CLINICAL EVALUATION. Clinical Evaluation Dermal Filler 20/2 Hyacorp Face/GeneFill Soft Fill/ SMS Solution/Hyacorp Face II Voluma Version 3.

Transcription

1 CLINICAL EVALUATION CONTENT Clinical Evaluation... 1 Content General Details Description of the device and its intended application Intended therapeutic and/or diagnostic indications and claims Context of the evaluation and choice of clinical data types Summary of the clinical data and appraisal Data analysis State-of-the-Art Performance Safety Risk analysis Post-marked data Conclusion References Attachments /41

2 1. General Details Manufacturer: Medical Devices: BioScience GmbH Walsmühler Straße Dümmer Germany Hyacorp Face GeneFill Soft Fill SMS Solution Hyacorp Face II Voluma GMDN-Code: Description of the device and its intended application Products with identical or similar composition are marketed by the manufacturer BioScience GmbH under different names Hyacorp Face, Hyacorp Face II Voluma, GeneFill Soft Fill, and SMS Solution. There are differences between the products under discussion regarding their indications (see section 3). The products under discussion are clear and viscous gel and are provided in a sterile form. The products are for single use only. The contained gel consists of cross-linked hyaluronic acid. The products under discussion are absorbable skin implants with a high level of purity. The contained hyaluronic acid is of non-animal origin. Hyacorp Face, Hyacorp Face II Voluma, GeneFill Soft Fill, and SMS Solution products are sterile, apyrogenic, visco-elastic, biologically compatible (non-immunising, non-inflammatory, non-toxic) gel implants that are insoluble in water and produced from a hyaluronic acid gained through fermentation. GeneFill Soft Fill is supplied in a 1 ml syringes. Hyacorp Face is supplied in 1 or 2 ml syringes. For Hyacorp Face, two package sizes are available, with either one 1 ml syringe or two 2 ml syringes per box. Hyacorp Face II Voluma is supplied in 2 ml syringes (two syringes per package). SMS Solution is supplied in 10 ml syringes. According to the Medical Device Directive 93/42/EEC, annex IX, rule 8, the products under discussion are classified as Class III Medical Devices. The products under discussion are already certified as medical devices and are already marketed in the European Union: Composition The products under discussion are composed identically or in a similar manner. 2/41

3 1 ml Hyacorp Face contains: Hyaluronic acid sodium salt Cross-linked Hylan gel Sodium chloride Water for injection ad 2.0 mg 20.0 mg 6.9 mg 1.0 ml 1 ml GeneFill Soft Fill contains: Hyaluronic acid sodium salt Cross-linked Hylan gel Sodium chloride Water for injection ad 2.0 mg 20.0 mg 6.9 mg 1.0 ml 1 ml Hacorp Face II Voluma contains: Hyaluronic acid sodium salt Cross-linked Hylan gel Sodium chloride Water for injection ad 2.0 mg 24.0 mg 6.9 mg 1.0 ml 1 ml SMS Solution contains: Hyaluronic acid sodium salt Cross-linked Hylan gel Sodium chloride Water for injection ad 0.2 mg 2.3 mg 6.9 mg 1.0 ml Physico-chemical characteristics The products are sterile and their maximum endotoxin content is specified at < 0,25 EU/mL (LAL). Unbound BDDE is reduced to trace amounts in all products (specified < 1ppm). Further specifications are presented in the table below. Viscosity (mpas) ph- Value Osmolarity (mosmol/kg) Particle size (µm) Degree of cross-linking (%) Volume Hyacorp Face mL/ 2 ml GeneFill Soft Fill ml Hyacorp Face Voluma II ml 3/41

4 Hyaluronic acid (HA) is a naturally occurring glycosaminoglycan disaccharide composed of alternately repeating units of D-glucuronic acid and N-acetyl-D-glucosamine. It is a major component of the extracellular matrix found in many human tissues, including the skin. In contrast to other glycosaminoglycans, it occurs free and is not linked to proteins in the dermis. The highly charged nature of HA renders it soluble and allows it to bind water extensively, which determines skin viscoelasticity. Hyaluronic acid is chemically, physically and biologically identical in the tissues of all higher organisms (Kablik, Monheit et al. 2009). Figure 2-1 Hyaluronic Acid (HA) (Kablik, Monheit et al. 2009) HA has excellent biocompatibility and affinity for water molecules, but it is a soluble polymer that is cleared rapidly when injected into normal skin. The two most common functional groups that can be modified in HA are the carboxylic acid and the hydroxyl group. Cross-linking strategies attempt to improve biomechanical properties while maintaining biocompatibility and biological activity. The hyaluronic acid contained in the products under discussion is crosslinked using 1,4 butanediol diglycidyl ether (BDDE). By BDDE-crosslinking, the hyaluronic acid chains are chemically stabilised through permanent epoxidic cross-links. After the crosslinking process, residual cross-linker is almost completely eliminated (specification: <1 ppm). Under basic conditions (ph>7) the epoxide groups of BDDE react with primary alcohols in the backbone of the hyaluronic acid forming ether bond connections and the epoxide groups are neutralised (figure 2-2). 4/41

5 Figure 1: Schematic showing the cross-linking reaction of hyaluronic acid chains with BDDE. The epoxide groups in BDDE preferentially react with the primary hydroxyl groups in the hyaluronic acid backbone resulting in "fully reacted cross-linker" (A) or "pendant cross-linker" (B). BDDE that has not reacted with hyaluronic acid can be present in its hydrolized form (C) or its native form (D). By purification the amount of residual native BDDE in the product can be reduced to trace levels. Since this schematic demonstrates the crosslinking process with reference to the product Restylane (Q-Med), residual amounts of unreacted BDDE are given as <2 ppm (De Boulle, Glogau et al. 2013). When manufacturers convey the concentration of a filler, they are articulating the total amount of HA found in the filler, typically expressed in mg/ml(kablik, Monheit et al. 2009). The total HA concentration consists of insoluble HA gel and soluble-free HA. 5/41

