FDA Panel Backs Radiesse Approval, With Conditions
FDA Panel Backs Radiesse Approval, With Conditions
FDA Panel Backs Radiesse Approval, With Conditions
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COSMECEUTICAL CRITIQUE: GINSENG, PAGE 18<br />
Skin & Allergy News<br />
www.skinandallergynews.com<br />
V OL. 37, NO. 10 The Leading Independent Newspaper for Medical, Surgical, and Aesthetic Dermatology O CTOBER 2006<br />
Dr. David Woodley is calling on dermatology leaders to support a<br />
clinical study in children with dystrophic epidermolysis bullosa.<br />
Funding Stalls DEB<br />
Therapy Advance<br />
BY ERIK L. GOLDMAN<br />
Contributing Writer<br />
S AN D IEGO — A gene therapy<br />
for dystrophic epidermolysis<br />
bullosa that could be delivered by<br />
office-based dermatologists is feasible<br />
and likely to be effective, but<br />
advancement of this therapeutic<br />
approach is hindered by lack of<br />
funding, said Dr. David Woodley<br />
at the American Academy of<br />
Dermatology’s Academy 2006<br />
meeting.<br />
Dr. Woodley and his investigative<br />
team at the University of<br />
Southern California, Los Angeles,<br />
have developed a method for<br />
intravenous delivery of either<br />
gene-corrected fibroblasts or the<br />
type VII collagen that EB patients<br />
lack, a therapy that would, in<br />
essence, correct the fundamental<br />
physiologic defect underlying this<br />
disease.<br />
In the fibroblasts of EB patients,<br />
the gene coding for type<br />
VII collagen is mutated. As a result,<br />
patients are unable to produce<br />
the anchoring fibrils that<br />
moor the epidermis to the dermis.<br />
Because the disorder is related<br />
to a relatively discrete genetic<br />
mutation, it is an ideal<br />
candidate for gene therapy.<br />
Dr. Woodley explained that he<br />
and other investigators interested<br />
in this disease have pursued several<br />
different approaches to genebased<br />
treatment.<br />
The first was modeled after<br />
advances in the treatment of severe<br />
burns. It is now possible to<br />
take biopsy samples from burn<br />
victims, grow out large sheets of<br />
keratinocytes, and graft these<br />
sheets onto the burn sites. “We<br />
wondered why this couldn’t<br />
work in EB kids. Using a lentiviral<br />
vector, we were able to genecorrect<br />
the fibroblasts so they are<br />
able to produce full-length type<br />
VII collagen. So we could reverse<br />
the EB phenotype.”<br />
But the practicalities of the<br />
grafting procedure dead-ended<br />
this strategy. “This approach re-<br />
See DEB Therapy page 28<br />
©IRENE FERTIK<br />
I N S I D E<br />
Port-Wine Stains<br />
New treatment combines<br />
PDT and verteporfin with<br />
pulsed dye laser therapy.<br />
PAGE 22<br />
Mysteries<br />
Of the Mouth<br />
Patch test before removing<br />
dental metals in suspected<br />
lichenoid contact stomatitis.<br />
PAGE 34<br />
Chronic<br />
Paronychia<br />
Topicals, not systemics, get<br />
to the root of this dermatitis.<br />
PAGE 51<br />
C A S E O F T H E M O N T H<br />
An 82-year-old man presented at a weekly conference of clinicians<br />
with nodules on his fingers of a few years’ duration. A<br />
rheumatologist suggested seeing him again in 3 weeks for tests,<br />
but a dermatologist found the cause of the nodules that same<br />
day. What’s your diagnosis? See Case of the Month page 71.<br />
COURTESY DR. BENJAMIN K. FISHER<br />
<strong>FDA</strong> <strong>Panel</strong> <strong>Backs</strong><br />
<strong>Radiesse</strong> <strong>Approval</strong>,<br />
<strong>With</strong> <strong>Conditions</strong><br />
Physician training program recommended.<br />
BY ELIZABETH<br />
MECHCATIE<br />
Senior Writer<br />
G AITHERSBURG, MD. — The<br />
majority of a federal advisory<br />
panel recommended approval of<br />
an injectable calcium hydroxylapatite<br />
implant for correcting<br />
HIV-related facial lipoatrophy<br />
and for correcting nasolabial<br />
folds, with a list of conditions for<br />
