Facial Soft-Tissue Fillers: Assessing the State of the Science conference Proceedings report

Transcription

1 Facial Soft-Tissue Fillers: Assessing the State of the Science conference Proceeings report C. William Hanke, MD, Ro J. Rohrich, MD, MarianoBusso,MD,AlastairCarruthers,MA,BM,BCh,JeanCarruthers,MD,StevenFagien,MD, RebeccaFitzgeral,MD,RicharGlogau,MD,PhyllisE.Greenberger,MSW,Z.PaulLorenc,MD, EllenS.Marmur,MD,GaryD.Monheit,MD,AnreaPusic,MD,MHS,MarkG.Rubin,MD, BertholRzany,MD,ScM,AnthonySclafani,MD,SusanTaylor,MD,SusanWeinkle,MD, MichaelF.McGuire,MD,DaviM.Pariser,MD,LaurieA.Casas,MD,KarenJ.Collishaw,RogerA.Dailey,MD, StephenC.Duffy,ElizabethJanEgar,MS,BarbaraL.Greenan,KellyHaenlein,MHA, RonalA.Henrichs,CAE,KeithM.Hume,MA,FloraLum,MD,DaviR.Nielsen,MD, Lisle Poulsen, Lori Shoaf, JD, William Sewar, MA, Weny Smith Begolka, MS, RobertG.Stanton,KatherineJ.Sveman,CAE,J.ReganThomas,MD,JonathanM.Sykes,MD, Carol Wargo, MA, an Robert A. Weiss, MD Dallas,Texas,anCarmel,Iniana Summary: The American Acaemy of Dermatology an the American Society of Plastic Surgeons, with the support of other sister societies, conucte the Facial Soft-Tissue Fillers: Assessing the State of the Science conference in December of The American Acaemy of Dermatology an the American Society of Plastic Surgeons establishe a panel of leaing experts in the fiel of soft-tissue fillers from researchers to clinicians an other stakeholers for the conference to examine an iscuss issues of patient safety, efficacy, an effectiveness in relation to the approve an off-label use of soft-tissue fillers, an other factors, incluing the training an level of experience of iniviuals aministering fillers. This report summarizes the eliberations an key points mae by the panel an presenters to the panel, an inclues a summary of the panel s near-term an longer term recommenations for next steps to help guie future efforts to aress the safety, efficacy, an effectiveness of facial soft-tissue fillers. This report represents the panel s assessment of the meical knowlege available on facial soft-tissue fillers at the time of the conference. ( J Am Aca Dermatol 2011;64:S53-65.) The implantation of soft-tissue or ermal fillers for cosmetic proceures continues to be on the rise. In 2008, nearly 1.6 million proceures using soft-tissue fillers were performe in the Unite States, a 144 percent increase over the 650,000 performe in More than two-thirs of these proceures use hyaluronic aciebase fillers, making their use the thir most performe cosmetic proceure in The steep increase in the use of these proceures is partly attributable to growth in the number of available proucts an options an increasing public interest in the proceure. 3 Recognizing the growth in consumer eman for soft-tissue fillers, the U.S. From the Department of Plastic Surgery, University of Texas Southwestern Meical Center, an the Department of Dermatology, Saint Vincent Carmel Meical Center, Laser an Skin Surgery Center of Iniana. Prepare for the American Acaemy of Dermatology an the American Society of Plastic Surgeons an by The Lewin Group. Disclosures: Ro J. Rohrich, MD, eclares he is the recipient of research grant funs receive by the University of Texas Southwestern Meical Center from Meicis, Contura, Mentor (ermal fillers or botulinum toxin type A stuies), an Baxter (fibrin sealant stuy). C. William Hanke, MD, eclares financial interest as a shareholer in Meicis an Allergan. In aition, he eclares having been the recipient of research support from Meicis, Allergan, Merz, Dermik, an Galerma. For aitional isclosure information, please see the Disclosure Appenix in this issue. This supplement in its entirety is jointly publishe by the Journal of the American Acaemy of Dermatology an Plastic an Reconstructive Surgery. Citation of the articles in the JAAD follows this format: Hanke CW, Rohrich RJ, Busso M, Carruthers A, Carruthers J, Fagien S, et al. Facial Soft-Tissue Fillers: Assessing the State of the Science conference Proceeings report. J Am Aca Dermatol 2011;64 (Suppl):S Citation of the articles in PRS follows this format: Rohrich RJ, Hanke CW. Facial Soft-Tissue Fillers: Assessing the State-of-the-Science Conference Proceeings Report. Plast Reconstr Surg 2011;127 (Suppl 2):9S-21S. Receive for publication May 25, 2010; accepte November 5, Corresponence to: Ro J. Rohrich, MD, Department of Plastic Surgery, University of Texas Southwestern Meical Center 1801 Harry Hines Boulevar, Dallas, Texas rjreitor_prs@plasticsurgery.org or C. William Hanke, MD, Department of Dermatology, Saint Vincent Carmel Meical Center, Laser & Skin Surgery Center of Iniana, North Meriian Street, Suite 290, Carmel, In cwmhanke@thelassi.com /$36.00 Ó 2011 by the American Acaemy of Dermatology, Inc an Copyright Ó 2011 by the American Society of Plastic Surgeons. oi: /j.jaa S53

2 S54 JAM ACAD DERMATOL APRIL 2011 Foo an Drug Aministration anticipates that submissions of premarket applications for these evices will continue not only for use in filling wrinkles (a U.S. Foo an Drug Aministrationeapprove use for available soft-tissue fillers) but also for new, currently off-label inications for soft-tissue fillers, such as augmenting an contouring of the face an boy. 4 In November of 2008, the U.S. Foo an Drug Aministration s General an Plastic Surgery Panel hel a meeting to receive an upate on safety information collecte on ermal fillers in the commercial setting, iscuss current premarket an postmarket approve stuy esigns, an make recommenations on general issues concerning the stuy of various ermal fillers. 5 A complete summary of this meeting is available. 