollment.

## KPNC study

**Inclusion Criteria:**
** ****Presence of at least one of the following:**
**Elevated ALT and/or AST at least on two occasions 6 to 18 months apart**
**Diagnosis of liver disease **
**Chronic Viral hepatitis **
**Metabolic disorders (Wilson’s disease, hemochromatosis)**
**Other Chronic Liver Diseases: e.g.  chronic liver disease, alcoholic fatty liver, biliary cirrhosis **

**Notes:**
Inclusion criteria include the presence of at least one of the following: 
Elevated ALT and/ Or AST  at least on two occassions 6 to 18 months apart
The presence of liver disease ( this is based on medical records diagnosis), presence of viral hepatitis, metabolic disorder such as Wilson’s disease, hemachromatosis), 
The Presence chronic liver disease daignosis for example, diagnosis of chronic liver disease, alcoholic fatty liver, biliary cirrhosis etc.

## KPNC study

**Exclusion  Criteria**
** ****Past Hx of the following diagnosis**
**Drug-induced liver disease**
**Disorders of bilirubin excretion**
**Cancer (except non-melanoma skin)**

**Notes:**
The exclusion criteria included any statin prescription one year prior to study enrollment and any past medical history of the following diagnosis:
Drug-induced liver disease
Disorders of bilirubin excretion 
Or any past medical history of cancer ( excpet non-melanoma of skin)

## Study Outcomes 

** ****Primary: **
**	****	**** ****Hy’s Rule (ALT > 3x ULN, Total Bili  > 2x ULN ****	****  and AP ****≤ 1.5 ULN)**
** ****Secondary: **
**Liver injury (ALT 3X ULN or Bili 3x ULN)**
**Cirrhosis    (automated medical records)**
**Liver Failure (automated medical records)**

**Notes:**
The study primary endpoint was based on the laboratory outcome of Hy’s Rule. Hy’s rule is prognositic indicator of drug induced liver injury and have three components;  ALT greater than 3x the upper limit of normal, Total Bilirubin greater than 2x the upper limit of normal and alkaline phosphotase less than or equal to 1.5 the upper limit of normal.
The study have three secondary endpoints
Liver injury which is a lab based endpoint defined as ALT 3x the upper limit of normal or Bili 3x the upper limit of normal
And two automated medical records based diagnosis outcome of Cirrhosis and Liver failure.

## Data analysis 

**Major Analysis: *****Primary and secondary outcomes***
**Incidence rate ratios (IRR) **
**       ****IRR= IR (exposed) / IR (unexposed)**
**Multivariate analysis **
**	**** *****adjustments for potential confounders*****:**
**Age**
**Gender**
**General health status**
**Concomitant medications **

**Notes:**
The study conducted a number of analysis 
For the Primary and secondary outcomes:
Incidence rate rations defined as Incident rate of the exposed devided by the incident rate of unexposed.
In addition, mutivariate analysis was also planned to be conducted for both primary and secondary outcomes. Mutivariate analysis with to be conducted with adjutsment for potential confouders  which were identified as
Age, Gender, general health status and concomitant medications

## Data analysis

**Secondary and sensitivity analyses:**
**Liver disease etiology subgroup **
**Dose-response (cumulative amount or cumulative number of days)**
**Lovastatin**** ****discontinuation **
**Channeling bias sub-study**
**Analysis for confounders: age, gender, general health status and concomitant medications)**

**Notes:**
The authors also conducted a number of small sub-studies and sensitivity analysis to assess for biases and confirm study results;
Some the small sub-studies condcuted include analysis for liver disease etilogy subgroup, 
Dose response analysis where dose-response was analysed base on cumulative amount or prescription or comulative number of days. I would like to note that there was specific dose such 20 mg which is planned for the OTC swith studied.
Lovastatin dis-continuation,and channeling bias sub studies and various analysis for earlier mentioned confounders were conducted on the secondary study outcomes.

## Study Results: Demographic Data 

|  | All
Patients | Exposed  | Unexposed
 |
| --- | --- | --- | --- |
| # (%) | 93,016 | 13,491(15) | 79,615 (85) |
| Age, Yrs  | 48.4 | 53.9 | 47.5 |
| Men (N, %) | 56,900 (61) | 8,394(62) | 48,506(61) |
| F/u (months) | 28.8  | 36.0 | 27.9 |

**Notes:**
The demographic data showed that the cohort consisted of about 93, 000 patients. Of these about 13, 500 or 15% had lovastatin exposure, while 85% or about 80, 000  of the cohort did not receive the drug during the study period.
The median age of the exposed population was about 54 years when compared to that unexposed which was about 48 years.
The presentage of men was higher in study accounting for about 61%
The Exposed population has a longer folllow up time of 36 months with median 9.1 months compared to that of the non-exposed population which was about 28 months.  
As you can see, the demographic data showed that patienst on lovastatin were older, and were followed up for a longer period than those who did not receive the drug. This consistent with clincal practice as patient who have a higher risk for cardiovascular disease are older have a closer follow up.