6 Figure 2-2: Concentration is a measure of the amount of HA in the gel. Given the same degree of cross-linking, low concentration will result in softer gels (A), whereas higher concentration gels result in stiffer gels (B) (Kablik, Monheit et al. 2009). Intended use The products under evaluation are intended to be implanted into the medium dermal tissue to supplement the intercellular matrix and the intradermal tissue and to restore lost anatomical structures of the skin. Its mechanism of action is based on the latest biotechnology in the production of injectable hyaluronic acid. The product is completely degraded over time. The products under discussion do not exert any pharmacological, metabolic, or immunological effects. 6/41

7 3. Intended therapeutic and/or diagnostic indications and claims Application The areas to be treated must be marked before treatment begins. A local anaesthetic can be administered in order to carry out the implant as painlessly as possible. An antibiotic can be administered at the doctor s discretion to prevent infection. Remove the syringe from the blister pack, remove the cap covering the tip of the syringe and fit a suitable sterile needle to the Luer Lock port. The implantation technique in terms of the depth of the injection and the amount administered can vary from case to case and according to the different degrees of augmentation required. The doctor must select the technique appropriate to the case in hand. The products under evaluation are injected with the aid of sterile needles. The implantation is effected in the dermis. Correct only up to 100 % of the volume of augmentation required. Do not carry out overcorrections. Explanations must be given to the patient before treatment is given about indications, warnings, intolerances as well as potential side effects and the results to be expected. The area to be treated must be carefully aseptically prepared before treatment. Warning: The graduation on the syringe is intended as a guide for users based on the final volume. It does not perform any measuring function; it merely indicates the amount used in relation to the nominal volume of 2 ml. The doctor administering treatment should check visually and by touch that a sufficient amount of the material has been injected. Indication Hyacorp Face HYAcorp Face is indicated for the restoration of the facial volume and contour: replaces lost hyaluronic acid in the skin, is used for volume replacement (filling of folds), medium to deep folds, nasolabial folds, cheek area, glabella folds. Do not inject HYAcorp Face in the periorbital region (eyelid, crow s feet, circles under the eyes) Genefill Soft Fill Genefill Soft Fill is indicated for the restoration of the facial volume and contour: replaces lost hyaluronic acid in the skin, is used for volume replacement (filling of folds), medium to deep folds, nasolabial folds, cheek area, lip augmentation, glabel-la folds. Do not inject Genefill Soft Fill in the periorbital region (eyelid, crow s feet, circles under the eyes) 7/41

8 Hyacorp Face II Voluma HYAcorp Face Face II Voluma is indicated for the restoration of the facial volume and contour: replaces lost hyaluronic acid in the skin, is used for volume replace-ment (filling of folds), deep folds, nasolabial folds, cheek area, glabella folds. Do not inject HYAcorp Face II Voluma in the periorbital region (eyelid, crow s feet, circles under the eyes) SMS Solution Replaces lost hyaluronic acid in the skin The results that can be achieved are dependent on the skin type and the changes requested. The treatment should be carried out only by doctors with knowledge and experience in the field of aesthetic treatments. Contraindications: The products must not be used in patients who: - Have a tendency to hypertrophic and keloid scarring - Have an intolerance towards gram-positive bacteria - Are prone to active inflammatory or infectious processes - Are suffering from acute or chronic skin diseases - Are undergoinhg anti-coagulant therapy - Have a known allergy against hyaluronic acid - Are suffering from autoimmune diseases No clinical data is available on the administration of the product during pregnancy or lactation or on its ad-ministration to adolescents under 18 years of age. Patients with multiple allergies should be excluded from treatment. The use for breast and genital augmentation is contraindicated. Adverse Effects As with any invasive procedure, treatment with the products under evaluation may also result in adverse effects. Treatment-related non-allergic reactions may occur such as itching, reddening, sensitivities and swelling at the puncture site, subcutaneous bleeding or haematoma as well as hardness or hypersensitivity reactions. In most cases these reactions occur immediately or up to one week after the injection and usually abate spontaneously within one or two weeks. Delayed side effects are very rare but can occur later after the injection. Known delayed side effects of dermal fillers are bacterial infections, biofilm formation, the formation of chronic inflammatory nodules, reactivation of herpes infections, migration of the filler material, skin necrosis, foreign body reactions and granuloma formation. The injection technique can cause overcorrections or bluish discolorations (Tyndall effect). It is essential that side effects are diagnosed by an experienced doctor and appropriate treatment carried out and monitored. 8/41