5 In response to the rapi growth in the use of soft-tissue fillers an the finings of the U.S. Foo an Drug Aministration panel, the following groups convene the Facial Soft-Tissue Fillers: State of the Science conference on December 6 through 7, 2009, in Washington, D.C.: American Acaemy of Dermatology (AAD) (sponsoring society) American Acaemy of Facial Plastic an Reconstructive Surgery (supporting society) American Acaemy of Ophthalmology (supporting society) American Acaemy of OtolaryngologyeHea an Neck Surgery (supporting society) American Society for Aesthetic Plastic Surgeons (supporting society) American Society for Dermatologic Surgery (supporting society) American Society of Plastic Surgeons (ASPS) (sponsoring society) A steering committee representing the ASPS, the AAD, an these supporting organizations was forme to help lea the effort, with co-chairs from the ASPS an the AAD. In aition to receiving support from these sponsoring organizations, the ASPS an the AAD receive funing for the conference from several meical evice companies involve in facial soft-tissue fillers (see the Appenix at the en of this article for a complete list). Throughout the process of eveloping the conference, the ASPS an the AAD receive input from the U.S. Foo an Drug Aministration. LITERATURE REVIEW A literature review to ientify an examine the available evience on key issues raise by the U.S. Foo an Drug Aministration, an those ientifie by the ASPS, the AAD, an the supporting meical specialty societies an organizations was conucte. In aition to presenting the current state of the evience, the literature review highlighte gaps in the available evience base. Key questions In creating a literature review search strategy, a set of key questions relate to the state of the science pertaining to soft-tissue fillers was ientifie. The following 10 multipart questions (Table I) were evelope base, in part, on the questions an issues iscusse by the U.S. Foo an Drug Aministration General an Plastic Surgery Panel at their meeting in November of These questions were reviewe by members of the steering committee an revise base on their feeback. Search strategy an esign A comprehensive search strategy was performe base on the key questions to search PubMe, which inclues access to MEDLINE, an citations for selecte articles in life science journals not inclue in MEDLINE. The search strategy was esigne to ensure broa capture of all relevant articles. Search strings using MeSH (Meical Subject Heaings, PubMe s controlle vocabulary for inexing stuies) terms an key text terms were combine to prouce the resulting search strategy: Varie constructs of search terms were capture with the use of truncation, as appropriate. Articles with abstracts in English. Articles focusing on humans. Stuies publishe since January 1, Letters, eitorials, an commentaries were exclue. Table II lists the search terms an parameters that we applie. This search yiele a total of 621 abstracts. A title an abstract review of these stuies, applying inclusion/exclusion criteria evelope in collaboration with the steering committee an base on stuy type an treatment type (Table III), was performe. The review of titles an abstracts yiele a total of 213 potentially relevant stuies. Full-text articles for these stuies were reviewe, an a precise classification of each article was performe. After the full-text review, a total of 198 unique, relevant stuies were ientifie for inclusion in this review. Base on the assumption that there was limite information on type an incience of averse events associate with use of soft-tissue fillers in general, case reports an case series, though methoologically limite for emonstrating cause an effect,

3 JAM ACAD DERMATOL VOLUME 64, NUMBER 4 S55 Table I. Key questions 1. What is the evience for the short- an long-term safety, efficacy, an effectiveness of soft-tissue fillers for approve an off-label inications (where efficacy refers to the effects of the tissue filler uner ieal conitions, an effectiveness refers to the effects uner normal/routine or real worl conitions)? 2. What is the evience for the types an frequency of occurrence of averse events associate with soft-tissue fillers for approve an off-label inications (e.g., use in the perioral area, incluing the lips, an volumization)? 3. What is the evience for the elaye onset of averse events (e.g., scarring an necrosis) following the aministration of soft-tissue fillers for approve an offlabel inications? 4. What is the evience that the occurrence of averse events varies by: a. Type of soft-tissue filler? b. Location of aministration (e.g., for off-label use)? c. Level of experience/training an supervision of staff aministering soft-tissue filler (e.g., physician, nurse or other nonphysician)?. Clinical setting of aministration? 5. What is the evience that safety an efficacy ata collecte in premarket approval stuies is consistent with an preictive of clinician experience with softtissue fillers in the postmarket setting? 6. What is the evience that patients with Fitzpatrick skin types IV through VI who are aministere soft-tissue fillers have outcomes similar to patients with Fitzpatrick skin types I through III who are aministere soft-tissue fillers? a. What is the evience from comparative stuies that these two subgroups respon with similar levels of safety an effectiveness to soft-tissue fillers? 7. What is the evience that valiate wrinkle severity an global aesthetic improvement scales are accurate an aequate for off-label inications (e.g., volume enhancement)? 8. What is the evience for evaluation tools for preicting the efficacy/effectiveness an safety of soft-tissue fillers for wrinkles? a. Is there evience that these tools are accurate an aequate for preicting the efficacy/effectiveness (e.g., functional outcomes) an safety of soft-tissue fillers use for other uses (e.g., augmentation, volume enhancement)? b. What is the evience that certain evaluation tools are more preictive of efficacy/effectiveness an safety than others? 9. What is the evience for the accuracy an aequacy of quantitative measures to evaluate the efficacy an safety of soft-tissue fillers? 