# Presentation: 836898

## Accutane® Use and  Epidemiology

- John E. La Flore, MD, MSPH
- Vice President, Drug Safety & Risk Management
- Hoffmann-La Roche Inc.

**Notes:**
Good morning,

I am John La Flore, Vice President of the Department of Drug Safety and Risk Management at Hoffmann - La Roche

## Topics

- Accutane use and severe recalcitrant nodular acne
- Pregnancies

**Notes:**
This section is intended to provided information on the current patterns of Accutane use and to set the context for the Pregnancy Prevention Program......PPP........ with regards to
Risk Assessment which will be addressed by 	Dr. Alan Mitchell 
Risk Management which will be addressed by Ms. Eileen Leach

## Objectives

- The increased use of Accutane does not imply increased use outside the indication
- While use is increasing, pregnancy rates have been declining and numbers of pregnancy reports have remained stable
- The overall pregnancy rate from the Accutane Survey 2.8/1000 is supported by additional data

**Notes:**
Even though the use of Accutane has increased over the years, it does not imply increased use outside the labeled indication
And, though the use is increasing......
pregnancy RATES are DECLININGand
ABSOLUTE NUMBERS of pregnancy reports are STABLE

The overall pregnancy rate from the Accutane Survey....... 2.8 per 1000...... supported by additional data

## Reporting of Accutane Use

**Reporting of Accutane Use**

-    Three sources of data are summarized to generate the estimates of new patients and total prescriptions each month
- Total retails prescription in the U.S.
- 3rd Party payment tracking
- Roche factory shipments

**Notes:**
In 1991, the agency and Roche agreed on a METHOD of Reporting Estimates of Use.  Three sources of data are used:
1.  Total retail prescription in the U.S. (Pharmacies)
2.  3rd Party payment tracking (Pharmacy Records)
3.  Roche factory shipments: The estimates are then adjusted to the Roche Factory Shipment Records

THESE data are patient based as opposed to physician based

## Estimated Number of Total Patients Using Accutane

**Number of****Patients**

**Notes:**
This graph shows that while the use of Accutane is increasing.....
The use by males AND females remains approximately EQUAL.

BUT, In order for a patient to be included in the previous graph, they would have to meet these 3 criteria

## Accutane Use

-    In order to be counted as an Accutane user in these data, the patient would have:
- 	A.  Been seen by a physician
- 	B.  Been diagnosed with acne (98%)
- 	C.  Been prescribed Accutane

**Notes:**

1.  Be seen by a physician 
2.  Have been diagnosed with acne - this was based on the ICD-9 coding which did not distinguish between grades of Acne
3.  Must have been prescribed Accutane

## Data Sources Used to Understand Accutane Use:

- US National Health And Nutrition Examination Survey (NHANES) 1972-1974
- supported by similar more recent, international data
- Large surveys of physicians
- Medical utilization data

**Notes:**
The data sources used to understand Accutane USE are shown here.
The first source is NHANES, the National Health and And Nutrition Examination Survey which was used to estimate the prevalence of severe acne 
We understand the concern that this survey is from 1974.  However it is the ONLY U.S. data source that can be used.
Furthermore, NHANES is supported by additional international studies (Post-Accutane ERA)
The second source is from large surveys of physicians that provides information on prescription practices regarding what patients they see and how they treat these patients
And finally......medical utilization data from NHAMCS (National Hospital Ambulatory Medical Care Survey)

## Accutane Use

**Accutane Use**

- 	The NHANES prevalence rate provides quantitative context for the use of Accutane in the treatment of severe recalcitrant nodular acne

**Notes:**
Unfortunately, there is no information on true incidence rate for severe acne ......due to the clinical characteristics of severe acne, with regards to duration of disease, relapse rates, and age and gender.  Any incident rate would be arbitrary.
Therefore, we will present prevalence rates as directly obtained from the NHANES survey.
NHANES survey provides a reasonable quantitative context for the use of Accutane in the treatment of severe recalcitrant nodular acne.

## Accutane Use

**Accutane Use**

- Daniel, et al, (2000)
- Kilkenny, et al, (1998)
- Lello, et al, (1995)

- Additional studies or surveys of prevalence since Accutane has been available are consistent with the NHANES point prevalence

**Notes:**
The data from NHANES are supported by additional international studies in the post ACCUTANE era.  

## Comparison of NHANES Prevalence of Severe Acne to Accutane Utilization in 1998

**Notes:**
This table shows the prevalence of persons with 	severe acne compared to Accutane prescriptions
We are aware of the limitations of this dataset and that the actual number of patients eligible for treatment may be somewhat lower.
However, the key findings are that there does not appear to be an excess of prescriptions in relation to the prevalence of severe acne.
I would like to point out the 20-29 year old female group........(POINT AT SLIDE)  
The prevalence is approximately 300,000 and the number of prescriptions is approximately 60,000
You will notice that although less women have severe acne after age 20 they receive more prescriptions than men, but it is because.......