9 In order to minimise the risk of side effects from the outset, a thorough anamnesis must be taken by the doctor carrying out the treatment and the use of a sterile injection technique rigorously maintained. Warnings The products under evaluation must not be injected into blood vessels as this could result in an occlusion of the vessels and an embolism. The products under evaluation should not be injected into an area in which a permanent implant has been placed. The products under evaluation should not be used on or in the vicinity of anatomical sites affected by an active skin disease, inflammation or associated conditions. The use of the product in areas that have already been treated with another augmentation solution is not recommended. The normal precautionary measures associated with intradermal injections must be observed. The products under evaluation are intended for injection into the medium dermal tissue. A technique and injection depth appropriate to the area treated must be chosen. To ensure the success of the treatment it is crucial that doctors using the product have the relevant expert knowledge and have undergone special technical training in injection techniques. In common with all procedures of this type the implantation of The products under evaluation are associated with the inherent risk of an infection. A thorough anatomical knowledge of the treatment site is absolutely vital and special care must be exercised if areas are being treated in the direct vicinity of vulnerable structures such as nerves and vessels. The doctor carrying out the treatment should be thoroughly conversant with the patient s anamnesis. Suitable precautionary measures should be taken in the case of patients suffering from pre-existing diseases and guidance and explanations should be provided. Patients taking medication affecting blood clotting, such as aspirins or non-steroidal anti-inflammatory drugs, will experience, as is the case with any injection, increased bruising or increased bleeding at the injection site. The area treated must not be exposed to excessive heat (sun, solarium, laser and IPL) or cold. Patients should refrain from sporting activities for a few days. The injection area should not be massaged in the days following the injection and not exposed to excessive pressure. If the needle is clogged, replace it with a new one. Do not increase the pressure on the piston. Used syringes needles should be treated as contaminated waste and must be disposed of in accordance with the generally accepted standards of medical practice. The products should be stored at room temperature (2 C to 25 C). 9/41

10 4. Context of the evaluation and choice of clinical data types The performance and safety of Hyacorp Face, GeneFill Soft Fill, Hyacorp Face II Voluma, and SMS Solution can be demonstrated based on equivalence to other products and established use. Hyacorp Face can be regarded as equivalent to the dermal filler Juvéderm Voluma (Allergan, Santa Barbara, California USA). Significant parameters of Hyacorp Face and Juvéderm Voluma have been tested and compared by the manufacturer. Equivalence could be verified (see figure below). Juvéderm Voluma is a sterile, biodegradable, non-pyrogenic, viscoelastic, clear, colorless, homogenised gel implant. It consists of crosslinked hyaluronic acid (HA) produced by Streptococcus equi bacteria, formulated to a concentration of 20 mg/ml. The intended use is equivalent to Hyacorp Face, since Juvéderm Voluma is intended for deep (subcutaneous and/or supraperiosteal) injection (see IFU of Juvéderm Voluma ). Furthermore, since the physico-chemical parameters of Juvéderm Voluma and Hyacorp Face are equivalent, the following can be concluded: Technical, biological, and clinical equivalence of Juvéderm Voluma and Hyacorp Face is demonstrated. Furthermore, the comparability of hyaluronic dermal fillers is discussed by (Sundaram, Voigts et al. 2010): The physicochemical structure of a soft tissue filler gel is established during the manufacturing process by the adjustment of variables such as concentration of the solid-phase molecules, the method and percentage of cross-linking of solid-phase molecules, and the proportion of the overall gel that the fluid phase constitutes (gel-to-fluid ratio). Soft tissue fillers with different physicochemical structures behave differently with respect to their rheology (their viscosity, elasticity, and plasticity). Two important rheological properties of a soft tissue filler gel that can be quantified are its complex viscosity and its elastic modulus. The physicochemical structure of soft tissue fillers and the resultant unique rheological properties are clinically relevant because they play a pivotal role in determining how the filler behaves during and after injection. The different physicochemical properties of dermal fillers were compared and evaluated. The results of the investigation are outlined in the figure below. 10/41

11 (Sundaram, Voigts et al. 2010) It can be deduced from the results presented in Sundaram et al that the reological properties of Juvéderm Ultra, Juvéderm Ultra Plus, Restylane, and Restylane SubQ are similar to Juvéderm Voluma. Restylane SubQ (20 mg/ml BDDE cross-linked hyaluronic acid of non-animal origin) is intended to be used for facial tissue augmentation. It is recommended to be used for shaping the contours of the face, e.g. more pronounced cheeks or chin. The depth of injection may vary from injection into the subcutaneous fatty tissue to supraperiostal administration depending on the treatment site (see IFU of Restylane SubQ). Thus, in addition to Juvéderm Voluma, Restylane SubQ is considered equivalent to Hyacorp Face. Restylane is a gel of hyaluronic acid generated by Streptococcus species of bacteria, chemically crosslinked with BDDE, stabilized and suspended in phosphate buffered saline at ph=7 and concentration of 20 mg/ml. Restylane is indicated for lip augmentation and for mid-to-deep 11/41