10. What is the evience for the accuracy of maske versus nonmaske evaluation, an live versus photographic evaluation of soft-tissue fillers? a. What is the evience that use of multiple observers is an effective evaluation tool? were inclue as important sources of averse event ata, which is of high priority for evaluating softtissue fillers. See the companion Literature Review article for a complete escription of the literature review process, ata abstraction, an graing process use for this stuy. OVERVIEW OF THE STATE-OF-THE- SCIENCE CONFERENCE Key questions an topic areas aresse Base in part on the literature review finings an the opinions an expertise of the conference panel, the ASPS an the AAD agree to aress the following issues. Appropriate stuy esign an nee for more basic research Panelists generally inicate that there is a nee to look at an generate comparative evience of the safety an effectiveness of soft-tissue fillers across the range of Fitzpatrick scores. The iscussion focuse on proviing guiance to inustry on appropriate stuy esign, an inclue the following relate issues for consieration: The istribution of Fitzpatrick scores in the population to etermine what percentages woul be representative of this istribution when recruiting for a stuy population. Appropriate stuy length of time for follow-up (e.g., by soft-tissue filler) or process for etermining appropriate follow-up time, particularly given the increasing evelopment an use of longer lasting proucts. Stuy of Fitzpatrick score subgroups as a requirement in the premarket approval or postmarket approval phase. Nee for an feasibility of larger stuies of softtissue fillers. Merits of histologic evaluation of soft-tissue fillers. Clinical enpoints for short- an long-term safety an efficacy/effectiveness that nee to be stuie (e.g., evice migration, local tissue response, chronic inflammatory response, function, nerve sensitization) an how these iffer by location of the soft-tissue filler. Consieration of appropriate control groups. Appropriate methos to collect low-incience but possible severe averse event information. Upate of labeling to reflect averse events The following issues emerge: How shoul an averse event resulting from a soft-tissue filler be efine?

4 S56 JAM ACAD DERMATOL APRIL 2011 Table II. PubMe literature search strategy Concept Search String Hits General terms for ermal fillers Collagen fillers Hyaluronic aci fillers Poly-L-lactic fillers Calcium hyroxylapatite fillers Polymethylmethacrylate fillers Limits ermal filler* [tiab] OR soft tissue filler* [tiab] OR soft-tissue filler* [tiab] OR injectable filler* [tiab] OR wrinkle filler* [tiab] OR skin filler* [tiab] OR facial filler* [tiab] OR collagen* filler* OR (( cosmetic techniques [MH] OR rejuvenation [MH]) AND ( collagen [MH] OR hyaluronic aci [MH] OR lactic aci [MH] OR urapatite [MH] OR polymethyl methacrylate [MH] OR silicone oils [MH])) cosmoerm OR cosmoplast OR cymetra OR fascian OR zyerm OR zyplast OR glutaralehye-cross-linke collagen OR evolence juveerm OR perlane OR restylane OR hylan-b gel [Substance Name] OR hylaform OR puragen OR captique sculptra OR new-fill [Substance Name] raiesse artefill (humans[mh] AND English[lang] NOT (eitorial[pt] OR letter[pt] OR comment[pt]) NOT (review[pt] NOT (review[pt] AND (systematic[tiab] OR comprehensive[tiab] OR metho*[tiab] OR meline*[tiab] OR pubme*[tiab]))) OR AND 621 The asterisk (*) is a truncation symbol or wilcar, which means that any characters that come after it are retrieve, incluing those with no other characters. The quotation marks ( ) mean that the search looke for the wors as a phrase. The [tiab] means the search looke for the inicate term in the title or abstract. A search term with the [MH] after the term oes not have the asterisk because it is a set MeSH thesaurus term an will not have any variations. Given the frequency with which soft-tissue fillers are aministere for off-label uses, what is the appropriateness of incluing information about averse events relate to these off-label uses on the labeling of soft-tissue fillers? What shoul the level of U.S. Foo an Drug Aministration tolerance be for averse events associate with soft-tissue fillers? Shoul it iffer from the U.S. Foo an Drug Aministration s tolerance level for averse events relate to rugs? What shoul be the reporting process for averse events? How is this reporting system affecte by the level of U.S. Foo an Drug Aministration tolerance for averse events associate with softtissue fillers? What other types of information shoul be reporte? How shoul averse events that may be relate to interactions between ifferent soft-tissue fillers be capture? How about potential averse events relate to repeate proceures in the same location? What shoul the threshol level be for averse event reporting by inustry? Communicating averse events to proviers an consumers Panelists inicate that labeling often oes little to eter or control off-label use; nevertheless, information about potential averse events nees to be communicate to proviers an consumers. Representatives of the U.S. Foo an Drug Aministration inicate that the pursuit of user-frienly information regaring these proucts shoul be a major focus, for boththehealthcareprovierantheconsumer. SUMMARY OF EVIDENCE AND CONFERENCE FINDINGS Short- an long-term efficacy an effectiveness Consensus finings an literature evience results. All 198 stuies ientifie in the literature review investigate an/or reporte on the safety (e.g., occurrence of averse events), efficacy, or effectiveness of soft-tissue fillers. Among these were 33 reports of ranomize controlle trials. Hyaluronic aci fillers were most often investigate, whereas nasolabial fols were the most commonly injecte area. Overall, the evience inicates that soft-tissue fillers are effective an well tolerate for correcting nasolabial fols, other moerate to severe wrinkles an fols, an volume loss in cheeks. These finings were observe among patients seeking aesthetic facial rejuvenation an patients with human immunoeficiency viruseassociate facial lipoatrophy. Specific finings pertaining to various facial softtissue fillers are summarize below. See the companion Literature Review article for aitional iscussion. Hyaluronic aci. Although the expecte uration of hyaluronic aci filler correction is 6 to 12 months, epening on the particular filler, 84 percent (36 of 43) of stuies conucte follow-up evaluations of 3 months or longer.