## Primary Outcome

*** Based on per person-days exposure**
**** unadjusted for all potential confounders **
***** Exposure to Lovastatin was associated with 72% decrease in the risk of achieving Hy’s Rule endpoint.**

|  |  Exposed  |  | Unexposed  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
| Outcome | #  | IR* | # | IR* | IRR** | 95% 
CI+ |
| Hy’s Rule  | 8 | 1.69 | 616 | 6.13 | 0.28*** | 0.12-0.55 |

**Notes:**
The primary outcome results showed that there were only eight observed  Hy’s Rule events in the exposed population during the study period compared to 616 of Hy’s rule events observed in the unexposed population. The calculated incidence rate, based on person-days of exposure was 1.69 for the exposed and 6.13 for unexposed. The calculated incident rate ration ( Incident rate of exposed over the incident rate of unexposed ) was 0.28.  Based on This incidence rate ration , exposure to lovastatin was associated with 72% decrease in the risk of achieving the Hy’s Rule Endpoint.
I would like to point out that due to the small number of Hy’s Rule events observed in the exposure group, the incidence rate was not adsjusted for all the potential identified confounders.

## Secondary Outcome

*** Laboratory diagnosis **
**** unadjusted for all potential confounders****  **

|  | Lovastatin Exposure |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  |     Yes  |  | No |  |  |  |
| Outcome | # | IR** | #  | IR** | IRR  | 95% CI |
| Injury* | 177 | 45 | 6661 | 89 | 0.5 | .43-.58 |
| Cirrhosis  | 39 | 8.4 | 3173 | 34 | .25 | .18-.34 |
| Liver failure | 24 | 5.1 | 2402 | 24.4 | .21 | .13-.31 |

**Notes:**
The results of the secondary endpoint showed, similar to the results of primary outcome, incidence rate ratios of less than one. The Incident rate ratio for the laboratory based outcome was 0.5 where as the two automated medical record outcomes of cirrhosis and Liver failure revealed a similar ration of 0.25 and 0.21. Again, I would like to point out that these results  were not adjusted for all potential confounders. 

## Secondary Composite Outcome

*******Combined secondary outcome are not mutually exclusive (1st occurrence of a liver injury, cirrhosis, or liver-failure****)**
**** ****unadjusted for all potential confounders**** **

|  |  Lovastatin  Exposure |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | Yes  |  | No  |  |  |  |
|  |  # | IR | #  | IR** | IRR | 95% CI |
| Combined
Outcome* | 201 | 52.5 | 7751 | 109 | 0.48 | .42-.55 |

**Notes:**
The author’s also analysis a composite combined outcome, where the first occurrence of a secondary was used since secondary outcomes were not mutually exclusive. The Incidence rate ratio was 0.48 which similar to the previous results. 

## Conclusions by Study Authors

**“****Fewer adverse outcomes in KPNC patients with baseline liver disease who were exposed  to lovastatin compared to non exposed”.**
**“****Lovastatin exposure appears to be protective of adverse outcomes in liver disease patients”.**

**Notes:**
Based on the results both the primary and secondary outcomes: The author’s concluded that “Fewer adverse outcomes in Kaiser Permanente Northern California patients with baseline liver disease who were exposed to lovastatin compared to those nonexposed.
In addition, the authors postulated that lovastatin exposure appears to be protective of adverse outcomes in liver disease patients. 

## Author’s Conclusions - Continued

**Sub-study and sensitivity analyses**
**Little evidence for channeling bias ****	****(or confounding by contraindication)**
**No significant evidence of lovastatin discontinuation in liver disease patients**
**Sensitivity analyses did not alter the conclusions**

**Notes:**
The results sub-studies and sensitivity analyses conducted showed that there was little evidence for channeling bias ( confounding by contraindication),  There was no significant evidence of lovastatin discontinuation in liver disease patients 
All sensitivity analyses conducted did not alter the author’s conclusions.

## FDA Analysis: Study Limitations

**Channeling Bias**
**	****- *****lovastatin preferentially prescribed (or channeled) to individuals at low risk for liver disease due to prominent labeling for risk of hepato-toxicity***
***	******- lovastatin preferentially avoided in patients at high risk for liver toxicity***

**Notes:**
The major limitation of the study is channeling bias. We know from clinical practice that lovastatin is preferentially prescribed (or channeled ) to individuals at low risk for liver disease due to prominent labeling of risk for hepatotoxicigty,
We also know from clinical practice that Lovastatin is preferentially avoided in patients at high risk for liver toxicity
Given the fact this is   a retrospective, observational study and given the limitations administrative data,  we are unable to address or adjust for this issues.  
In addition, residual confounding can not be measured accurately. 