12 dermal implantation for the correction of moderate to severe facial wrinkles and folds, such as nasolabial folds (see IFU Restylane). Since the specifications of Hyacorp Face and GeneFill Soft Fill are equivalent, the same physico-chemical properties are assumed. Furthermore, the indications of Restylane are equivalent to GeneFill Soft Fill. Thus, Restylane is considered to an equivalent product to GeneFill Soft Fill. Juvéderm Ultra injectable gel is a sterile, biodegradable, nonpyrogenic, viscoelastic, clear, colorless, homogenised gel implant. Juvéderm Ultra injectable gel consists of crosslinked hyaluronic acid produced by Streptococcus equi bacteria, formulated to a concentration of 24 mg/ml and suspended in a physiologic buffer. Juvéderm Ultra injectable gel is indicated for injection into the mid to deep dermis for correction of moderate to severe facial wrinkles and folds (such as nasolabial folds) (see IFU Juvéderm Ultra). Although the HA concentration is slightly higher in Juvéderm Ultra compared with GeneFill Soft Fill, it is regarded as essentially similar and is therefore taken into consideration as well. Furthermore, Juvéderm Ultra / Ultra Plus is considered equivalent to Hyacorp Face II Voluma. A further product that can be regarded as equivalent to Hyacorp Face II Voluma is Teosyal Ultra Deep. According to MEDDEV 2.7/1 rev3 evaluation of performance and safety of the products under discussion based on published data regarding Juvéderm Voluma, Restylane SubQ, Restylane, Juvéderm Ultra, and Teosyal Ultra Deep is feasible. A tabulated summary on the equivalence analysis is given in attachment 2. Therefore, a thorough literature search in established databases is performed to demonstrate the performance and safety of Hyacorp Face, GeneFill Soft Fill, Hyacorp Face II Voluma, and SMS Solution by taking products that are regarded as equivalent and the state-of-the-art of dermal fillers into consideration. 5. Summary of the clinical data and appraisal Following publications are regarded to contain sufficient information for a rational and objective assessment. All articles are relevant for the products under evaluation. The quality of the data is considered satisfactorily for articles taken into consideration. Protocol of the literature survey, corresponding results and appraisal criteria are outlined in attachment 1. The publications are categorised into the following sections: description of state-of-the-art, demonstration of performance and demonstration of safety. For description of the current state-of-the-art mainly review articles are assessed. The performance of Juvéderm Voluma, Restylane SubQ, Restylane, Teosyal Ultra Deep, and Juvéderm Ultra is mostly gained from prospective trials providing sufficient information for a detailed assessment. Although representing a low level of clinical evidence, case reports were evaluated to investigate rare complications for the use of hyaluronic acid as dermal filler. The final result of the appraisal of the literature is discussed below: 12/41

13 State-of-the-Art Baumann, L. S., A. T. Shamban, et al. (2007). "Comparison of smooth-gel hyaluronic acid dermal fillers with cross-linked bovine collagen: a multicentre, double-masked, randomised, within-subject study." Dermatol Surg 33 Suppl 2: S Gold, M. (2009). "The science and art of hyaluronic acid dermal filler use in esthetic applications." J Cosmet Dermatol 8(4): Hoffmann, K. (2009). "Volumizing effects of a smooth, highly cohesive, viscous 20- mg/ml hyaluronic acid volumizing filler: prospective European study." BMC Dermatol 9: 9. Kablik J. (2009). Comparative physical properties of hyaluronic acid dermal fillers. Dermatol Surg. Feb;35 Suppl 1: Kim, J. E. and J. M. Sykes (2011). "Hyaluronic acid fillers: history and overview." Facial Plast Surg 27(6): A total of 439 subjects with moderate or severe nasolabial folds received one of three types of smooth-gel HA dermal fillers (in one NLF) and cross-linked bovine collagen (in the other NLF) and were evaluated for 24 weeks. The study was approved by the relevant institutional review boards, all subjects signed informed consent, and the study protocol conformed to the guidelines of the 1975 Declaration of Helsinki. This article provides an overview of the HA fillers, focusing on interweaving of artistic concepts with scientific principles of dermal filling. This was a prospective, open-label, nonrandomised study in which a 20-mg/mL smooth, highly cohesive, viscous HA volumising filler (Juvéderm VOLUMA, Allergan, Pringy, France) was evaluated within its indicated use of restoring facial volume. The study was funded by Allergan, Inc. This Europe-wide evaluation was conducted under the guidelines of the World Association of Opinion and Marketing Research (ESOMAR) to evaluate current usage of the 20mg/mL smooth, cohesive HA volumising filler in European countries in which the product is CEmarked or licensed and available. Evaluations took place within standard practice procedures without the inclusion of any additional monitoring or diagnostic procedures. The conduct of the trial complied with the provisions of the Helsinki Declaration for studies in humans. Written informed consent was obtained from the patients. The objective of this article was to discuss the key physical properties and methods used in characterizing dermal fillers. These methods were then used to analyze several well-known commercially available fillers. Hyaluronic acid (HA) fillers have many favorable characteristics that make it a popular injectable filler device. Its minimal immunogenicity and relative ease of use has helped HA become the most commonly used injectable filler today. A brief history of injectable fillers, the various injection techniques, and legal ramifications are discussed. A review of the most recent literature compares the efficacy and safety of HA to other injectable filler, A1, P1, R1 A1, P2, R1 A1 P1 R2 R1 A2 P2 R1 13/41

14 substances. Lupo, M. P. (2006). "Hyaluronic acid fillers in facial rejuvenation." Semin Cutan Med Surg 25(3): Matarasso, S. L., J. D. Carruthers, et al. (2006). "Consensus recommendations for soft-tissue augmentation with nonanimal stabilised hyaluronic acid (Matarasso, Carruthers et al.)." Plast Reconstr Surg 117(3 Suppl): 3S-34S; discussion 35S-43S. Newman, J. (2009). "Review of soft tissue augmentation in the face." Clin Cosmet Investig Dermatol 2: Price, R.D, et al (2007). Hyaluronic acid: the science and clinical evidence. J Plast Reconstr Aesthet Surg. 60, Rohrich, R. J., A. Ghavami, et al. (2007). "The role of hyaluronic acid fillers (Restylane) in facial cosmetic surgery: review and technical considerations." Plast Reconstr Surg 120(6 Suppl): 41S- 54S. Smith, K. C. (2008). "Reversible vs. nonreversible fillers in facial aesthetics: concerns and considerations." Dermatol Online J 14(8): 3. Review article. This publication represents an overview for hyaluronic acid as a dermal filler. The advantage of hyaluronic acid compared other dermal fillers like collagen is discussed. The article represents and summarizes publications from 1986 to Restylane and other sorts of hyaluronic acid (avian origin) are described. Review article and consensus statement, mainly focusing on the product Restylane. Besides products, procedural aspects were discussed in detail. The time period from 2000 to 2005 is covered. Review article covering the time period from 2000 to 2008; This article describes the current options of tissue augmentation; pro and cons are discussed in an objective manner. In addition, absorbable fillers, non-absorbable material and methods using autologous material are discussed. This review represents an overview about the scientific evidence of HA used in different fields such as skin regeneration, wound healing and cosmetic surgery. Review article. The product Restylane is described in detail; procedural aspects are discussed as well. Main focus of this article is the facial rejuvenation. The performance of Restylane is shown. Possible complications and there occurrence are discussed. Review article dealing with hyaluronic acid as dermal filler in general. History, development and alternatives in tissue augmentation are presented. The major and unique advantage of HA fillers, the reversion by hyaluronidase is outlined. A1, P1, R2, A1, P2, R2, A1, P1, R2, A2, P2, R1 A1, P2, R1 A2, P1, R2 Tezel, A. and G. H. Fredrickson (2008). "The science of hyaluronic acid dermal fillers." J Cosmet Laser Ther 10(1): The use of injectable materials for soft-tissue augmentation has been increasing, reflecting the introduction of new hyaluronic acid based dermal fillers. Hyaluronic acid dermal fillers vary widely in their physical and chemical characteristics. This article explains the basic science of hyaluronic acid 14/41 A1 P1 R1