5 JAM ACAD DERMATOL VOLUME 64, NUMBER 4 S57 Table III. Inclusion/exclusion criteria for abstract/title review Inclue stuy types Meta-analysis Systematic review Clinical trial Ranomize controlle trial Ranomize crossover trial Controlle clinical trial Uncontrolle clinical trial Epiemiologic stuy Cohort stuy Case-control stuy Cross-sectional stuy Follow-up stuy Evaluation stuy Case report/series Exclue stuy types* Nonsystematic reviews Guielines Inclue treatment types Soft-tissue fillers, incluing the following: Collagen Hyaluronic aci Poly-L-lactic aci Calcium hyroxylapatite Polymethylmethacrylate Silicone oil fillers Polyacrylamie gels Exclue treatment types Botulinum toxin Polymers an collagen-relate implants Other ermal stimulators *Particularly informative reviews an guielines were retaine to inform the backgroun section. Collagen. The expecte uration of collagen filler correction is 3 to 4 months, an 94 percent of stuies (16 of 17) conucte follow-up evaluations of 3 months or longer. Calcium hyroxylapatite. Calcium hyroxylapatite was foun to be superior to collagen (CosmoPlast; Iname Corp., Santa Barbara, Calif.), an both fillers were foun to have comparable safety an tolerability profiles. The two ranomize controlle trials comparing calcium hyroxylapatite to hyaluronic aci fillers [Restylane (Q-Me Esthetics, Uppsala, Sween) an Juveerm (Allergan, Inc., Irvine, Calif.)] foun calcium hyroxylapatite to be more effective in correcting nasolabial fols, whereas averse event rates for both treatments were comparable. Although the expecte uration of calcium hyroxylapatite filler correction is 1 year, 43 percent of stuies (nine of 21) conucte followup evaluations of 1 year or longer. Poly-l-lactic aci. Although the expecte uration of poly-l-lactic aci filler correction is 2 years, 54 percent of stuies (seven of 13) conucte follow-up evaluations of 2 years or longer. Polymethylmethacrylate. Polymethylmethacrylate is the only U.S. Foo an Drug Aministratione approve filler with ocumente urability over a 5-year perio. 6 Key points There are major gaps in the evience base for the effectiveness of most injectable soft-tissue fillers for inications other than nasolabial fols. Furthermore, as most of the evience is for the use of hyaluronic aci an collagen fillers, there is a lack of evience relate to the use of other important soft-tissue fillers. Another gap is evience for effectiveness of various techniques; for example, injector techniques in the more carefully manage setting of clinical trials are likely to iffer from those use in clinical practice (e.g., for facial contouring). As clinical practice evolves, the evience neee to meet regulatory requirements is not necessarily the same as the evience neee for market clearance an approval, further challenging the use of evience-base meicine in this fiel. Perioic evaluation of the evience. The following recommenations are mae: Establish the means to etermine, on a perioic or ongoing basis, the current levels of evience on efficacy an effectiveness. Determine the priority gaps in these boies of evience as they evolve with the introuction of new technology an inications. Develop a timeline an set of approaches with which to conuct this evience review effectively. Where possible, istinguish the priority gaps in evience for the respective purposes of regulatory requirements for market clearance/approval an informing clinical practice. Develop a stronger evience base. Encourage evelopment of a stronger evience base for currently recognize gaps, incluing the following: Soft-tissue filler classes other than hyaluronic aci an collagen. Important off-label inications (i.e., on- an off-face). Various injection techniques in all injection areas. The histology of egraation an prouct resorption.