## FDA Analysis: Study Limitations

**Channeling Bias (continued) **
**	****- *****unable to address / adjust for this issue given limitations of administrative data***
***	******- results in residual confounding***

**Notes:**
The major limitation of the study is channeling bias. We know from clinical practice that lovastatin is preferentially prescribed (or channeled ) to individuals at low risk for liver disease due to prominent labeling of risk for hepatotoxicigty,
We also know from clinical practice that Lovastatin is preferentially avoided in patients at high risk for liver toxicity
Given the fact this is   a retrospective, observational study and given the limitations administrative data,  we are unable to address or adjust for this issues.  
In addition, residual confounding can not be measured accurately. 

## FDA Analysis: Study Limitations

**Channeling Bias (continued)**
**  ****	****- ****Of 6391 patients with both hypercholesterol-emia (LDL > 160 mg/dL)  and liver disease, only 2746 ( 43%) were treated with lovastatin****.  **
**      *****No explanation was provided why 57% of hypercholesterolemic (LDL > 160 mg/dL) patients did not receive  lovastatin; suggesting confounding by diagnosis.***

**Notes:**
For example, during the conduct of lovastatin surveillance sub-study, the authors identified 6391 patients with both hypercholestrolemia with LDL greater than 160 mg/ dL and liver disease.  Of the 6391 patients only 2746 (43%) were treated with lovastatin. 
There was no explanation provided why 57% of these hypercholestrolemic patients did not receive the drug. The fact that 57% of patients were not of lovastatin is suggestive of confounding by diagnosis.

## FDA Analysis: Study Limitations

**2. Baseline liver disease**
**The cohort of patients with liver disease consisted multiple potentially disparate clinical entities, resulting in clinical heterogeneity and disparate outcomes**
**Misclassification**
**Stratification**

**Notes:**
The second limitation of the study is composition of the cohort population. The cohort of patients with liver disease consisted of multiple potentially disparate clinical entities, resulting in clinical heterogeneity and disparate outcomes
The multiple clinical entities also result another potential significant bias by Misclassification of diagnosis and outcomes
The fact that were many potential disparate clinical entities and  a very small number of observed primary outcome Of Hy’s Rule, further analysis by stratification and/or adjustments  were not possible. Limiting the validity of study results.

## FDA Analysis: Study Limitations

|  |  Events
Exposed  | Events
Unexposed |
| --- | --- | --- |
|      Hy’s Rule  | 8 | 616 |
| Baseline diagnosis  |  |  |
|     Viral Hepatitis  | 0 | 269 |
|     ALD (alcoholic Liver disease) | 2 | 54 |
|     FLD (fatty liver disease) | 0 | 6 |
|     other diagnosis | 1 | 161 |
| Abnormal LFTs | 5 | 126 |

**Notes:**
As can be seen from this table, of the eight primary endpoints observed in the exposed patients, the majority (5/8) were in the group with baseline diagnosis of abnormal liver function tests, where as the group with the diagnosis of fatty liver disease had the least amount of observed events. Again, due to the small and disparate events observed, adjustments for confounding factors and stratification were not conducted.

## FDA Analysis: Study Limitations

** ****3****. ****Surveillance bias**
**Tendency to discontinue lovastatin after a positive test or after a liver disease diagnosis**
**Surveillance bias Sub Study showed increased frequency of liver enzyme testing in subjects with liver disease **
**lovastatin exposed had 46% more LFT testing compared to non-exposed**
**Impact of differential surveillance on study outcome is not clear**

**Notes:**
The third major study limitation is surveillance bias. A surveillance bias  sub study conducted by the authors showed increased frequency of liver enzyme testing in subjects with liver disease. Lovastatin exposed subjects had 46% more testing compared to non-exposed. The impact of such differential surveillance on study outcome is not clear.

## Overall   Conclusions

**A well conducted large study**
**Most of the limitations are associated  with observational studies: **
**Evidence of channeling **
**Disparate baseline disease**
**Surveillance bias**

## Summary  Conclusions

**The study’s findings are consistent with results of other published studies and suggest that exposure to lovastatin in patients with baseline liver abnormalities do not appear to increase the risk of hepatotoxicity.**

## Summary  Conclusions

**Because of  the limitations and nature (retrospective observational) of the study, a clinically significant hepatotoxic effect of lovastatin cannot be ruled out. **
**Furthermore, it is not possible to determine if there is a protective role for lovastatin in the setting of baseline liver disease.**

## Acknowledgements

**CDER Review Team**
**Mark Avigan, M.D., C.M. ****Division of Drug Risk Evaluation **
**Allen Brinker M.D., M.S.  ****Division of Drug Risk Evaluation **
**Eileen Craig, M.D., ****Division of Metabolic and Endocrine Products**** **