15 and describes how the physical properties of hyaluronic dermal fillers may influence clinical outcomes. Performance Bechara, F. G., T. Gambichler, et al. (2008). "Hyaluronic acid new formulation: experience in HIVassociated facial lipoatrophy." Dermatology 217(3): Callan, P., et al., Efficacy and safety of a hyaluronic acid filler in subjects treated for correction of midface volume deficiency: a 24 month study. Clin Cosmet Investig Dermatol, : p males with FLA were enrolled in this prospective, open-label, monocentre pilot study. Each patient received subcutaneous implantation of high-density hyaluronic acid. The aesthetic outcome was evaluated using the Global Aesthetic Improvement Scale every 3 months until 12 months after implantation. Additionally, patient satisfaction was analysed, changes in patient quality of life were recorded using the Dermatology Life Quality Index (DLQI), and side effects were documented. The study was conducted according to the declaration of Helsinki. All subjects who participated in the investigation signed an informed consent. The treatment with Juvéderm Voluma was administered in one or two sessions over an initial 4-week period. Supplementary treatment was permissible at week 78, based on protocoldefined criteria. Of the 103 subjects enrolled, 84% had moderate or significant volume deficiency at baseline. The study was approved by a central institutional review board and conducted at six Australian private aesthetic clinics, in full accordance with Good Clinical Practice regulations and guidelines, including the International Conference on Harmonization. All subjects were required to provide written informed consent and sign a photography release form prior to any study-related procedures. This study is listed on the Clinical Trials.gov registry (NCT ). A1 P2 R2 A1 P1 R2 DeLorenzi, C., M. Weinberg, et al. (2009). "The long-term efficacy and safety of a subcutaneously injected large-particle stabilised hyaluronic acid-based gel of nonanimal origin in esthetic facial contouring." Dermatol Surg 35 Suppl 1: Fifty-seven adult patients seeking aesthetic cheek or chin augmentation or both received subcutaneous or supraperiosteal injections or both of large-particle stabilised hyaluronic acid based gel (20mg/mL). Efficacy was assessed subjectively using the Global Aesthetic Improvement Scale at intervals up to 12 months after treatment. The Western Institutional Review Board (Olympia, WA) and the Canadian regulatory authorities (Therapeutic 15/41 A2 P1 R2

16 Program Directorate, Ottawa) approved the study protocol, and the study was performed in accordance with the principles of the Declaration of Helsinki, the ICH guidelines for Good Clinical Practice, and local regulatory requirements. All patients provided written informed consent before entry to the study. Fischer, T. C. (2010). "A European evaluation of cosmetic treatment of facial volume loss with Juvederm Voluma in patients previously treated with Restylane Sub-Q." J Cosmet Dermatol 9(4): Glogau, R. G., D. Bank, et al. (2012). "A randomised, evaluatorblinded, controlled study of the effectiveness and safety of small gel particle hyaluronic acid for lip augmentation." Dermatol Surg 38(7 Pt 2): This study comprised a European postmarket research evaluation on the use of Juvederm Voluma and was conducted from February 23 to May 4, 2009 under the World Association of Opinion and Marketing Research (ESOMAR) guidelines. All patients provided written informed consent prior to commencement of any study procedures. There was no assignment of patients to a particular therapeutic strategy. Key patient inclusion criteria comprised women and men aged >30 years requesting treatment for correction of facial volume loss and who accepted injection with Voluma. Eligible patients were adult men and women no older than 65 seeking lip augmentations at 12 investigational centres A central institutional review board (Quorum Review IRB, Seattle, WA) approved the study protocol and documents. Patients provided written informed consent before being admitted to the study. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. A2 P1 R1 A1 P1 R1 Hoffmann, K. (2009). "Volumizing effects of a smooth, highly cohesive, viscous 20-mg/mL hyaluronic acid volumizing filler: prospective European study." BMC Dermatol 9: 9. This was a prospective, open-label, nonrandomised study in which a 20-mg/mL smooth, highly cohesive, viscous HA volumising filler (Juvéderm VOLUMA, Allergan, Pringy, France) was evaluated within its indicated use of restoring facial volume. The study was funded by Allergan, Inc. This Europe-wide evaluation was conducted under the guidelines of the World Association of Opinion and Marketing Research (ESOMAR) to evaluate current usage of the 20mg/mL smooth, cohesive HA volumising filler in European countries in which the product is CE-marked or licensed and available. Evaluations took place within standard practice procedures without the inclusion of any additional monitoring or diagnostic procedures. The conduct of the trial complied with the provisions of the Helsinki Declaration for studies in humans. 16/41 A1 P1 R2

17 Humphrey, S., et al. (2015). "Clinical Experience With 11,460 ml of a 20-mg/mL, Smooth, Highly Cohesive, Viscous Hyaluronic Acid Filler." Dermatol Surg 41(9): Morris, C. L., S. S. Stinnett, et al. (2008). "Patient-preferred sites of restylane injection in periocular and facial soft-tissue augmentation." Ophthal Plast Reconstr Surg 24(2): Narins, R. S., F. Brandt, et al. (2003). "A randomised, doubleblind, multicentre comparison of the efficacy and tolerability of Restylane versus Zyplast for the correction of nasolabial folds." Dermatol Surg 29(6): Pinsky, M. A., J. A. Thomas, et al. (2008). "Juvederm injectable gel: a multicentre, double-blind, randomised study of safety and effectiveness." Aesthet Surg J 28(1): Raspaldo, H. (2008). "Volumizing effect of a new hyaluronic acid subdermal facial filler: a retrospective analysis based on 102 cases." J Cosmet Laser Ther 10(3): Schweiger, E. S., C. C. Riddle, et al. (2008). "Successful treatment with The authors conducted a retrospective chart review of patients who received Juvéderm Voluma between February 1, 2009, and May 1, Over 68 months, the authors performed a cumulative total of 4,702 treatments using 11,460mL of Juvéderm Voluma in 2,342 patients aged 20 to 85 years. The midface area was treated most frequently, although treatment targeted a variety of indications. The authors respectively reviewed the records 145 patients who received subcutaneous facial injections of Restylane. Location, amount, supplemental anaesthetic, injection frequency, follow-up time, patients satisfaction, revision rate, and adverse reactions were noted and analysed. This randomised patient- and evaluator-blinded study was conducted at six centres in the United States, and subjects seeking soft tissue augmentation treatment for correction of bilateral nasolabial folds were recruited. Outcomes were evaluated by blinded observer at 2, 4, 6 month after baseline. The study was performed in accordance to the Declaration of Helsinki, the ICH guidelines for Good Clinical Practice. In the multicentre study approved by the Food and Drug Administration, subjects were randomised to treatment with Juvéderm Ultra or Ultra Plus in one nasolabial fold (NLF) and Zyplast collagen in the other. After optimal correction was achieved (treatment plus up to 2 touch-ups at 2-week intervals), effectiveness was assessed on a 5-point scale through the 6- month study period. An additional poststudy visit provided long-term effectiveness data. Safety was evaluated through subjects daily diaries for 14 days after treatment. Retrospective record analysis was made for 102 patients (93 females, nine males; mean age: years) who received Juvederm Voluma injected into the midface. All patients were assessed at baseline and at 1 month and 6 18 months post-injection. Surgical repair of cleft lip, while correcting deformity and dysfunction, may leave residual A1 P1 R1 A1 P1 R2 A1 P1 R1 A1 P1 R1 A1 P1 R2 A1 17/41

18 injected hyaluronic acid in a patient with lip asymmetry after surgical correction of cleft lip." Dermatol Surg 34(5): Skeie, L., H. Bugge, et al. (2010). "Large particle hyaluronic acid for the treatment of facial lipoatrophy in HIV-positive patients: 3-year follow-up study." HIV Med 11(3): Smith, S. R., D. Jones, et al. (2010). "Duration of wrinkle correction following repeat treatment with Juvederm hyaluronic acid fillers." Arch Dermatol Res 302(10): Solish, N. and A. Swift (2011). "An open-label, pilot study to assess the effectiveness and safety of hyaluronic acid gel in the restoration of soft tissue fullness of the lips." J Drugs Dermatol 10(2): cosmetic imperfections. The resultant asymmetry and low volume of the upper lip can be addressed surgically and via less invasive methods. The authors present the first reported use of injectable hyaluronic acid to correct the characteristic lip asymmetry and poor volume after surgical repair of a cleft lip. HIV-infected patients older than 18 years of age with severe nasogenian atrophy (readily noticeable to a casual observer) that had not previously been treated with injectable fillers were considered eligible for inclusion. The study protocol was evaluated by the Regional Committee for Medical Research Ethics and approved by the Norwegian Data Inspectorate. This study has been conducted in full accordance with the World Medical Association Declaration of Helsinki. Upon completion of the pivotal IDE clinical trial for Juvederm 30, Ultra, and Ultra Plus, five of the original 11 study sites were selected to participate in an extended follow- up evaluation. Sites were selected based on their continued abilities to participate in the follow-up protocol, their track record of visit schedule compliance, and the planned sample size of 150 subjects. No consideration was given to duration of filler correction in the selection of sites. Subjects who were eligible and agreed to participate in the follow-up study signed an informed consent and were followed from 4 through 48 weeks after their repeat treatments. Routine follow-up visits for effectiveness occurred at 4, 12, and 24 weeks, and an amendment to the protocol added visits at 36 and 48 weeks after repeat treatment. Safety and effectiveness were evaluated at each office visit. Investigators treated 21 adults. The primary efficacy endpoint was an increase in lip fullness at eight weeks post-treatment. Adverse events were reported using patient diaries. This study was approved by the Institutional Review Board performed in accordance to the Declaration of Helsinki, and conducted in compliance to good clinical practice. All patients gave informed consent to participate. P2 R2 A1 P2 R2, A1, P1, R2 A1 P1 R2 18/41

19 Wu, Y., et al. (2016). "Clinical comparison between two hyaluronic acid-derived fillers in the treatment of nasolabial folds in Chinese subjects: BioHyalux versus Restylane." Arch Dermatol Res. This multicenter, double-blinded, randomised, controlled, non-inferiority study was conducted to compare the efficacy, tolerability, and durability of the cosmetic effect of BioHyalux versus Restylane in correcting nasolabial folds (NLF). Eighty-eight subjects aged between 18 and 65 years with moderate or severe NLF (Wrinkle Severity Rating Scale (WSRS) score of 3 or 4, as evaluated by the investigators) were recruited in this study. The study was approved by a central institutional review board and conducted at two Chinese hospitals, in full accordance with the Good Clinical Practice regulations and guidelines. All subjects provided a written informed consent. A1 P1 R1 Safety Andre, P., N. J. Lowe, et al. (2005). "Adverse reactions to dermal fillers: a review of European experiences." J Cosmet Laser Ther 7(3-4): Beasley, K.L. (2009). Hyaluronic Acid Fillers: A comprehensive Review. Facial Plast Surg. 25: Callan, P., et al., Efficacy and safety of a hyaluronic acid filler in subjects treated for correction of midface volume deficiency: a 24 month study. Clin Cosmet Investig Dermatol, : p This review article summarised publications and case reports. It described the clinical aspects of adverse reactions following injections of dermal filler (absorbable, non biodegradable and permanent) And provides valid information on safety of dermal fillers Since 85 % of all dermal filler procedures occurred with a hyaluronic acid derivate this review summarised the composition, specific differences and pivotal clinical studies of all the hyaluronic acid fillers currently available in the US. The treatment with Juvéderm Voluma was administered in one or two sessions over an initial 4-week period. Supplementary treatment was permissible at week 78, based on protocoldefined criteria. Of the 103 subjects enrolled, 84% had moderate or significant volume deficiency at baseline. The study was approved by a central institutional review board and conducted at six Australian private aesthetic clinics, in full accordance with Good Clinical Practice regulations and guidelines, including the International Conference on Harmonization. All subjects were required to provide written informed consent and sign a photography release form prior to any studyrelated procedures. This study is listed on the Clinical Trials.gov registry (NCT ). A2 P1 R1, A1, P2, R1 A1 P1 R2 19/41

20 Funt, D. and T. Pavicic (2015). "Dermal fillers in aesthetics: an overview of adverse events and treatment approaches." Plast Surg Nurs 35(1): Gilbert, E., A. Hui et al. (2012). The basic science of dermal fillers: past and present Part II: adverse effects. J Drugs Dermatol 11(9): Hirsch R.J. and Stier M. (2008). Complications of soft tissue augmentation. J Drugs Dermatol. Sep; 7(9): Hoffmann, K. (2009). "Volumizing effects of a smooth, highly cohesive, viscous 20-mg/mL hyaluronic acid volumizing filler: prospective European study." BMC Dermatol 9: 9. Matarasso, S. L., J. D. Carruthers, et al. (2006). "Consensus The objective of this article was to describe potential adverse events associated with dermal fillers and to provide structured and clear guidance on their treatment and avoidance. Reports of dermal filler complications in the medical literature were reviewed including those reported for Restylane for example and, based on the publications retrieved and the authors extensive experience, recommendations for avoiding and managing complications are provided. Part I of this article reviews the basic science and evolution of both historical and contemporary dermal fillers; Part II examines their adverse effects. This article describes a range of complications resulting from dermal filler injections, reviews key case studies, and discusses possible treatment options for adverse effects. While biodegradable fillers offer the least risk for the patient, location, allergic reactions, granulomas, necrosis, and infection are all serious complications that must be considered before performing soft tissue augmentation with any approved dermal filler. This was a prospective, open-label, nonrandomised study in which a 20-mg/mL smooth, highly cohesive, viscous HA volumising filler (Juvéderm VOLUMA, Allergan, Pringy, France) was evaluated within its indicated use of restoring facial volume. The study was funded by Allergan, Inc. This Europe-wide evaluation was conducted under the guidelines of the World Association of Opinion and Marketing Research (ESOMAR) to evaluate current usage of the 20mg/mL smooth, cohesive HA volumising filler in European countries in which the product is CEmarked or licensed and available. Evaluations took place within standard practice procedures without the inclusion of any additional monitoring or diagnostic procedures. The conduct of the trial complied with the provisions of the Helsinki Declaration for studies in humans. Review article and consensus statement, mainly focusing on the product Restylane. A1 P1 R1, A1, P2, R2, A1, P2, R2 A1 P1 R2, A1, 20/41

21 recommendations for soft-tissue augmentation with nonanimal stabilised hyaluronic acid (Matarasso, Carruthers et al.)." Plast Reconstr Surg 117(3 Suppl): 3S-34S; discussion 35S-43S. Newman, J. (2009). "Review of soft tissue augmentation in the face." Clin Cosmet Investig Dermatol 2: Price, R.D, et al (2007). Hyaluronic acid: the science and clinical evidence. J Plast Reconstr Aesthet Surg. 60, Winslow, C. P. (2009). "The management of dermal filler complications." Facial Plast Surg 25(2): Besides products, procedural aspects were discussed in detail. The time period from 2000 to 2005 is covered. Review article covering the time period from 2000 to This article compared the current options of tissue augmentation and discussed the composition and characteristics of available dermal fillers. This review represents an overview about the scientific evidence of HA used in different fields such as skin regeneration, wound healing and cosmetic surgery. The purpose of this article is to review the most commonly encountered complications and management thereof. Literature published between 2006 and 2008 is taken into consideration. P2, R2, A1, P1, R2, A2, P2, R1, A2, P2, R1 21/41

22 6. Data analysis 6.1. State-of-the-Art Pathogenesis Dermal aging is a consequence of multiple, interacting intrinsic and extrinsic factors. When the dermis ages, wrinkles, grooves, and ptotic tissue become more and more prominent. Superficial wrinkles are largely due to photo damage and resulting solar elastosis. This is characterized by loss of collagen mass in the epidermal dermal junction and an increased array of elastin whirls in the deeper dermis. Sun exposure, or photoaging, contributes importantly to the intrinsic changes associated with aging. Another factor in the appearance of facial aging is the lifelong activity of the muscles of facial expression, which produces the dynamic and, ultimately, static facial lines and folds. It has also long been recognized that gravity exerts a toll on the dermal structures as tissue loses its elasticity and becomes less able to resist stretching (Hoffmann 2009). Grooves appear deeper in the nasolabial and marionette zones with the additional feature of fat atrophy. As a result of the loss of fat volume, the static suspensory ligaments become more lax and the face takes on attributes of ptotic jowls, ptotic malar mounds, and nasolabial folds. Skeletal changes resulting in decreased height of the maxilla and the mandible occur in the later decades of life (6th 8th decades) and accentuate the above findings. Facial rejuvenation requires an accurate diagnosis of the above findings, and therapies are directed at correcting multiple layers. The pillars of dermal rejuvenation: 1) ensuring adequate skeletal framework and support, 2) tightening and repositioning of the investing musculofascial aponeurotic system of the face and neck (galea, superficial muscular aponeurotic system, and platysma), 3) replacement (Newman 2009). History of dermal fillers A major step in the development of injectable fillers occurred in 1981, when bovine collagen (Zyderm, Zyplast; Inamed Corp., Santa Barbara, CA) became the first FDA-approved injectable filler for cosmetic use. Zyderm s smooth flow characteristics made it a popular choice for the treatment of fine wrinkle lines. But bovine collagen has some notable disadvantages. Approximately 3 to 3.5 % of the population demonstrate hypersensitivity to bovine collagen, requiring skin testing prior to injection. Even after an initially negative skin test, 1 % of the population will still demonstrate hypersensitivity. Other disadvantages include the short duration of effect and the need for refrigeration of the product. To compound this, bovine collagen became even less popular during the height of the bovine spongiform encephalopathy fear. The modern era of injection with synthetic selective bioactive materials began in December of 2003 with the FDA s approval of Restylane (Q-Med, Uppsala, Sweden), a hyaluronic acid (HA) product. Since the introduction of Restylane, various other forms of HA, like Juvederm (Allergan) have been approved by the FDA for cosmetic use. This has led to a boom in the popularity of injectable fillers (Kim and Sykes 2011). Today, a wide range of treatment options are available for managing volume loss in the aging face, back of the hands and décolleté, including permanent, semi-permanent, and non- 22/41

23 permanent options. A complete aesthetic evaluation of the patient and a thorough understanding of the patient s goals and preferences are crucial in any treatment plan. Interventions can include topical therapy, energy-based therapies, including laser-, radio frequency-, and light (visible and infrared)-based therapies, surgical procedures, and injectable products, including neurotoxins such as botulinum toxin type A and fillers (Matarasso, Carruthers et al. 2006). Epidemiology As an increasing number of patients seek aesthetic improvement through minimally invasive procedures, interest in soft tissue augmentation and filling agents is at an all-time high. The American Society of Plastic Surgeons reported on millions of conducted aesthetic minimally-invasive procedures in the U.S. in 2013 (in contrast to 1.67 millions of aesthetic surgical procedures). About 2.24 millions of soft tissue filler injections were administered to patients, of which 1.68 millions were hyaluronic acid injections (numerous different products) ( Dermal fillers and subcutaneous volume enhancers have enjoyed the greatest degree of development and differentiation because they are also administered in an office-based setting. The ideal dermal filler is one that is biocompatible, predictable, adjustable to the anatomy of the patient, long-lasting, reversible, and natural in appearance, while no single filler possesses all of these characteristics (Newman 2009). HA fillers are commonly used for wrinkle treatment, fold filling, and regional volumising. Treatment Options Although soft tissue augmentation dates back over a century to when autologous fat was used, injectable fillers entered mainstream cosmetic medicine when bovine collagen injections were developed in the 1980s. Autologous fat, once a staple in the filler arena, has been largely replaced by the new generation of fillers because aesthetic results and duration of benefit after fat injection have a degree of variability that is unacceptable to many physicians and their patients. Reports on the fat-grafting technique are anecdotal and no statistics on the "take" of fat have been published (Smith 2008). In general the dermal fillers can be classified in absorbable fillers like collagen or hyaluronic acid based products, biodegradable microparticle injectable implants (calcium hydroxylapatite or Poly-L-lactic acid), or non-absorbable fillers containing poly-methylacrylate or silicone. Injectable microparticles are absorbed much slower than collagen or hyaluronic acid. This fact is considered as an advantage if compared to absorbable fillers. The disadvantage of these materials is that the procedure is not reversible; corrections are not possible or even in an invasive way. With non-absorbable fillers there is only limited experience. Based on the available literature, the risk of side effects is higher compared to absorbable material (Newman 2009). Hyaluronic Acid Hyaluronic acid (HA)-based gels are now the gold standard in dermal fillers, with more cosmetic procedures in the United States using these fillers than all other fillers combined. The 23/41