6 S58 JAM ACAD DERMATOL APRIL 2011 Measures for soft-tissue efficacy an effectiveness Consensus finings an literature evience results. Across the literature on soft-tissue fillers, effectiveness is often etermine by the level of aesthetic improvement. Although aesthetic improvement may be subjective an ifficult to quantify, a variety of evaluation tools have been evelope to improve the valiity an reliability of assessments. These tools inclue ratings of appearance, patient satisfaction, an treatment success, which were use in stuies evaluating on-label or off-label uses of soft-tissue fillers. For stuies on facial augmentation for human immunoeficiency viruseassociate lipoatrophy, evaluation tools often inclue methos to etermine skin thickness. Evaluation tools that were less frequently use inclue patient questionnaires on quality of life an psychological state, an three-imensional imaging. Ratings of appearance. Despite the large variation across the evience with regar to soft-tissue filler type, injection technique, injection site, stuy population, an on-label versus off-label uses, the majority of stuies evaluating aesthetic appearance inclue the use of a valiate scale, such as the Global Aesthetic Improvement Scale, the Wrinkle Severity Rating Scale, the Facial Fol Assessment scale, the Lemperle Rating Scale, the Nasal Fol Severity scale, an the Moifie Fitzpatrick Wrinkle Scale. Ratings of treatment success. Several stuies use scales to rate treatment success; however, none of these scales appeare to have been valiate. Furthermore, these stuies provie very little etail on how the scales were evelope or what the criteria were for each score within the scale. Measurements of skin thickness. Particularly in stuies focusing on human immunoeficiency viruseassociate lipoatrophy, skin thickness was a frequently assesse outcome measure. None of the methos for etermining skin thickness was valiate in these stuies. The most frequently use metho for measuring skin thickness involve skin calipers. Although there are some valiate scales that are available, training on the use of these scales an stanarization across these valiate scales is still neee. Base on an assessment of the available literature, the review conclue that there is a nee for patient-reporte outcome measures esigne to measure satisfaction with facial appearance following aesthetic proceures. 7 Research on patient-reporte outcome measures to ate inclues creation of FACE-Q, a tool being evelope an valiate to measure clinically useful patient-reporte outcome measures of satisfaction an quality of life following elective surgical an nonsurgical facial rejuvenation. Sponsore in part by the ASPS, the FACE-Q uses in-epth patient interviews to ientify questions using specific language mirroring patient verbiage. It inclues measures for specific areas of the face an has resulte in 36 ifferent scales that can be use in combination to assess various patient-reporte outcome measures. Increasingly, patient-reporte outcome measures are being use as primary enpoints. The U.S. Foo an Drug Aministration has inicate that it is receptive to patient-reporte outcome measure research an has issue a guiance ocument on patient-reporte outcome measure evelopment. To emonstrate efficacy an effectiveness, however, clinically meaningful an scientifically rigorous patient-reporte outcome measures are neee. Key points Soft-tissue filler injection relies on the subjective evaluation of aesthetic improvement to etermine efficacy an effectiveness. As such, the lack of valiation an stanarization in accepte outcome measures (or scales or inexes) reuces the ability to generate rigorous evience about the efficacy an effectiveness of soft-tissue fillers. Many of the current outcome measures have not been valiate inepenently. The evelopment of improve patient-reporte outcome measures coul strengthen clinical trials an generate evience of greater relevance to clinicians an patients. Develop an valiate clinically meaningful outcome measures. These measures shoul incorporate psychometric variables, inclue three-imensional aspects (e.g., using volumetric scales) of soft-tissue filler injection, an be base on techniques that are not limite to patient photography. The evelopment an valiation of patient-reporte outcome measures shoul be encourage as a primary metho of assessing the efficacy an effectiveness of soft-tissue fillers in a clinically relevant way. Aopt stanarize valiate outcome measures. Move towar scientifically base consensus regaring a small set of valiate outcome measures for use in clinical trials an clinical practice in response to a nee for more stanarization across scales. Short- an long-term safety Consensus finings an literature evience results. There was great variation in the level of averse event reporting across the stuies reviewe from the literature. Most interventional an

7 JAM ACAD DERMATOL VOLUME 64, NUMBER 4 S59 epiemiologic stuies (i.e., nonecase series/reports) simply reporte the incience an severity of local an systematic averse events. Several stuies reporte safety ata beyon averse event incience an escriptions of severity. A total of five stuies foun that the examine collagen filler ha low potential for immunologic reactions. There remains a significant evience gap for averse events resulting from the use of softtissue fillers, incluing averse events associate with the type of filler an technique use. Key points Major gaps in evience relate to soft-tissue fillers call for more organize an systematic collection of safety ata. Increasing on-label use, expansion of off-label use, an varying injector technique are all major contributors to the nee for improve safety ata. Aitional concerns about safety arise as more patients unergo multiple proceures involving the same or ifferent fillers over time, often at ifferent sites an performe by proviers of varying expertise an experience. More research is neee on injection migration anatomy an relate anatomical moels. In looking to further this research, other clinical areas offer potential lessons in using best practices research an other systematic approaches to ientifying an mitigating patient risk. Patients unergoing proceures with multiple fillers. Establish ata collection mechanisms to investigate risks to patients who unergo proceures involving the same or multiple fillers either simultaneously or over time. Site preparation before filler use. Conuct research to etermine whether site preparation before soft-tissue filler injection affects infection rates. Use the finings of this research to evelop best practices or other protocols, as appropriate. Data collection mechanisms. Establish ata collection mechanisms to ientify associations between various proceures/techniques an averse outcomes. Establish ata collection mechanisms to track/investigate the postinjection anatomical