approval that included an adequate<br />
physician training program<br />
and postmarketing followup<br />
studies.<br />
At a meeting of the Food and<br />
Drug Administration’s general<br />
and plastic surgery devices panel<br />
last month, the panel voted 5-2 in<br />
favor of the conditional approval<br />
Sunscreen <strong>Approval</strong> Paves<br />
The Way for UVA Blockers<br />
BY BETSY BATES<br />
Los Angeles Bureau<br />
C ORONADO, CALIF. — The<br />
arrival of two new sunscreen<br />
formulations in the U.S. market<br />
will undoubtedly lead to better<br />
UVA protection for patients, but<br />
it remains to be seen whether either<br />
will stack up to products<br />
that are available in Canada and<br />
Europe, Dr. Vincent DeLeo asserted<br />
at the annual meeting of<br />
the California Society of Dermatology<br />
and Dermatologic<br />
Surgery.<br />
Earlier this year, the Food and<br />
Drug Administration approved<br />
of the product, <strong>Radiesse</strong>, for<br />
these two indications. <strong>Radiesse</strong>, a<br />
sterile, semisolid cohesive granular<br />
implant that contains calcium<br />
hydroxylapatite (CaHA)<br />
granules in a gel, is manufactured<br />
by BioForm Medical Inc.<br />
and is approved in the United<br />
States for treating vocal cord insufficiency<br />
and oral maxillofacial<br />
defects, and for tissue marking.<br />
The same product is marketed in<br />
Europe for facial aesthetics. (Another<br />
version, Coaptite, which<br />
contains larger CaHA particles, is<br />
used for treating stress urinary incontinence<br />
and other applications.)<br />
A condition that physicians be<br />
adequately educated and trained<br />
See <strong>Radiesse</strong> page 20<br />
Anthelios SX, which is an overthe-counter<br />
product from La<br />
Roche-Posay that contains a camphor<br />
derivative (ecamsule/Mexoryl<br />
SX) that is photostable and<br />
specifically targets UVA radiation<br />
(SKIN & ALLERGY NEWS, August<br />
2006, p. 9).<br />
The sunscreen also includes<br />
two well-known but relatively<br />
unstable UVA organic absorbers,<br />
octocrylene and avobenzone<br />
(Parsol 1789). It will have a sun<br />
protection factor (SPF) of 15.<br />
In other countries, Mexorylcontaining<br />
Anthelios has been<br />
available for several years at high-<br />
See Sunscreen page 29
20 Dermatologic Surgery S KIN & ALLERGY N EWS • October 2006<br />
Two Indications Green Lighted<br />
<strong>Radiesse</strong> from page 1<br />
in how to use the product received unanimous<br />
endorsement from the panel. Bio-<br />
Form is planning a training program and<br />
will incorporate some of the panel’s recommendations,<br />
Stephen L. Basta, president<br />
and CEO of the company, said at the<br />
meeting.<br />
Another condition recommended for<br />
the HIV-associated lipoatrophy indication<br />
was completion of the 18-month followup<br />
study being conducted by BioForm,<br />
which panelists said should include data on<br />
the texture of the implant, ease of injection,<br />
events that require further evaluation,<br />
and time needed to reinjection. The<br />
label should also state that <strong>Radiesse</strong> was<br />
studied specifically in patients with HIVrelated<br />
lipoatrophy and that use for other<br />
indications was unproved.<br />
Nasolabial Fold Indication<br />
For the nasolabial fold indication, the panel<br />
agreed that <strong>Radiesse</strong> was effective for up<br />
to 6 months, the length of the study submitted<br />
for approval. But as a condition for<br />
approval, the panel recommended that the<br />
company conduct a postapproval study<br />
specifically looking at the duration of the<br />
cosmetic effects beyond 6 months, the effect<br />
of repeated injections, and safety.<br />
Other conditions were that the company<br />
conduct a study of <strong>Radiesse</strong> in “people<br />
of color”—who tend toward hypertrophic<br />
scarring and keloid formation and were underrepresented<br />
in the study submitted to<br />
the <strong>FDA</strong> for approval of this use—and<br />
that a statement be added to the product’s<br />
label cautioning that safety and efficacy of<br />
the product in black patients was not<br />
known. In this study, there were 2 African<br />
Americans, 11 Hispanic patients, and 2 patients<br />
whose race was described as “other.”<br />
(In the lipoatrophy study, about half the<br />
patients were Fitzpatrick skin type IV-VI,<br />
which was not associated with a greater<br />
rate of adverse events; the company cited<br />
these to address the issue of safety for<br />
treating nasolabial folds. But the <strong>FDA</strong> executive<br />
summary noted that the two patient<br />
populations are not homogeneous<br />
and that the HIV-positive patients in the<br />
lipoatrophy study may have had a “diminished<br />
capacity to mount a hypersensitivity<br />
reaction.”)<br />
According to the company, the proposed<br />
label already includes a statement that the<br />
product has not been studied for use in lip<br />
augmentation and that adverse events have<br />
been reported, so the panel did not include<br />
this as a condition. The use of <strong>Radiesse</strong> for<br />
lip augmentation has not been studied, and<br />
based on reports the company has received,<br />
lips are the most common site of<br />
nodular formation associated with use of<br />
<strong>Radiesse</strong>, Mr. Basta said.<br />
Register now for this archived webcast at www.viralskindiseases.com<br />
Introduction<br />
Stephen K. Tyring, MD, PhD, MBA<br />
Professor of Dermatology<br />
Department of Dermatology<br />
University of Texas Health Science Center<br />
Houston, Tex.<br />
Human Papillomaviruses:<br />
Basic Virology to Clinical Management<br />
Stephen K. Tyring, MD, PhD, MBA<br />
Molluscum Contagiosum<br />
and Treatment Options<br />
Douglas W. Kress, MD<br />
Chief of Pediatric Dermatology<br />
Children’s Hospital of Pittsburgh<br />
Pittsburgh, Penn.<br />
Treatment of Cutaneous Warts:<br />
An Updated Inventory<br />
of Therapeutic Options<br />
Robert B. Skinner, MD<br />
Professor of Medicine<br />
Department of Dermatology<br />
University of Tennessee<br />
Health Science Center<br />
Memphis, Tenn.<br />
PROGRAM DESCRIPTION<br />
Viral skin diseases represent a major component in the busy practices of dermatologists. In this activity,<br />
the focus is on the most common cutaneous viral diseases, genital/anal warts (condylomata acuminatum)<br />
and common warts, caused by human papillomaviruses (HPV), and molluscum contagiosum, caused by<br />
Poxviruses.<br />
The manifestations of cutaneous viral infections range from simple erythematous, macular presentations to<br />
papules, vesicles, pustules, ulcers, and crusting that may represent any of a long list of possible etiologies.<br />
Clinicians must be able to accurately assess and differentiate among these manifestations and presentations,<br />
particularly now because of the emerging possibility that the causative organisms may be the etiologic agents<br />
responsible for smallpox infections or disseminated vaccinia. The poxviruses, especially, may mimic or be<br />
mimicked by vaccinia, and clinicians should know the differences in the morphology of the lesions as well as<br />
in the presentation, timing, and progression of these lesions.<br />
Advances in the understanding of the natural history and treatment of common viral skin diseases highlight<br />
the need for a continuing educational process that guides the clinician in patient management, including the<br />
latest treatment options, such as topical immune response modifier therapy.<br />
This activity will provide dermatologists with current information regarding the nature of viral skin diseases<br />
caused by HPV and poxviruses and will help clinicians remain up-to-date on patient applied and physician<br />
applied therapies in the treatment of genital warts, common warts, and molluscum contagiosum.<br />
INTENDED AUDIENCE<br />
This activity has been developed for dermatologists, primary care physicians, and other clinicians who are<br />
involved in the diagnosis and treatment of viral skin diseases.<br />
EDUCATIONAL OBJECTIVES<br />
After reading this supplement and taking the test, participants should be able to:<br />
• Summarize the current understanding of the pathogenesis of human papillomavirus (HPV) infections of<br />
the skin—as manifested by genital/anal and common warts—and the role of local immune responses in<br />
the clearing of infection.<br />
• Discuss the HPV types that are associated with external genital/anal warts and with cervical<br />
malignancies, and explain the role of diagnostic testing in the management of patients with external<br />
genital/anal warts.<br />
• Recognize the most common presentations of human papillomavirus (HPV) and poxvirus infections, as<br />
well as the atypical morphologic characteristics that must be considered in diagnosing various types of<br />
warts and molluscum contagiosum.<br />
• Describe the methods that may be used to confirm a clinical diagnosis of molluscum contagiosum, and<br />
explain when such methods should be used.<br />
• List and explain the destructive/ablative methodologies and the pharmacologic treatments that are<br />
currently available for treating genital/anal and common warts and molluscum contagiosum.<br />
• Name and describe the factors that should be considered in choosing a specific therapeutic regimen<br />
for individual patients.<br />
ACCREDITATION STATEMENT<br />
This activity has been planned and implemented in accordance with the Essential Areas and Policies of<br />
the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of<br />
the Elsevier Office of Continuing Medical Education (EOCME) and Skin & Allergy News. The EOCME<br />
is accredited by the ACCME to provide continuing medical education (CME) for physicians.<br />
CME CREDIT STATEMENT<br />
The EOCME designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit .<br />
Physicians should only claim credit commensurate with the extent of their participation in the activity.<br />
Financial Support: This CME activity is supported by an educational grant from<br />
<strong>Panel</strong> Members’ Concerns<br />
Like others on the panel, Dr. Michael<br />
Miller, professor and deputy chairman in<br />
the department of plastic surgery at the<br />
University of Texas M.D. Anderson Cancer<br />
Center, Houston, agreed that there<br />
was reasonable assurance that <strong>Radiesse</strong><br />
was safe and effective for the lipoatrophy<br />
indication. The benefits for this population<br />
were “enormous,” and although the cosmetic<br />
effect of <strong>Radiesse</strong> was not permanent,<br />
its effect was “good, if not better<br />
than anything else” used for HIV-associated<br />
lipoatrophy. He cautioned, however,<br />
that <strong>Radiesse</strong> works by creating a volume-filling<br />
scar, which is acceptable only<br />
if it achieves the desired effect.<br />
Several panelists agreed with Dr. Miller,<br />
who said that the study convincingly<br />
showed efficacy and that its long history<br />
of use for various indications helped mitigate<br />
the unknowns.<br />
Dr. Michael Olding, chief of the division<br />
of plastic surgery, George Washington<br />
University, Washington, said that while<br />
he had concerns about the lack of information<br />
in histology and the length of<br />
durability, he pointed out that no significant<br />
complications were observed in the<br />
study and the quality of improvements<br />
seen in the patient photographs, in his<br />
view, “surpassed” the results of other<br />
treatments, at least photographically.<br />
The dermatologist on the panel, Dr.<br />
Amy E. Newburger of Scarsdale, N.Y.,<br />
who voted against approval for both indications,<br />
expressed concern about the extensive<br />
off-label cosmetic use of <strong>Radiesse</strong><br />
that has already occurred and is expected<br />
post approval, and about the lack of human<br />
histologic data for the product. She<br />
said the study in HIV-associated lipoatrophy<br />
was not large or rigorous enough to<br />
make her feel comfortable about effectiveness<br />
and safety, referring to reports of<br />
serious adverse reactions associated with<br />
<strong>Radiesse</strong> reported to the <strong>FDA</strong>’s adverse<br />
event reporting database, including reports<br />
resulting from unapproved use in lips.<br />
And while the study on the nasolabial<br />
folds indication was a better study than the<br />
lipoatrophy study, she said there were<br />
“too many unknowns remaining” to vote<br />
for approval for this indication. <strong>Radiesse</strong><br />
Continued on following page
October 2006 • www.skinandallergynews.com Dermatologic Surgery 21<br />
Continued from previous page<br />
lasts longer than hyaluronic acid fillers, so<br />
a more rigorous study is needed to achieve<br />
“any level of comfort regarding safety,” she<br />
said.<br />
Stephen Li, Ph.D., president of Medical<br />
Device Testing and Innovations, Sarasota,<br />
Fla., who also voted against approval for<br />
both indications, echoed the concern about<br />
the lack of human histologic data, pointing<br />
out that <strong>Radiesse</strong>’s migration and dissipation<br />
patterns and its reaction with other<br />
fillers in patients were unknown.<br />
The <strong>FDA</strong> usually follows the recommendations<br />
of its advisory panels, which<br />
are not binding.<br />
The safety profile of both products was<br />
comparable, with the typical injection-related<br />
side effects seen with other dermal<br />
fillers, including ecchymoses and a significant<br />
amount of erythema. Only 2 African<br />
American patients were enrolled, which<br />
was one of the main concerns raised in the<br />
<strong>FDA</strong> review, although the company reported<br />
no scarring, hyperpigmentation, or<br />
keloid formation among the 15 patients of<br />
color in the study, including the 2 African<br />
Americans.<br />
The <strong>FDA</strong> review also raised concerns<br />
that <strong>Radiesse</strong> implants could mimic a tumor<br />
in the soft tissue or interfere with x-<br />
ray evaluations, because CaHA is visible radiographically,<br />
and that nodules were not<br />
better identified. (Although the company<br />
did not report any evidence of nodules,<br />
there were adverse event reports that could<br />
have been interpreted to be nodules.)<br />
To determine whether <strong>Radiesse</strong> implants<br />
could mimic or obscure tumors, the company<br />
performed a study of x-rays and CT<br />
scans of 58 patients who had received<br />
<strong>Radiesse</strong> injections for correction of nasolabial<br />
folds or HIV lipoatrophy, including<br />
patients who had received the first injections<br />
at least 12 months earlier. In that<br />
study, there was no evidence on CT scans<br />
that <strong>Radiesse</strong> migrates from the point of injection.<br />
Neither was there a significant risk<br />
that <strong>Radiesse</strong> would mask or mistakenly be<br />
interpreted as a benign or malignant tumor,<br />
or that the implants would prompt biopsies<br />
or further work-ups—even by radiologists<br />
who don’t know the patient has had<br />
them—because of the benign appearance<br />
and bilateral placement, according to the<br />
company. The implants are not always seen<br />
on x-rays, as with CT scans.<br />
The panel had some concerns about this<br />
issue and that the presence of <strong>Radiesse</strong><br />
could be potentially confusing on an x-ray<br />
or CT scan and would require more follow-up.<br />
The panel also agreed that the<br />
question of migration had not been completely<br />
answered.<br />
■<br />
<strong>Radiesse</strong><br />
lasts longer than<br />
hyaluronic acid<br />
fillers, so a more<br />
rigorous study is<br />
needed to<br />
achieve ‘any<br />
level of comfort<br />
regarding<br />
safety.’<br />
Lipoatrophy Indication<br />
For approval of the lipoatrophy indication,<br />
the company presented the results of an<br />
open-label, nonrandomized, noncomparative<br />
multicenter study using <strong>Radiesse</strong> in<br />
100 HIV-positive patients, whose mean<br />
age was 48 years and who had been receiving<br />
highly active antiretroviral therapy<br />
for at least 3 years.<br />
Three months after the final treatment,<br />
98% of the patients were very much improved<br />
or much<br />
improved from<br />
baseline on the<br />
Global Aesthetic<br />
Improvement<br />
Scale (GAIS),<br />
the primary<br />
end point of<br />
the study (the<br />
remaining 2%<br />
were improved).<br />
GAIS<br />
ratings remained<br />
improved<br />
at 6 and<br />
12 months,<br />
with increased skin thickness that was<br />
maintained until about 12 months. The<br />
majority of patients said they were satisfied<br />
and would recommend the treatment<br />
at all three time points.<br />
There were no unanticipated adverse<br />
events, with injection-related adverse<br />
events typical of dermal fillers, such as ecchymoses,<br />
pain, erythema, and pruritus,<br />
the most commonly observed. They were<br />
mostly mild and occurred at the time of<br />
injection or shortly afterward, and they did<br />
not last long, according to Dr. Stacey Silvers<br />
of the New York Eye and Ear Infirmary,<br />
who presented these results on behalf<br />
of BioForm. Contour irregularities<br />
occurred but were transient and quickly<br />
resolved, said Dr. Silvers, who reported no<br />
financial ties to BioForm.<br />
The nasolabial fold, split-face study<br />
compared <strong>Radiesse</strong> to Cosmoplast in the<br />
correction of nasolabial folds in 117 patients<br />
aged 31-72 years, with nasolabial<br />
folds rated 3 (a moderately deep wrinkle)<br />
or 4 (a deep wrinkle with well-defined<br />
edges) on the Lemperle Rating Scale<br />
(LRS), with 12-month safety data on 47 patients.<br />
At 3 months, nearly 85% of<br />
<strong>Radiesse</strong>-treated folds were rated as superior,<br />
based on the LRS, to the Cosmoplasttreated<br />
folds, the primary effectiveness<br />
end point. At 6 months, nearly 79% of<br />
<strong>Radiesse</strong>-treated folds were considered superior<br />
to the Cosmoplast-treated folds,<br />
16% were equivalent, and 5% were inferior,<br />
a secondary effectiveness end point.<br />
www.finacea-us.com<br />
FINACEA is indicated for topical treatment of inflammatory papules and pustules of mild to moderate rosacea.<br />
Although some reduction of erythema which was present in patients with papules and pustules of rosacea<br />
occurred in clinical studies, efficacy for treatment of erythema in rosacea in the absence of papules and pustules<br />
has not been evaluated.<br />
FINACEA is for dermatologic use only, and not for ophthalmic, oral, or intravaginal use. FINACEA is contraindicated<br />
in individuals with a history of hypersensitivity to propylene glycol or any other component of the formulation.<br />
In clinical trials, sensations of burning/stinging/tingling occurred in 29% of patients, and itching in 11%,<br />
regardless of the relationship to therapy. Post-marketing safety—Skin: facial burning and irritation; Eyes:<br />
iridocyclitis on accidental exposure to the eye. There have been isolated reports of hypopigmentation<br />
after use of azelaic acid. Since azelaic acid has not been well studied in patients with dark<br />
complexion, these patients should be monitored for early signs of hypopigmentation.<br />
Please see brief summary of Prescribing Information on following page.<br />
Results shown are the results for one patient.<br />
Not all patients may have the same results.<br />
*FINACEA was only studied in clinical trials for 12 weeks.<br />
In the treatment of mild to moderate rosacea<br />
RESULTS<br />
MATTER<br />
Baseline<br />
Week after week after week, dermatologists<br />
and patients see the benefits of FINACEA*<br />
After 4 weeks of FINACEA bid<br />
Seeing is Believing