# Presentation: 695086

## FVIII PRODUCT USAGE IN CLINICAL SETTINGS

**TSEAC**
- October 31, 2005
- Mark Weinstein, Ph.D.
- Office of Blood Research and Review
- CBER, FDA

## Topics

- Issue:   What data should be used to estimate how much FVIII is used by typical patients?
- Need to know:
- Definition of typical patient
- Dosage
- Frequency of dosage
- Period of time to be evaluated
- Background: patient characteristics
- Available estimates, data and limitations
- Proposal

**Notes:**
As Dr. Anderson mentioned, I will talk about the untilization of FVIII product usage in clinical settings.  Utilization factors being considered for the model include the severity of the disease and treatment regimans. I will also talk about our proposal to model cumulative VCJD exposure per year assuming a linear ID50 dose-response. 
The first question is What data should be used to estimate how much FVIII is used by typical patients?  
For this estimation, we need to know what is the definition of a typical patient,how much product is used per treatment, what is the frequency of dosage, and the period of time to be evaluated.

To answer these questions, I will breifly review some of the characteristics of the patient populations we are considering, available data sources for estimates of dosage, dosage regimin, and their limitations.

## Background: Hemophilia A and von Willebrand Disease (vWD)

**Notes:**
Hemophilia A is inherited as a x-linked recessive trait. It is caused by a deficiency of coagulation factor VIII (FVIII) related to mutations of the clotting factor gene.
The age adjusted prevalence of hemophilia A in the US is approximately 1 in 10,000 males. 
FVIII normally circulates in the plasma bound to a second very large protein, von Willebrand factor. wWF protects FVIII from proteolysis, enhances FVIII synthesis, and concentrates FVIII at the site of active hemostasis.  vWF is also needed for binding platelets to wound sites
If you have reduced levels of vWF activity, you have von Willebrands disease.  There are several different types and subtypes of vWD, but we will consider in our model Type III, which is the most severe and requires treatment with plasma derived products.
vWF occurs in higher concentration than FVIII.  In hemophilia A you can have no circulating FVIII but normal levels of VWF.  But in severe forms of vWF, with little or no vWF present, there will be little circulating FVIII.
To treat hemophilia A you need products that contain FVIII but may or may not contain vWF.  
To treat type III vWD, you need concentrates that contain both FVIII and vWD

## Background: Hemophilia A and vWD

| Severity  | Clotting Factor Level            
 (% activity) | Bleeding Episodes  | U.S. Population (Est.) 2002   
(% patients)  |
| --- | --- | --- | --- |
| Severe  | <1%  | Spontaneous bleeding, predominantly in joints and muscles  | 6200 (43%)* |
| Moderate  | 1% - 5%  | Occasional spontaneous bleeding.  Severe bleeding with trauma, surgery  | 3600 (25%)* |
| Mild  | 6%- 30%  | Severe bleeding with major trauma or surgery  | 4600 (32%)*  |
| Type III vWD  | <1% vWF,
2-3% FVIII  | Mucosal, joint, muscle bleeding, Severe bleeding with trauma, surgery  | 250**  |

- *Soucie et al, Am J Hematol, 1998
- **Universal Data Collection Project

**Notes:**
This chart outlines some of the characteristics of the HA and vWD populations we are considering.  Each of the populations are treated on average with different total doses of product and at different frequencies.
HA with severe disease have less than 1% F8 and have spontaneous bleeding predominantly in joints and muscles.  They constitute the largest proportion of the HA population.  There were  roughly 6200 patients in the US in 2002.  
Those with moderate disease, with f8 levels of 1 to 5%, have occasional spontaneous bleeding, with severe bleeding accompanying trauma or surgery.  We estimate there are about 3600 individuals in this category, or 25% of the total HA population.
Those with mild hemophilia, characterized by severe bleeding with major trauma or surgery, are around 32% of the HA population, at about 4600 individuals.
Type III vWD patients have less than 1% vWF with 2-3% FVIII.  They often have mucosal bleeding, and severe bleeding with trauma or surgery.  We estimate there are about 250 of these individuals in the US.

## Product Usage

- Most Hemophilia A patients use recombinant FVIII first licensed in 1991
- Type III vWD patients use plasma derived products containing FVIII and vWF.  Hemophilia A patients can use either FVIII or FVIII/vWF products
- Frequency and dosage of product are highly variable depending on patient weight, type of bleed, clinical severity of disease
- Frequency of usage
- Prophylaxis: variable definition: e.g. 2 - 3.5 [i.e. on alternate days] x per week
- Intermittent Prophylaxis: product used to prevent bleeding for certain events, followed by return to episodic treatment
- Episodic: on demand in response to bleeding complications

**Notes:**
Regarding product usage, the picture is complex.
First, most HA patients, we estimate in the range of 70 to 80%, use recombinant FVIII.  This is particularly true of children.
As I mentioned previously, vWD patients have to use products containing vWF, 
The frequency of product usage and dosage are highly variable, and depend on the patient’s weight, type of bleed, and clinical severity of disease.
Analyzing data about product usage from different data sources is complicated because of  the variation in how investigators define terms such as prophylaxis, intermittent or secondary propylaxis, and episodic or on demand treatment.  For example, in some studies prophylaxis has been defined as receiving product every other day, or once every other 2 days for 45 wks or more, per year.  However, on the form used by the CDC to collect data, prophylaxis is defined as the receipt of treatment products to prevent bleeding or to prevent rebleeding. Prophylaxis is further divided into continuous if products are to be administered indefinitely on a regular schedule to prevent any and all bleeding.  Intermittent prophylaxis is defined as the patient receiving treatment products on a regular schedule for a period of at least 28 days on at least one occasion since the last annual visit, but therapy was not expected to last indefinitely.  Episodic is defined as receiving product only in response to bleeding complications.

## CDC Data for Numbers of Patients Who Receive a Given Product

- 1993-1998 survey of _all_ HA patients in six states. Data includes for each patient:
- Severity of disease based on FVIII activity range
- Total number of bleeding episodes per year
- Estimate of amount of product used per year
- Pattern of usage, e.g. prophylaxis
- Number of weeks scheduled for prophylaxis
- Brand of product(s) used
- Limitations:
- Current usage may not be the same as in 1993-1998
- Extrapolations may not represent use in other states in the US
- No information on vWD type

**Notes:**
The best quantitative data that we currently have access to is from a CDC study carried out from 1993 to 1998 of all HA patients in six states:  Massachusets, New York, Colorado, Georgia, Louisianna, and Oklahoma.  Data was obtained from patient reports obtained from physicians, clinical labs, hospitals, clinical labs, and hemophilia treatment centers.
The list of information obtained in this study included {read slide]
Possible limitations in this data include that it might not reflect current usage. Changes in the average weight, and activity level of patients using plasma derived products may have changed, as the average amount of product used.
Extrapolations to other states in the US might not be accurate although diversity of states in the original study was planned to be representative of the entire country.
Unfortunately, for our purposes, no data was collected specifically on Type III vWD patients. 

## CDC Universal Data Collection Program (UDC)

- The UDC program started in 1998 in Hemophilia Treatment Centers. Data includes:
- Numbers of HTC patients from start of program
- Disease type: Hemophilia A, Severe, moderate, mild, Type III vWD
- Treatment prescription: episodic; continuous or intermittent prophylaxis; immune tolerance
- Product brand used by patient
- Limitations in use of available data for purposes of risk estimate
- Amount of product used per patient was not collected
- Not all patients visit HTCs
- HTC patient population may differ from non-HTC population
- Prophylactic or episodic are broadly defined with respect to amount of product used
- Some patients use more than one product

**Notes:**
The second major source of data we have comes from the Universal data collection program started by the CDC in 1998.  Patients voluntarily give information about [read slide].  
Importantly we can get some information about Type III vWD and product brands used.
No information is collected about the amount of product used.  We therefore have to extrapolate amount of product used from the survey study.
About 85% of patients who go to HTCs are enrolled in the UDC, and from the 1993-1998 survey, about 70% of the total HA population visit HTCs.  The patient population that doesn’t visit HTCs may be different from those that do, for example they may have milder forms of the disease. 
Also we know some patients may use more than one product brand or type of product. 

## Estimated Numbers of Hemophilia A Patients Using pd FVIII Derivatives (2002)*

| TREATMENT | SEVERE | MODERATE | MILD |
| --- | --- | --- | --- |
| Monoclonal purified FVIII |  |  |  |
| Prophylaxis | 324 | 50 | 0 |
| Episodic | 1381 | 350 | 196 |
| Other pd FVIII Products |  |  |  |
| Prophylaxis | 33 | 3 | 3 |
| Episodic | 56 | 14 | 62 |
|  |  |  |  |
| TOTAL HA Patients | 6200 | 3600 | 4600 |
| Percent pd FVIII Treated | 28.9% | 11.6% | 5.7% |

- *Patient numbers are _estimates_, derived from CDC data obtained in 2002 from Hemophilia Treatment Centers as part of the Universal Data Collection Project and extrapolated to the total estimated hemophilia population for 2002

**Notes:**
Nevertheless, using a combination of data from the survey and from the UDC data we have calculated the following information.
Most of the patients who use plasma derived products are in the episodic category, most use monoclonal affinity purifed FVIII.  Of the total 6200 hemophilia patient population in the sever category, about 29% use plasma derived products.  12% of the 3600 ptns in the moderate category use pd f8, and 6% of the 4600 in the mild category use pd f8.

## Estimated Number of Type III vWD Patients Using pd FVIII/vWF Derivatives (2002)*

| TREATMENT | Type III Patient Number |
| --- | --- |
| Episodic | 189 |

- *Patient numbers are _estimates_, derived from CDC data obtained in 2002 from Hemophilia Treatment Centers as part of the Universal Data Collection Project and extrapolated to the total estimated hemophilia population for 2002

**Notes:**
Of the 189 type III vWD patients who received plasma derived clotting factors, all were on episodic treatment. 

## Estimated Range of F VIII Doses for Severe Hemophilia A

- Prophylactic Use (70 kg man) a:
- Episodic Use (70 kg man) b:

| 25 IU/kg
2 Doses/Wk | 182,000 IU |
| --- | --- |
| 50 IU/kg
3.5 Doses/Wk | 637,000 IU |

- a.) Personal Communications
- b.) Liesner RJ, 1996

| 12.5 IU/kg
0.08 Doses/ Week | 3,500 IU |
| --- | --- |
| 25 IU/kg
0.5 Doses/Wk | 45,500 IU
(Median # Doses) |
| 53 IU/kg
1.38 Doses/Wk | 267,120 IU |

**Notes:**
As to the amount of product used, we can make some educated guesses, based on current practice.  For example regarding prophylactic use,  some clinicians have defined it as using 25 to 50 IU per kg, 2 to 3.5 doses per week.  A 70 kg man using 25 iu/kg for 52 wks per year , would use 182000 units/yr  At 50 iu per kg, 3.5 times per wk, he would use 637,000 ius.

The term episodic is ill defined for our purposes, but just to site one study, product was used at a dose of from 12.5 to 53 iu/kg, and was infused from 4 times to 72 times per year.  That study was in children, but for our 70 kg man, this would amount to receiving anywhere from 3500 to 270,000 IU per year.  He would receive 45,500 Iu if he received a median number of doses.

## Reported Mean I.U. Factor VIII Prescribed for Hemophilia A Patients (1998)++

|                      SEVERITY |  |  |  |
| --- | --- | --- | --- |
| Treatment | Severe | Moderate | Mild |
| Prophylaxis | 199,160 IU* | 102,055 IU | 24,556 IU |
| Episodic | 78,559 IU | 20,798 IU | 3,576 IU |

**Linden et al, Transfusion, 2003     **Based on 826 patients in New York State derived from a CDC 1993-1998 population-based study.

**++**Includes both F VIII and F IX deficient patients
*****19% were prescribed more than 250,000 IU; 3.8% more than 500, 000 IU, and       1% more than 1,000,000 IU

**Notes:**
We get a sense that we are in the right ball park about amounts of product per year from a study by Linden.  She used the information obtained in the 1993 – 1998 study, and extracted only that information pertaining to NYS.   She reported that patients under prophylaxis in the severe, moderate, and mild category used about 200000, 100,000 and 25,000 iu per year on average.  Those on episodic treatment, severs used about 80 k, moderates 21k, and milds 3600 iu.  The data is confounded however because estimates were combined from both hemophilia a and b patients.  
An important point however is that we can go back to the original data from all 6 states and with the extremely generous help from Mike Soucie at CDEC we can separate out data about hemophilia a from b patients.

## Conclusions Regarding Clinical Use

- The existing data are limited and have not been analyzed for estimates of clinical use of specific brands of FVIII products in patient groups.
- We plan to analyze data from the ongoing UDC survey (1998-present) to estimate the numbers of patients using specific product brands, and the distribution of disease types, e.g.HA severe, moderate, mild; Type III vWD.
- We also plan to extrapolate data from the 1993-1998 survey in six states to estimate the total number of U.S. patients, and product consumption per patient, with stratification by clinical setting.
- If there is inconsistent information from these two analyses it will be reconciled using patient based medical record data.

**Notes:**
Read slide
We also know that in the future we may be able to get more accurate data about product usage from a survey study of inhibitor formation in hemophilia patients.  This study is part of a larger data collection effort called the National Bleeding Disorders Coalition.  These projects however are still in the planning stage.
We are interested in whether the committee has further ideas about data collection.

## Do Repeated Exposures to Low Doses of vCJD Infectivity Lead to Clinical Disease?

- Hamster Study (Diringer H, et al. 1998)
- Hamsters fed one dose of scrapie infected Hamster brain for one day, one dose each day for 10 days, or one dose every four days for 10 exposures

|  | Fed 1 x (single dose) | Every Day x 10 | Every 4 days x 10 |
| --- | --- | --- | --- |
| Cumulative death rate | 1% | 8% | 4% |

- Can a cumulative effect from repeated exposures to low doses of vCJD agent be incorporated in the risk model?

- Hamsters receiving  a repeated standard infectious dose several times have a higher risk of developing scrapie than those receiving a single infectious dose.

- N= ~ 60 per Group

**Notes:**
I’d next like to turn to the question of whether repeated exposures to low doses of vCJD infectivity lead to clinical disease?

The data about the risk of cumulative exposure is limited to a few studies in animals.  I will describe on such study by Diringer.  
Hamsters were fed one dose of scrapie infected hamster brain for one day, one dose each day for 10 days, or one dose every four days for 10 exposures. There were about 60 animals in each group of animals
About 1% of the animals fed a single dose died, while 8% receiving a dose every day for 10 days died, and 4% died of those receiving a single dose once every four days for 10 exposures.  
The authors concluded that hamsters receiving a repeated standard infectious dose several times have a higher risk of developing scrapie than those receiving a single infectious dose.

## Do Repeated Exposures to Low Doses of vCJD Infectivity Lead to Clinical Disease?

|  | Fed once (dose equivalent to total spread out over 10 feedings for other test groups) | Fed 1/10th dose every day x 10 | Fed 1/10th dose every 4 days x 10 |
| --- | --- | --- | --- |
| Risk of infection  | 11% | 8% | 4% |

- A smaller risk of infection is associated with longer intervals between feeding

- Hamster Study (Diringer H, et al. 1998)
- Hamsters fed a dose of scrapie infected Hamster brain once, 1/10th dose daily for 10 days, or 1/10th dose every four days for 10 exposures

- N = ~ 60/ Group

**Notes:**
In a second part of this study, the authors fed the hamsters one infectious dose once.  They divided the dose into 10 tenths, and gave a tenth every day for ten days to one group of animals, and a 10th every 4th day for 10 exposures.
The animals who received the full dose all at once had an 11% risk of infection, while 8% had a risk of infection when the dose was spread out over 10 days, and 4% had a risk when it was spread out over 40 days.
This study suggests that there is a smaller risk of infection associated with longer intervals between feeding.

## Interpretation

- These findings suggest that exposure to repeated low doses of vCJD infectious material by the oral route increases the potential of infection, but that increasing the time between doses may decrease the risk.

**Notes:**
Read slide

## Conclusions and FDA Proposal

- Conclusions:
- The risk of vCJD infection may not be linearly related to cumulative exposure.
- Nevertheless, despite possible low prevalence of vCJD in plasma donors and limitations to pool size, repeated dosing substantially increases potential risk of vCJD exposure in F VIII product recipients
- FDA Proposal
- Based on these considerations, we propose to estimate the risk per annum in pd FVIII or vWF product users rather than the risk per dose
- Does the Committee concur with this approach?

**Notes:**
Read slide