location of fillers. Three-imensional application of fillers. Develop a new anatomical atlas for use in research an clinical practice that incorporates current research an accounts for the three-imensional application of fillers. Averse event reporting Consensus finings an literature evience results. A review of the literature ientifie 100 stuies relate to averse event reporting. Of these stuies, four provie analyses of iniviual atabases, whereas the remaining 96 were case series or reports presenting a variety of averse events. Aitional presentations given at the state-of-thescience conference that reflecte experience in practice reinforce the finings of the literature review. Averse event registries. Registries an atabases have been use to collect averse event ata associate with injectable soft-tissue filler evices. Although it is ifficult to use such ata to emonstrate causal relationships between particular softtissue fillers an averse events, they can help to ientify possible associations. The largest averse event registry ientifie by the literature review comprise a atabase maintaine by Q-Me Esthetics (manufacturers of Restylane, Perlane, an Restylane Fine Lines). The atabase inclues averse event ata from 1999 an 2000, which were collecte from physicians in Europe, Canaa, Australia, South America, an Asia. A retrospective review of these ata foun that approximately 144,000 patients were treate with hyaluronic aci in The stuy conclue that hypersensitivity was the greatest risk associate with hyaluronic aci fillers. 8 Manufacturer an User Facility Device Experience Database. The U.S. Foo an Drug Aministration maintains the Manufacturer an User Facility Device Experience atabase, which represents voluntary reports of averse events involving meical evices, such as soft-tissue fillers. A recent U.S. Foo an Drug Aministration analysis of soft-tissue filler evices state that 930 cases of averse events were reporte from January 1, 2003, through September 20, The most frequently reporte injection site was the nasolabial fol, accounting for 35.6 percent of the reports in which the site of injection was specifie. However, the majority of reporte averse events occurre in sites other than the nasolabial fol (e.g., lips, periorbital, perioral areas). Although the U.S. Foo an Drug Aministration s analysis provies some insights into averse events associate with soft-tissue fillers, the U.S. Foo an Drug Aministration note the limitations of the ata analysis. There are significant limitations of the U.S. Foo an Drug Aministration s Averse Event Reporting System, MeWatch, an the Manufacturer an User Facility Device Experience atabase. For example, although the Averse Event Reporting System atabase is intene to encourage physicians to report any rug reaction, the report of the event

8 S60 JAM ACAD DERMATOL APRIL 2011 oes not mean that the treatment cause the averse event, just that the event occurre after treatment with the rug. In aition, although the aforementione review was able to ientify cases of averse events in the Manufacturer an User Facility Device Experience atabase, the presenters experience significant ifficulty using the atabase interface, as there is only very limite terminology in the Manufacturer an User Facility Device Experience atabase relate to soft-tissue fillers. There nees to be much more information in the atabase (incluing terminology about chemical classes of fillers, location of fillers, averse events, metho of treatment, an practitioner experience) for it to be a more informative tool for practice. The core specialty groups coul collaborate with the U.S. Foo an Drug Aministration to clarify this terminology to ensure that it is consistent with practitioner terminology an relevant to current practice. Injectable Filler Safety registry. Another atabase ientifie in the literature an further escribe uring the conference was the Berlin-base Injectable Filler Safety registry. The registry has become an important source of clinical information, as clinicians have contacte the registry to ask how to treat averse events that occur in their patients. Case series/reports. In aition to the three averse event registries, our review ientifie 96 case series/reports presenting a variety of averse events. Table IV presents a istribution of the case series/ reports by the types of averse events reporte. The classification of averse events is base on a 2008 U.S. Foo an Drug Aministration report on ermal filler evices. Among the various types of averse reactions reporte, swelling, inflammatory reaction, an erythema were most often reporte. Key points Current averse event reporting is voluntary an limite, in part because of concerns regaring liability, which varies across states, an relate lack of information. These limitations in averse event reporting iminish opportunities to improve practice. In aition, although the current U.S. Foo an Drug Aministration safety information an averse event atabase for evices (Manufacturer an User Facility Device Experience) offers some useful information, its utility to clinicians, patients, an others intereste in the safety of soft-tissue fillers is limite in several ways. Compare with other searchable atabases, this atabase uses ruimentary search functions an ambiguous search terms. Furthermore, Table IV. Distribution of case series/reports by averse event type Averse Event No. of Stuies Swelling 24 Inflammatory reaction 20 Erythema 18 Nonspecific mass 15 Beaing 13 Blister/cyst 8 Pain 7 Allergic reaction 5 Infection 4 Vascular event 2 Migration 1 Other averse event 14 the atabase search terms lack categories relevant to soft-tissue fillers. Improve the facial soft-tissue filler averse event reporting system. Collaboration with a number of national an international stakeholers may result in more effective an useful averse event reporting. This initiative coul involve working with the U.S. Foo an Drug Aministration to improve the Manufacturer an User Facility Device Experience atabase to incorporate improve search functions an terminology relate to soft-tissue fillers. Injectors profile information (e.g., professional status) an patient-reporte outcome measures woul also be useful to collect in this atabase. In aition or alternatively, the initiative coul examine the Berlin registry as a moel whose attributes coul be aapte for use in the Unite States. Another potential moel coul involve establishing averse reporting systems with patient safety organizations. Clarify the legal implications an requirements for reporting averse events. Currently, physicians may be hesitant to report averse events because of potential exposure to legal actions. Furthermore, ifferences between an across states may lea to confusion in averse event reporting requirements. It woul benefit the valiity of averse event reporting an core cosmetic specialists to investigate an clarify the legal status an associate requirements of averse event reporting for clinicians, incluing any important ifferences across states. Training an eucation of practitioners aministering soft-tissue fillers Consensus finings an literature evience results. None of the stuies ientifie in the