## Females Have More Visits Than Males

- NHAMCS

- Age (Years)	Female Thousands	Male Thousands
- 	(%)	(%)

- *Value corrected from Briefing Document

**Notes:**
More women see their physicians for the treatment of acne.

Also, women see their physicians more often for treatment of their acne. 

## Treatment Visits

- Less than 5% of female patients receive Accutane at their first visit to the dermatologist
- Female patients are 3.5 times more likely to receive antibiotics than Accutane at a visit
- Female Accutane patients are on average 5 years older than male patients

- NHAMCS

**Notes:**
Medical utilization data also shows us that female acne patients are usually older, and are more likely to receive antibiotics at their first visit.  

They are RARELY prescribed Accutane at their first visit.

## Prescription Patterns for Accutane

- Severe acne patients are seen on average 9 times per year
- 56% of patients with severe acne are treated with Accutane by the dermatologist
- Dermatologists use variety of medications before prescribing Accutane
- Physicians prescribe Accutane in small percentage of patients with less severe acne

- Market Measures Inc.

**Notes:**
When physicians were surveyed about prescription patterns, the responses indicate that :
Severe acne patients are seen on average 9 times per year
56% of patients with severe acne were treated with Accutane by the dermatologist
44% of the patients with severe acne, received treatments other than Accutane 
Dermatologists use variety of acne medications before prescribing Accutane 
Physicians prescribe Accutane in small percentage of patients with less severe acne

## Accutane Use

-   The increased use of Accutane does not imply increased use outside the indication

**Notes:**
Taking all of these data together, the increased use of Accutane does not imply increased use outside of the labeled indication

USE for SUMMARY

## Number of Reported Pregnancies 1982- Present by Year of Therapy (US) 

- Accutane Survey

- Reported Pregnancies

- Year

- DateUnknown

- Note: Cumulative data cut-off date of March 31, 2000; data were submitted to FDA in the 2nd Accutane Quarterly Report for 2000.

## Reports of Pregnancy

- Solicited reports of pregnancies are collected from a defined denominator from the Accutane Survey by the Slone Epidemiology Unit
- This generates the pregnancy rate
- Spontaneous reports of pregnancies are received by
- Roche
- FDA
- CDC

**Notes:**
Reports of pregnancy are collected via:
Solicited reports of pregnancies collected from a defined denominator from the Accutane Survey by the Slone Epidemiology Unit 
- This generates the pregnancy rate
- Of the 1⁄2 million women enrolled>80% have responded since the program 	began

Second, Spontaneous reports of pregnancies are received by 
Roche
FDA
CDC Spontaneous Reports

## Analysis of Adverse Events and Pregnancies Associated with Accutane Therapy

**Per ****1000 Patients**

**Notes:**
One might expect that pregnancy reports are decreasing since reporting of adverse events generally decrease with most products over time
But as this graph shows, the spontaneous reports of pregnancies have been stable while reports of adverse events have not decreased.
This suggests that it there is NO decline in the reporting pregnancy rate.

## Does the Age of Patients in the Accutane Survey Represent the User Population?

- Age proportionality in Accutane Survey compared to Accutane users has remained consistent
- Proportional distribution of age in the Accutane Survey is similar to Accutane users except for:
- Overrepresentation in age 20-29 years old
- Underrepresentation in age > 40 years old

**Notes:**
One may ask, does the Accutane Survey represent the actual user population?
The Proportional distribution of age in the Accutane Survey is similar to Accutane users . 
If anything, the survey overrepresents the high risk group:........Women 20-29 years old 
Later, Dr. Mitchell will go into the details of the Accutane Survey

## Frequency and Incidence Rate of Pregnancy Among Female Accutane Users

-  * Rate adjusted for median of 140-day courses
- ** Median duration of therapy was approximately 140-day courses.

**Notes:**
To validate the pregnancy rates from the Accutane Survey, we  looked at  other sources.
We looked at the United Health Care (UHC) database, one of the largest healthcare plans.
There was NO significant difference in the pregnancy rates between the UHC database and the Accutane Survey. 

## Frequency and Incidence Rate of Pregnancy Among Female Accutane Users

- ** Median duration of therapy was approximately 140-day courses.

**Notes:**
The pregnancy rate from the Phase III clinical trial was the same.  3 per 1000. 

This goes to show that, even in the setting of a clinical trial, the most controlled, mandatory environment, a patent still got pregnant.

## Summary

-    The overall pregnancy rate from the Accutane Survey 2.8/1000
- Supported by additional supporting evidence
- Declining since the initiation of Pregnancy Prevention Plan

**Notes:**
In summary, the data presented for the Accutane Survey shows that the pregnancy rate is 2.8 per 1000 and that this is supported by additional evidence.
Also, the pregnancy rate has been declining since the initiation of Pregnancy Prevention Plan
In all our discussions going forward, we will be using the rate of 3/1000 patients

## Conclusion

-    The evidence presented indicates that for every 1000 women treated with Accutane, pregnancy has not occurred in 997.

**Notes:**
The evidence presented above indicates that for every 1000 women on Accutane, 997 avoid becoming pregnant.
Dr. Mitchell will now present the Accutane Survey which is a critical component of the PPP in terms of Risk Assesment