# Presentation: 422008

## Sculptra- P030050

- Herbert Lerner, MD
- Division of General, Restorative and Neurological Devices
- Plastic and Reconstructive Surgical Devices Branch
- FDA
- March 25, 2004

**Notes:**
Good morning.
Dr. Choti, Dr. Krause, members of the panel and guests.
I am Dr. Herb Lerner, a reviewer for the Plastics and Reconstructive Surgery Devices Branch of the ODE.
Today, I will be presenting the FDA’s review of this PMA. 

## Sculptra- Indication for Use

- Sculptra is intended to correct shape and contour deficiencies resulting from facial fat loss (lipoatrophy) in people with human immunodeficiency virus.

**Notes:**
Read slide

## Material

- Sculptra is a sterile solution consisting of:
- PLLA
- Sodium Carboxy-methyl cellulose
- Mannitol
- Sterile Water

**Notes:**
Read slide

## SCULPTRAP030050

- FDA Review Team
- Herb Lerner, MD- Clinical & Lead
- Charles Durfor, PhD- Pre-clinical
- David Berkowitz, VMD- Toxicology
- Phyllis Silverman, MS- Statistics
- Kim Struble- PharmD- Clinical (CDER)
- Sybil Wellstood- Manufacturing
- Mary Wollerton- Patient Labeling

**Notes:**
Listed on the screen are the members of the review team for this PMA.
Dr. Berkowitz will be making a few remarks regarding the toxicology of the device, and then I will be presenting the PMA.
Dr. Berkowitz.

##       Sculptra Toxicology

- Previous Medical uses of Sculptra Components

**Notes:**
The components of Sculptra have a long histories of medical use. 

The components of Sculptra are carboxymethylcellulose, polylactic acid, and mannitol.  All three have histories of use medicine.  Carboxymethylcellulose is used in wound dressings and adhesion barriers. Large amounts are used orally as bulking agents in laxatives.  

Polylactic acid is used in orthopedic implants and sutures.  If all of the lactate from 3 vials of Sculptra were hydrolyzed at once, the lactic acid produced would be less than the amount present in 500 ml of lactated Ringers Solution.      

Mannitol has been used systemically at doses of 2 g per kilogram to reduce intracranial pressure.  The dose of mannitol in 3 vials of Sculptra is 6.4 mg/kg for a 60 kg patient.

The purpose of the toxicology testing is to assess the safety of this particular combination of these components.   The slide summarizes the testing performed.

## P030050 Toxicology Testing 

| ISO/FDA Test Recommendation | Results/Comments |
| --- | --- |
| Cytotoxicity | No cytotoxicity.  Test article placed directly on agar surface.  |
| Sensitization | No significant sensitization. Sixteen guinea pigs injected intradermally. |
| Systemic Toxicity | No Toxicity. Intraperitoneal injections in mice at IP at 5.6 ml/kg.  |
| Subchronic Toxicity | No Toxicity. Intracutaneous 90-days.  Normal foreign body reaction to implant material (only 5 sites examined). |
| Genotoxicity | No significant mutagenesis. Bacterial reverse mutation assay. No increase in aberrations. Chromosomal aberration assay. No increase in micronuclei. Mouse micronucleus Assay. |
| Hemocompatibility | Complement activation not affected. Measured CH50 and SC5b-9.Normal hemolysis testing not needed. |

**Notes:**
1. Cytotoxicity was tested by placing Sculptra directly on a lawn of L929 cells.   There was no significant toxicity. 
2. Sensitization was tested in the Magnusson Kligman test.  The Sculptra was diluted 1:1 for the sensitization, but was used undiluted in the challenge. There was no significant sensitization. 
3. Acute Systemic Toxicity. Sculptra Tested by IP injection in mice at dose of 5g/kg.  No toxicity.   
4. Subchronic toxicity was tested by following intracutaneous injection for 90 days in rats. Extensive general toxicology reporting. No toxicity. At implant site normal foreign body rxn.  Implant material was present at 90 days. Only 5 injection sites were examined. 
5. Genotoxicity was tested in a bacterial reverse mutation assay, a chromosomal aberration assay, and an in vivo mouse micronucleus test.  SculptraTM did not increase mutations, chromosomal aberrations, or micronuclei in mice.
6. Complement activation was not affected by SculptraTM.   Both the CH50 and SC5b-9 generation were measured. The CH50 and SC5b-9 (membrane attack complex) were normal. 

None of the testing raised significant toxicological issues.  All of the essential toxicological testing was completed.

## Sculptra Physical Characteristics

- Molecular weight 40 – 50 thousand
- PLLA particles irregular shape
- 40-63 microns ±
- 2 hours required for optimal suspension
- Physically chemically and microbiologically stable for 72 hours after suspended.

**Notes:**
READ SLIDE

The particles are irregularly shaped.  40-63 microns. 10% of the particles may be smaller than 40 microns. Not more than 2% larger than 63. 

## Sculptra Resorption Kinetics

- No weight loss for 24 weeks in phosphate buffer at pH 7.4 at 37 degrees C.
- 19% weight loss at 50 degrees C.
- Foreign  material seen histologically after intradermal implantation for 90 days in rats.

**Notes:**
READ Slide

Amounts based on the loss of weight from the sedimentable.

## Resorption rate is function of molecular weight, crystallinity, and particle size.
Compact PLLA rods of 95,000 Daltons were implanted subcutaneously in rats. 
   1 month       19% degraded
   3 months	40% degraded
   6 months	56% degraded

- Compact PLLA rods of 95,000 Daltons were implanted subcutaneously in rats.
-    1 month       19% degraded
-    3 months	40% degraded
-    6 months	56% degraded

- Published In-Vivo Resorption Studies on PLLA

**Notes:**
Gogolewski et al. (1993) implanted as 4 x 7 mm rods subcutaneously in rats.  The 95,000 molecular weight material was degraded by 19% at 1 month, 40% at 3 months, and 56% at 6 months.  The fibrous tissue outlasts the polylactide.  The absorption of Sculptra may be faster because of the much larger surface area. 

## Sculptra	

- New-Fill is the name of the device as it is commercially available outside the US. Sculptra is the intended name of the device as it will be marketed in the US. For this review, the use of these names is interchangeable. The components of the two are identical.

**Notes:**
Read slide

## SCULPTRASTUDY DESIGN 	

- Presented are 5 investigator-sponsored studies.
- 2 studies are from Europe
- 3 studies are from the US
- All were single center studies
- No study was a randomized, controlled, or blinded study as we are used to seeing for a PMA
- All were Open label
- TCT (Total Cutaneous Thickness)

**Notes:**
The safety and effectiveness of the device is supported by five investigator-sponsored clinical studies. As noted on the slide, two studies were done in Europe, one in France and the other in England. The US studies were done in Florida and California. None of the trials were a controlled, randomized, or blinded study. All were open label, and were single center studies. ( NOTE: the C&W study had a delayed treatment group to serve as a “control”), 

Additionally, photographs were taken during all studies. Panel members were presented a copy of these photos for their review. Patient confidentiality does not allow us to project these photos for public viewing.
All the studies used some measurement of skin thickness to assess the effect of device implantation.
In the Vega study, TCT was measured by summing the ultrasound measurements of the buccal fat pad and skin thickness, in the C&W study there was a doppler ultrasound measurement of the full thickness of the area to assess thickness. 

Common to all the studies I will be presenting is the inclusion criteria  that the patients be HIV+ and have been on antiretroviral therapy prior to enrolling in the study.. It is recognized that some patients stop these medications to prevent the sequelae of lipoatrophy. This was taken into consideration when FDA determined that this PMA should receive expedited status.

## Vega Study-France

- Inclusion Criteria:
- HIV+
- Plasma HIV viral load <5000 copies/ml
- Current HAART treatment ≥3 months
- HAART for at least 3 years
- Buccal adipose tissue <2mm

**Notes:**
Read slide then:
As noted on the slide, the sponsor used the measurement of buccal adipose tissue as a criteria for inclusion and for success of treatment. As I will discuss shortly, the TCT (Total Cutaneous Thickness) measurements were determined for  each of these patients, and used to evaluate effectiveness.

Measurements were made by doppler ultrasound at several predetermined locations on the face, including the zygomatic arch and center of the buccinator muscle. Mean values were used to demonstrate effectiveness.

## Exclusion Criteria:
Cutaneous Kaposi’s Sarcoma of the face
Infection or concurrent herpes labialis
Previous facial fillers within 6 months
Unwilling to meet study follow-up time tables.

- Cutaneous Kaposi’s Sarcoma of the face
- Infection or concurrent herpes labialis
- Previous facial fillers within 6 months
- Unwilling to meet study follow-up time tables.

- Vega Study-France

**Notes:**
Read slide

## Study Design
Fifty (50) patients enrolled to study effects if the device over time
47 patients completed the trial, 2 withdrew at 72 weeks (schedules) and 1 withdrew due to an unrelated event.
Open label, non-randomized, uncontrolled

- Fifty (50) patients enrolled to study effects if the device over time
- 47 patients completed the trial, 2 withdrew at 72 weeks (schedules) and 1 withdrew due to an unrelated event.
- Open label, non-randomized, uncontrolled

- Vega Study-France

**Notes:**
Read slide

## Study Design
Patients were given bi-weekly injections
Safety endpoints designed to look for changes in biological parameters and AE’s
Efficacy endpoints change in TCT

- Patients were given bi-weekly injections
- Safety endpoints designed to look for changes in biological parameters and AE’s
- Efficacy endpoints change in TCT

- Vega Study-France

**Notes:**
Patients were given bi-weekly injections, to maximum correction. In this study, the device was mixed with 3cc of sterile water.  All patients had at least 3 treatments, 3 patients had 6 injections. They were then followed for up to 96 weeks to gather data on adverse events and TCT measurements.

There was one patient with injection site hemorrhage, and another with edema.

Several events, such as injection site bruising- 3%, hematoma 30%, nodule 52% were noted during the study. Nodules appeared from 9 days to 2 years post treatment. Most nodules were of mild intensity (78%) as judges by the investigators.

## Demographics:
Age- (mean)		     44.9 ± 6.8
Gender-		     98% male
Race-		     84% Caucasian
                             6% Hispanic
                             4% North African 
                             2% Black African
                             4% Carribean

- Age- (mean)		     44.9 ± 6.8
- Gender-		     98% male
- Race-		     84% Caucasian
-                              6% Hispanic
-                              4% North African
-                              2% Black African
-                              4% Carribean

- Vega Study-France

**Notes:**
Read slide

## Demographics:
AIDS defining event-     	50%
CD4 count- 		397.1± 168
HIV viral load-(median)-	200 copies/ml (50-96k)
	(viral load <5000 copies/ml-  86% of pts.)
TCT cheeks-	mean	 3.0mm
Adipose tissue <2mm

- AIDS defining event-     	50%
- CD4 count- 		397.1± 168
- HIV viral load-(median)-	200 copies/ml (50-96k)
- 	(viral load <5000 copies/ml-  86% of pts.)
- TCT cheeks-	mean	 3.0mm
- Adipose tissue <2mm

- Vega Study-France

**Notes:**
Read slide

## Endpoints:
Safety- adverse events
Treatment-related events
Local and systemic
Change from baseline CD4 cells
Viral load
Blood Lactic Acid levels

- Safety- adverse events
- Treatment-related events
- Local and systemic
- Change from baseline CD4 cells
- Viral load
- Blood Lactic Acid levels

- Vega Study-France

**Notes:**

As noted, safety endpoints were designed to look for changes in standard biological parameters.
There were no clinically significant changes in CD4 cell count,
 There were no clinically significant changes from baseline in viral load
 There were no clinically significant changes in lactic acid levels during the study.

## Results
Bruising- 3%
Hematoma- 30%
Nodule- 52%

- Bruising- 3%
- Hematoma- 30%
- Nodule- 52%

- Vega Study-France

**Notes:**
Read slide

- Efficacy- Change from baseline in TCT (mm)
- Study demonstrated statistically significant increases from baseline to week 96-
- At 8 weeks mean change 5.2 mm (SD 1.7)
- At 24 weeks change was 6.4 mm (SD 1.6)
- At 48 weeks, change was 7.2mm (SD 1.3)
- At 72 weeks, change was 7.2 mm (SD 1.3)
- At 96 weeks, change was 7.0mm (SD 1.4)
- Photographic Assessment
- Visual Analogue Scale 0-10 scale (with 10 the most satisfying physical/emotional state)

- Vega Study-France

**Notes:**

The mean increases above baseline ranged from 5.2 to 7.2mm throughout the study period; these were statistically significant at each time point.

The number of “responders”, those with a gross TCT ≥10 mm, peaked at week 48. This definition is arbitrary

In addition to the TCT, the sponsor performed a Visual Analogue Scale for evaluating “Global well being” assessed the quality of life. At baseline the median score was between 6.1 and 6.7- indicating “satisfactory physical or emotional state”. After treatment, the scores increased 0.3-0.8.(stat. signif. At months 6 and 12). Remember, there were no controls for evaluating these results, and the data must be looked at accordingly. 

## Figure 1:  Profile of Dermal Thickness by Ultrasound by Weeks From First Injection

|  |  |   |
| --- | --- | --- |
|   |  |  |
|  |  |  |

- Vega Study-France

**Notes:**
You have copies of the photos presented by the sponsor in the PMA, and have seen those presented earlier today by Dr. Engelhard. The efficacy endpoint was established as the improvement in TCT over time, and as you can see from the slide, the increase is constant  and reproducable.

## Chelsea & Westminster- England

- Inclusion Criteria:
- HIV+
- Moderate to severe lipoatrophy
- Not pregnant or lactating

**Notes:**
Read slide

## Exclusion Criteria
Active opportunistic disease or wasting
Current growth hormone therapy
Current chemotherapy for malignancy
Known hypersensitivity to PLLA

- Active opportunistic disease or wasting
- Current growth hormone therapy
- Current chemotherapy for malignancy
- Known hypersensitivity to PLLA

- Chelsea & Westminster- England

**Notes:**
Read slide

## Study Design
30 patients
Half of group delayed 12 weeks as a comparator
30 pts. Treated
29 pts. Reported (1 declined data disclosure)

- 30 patients
- Half of group delayed 12 weeks as a comparator
- 30 pts. Treated
- 29 pts. Reported (1 declined data disclosure)

- Chelsea & Westminster- England

**Notes:**
Read slide

## Study design
 Two groups of 15, the second group had injections delayed for 12 weeks
Clinical exam, serum CD4 and viral loads obtained
 Facial Ultrasound
VAS and HAD  (Anxiety/ Depression scores) 

-  Two groups of 15, the second group had injections delayed for 12 weeks
- Clinical exam, serum CD4 and viral loads obtained
-  Facial Ultrasound
- VAS and HAD  (Anxiety/ Depression scores)

- Chelsea & Westminster- England

**Notes:**
Patients in this study received 3 treatments, spaced approx. 2 weeks apart.
The patients in the delayed group had treatments at weeks 12,14,16.
In this study, the device was mixed with 2cc sterile water and 1cc lidocaine. 

Ultrasound was used to determine facial thickness, at the nasolabial folds, corner of the mouth, zygomatic arch and centrally in the buccal fat pad.

Visual Analogue Scores were between 0 and 10, 0 being “ as thin as it has ever been” to 10 “not thin at all”.
Antidepression/anxiety scores were scored between 0-21, where 0-7 is normal, 8-10 is suggestive of a mood disorder, 11-21 possible presence of a mood disorder.

For both measusres, there was significant improvement form baseline-
	For the face, VAS scores improved from 2.3 (mean) at baseline to 7.2 (change of 4.9)at week 12 and 2.3 to 6.1 (change of 3.7) at week 24.
	HAD scores changes from 7.9-7.2 for anxiety and 5.1 to 4.8 depression- indicating improvement in patient self assessment.

## Demographics:
Age- 		41 years (mean)
Gender-     	28 males/ 2 females
Race-	       	72% Caucasian	
                     3% Black
                      24% Hispanic

- Age- 		41 years (mean)
- Gender-     	28 males/ 2 females
- Race-	       	72% Caucasian
-                      3% Black
-                       24% Hispanic

- Chelsea & Westminster- England

**Notes:**
Read slide

## Demographics:
Mead duration of HAART- 5.1 years
Mean baseline CD4 count- 473.6
Viral load (median) - 72.0 copies/ml

- Mead duration of HAART- 5.1 years
- Mean baseline CD4 count- 473.6
- Viral load (median) - 72.0 copies/ml

- Chelsea & Westminster- England

**Notes:**
Read slide

## Endpoints:
Safety-
Change in viral load
Change in CD4 count
Change in blood chemistry
Adverse Events
Efficacy-
Buccal skin thickness measurements
Change in facial appearance- MD and Pt. assessments

- Safety-
- Change in viral load
- Change in CD4 count
- Change in blood chemistry
- Adverse Events
- Efficacy-
- Buccal skin thickness measurements
- Change in facial appearance- MD and Pt. assessments

- Chelsea & Westminster- England

**Notes:**
Read slide

## Chelsea & Westminster	

- Adverse events-combined groups
- Injection site bruising- 38%
- Injection site discomfort- 10%
- Injection site erythema- 10%
- Injection site inflammation- 10%
- Injection site nodule- 31%
- VAS scores improved
- Clinical lab parameters unchanged

**Notes:**
As in the Vega study, the  most common adverse events were treatment related, with 80% patients experiencing at least one event. The most common event was bruising. 31% of the patients developed an injection site nodule. Few of the events were severe.
One patient developed an skin infection

There was no significant change in viral load or CD4 counts over time for either treatment group.

There were significant changes in dermal thickness, from baseline, in each group. Generally, there was a 4-5.5 mm improvement in buccal thickness at week 12 and 24 in the first group, and at week 24 in the second.

VAS scores showed improvements in body perception, and HAD scores changed from “suggestive of a mood disorder” to “normal” after treatment. Again, there are no controls and these measurements are not validated. 

## BASELINE TO WEEK 12

|  |
| --- |
|  |

- Chelsea & Westminster

**Notes:**
In this study, the device was injected into several areas of the face. This side shows the improvement in buccal thickness for the initial group of patients. The results are comparable for the delayed group. Please note the improvement in the cheek areas. 

## Common Finding In Both Studies-
Nodule at injection site
52% VEGA
31% C&W
Discussion-
Onset average up to 218 days (9 to 748)
Most reported as mild and not visible
No histological data available

**Nodule** at injection site
- 52% VEGA
- 31% C&W
- Discussion-
- Onset average up to 218 days (9 to 748)
- Most reported as mild and not visible
- No histological data available

**Notes:**

Read slide

## US Studies

- APEX-001
- Investigator Sponsored Compassionate Use Study
- Open label, uncontrolled, non-randomized study
- 100 patients
- 1-6 treatment sessions (average-3)
- 1-8 cc of New-Fill per treatment session
- Demographics similar to previous studies
- HIV+  14 years
- Mean age  44.5
- 82/96 patients Caucasian

**Notes:**

This study, and the two which follow, are primarily valuable for their safety analysis. Pts were treated with 1-8 cc of New-Fill.

Treatment could be to the cheeks and temples, but not temples alone.
Subjects could receive up to 6 treatments, the majority had 1 to 3.

 Treatment was at 3-4 week intervals with up to 6 treatment sessions

Two patients in this group have died, one due to Cryptosporidiosis and the other to Mycobacterium infections
4 patients did not return for their first visit
38 of 96 have not completed 24 months of follow-up, 58 have reached the 1 year point but not 2 years.

## Inclusion Criteria
HIV+
Demonstrable photographic lipoatrophy
Exclusion Criteria
Active Infection, Kaposi’s sarcoma or Herpes on the face
Facial injections within last 3 months
Treatment with interferon or steroids

- HIV+
- Demonstrable photographic lipoatrophy
- Exclusion Criteria
- Active Infection, Kaposi’s sarcoma or Herpes on the face
- Facial injections within last 3 months
- Treatment with interferon or steroids

- US Studies

**Notes:**
In general, the inclusion and exclusion criteria are similar to the European studies. Read slide

## Safety results-
Adverse events considered mild
6 nodules reported in 85 patients at 3 weeks
39 nodules in 70 patients seen at 12 months
Efficacy results-
High patient satisfaction- 8.8/10
High investigator rating – from 3.2 to 1.36 (lower score is better)

- Adverse events considered mild
- 6 nodules reported in 85 patients at 3 weeks
- 39 nodules in 70 patients seen at 12 months
- Efficacy results-
- High patient satisfaction- 8.8/10
- High investigator rating – from 3.2 to 1.36 (lower score is better)

- US Studies

**Notes:**
Nodules were reported as the main device related adverse event.

Subject satisfaction with the correction 6-12 months after treatment was high, ranging from 8.1 to 10 on a 10 point scale. At 24 months, it is 7.5. These are not validated scales, but do reflect patients responses.

Investigator rating showed continued improvement, with almost complete facial satisfaction at 12 months. Although not validated, investigator rating went from 3.2 at baseline (0n a 5 point scale with 5 being worse) to 1.36 at 12 months.

## APEX002
Investigator sponsored IDE
HIV+
100 patients
Average of 3.5 treatments/patient
Similar demographics
Average time HIV+ 11.9 yrs
Average years HAART therapy- 13

- Investigator sponsored IDE
- HIV+
- 100 patients
- Average of 3.5 treatments/patient
- Similar demographics
- Average time HIV+ 11.9 yrs
- Average years HAART therapy- 13

- US Studies

**Notes:**
100 subjects enrolled, 37 of 99 patients have completed their 6 month follow-up, 34 subjects have completed their 12 month follow-up. The remainder are still within study guidelines at time of closure of the database.

The majority of patients received 3 to 4 treatments at 4-6 week intervals.
Subjects received an average of 7.8cc of New-Fill at each treatment session.

Please note similar HIV and HAART data compared with the previous studies.

## Adverse Events- mild
Soreness and nodules
6 nodules in 99 patients
19 pts. With injection site soreness
2 pts. With transient fever
High patient satisfaction-
Scores went from 3.71 to under 1 (lower score is better)

- Soreness and nodules
- 6 nodules in 99 patients
- 19 pts. With injection site soreness
- 2 pts. With transient fever
- High patient satisfaction-
- Scores went from 3.71 to under 1 (lower score is better)

- US Studies

**Notes:**
As in the other studies, treatment related events predominate and are generally mild. There have been 6 nodules reported to close of data. 

Subjects rated their lipoatrophy on a scale of 1-5(most severe). At baseline, the average score was 3.71 and at 6 and 12 months were under 1.

.

## US Study- Hermosa Beach
Open label, uncontrolled, non-randomized
Similar demographics and treatment schedule
1-6 treatments/patient
Up to 6 cc per treatment
Average time HIV+ 13 years
Average time HAART- 9 years

- Open label, uncontrolled, non-randomized
- Similar demographics and treatment schedule
- 1-6 treatments/patient
- Up to 6 cc per treatment
- Average time HIV+ 13 years
- Average time HAART- 9 years

- US Studies

**Notes:**
Hermosa Beach, Ca. study.
This Study is ongoing- only 15 of 95 enrolled patients completed 6 month follow-up.

Patients received 1-6 cc at each treatment, up to 6 treatments.

AE’s again mainly treatment related, with 8 nodules in 87 patients.
Again, note similar HIV and HAART data.

## Inclusion/Exclusion criteria
Similar to Apex studies
HIV+
Lipoatrophy
Infections of face, Kaposi's sarcoma
Treatment with interferon or steroids
Uncontrolled DM, lactic acidosis

- Similar to Apex studies
- HIV+
- Lipoatrophy
- Infections of face, Kaposi's sarcoma
- Treatment with interferon or steroids
- Uncontrolled DM, lactic acidosis

- US Studies

**Notes:**
Read slide

## Endpoints
To evaluate the quantifiable improvement in facial wasting after serial intradermal injections of New-Fill
Safety-
In repeated treatments
Efficacy
Durability of New-Fill
Psychological impact on patients

- To evaluate the quantifiable improvement in facial wasting after serial intradermal injections of New-Fill
- Safety-
- In repeated treatments
- Efficacy
- Durability of New-Fill
- Psychological impact on patients

- US Studies

**Notes:**

Read slide and add:
Caliper skin measurements were taken at treatment sessions and up to 12 months. 

## Results
Adverse events-mild
8 nodules in 87 patients
High patient satisfaction
Average increase TCT- 6mm @ 6 mos.
Average mm initial		7.44
Average mm-end of tx.	13.92
Average mm- 6 mos.	13.22
Average mm- increase 	5.78

- Adverse events-mild
- 8 nodules in 87 patients
- High patient satisfaction
- Average increase TCT- 6mm @ 6 mos.
- Average mm initial		7.44
- Average mm-end of tx.	13.92
- Average mm- 6 mos.	13.22
- Average mm- increase 	5.78

- US Studies

**Notes:**
Read slide

## Conclusion- Overall Safety

- In general, the majority of treatment related events are mild pain, bruising and swelling at the injection site.
- Device events are generally palpable subcutaneous nodules (up to 50%)
- No major AE’s reported

**Notes:**
Read slide

## Conclusion- Overall Efficacy

- TCT analysis in VEGA study demonstrates increased TCT.
- Dermal thickness changes in the C&W study also demonstrate significant enhancement of dermal thickness
- Photographic evidence of sustained efficacy is shown

**Notes:**
While the study did not use a validated, statistical method, my review of the photos shows effectiveness. We await your review of the photos.

## Quality of Life assessments show improvement from the baseline 

- Conclusion- Overall Efficacy

**Notes:**
And finally, I will be presenting a brief statistical summary of the data presented in the PMA. 
However, the FDA statistician is present today to answer any further questions.

Next Slide

## No masking or use of validated severity scale
Total Skin Thickness (TCT) was used as surrogate endpoint for improved appearance
Statistically significant (p<0.001) increases in TCT observed in Vega and C&W Studies
Treatment effect was independent of time on HAART, baseline CD4 counts, or baseline skin thickness
Increase in skin thickness correlated pictorially with improved appearance

- Total Skin Thickness (TCT) was used as surrogate endpoint for improved appearance
- Statistically significant (p<0.001) increases in TCT observed in Vega and C&W Studies
- Treatment effect was independent of time on HAART, baseline CD4 counts, or baseline skin thickness
- Increase in skin thickness correlated pictorially with improved appearance

- Statistical Summary

**Notes:**
A masked assessment using a validated severity scale was not performed.  Changes in ultrasonic measurements of cutaneous skin thickness were taken to be a surrogate endpoint for improvement in facial appearance.  There was a statistically significant increase from baseline in Total Cutaneous Thickness at every follow-up through 2 years for the Vega Study and through Week 24 for the Chelsea & Westminster Study.  There was no evidence that the effect of the treatment was related to length of time on anti-retroviral therapy, baseline CD4 count, or baseline skin thickness.  However, there was more change in skin thickness observed among those patients whose skin was thinner to start.  Overall, the sponsor demonstrated that increase in skin thickness was pictorially correlated with improved appearance.

## Thank you

## Panel Question-1

- 21 CFR 860.7(d)(1) states that there is a reasonable assurance that the device is safe when it can be determined that the probable benefits to health from use of the device for its intended uses, when accompanied by adequate instructions for use and warnings against unsafe use, outweigh any probable risks. Considering the data in the PMA, please comment on whether there is a reasonable assurance that the device is safe.

## Panel Question- 2

- 21 CFR 860.7(e)(1) states that there is a reasonable assurance that a device is effective when it can be determined, based on valid scientific evidence, that in a significant portion of the target population, the use of the device for its intended uses and conditions of use, when accompanied by adequate directions for use and warnings against unsafe use, will produce clinically significant results.  Considering the data in the PMA, is there reasonable assurance that the device is effective?

## Panel Question- 3

- Patients in the European studies (79) were followed-up for periods ranging from 24 weeks to 2 years, and those in the U.S. studies (286) were followed up to 2 years.  If you agree that there is enough evidence in the PMA to support the safety and effectiveness of the device, do you feel that a post-approval study to assess the long term use of this device should be initiated, and if so, please advise FDA as to the type of data you feel should be collected, and the appropriate duration of follow-up.

## Panel Question- 4

- A large volume of this device (up to 11cc. per treatment) is required to achieve an optimal cosmetic effect, and precise placement of the material in the correct dermal plane (deep dermis or subcuticular layer) is important. Please advise FDA whether a physician training program is indicated for those wishing to use this device, and if so, what type of training would be appropriate.