9 JAM ACAD DERMATOL VOLUME 64, NUMBER 4 S61 literature review irectly evaluate the level of experience or training of practitioners aministering the filler. In most cases, stuies i not inicate who provie the injections. Finings suggest risks involve with soft-tissue filler injections aministere by unlicense practitioners an the importance of public health officials awareness of averse events associate with such injections. 9 In aition to injector training, technique may also have an effect on averse events. Key points Given the evolving nature of soft-tissue fillers, expaning inications, an the variable practices associate with their use, there is consierable nee for training an eucation to improve an ensure quality of care an patient outcomes. As many health care practices are regare increasingly as commoities, the role of physicians coul be iminishe. Efforts must be mae to counter unsafe trens an ensure that consumers are aware of the risk associate with using unqualifie practitioners. Develop evience-base training an eucation programs. Core cosmetic meicine specialty an subspecialty societies shoul collaborate in eveloping an proviing evience-base training an eucation programs intene to improve quality of care an patient outcomes. These programs must istinguish between on-label an off-label uses as appropriate. The certification associate with such training an eucation will help patients to ientify properly creentiale/qualifie clinicians to perform soft-tissue filler proceures. Develop a consumer awareness/information campaign. The core cosmetic meicine specialty an subspecialty societies shoul evelop a consumer awareness/information campaign that conveys the importance of receiving soft-tissue filler proceures from properly creentiale/qualifie clinician injectors. Information shoul pertain to the potential for averse events an other risks associate with receiving injections from an uncertifie injector. Improve communication Consensus finings an literature evience results. Although our literature review i not evaluate communication challenges surrouning the state of the science of ermal fillers, for any of the aforementione areas for improvement to occur, it will be necessary for the core specialty societies to increase communications with the U.S. Foo an Drug Aministration an improve communications within an among their member organizations. Key points Consistent with prevailing regulations, inustry is prohibite from sharing information about off-label use of soft-tissue filler materials. Furthermore, communications with the U.S. Foo an Drug Aministration are limite regaring evience requirements for expaning approve inications for soft-tissue fillers. The evelopment of soft-tissue fillers an clinical trials to establish their safety an efficacy/effectiveness woul be improve by new guiance from the U.S. Foo an Drug Aministration on such aspects as appropriate trial esign, patient selection, an outcome measures. Although communication has improve in recent years, better pretrial communication with the U.S. Foo an Drug Aministration woul improve the efficiency an usefulness of clinical trials conucte for gaining market approval/clearance of soft-tissue fillers. In aition to the nee to further engage with the U.S. Foo an Drug Aministration, current communication levels an collaboration among core cosmetic meicine specialty an subspecialty societies nee to keep pace with the evolving nees of stakeholers. This state-of-the-science conference was a step towar increasing communication an collaboration between the core cosmetic meicine specialty an subspecialty societies. Establish a ialogue. The core specialty an subspecialty societies shoul establish a ialogue involving the U.S. Foo an Drug Aministration, clinicians, an inustry to ientify clinically relevant outcome measures an averse events for soft-tissue fillers, which woul inform the esign of clinical trials, postmarketing surveillance, an other stuies. This ialogue woul aress, for example, esigning stuies with appropriate uration for capturing outcomes an averse events commensurate with various classes of soft-tissue fillers. Engage in evelopment of U.S. Foo an Drug Aministration guiance. The core specialty an subspecialty societies shoul involve inustry in working closely with the U.S. Foo an Drug Aministration to evelop current guiance for clinical trials an other ata collection relate to obtaining market approval/clearance for new inications, particularly beyon nasolabial fols. The core specialty an subspecialty societies shoul also work with an encourage the U.S. Foo an Drug Aministration to reuce the length of regulatory

10 S62 JAM ACAD DERMATOL APRIL 2011 review cycles, incluing U.S. Foo an Drug Aministration time an inustry sponsor time, as appropriate, without iminishing the quality of the review process. Establish an electronic mailing list. The core specialty an subspecialty societies shoul establish an electronic mailing list for the membership of the core cosmetic meicine specialty an subspecialty societies on the science, evience base, an quality of care relate to soft-tissue fillers. Improve communication with patient avocacy groups. The core specialty an subspecialty societies shoul improve communication with patient avocacy groups whose missions may inclue matters relate to cosmetic meicine, incluing for such purposes as eveloping an valiating patientreporte outcome measures, sharing information about quality of care associate with soft-tissue fillers, an gaining patient/consumer input on these an relate matters. Develop a monitoring function. The core specialty an subspecialty societies shoul evelop a monitoring function to capture relevant research finings, evience reports/syntheses, upate evience-base practice guielines, an other information that may be share with clinicians an other stakeholers in soft-tissue fillers. Current an future research nees Consensus finings an literature evience results. The majority of stuies ientifie in our literature review were case series or reports ocumenting the use of hyaluronic aci (n = 39). The most common stuy type ientifie in all soft-tissue filler stuies was case series/case reports (n = 97). Although case reports an small case series are not typically inclue in an evience review, we reviewe these stuy types for this report given our awareness that there is little information from available sources on averse events associate with use of soft-tissue fillers. Case reports an case series, though methoologically limite for emonstrating causal relationships between interventions an outcomes, can be useful sources of averse event ata, especially where such ata are scarce, as is the case for soft-tissue fillers. Furthermore, although the boy of evience we ientifie emonstrate that soft-tissue fillers are efficacious, effective, an in general fairly safe, the vast majority of stuies we examine ha short follow-up perios. Only one stuy followe patients for at least 5 years. Table V summarizes the istribution of the articles ientifie by stuy esign an soft-tissue filler type. Table V. Full-text stuies by type of stuy an type of soft-tissue filler Type of Stuy Collagen HA PLLA CaHA PMMA Other Total* SR RCT CCT UCT Cohort Cross-sectional Case series Total HA, Hyaluronic aci; PLLA, poly-l-lactic aci; CaHA, calcium hyroxylapatite; PMMA, polymethylmethacrylate; SR, systematic review; RCT, ranomize controlle trial; CCT, controlle clinical trial; UCT, uncontrolle clinical trial. *Citations pertaining to more than one soft-tissue filler type within a stuy are counte for soft-tissue filler, but only once for the Totals column. Encourage an work with inustry to esign clinical trials. To evelop a stronger evience base that aresses evience gaps previously mentione, the core specialty an subspecialty societies shoul encourage an work with inustry to esign clinical trials that: Involve hea-to-hea comparisons of new an existing fillers using comparators representing stanar care. Inclue stanarize valiate methos for assessing outcomes. Examine long-term safety an effectiveness. Incorporate clinically meaningful patient-reporte outcome measures to the extent possible. Inclue evaluation of injection techniques (where such techniques may affect outcomes). Involve appropriately representative patient types (e.g., Fitzpatrick skin types IV through VI, sex, age). Provie for specific an etaile reporting of averse events. As iscusse throughout the conference, there remains an unmet nee for clinical trials that reflect current clinical practice. By encouraging research that incorporates these recommenations, the fiel will be much closer to aressing this nee. CONCLUSIONS The Facial Soft-Tissue Fillers: Assessing the State of the Science conference, hel December 6 through 7, 2009, represents the first multistakeholer conference focuse on soft-tissue fillers. The key finings an recommene areas for improvement that emerge from the conference are an important initial

11 JAM ACAD DERMATOL VOLUME 64, NUMBER 4 S63 step towar aressing concerns over the safety, efficacy, an effectiveness of facial soft-tissue fillers. Ami this growing eman for facial soft-tissue fillers are major gaps in the evience base for the effectiveness of most injectable soft-tissue fillers for inications other than nasolabial fols. The majority of the current evience base pertains to the use of hyaluronic aci an collagen fillers, with little evote to the use of other important soft-tissue filler classes. To generate rigorous evience about the efficacy an effectiveness across soft-tissue fillers, off-label inications, an varying injection techniques, it is imperative that valiate an stanarize outcome measures are establishe. As they are in other areas of health care, patient-reporte outcome measures must play a greater role in the evaluation of soft-tissue filler injection. Demonstrating an improvement in patient-reporte outcome measures, for example, can strengthen the valiity an relevance of clinical trial finings for physicians an patients. Major gaps in the soft-tissue filler evience base can also be aresse, with increase efforts for organize an systematic collection of safety ata. As more patients unergo multiple proceures an the applications of fillers continue to expan, more research is neee to unerstan, for example, injection migration an relate anatomical moels. Another important component of safety is averse event reporting in the various at-risk patient populations. Currently, averse event reporting is voluntary an limite, an improving this ata collection an reporting capacity is neee to provie ongoing monitoring an feeback towar improving softtissue filler technology, clinical practice, an quality stanars. The rapily expaning use of an inications for soft-tissue fillers necessitates commensurate evelopment of training an eucation programs to improve the quality of care an patient outcomes. Furthermore, it is critical that consumers are aware of the risks associate with using unqualifie practitioners an of other risks that may arise associate with these proceures. Finally, an increase in the level an types of communication involving U.S. Foo an Drug Aministration, inustry stakeholers, an clinical investigators will improve the efficiency an usefulness of clinical trials conucte to gain market approval for facial soft-tissue filler proucts. The ASPS an the AAD contracte with The Lewin Group, a health an human services consulting firm locate in the Washington, D.C., metropolitan area, to provie analytical support to the conference, incluing a systematic literature review to inform the work of an expert panel that was to be establishe for the conference. The Lewin Group was also contracte to facilitate the expert panel iscussion uring the conference an summarize the finings of the conference in the present report. REFERENCES 1. American Society of Plastic Surgeons Report of the 2008 Statistics: National Clearinghouse of Plastic Surgery Statistics. Available at: _Statistics.html. Accesse March 25, American Society for Aesthetic Plastic Surgery National Totals for Cosmetic Proceures. Available at: surgery.org/ownloa/2008stats.pf. Accesse March 25, Cohen JL. Unerstaning, avoiing, an managing ermal filler complications. Dermatol Surg 2009;34:S Dang JM, Francis J, Durfor CN, Mirsaii N, Shoaibi A. Executive summary ermal filler evices. Available at: gov/ohrms/ockets/ac/08/briefing/ b1-01%20-%20fda %20Executive%20Summary%20Dermal%20Fillers.pf. Accesse March 25, U.S. Department of Health an Human Services, U.S. Foo an Drug Aministration. Panel Meeting Summary: November 18-19, 2008, Meeting of the General an Plastic Surgery Devices Panel. Available at: gps html. Accesse March 22, Cohen SR, Berner CF, Busso M. Five-year safety an efficacy of a novel polymethylmethacrylate aesthetic soft tissue filler for the correction of nasolabial fols. Dermatol Surg 2007;33(Suppl 2): S Kosowski TR, McCarthy C, Reavey PL. A systematic review of patient-reporte outcome measures after facial cosmetic surgery an/or nonsurgical facial rejuvenation. Plast Reconstr Surg 2009;123: Frieman PM, Mafong EA, Kauvar AN, Geronemus RG. Safety ata of injectable nonanimal stabilize hyaluronic aci gel for soft tissue augmentation. Dermatol Surg 2002;28: Centers for Disease Control an Prevention. Acute renal failure associate with cosmetic soft-tissue filler injections: North Carolina, MMWR Morb Mortal Wkly Rep 2008;57: