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Clinical Evaluation

Dermal Filler 20/2

Hyacorp Face/GeneFill Soft Fill/

SMS Solution/Hyacorp Face II Voluma

Version 3.0

CLINICAL EVALUATION

CONTENT

Clinical Evaluation ............................................................................................................................ 1

Content ............................................................................................................................................. 1

1. General Details ........................................................................................................................ 2

2. Description of the device and its intended application .............................................................. 2

3. Intended therapeutic and/or diagnostic indications and claims ................................................ 7

4. Context of the evaluation and choice of clinical data types ....................................................... 9

5. Summary of the clinical data and appraisal ........................................................................... 12

6. Data analysis ......................................................................................................................... 22

6.1. State-of-the-Art ............................................................................................................................................. 22

6.2. Performance ................................................................................................................................................. 25

6.3. Safety .......................................................................................................................................................... 32

6.4. Risk analysis ................................................................................................................................................. 37

7. Post-marked data .................................................................................................................. 37

8. Conclusion ............................................................................................................................ 37

9. References ............................................................................................................................. 39

10. Attachments .......................................................................................................................... 41

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1. General Details

Manufacturer: BioScience GmbH

Walsmühler Straße 18

19073 Dümmer

Germany

Medical Devices: Hyacorp Face

GeneFill Soft Fill

SMS Solution

Hyacorp Face II Voluma

GMDN-Code: 17876

2. 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.

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1 mL Hyacorp Face contains:

Hyaluronic acid sodium salt 2.0 mg

Cross-linked Hylan gel 20.0 mg

Sodium chloride 6.9 mg

Water for injection ad 1.0 mL

1 mL GeneFill Soft Fill contains:





1 mL Hacorp Face II Voluma contains:





1 mL SMS Solution contains:





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

18.000-

24.000

7.0 – 7.2 280-360

80 – 150 0 – 20 1mL/ 2

mL

GeneFill

Soft Fill

18.000-

24.000

7.0 – 7.2 280-360

80 – 150 0 – 20 1 mL

Hyacorp

Face II

Voluma

22.000-

28.000

7.0 – 7.2 280-360

80 – 150 0 – 20 2 mL

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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 cross-

linked using 1,4 butanediol diglycidyl ether (BDDE). By BDDE-crosslinking, the hyaluronic

acid chains are chemically stabilised through permanent epoxidic cross-links. After the cross-

linking 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).

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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.

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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.

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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)

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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.

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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).

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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.

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(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

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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:

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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: S128-135.

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.

D2,

A1,

P1,

R1

Gold, M. (2009). "The science

and art of hyaluronic acid dermal

filler use in esthetic applications."

J Cosmet Dermatol 8(4): 301-307.

This article provides an overview of the HA fillers,

focusing on interweaving of artistic concepts with

scientific principles of dermal filling.

A1,

P2,

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. Written

informed consent was obtained from the patients.

D2

A1

P1

R2

Kablik J. (2009). “Comparative

physical properties of hyaluronic

acid dermal fillers”. Dermatol

Surg. Feb;35 Suppl 1:302-12.

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.

R1

Kim, J. E. and J. M. Sykes (2011).

"Hyaluronic acid fillers: history

and overview." Facial Plast Surg

27(6): 523-528.

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

D2

A2

P2

R1

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substances.

Lupo, M. P. (2006). "Hyaluronic

acid fillers in facial rejuvenation."

Semin Cutan Med Surg 25(3):

122-126.

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 2005. Restylane and other sorts of hyaluronic

acid (avian origin) are described.

A1,

P1,

R2

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.

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.

D2,

A1,

P2,

R2

Newman, J. (2009). "Review of

soft tissue augmentation in the

face." Clin Cosmet Investig

Dermatol 2: 141-150.

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.

D2,

A1,

P1,

R2

Price, R.D, et al (2007).

“Hyaluronic acid: the science and

clinical evidence”. J Plast

Reconstr Aesthet Surg. 60, 1110-

1119

This review represents an overview about the

scientific evidence of HA used in different fields

such as skin regeneration, wound healing and

cosmetic surgery.

D2,

A2,

P2,

R1

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.

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.

A1,

P2,

R1

Smith, K. C. (2008). "Reversible

vs. nonreversible fillers in facial

aesthetics: concerns and

considerations." Dermatol Online

J 14(8): 3.

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.

A2,

P1,

R2

Tezel, A. and G. H. Fredrickson

(2008). "The science of

hyaluronic acid dermal fillers." J

Cosmet Laser Ther 10(1): 35-42.

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

D2

A1

P1

R1

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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 HIV-

associated facial lipoatrophy."

Dermatology 217(3): 244-249.

21 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.

D2

A1

P2

R2

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, 2013. 6: p. 81-9.

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 protocol-

defined 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 (NCT01029535).

D2

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: 313-321.

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

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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): 291-296.

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.

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Glogau, R. G., D. Bank, et al.

(2012). "A randomised, evaluator-

blinded, controlled study of the

effectiveness and safety of small gel

particle hyaluronic acid for lip

augmentation." Dermatol Surg 38(7

Pt 2): 1180-1192.

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.

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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.

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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): 1060-

1067.

The authors conducted a retrospective chart

review of patients who received Juvéderm

Voluma between February 1, 2009, and May 1,

2014. 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.

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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):

117-121.

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.

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Narins, R. S., F. Brandt, et al.

(2003). "A randomised, double-

blind, multicentre comparison of the

efficacy and tolerability of

Restylane versus Zyplast for the

correction of nasolabial folds."

Dermatol Surg 29(6): 588-595.

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.

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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):

17-23.

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.

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Raspaldo, H. (2008). "Volumizing

effect of a new hyaluronic acid sub-

dermal facial filler: a retrospective

analysis based on 102 cases." J


Retrospective record analysis was made for 102

patients (93 females, nine males; mean age:

51.27 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.

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Schweiger, E. S., C. C. Riddle, et al.

(2008). "Successful treatment with

Surgical repair of cleft lip, while correcting

deformity and dysfunction, may leave residual

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injected hyaluronic acid in a patient

with lip asymmetry after surgical

correction of cleft lip." Dermatol

Surg 34(5): 717-719.

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.

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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):

170-177.

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.

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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): 757-

762.

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.

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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):

145-149.

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.

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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


conducted at two Chinese hospitals, in full

accordance with the Good Clinical Practice

regulations and guidelines. All subjects

provided a written informed consent.

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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): 171-176.

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

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Beasley, K.L. (2009). “Hyaluronic

Acid Fillers: A comprehensive

Review”. Facial Plast Surg. 25:86-

94.

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.

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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,

2013. 6: p. 81-9.

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 protocol-

defined criteria. Of the 103 subjects enrolled,

84% had moderate or significant volume

deficiency at baseline. The study was approved


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 (NCT01029535).

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Funt, D. and T. Pavicic (2015).

"Dermal fillers in aesthetics: an

overview of adverse events and

treatment approaches." Plast Surg

Nurs 35(1): 13-32.

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.

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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): 1069-1077.

Part I of this article reviews the basic science

and evolution of both historical and

contemporary dermal fillers; Part II examines

their adverse effects.

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Hirsch R.J. and Stier M. (2008).

“Complications of soft tissue

augmentation”. J Drugs Dermatol.

Sep; 7(9):841-5.

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.

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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.

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Matarasso, S. L., J. D. Carruthers, et

al. (2006). "Consensus

Review article and consensus statement,

mainly focusing on the product Restylane.

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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.

Besides products, procedural aspects were

discussed in detail. The time period from 2000

to 2005 is covered.

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Newman, J. (2009). "Review of soft

tissue augmentation in the face." Clin

Cosmet Investig Dermatol 2: 141-

150.

Review article covering the time period from

2000 to 2008. This article compared the current

options of tissue augmentation and discussed

the composition and characteristics of available

dermal fillers.

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Price, R.D, et al (2007). “Hyaluronic

acid: the science and clinical

evidence”. J Plast Reconstr Aesthet

Surg. 60, 1110-1119

This review represents an overview about the

scientific evidence of HA used in different

fields such as skin regeneration, wound healing

and cosmetic surgery.

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Winslow, C. P. (2009). "The

management of dermal filler

complications." Facial Plast Surg

25(2): 124-128.

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.

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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-

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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 13.48 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)

(http://www.plasticsurgery.org/news/plastic-surgery-statistics/2013.html).

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

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widespread acceptance of HA fillers is testament to their biocompatibility (unlike protein-based

fillers, they are composed of polysaccharides that exhibit no species specificity), the stability of

their cross-linked HA in vivo (which promotes longevity of clinical improvement), and their

good record of safety and effectiveness in other countries where they have been in use for many

years (Baumann, Shamban et al. 2007).

Hyaluronic acid, or hyaluronan, is a glycosaminoglycan that consists of regularly repeating non-

sulfated disaccharide units of glucuronic acid and N-acetylglucosamine. Hyaluronan is a

naturally occurring biopolymer that exhibits no species or tissue specificity. It is an essential

component of the extracellular matrix of all adult animal tissues and is especially abundant in

early embryos. Hyaluronan normally exists in tissues as a free polymer of linked disaccharide

units and is highly negatively charged. However, in some tissues, such as cartilage and bone,

hyaluronan is bound to large glycoprotein structures or specific cell receptors. In healthy

tissues, the average molecular weight of hyaluronan is 5 to 10 million with up to 25,000

disaccharide units, and the average adult concentration is 200 mg/kg (0.02 %) (Matarasso,

Carruthers et al. 2006, Price, Berry et al. 2007).

A series of chemical modifications and processing steps must be applied to HA to develop

viable formulations for use as dermal fillers. The raw HA polymer used to produce dermal

fillers is usually supplied to the manufacturer in dry powder form. In order to overcome the lack

of persistence of uncross-linked HA, dermal filler manufacturers use crosslinkers. The

crosslinkers bind HA polymer chains to each other, creating a polymer ‘network’ and

transforming the viscous liquid into a gel. The resulting HA gel acts as a single unit, imposing a

physical and chemical barrier to enzymatic and free radical breakdown (Tezel and Fredrickson

2008).

Cross-linked derivatives have been shown to be well tolerated when injected into locations such

as the skin and vocal folds. The use of HA is particularly attractive for soft-tissue augmentation,

because it is hydrophilic and a normal extracellular component of skin. Factors that impact HA

persistence include HA concentration, percentage of cross-linkage, type of cross-linking, its

fluid retention (i.e. water binding capacity), and injection technique. The two most important

factors are the percentage of cross-linking and the water binding capability of the hyaluronic

gel. If uncross-linked HA is added to water, it produces a highly viscous liquid that would only

last a few days in human skin. For that reason manufacturers use various agents to cross-link

the HA. As a result, the final proportion of cross-linked HA and the degree of cross-linking

impact the physical characteristic of the final product (Newman 2009).

Almost all HA fillers on the world market use 1 of 3 basic cross-linking chemistries. Of these 3,

butanediol diglycidyl ether (BDDE) has by far the longest track record (about 20 years as of

July 2008), and the greatest amount of clinical experience (many millions of patients treated

worldwide including North America) (Smith 2008).

One very important characteristic of HA products is the ability of clinicians to break down the

cross-linking of each product with the use of an enzyme known as hyaluronidase. This enzyme

breaks the cross-links by hydrolysis of the glucosamine and glucornic acid moiety. This result

in the breakage of the cross-links and the three-dimensional structure of HA becomes absorbed

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within hours by the surrounding interstitial fluid. One note of caution is the possibility of

allergic reaction with purified bovine testicular hyaluronidase or with preparations that contain

metabisulfite (Newman 2009).

In general clinical trials have documented the safety profile of all forms of HA. Transient and

self-limiting redness and swelling are common following injections of HA and this is due to the

hydrophilic nature of HA. Pain associated with injection may be managed by the use of both

topical and injected anaesthetic agents. Despite adequate anaesthesia, patients can expect

tenderness for 1 to 2 days after injection (Lupo 2006).

Potential adverse reactions are minimal and are mainly injection-related and self-resolving.

These include local bruising, purpura, erythema, and tenderness, itching, and swelling. A major

adverse event that has been reported is hypersensitivity, but true immunoglobulin G- and E-

mediated reactions are rare (Rohrich and Ghavami 2007).

Although no treatment is entirely without risk, the side effect profiles of HAs and other dermal

fillers have been reviewed extensively. HAs in general have demonstrated excellent benefit–risk

profiles. Serious adverse events are rare, and most reactions are transient, injection-site related,

and mild to moderate in severity (Gold 2009).

Manufacturers may provide free HA as a soluble fluid component to the gel to facilitate the

extrusion of the filler through fine-bore needles. This fluid component is often present and

contains unmodified and modified soluble HA that is generated during the manufacturing

process (Kablik, Monheit et al. 2009). Gel hardness or G’ plays an important role in how the

gels must be sized for easy delivery through fine-bore needles.

By virtue of HAs biocompatibility and non-toxicity, it is used in many biomedical fields, such

as ophthalmology, dermatology and rheumatology.

6.2. Performance

Juvéderm Voluma

Hoffmann et al. report a prospective, open-label, non randomised trial investigating the

performance of Juvederm Voluma. Fifteen sites in Europe participated in the study. A total of

70 patients were recruited. As shown in this study, the physical and chemical properties of the

20-mg/mL smooth, cohesive, HA volumising filler make it robust and ideal for volumising, yet

still easy to inject, mold, and sculpt. Regardless of technique, treatment area, or specialty, the

vast majority of physicians found the 20mg/mL smooth, cohesive HA volumising filler to be

easy to inject, sculpt, and mold. Treatment with the 20mg/mL smooth, highly cohesive, viscous

HA volumising filler resulted in statistically significant improvements in facial volume. Indeed,

70 % of patients were rated as having a low degree of volume loss post-treatment, a substantial

change from pre-treatment. The vast majority of patients and physicians rated the changes in

appearance as much or very improved, and the majority of patients did not experience any

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adverse events. The authors came to the conclusion, that Juvederm Voluma is indicated for

restoring facial volume loss (Hoffmann 2009).

Raspaldo investigated 102 patients in a retrospective analysis, who received Juvederm Voluma

injected into the midface. All patients were assessed at baseline and at 1 month and 6 to 18

month post-injection. This retrospective case analysis indicates that Voluma injectable-HA-sub-

dermal facial filler treatment results in clear aesthetic improvements, comprising a pleasing

attractive midface area that resulted in increased self-esteem and greater confidence in the

majority of patients, according to both the investigator and patient assessment, for up to 18

months post-treatment. Its beneficial effects are achieved due to the fact that the chemical

composition of Voluma is high viscosity and high cohesivity. With a total of 99 % of patients

considered ‘very much improved’, ‘much improved’ or ‘improved’ according to investigator

assessment at 6–18months, these results concur with other studies that demonstrate the benefits

of HA fillers compared with other facial fillers, such as bovine collagen and autologous fat

(Raspaldo 2008).

Fischer reports a phase IV market research study in which Juvederm Voluma was used as per

the instruction for use in a real life setting and was designed to determine a general comparison

of experience between Restylane SubQ and Juvederm Voluma. Overall, most injectors found

Voluma very ⁄ fairly easy to inject (75 %) and very ⁄ fairly easy to sculpt ⁄ massage (84.5 %),

with overall effect of cosmetic treatment considered improved in 98 % of cases. Physicians

rated the overall effectiveness of Voluma in the malar region as being effective in 98% of cases,

and smoothness was considered improved in 99 % of patients. Regarding preferred volumising

treatment, overall, injectors expressed a preference for Voluma compared to Restylane in

71.4 % of their patients (P < 0.0001). Ninety-eight percent of patients rated the overall

cosmetic effect of Voluma as very much improved ⁄much improved ⁄ improved, with the remaining patients indicating no change. No patients indicated there was a worsening of

cosmetic effect associated with use of Voluma. Most patients (97 %) reported that they were

either happy or delighted with the experience of Voluma treatment. Regarding overall safety,

the majority of patients did not experience adverse events. Of the 83 patients who participated

in the study (data missing for one patient), seven patients (8.4 %) were reported to have suffered

an adverse event. All adverse events were ‘‘moderate’’ in intensity, with Italy reporting the

most adverse events followed by Benelux. All adverse events were transient, and the average

duration of adverse events was 6.57 days (range: 2–10 days) (Fischer 2010).

Bechara et al investigated Juvederm Voluma in HIV-associated facial lipoatrophia (FLA).

Twenty-one HIV patients with FLA were included in the present prospective, monocentre,

open-label pilot study. The study was designed to assess FLA changes and the incidence of

adverse events in patients receiving hyaluronic acid treatment, with follow-up evaluations at 3,

6, 9 and 12 months after initial treatment. Study selection criteria included the following: 18

years of age or older, HIV-positive, CD4 count greater than 250/mm 3 and HAART regimen.

Nineteen patients (n = 19; 90.5 %) were much improved or better 3 months after implantation,

while 2 patients (n = 2; 9.5 %) were improved and received a touch-up. Twelve months after

implantation, still 16 patients (n = 16; 76.2 %) were much improved or better, and 4 patients (n

= 4; 19 %) were improved. Patient satisfaction was high at every evaluation point over 12

months. The median DLQI before treatment was 16 (range: 13–19). Twelve months after

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augmentation, a significant decrease in the DLQI was observed (median: 9; range: 6–14)

resulting in a relative reduction and significant improvement of the DLQI of 43.75 % (p<0.05),

respectively. Side effects were mild and temporary (ecchymosis, edema and erythema). The

present pilot study clearly demonstrates that HAHD is effective for soft tissue augmentation of

FLA and allows improvement in appearance immediately after the first injection. The patient

satisfaction ratings revealed that all patients were highly satisfied with the results, and

significant improvement of their quality of life was achieved (Bechara, Gambichler et al.

2008).

Callan et al enrolled 103 patients with mild to severe midface volume deficit who were injected

with Juvéderm Voluma. The mean age of the subjects was 47 (range 29–60) years, with the

majority being female (81%). At the first treatment a maximum injection of 2 mL per side was

allowed. An additional injection could be given at week four under distinct premises and after

week 78 (18 months). The first post-treatment evaluation for efficacy was conducted at week 8.

The severity of the midface volume deficiency was graded by the investigators at baseline

(week 0) and at the scheduled on-study clinic visits (weeks 8, 52, 78, and 104), based on the

midface volume deficit scale (MFVDS). In addition, at each of these on-study visits, both

investigators and subjects were asked to independently evaluate the aesthetic improvement in

the subject’s midface from his/her pretreatment state, using the Global Aesthetic Improvement

Scale (GAIS). The proportion of subjects who achieved a 1 grade or better improvement in their

baseline MFVDS score had been defined as responders. Based on this outcome measure, 96%

of subjects were responders at week 8. This treatment effect was maintained in 88.2% and

81.5% of the subjects at weeks 52 and 78, respectively, without supplementary treatment after

week 0 or 4. For evaluation of outcome at week 104, only a subset of 45 of the 72 subjects who

completed the study were included in this analysis. These subjects did not receive

supplementary treatment with the study product at the week 78 visit and up to the time of the

last outcome evaluation in this study. In this cohort, 43/45 (95.6%) of subjects were still

MFVDS responders at week 104, as evaluated by the investigators. At the week 8 visit, the

investigators rated 100% of subjects as GAIS responders. This was consistent with subject self-

evaluation, for which a 98% response rate was reported. At week 52, the investigators

determined that 88.2% of subjects responded, while the subject GAIS responder rate was

79.4%. At week 78, this improvement continued to be maintained in 78.1% and 73.2% of the

subjects, respectively. In the cohort of 45 subjects who completed the study and who did not

receive supplementary study treatment after the week 0 or 4 visits, 91.1% and 82.2% were

documented as GAIS responders at the week 104 visit, respectively. Moreover, Of the 72

subjects who completed the 24-month study, 66 (91.6%) were either satisfied or very satisfied

with the study treatment, based on the five-point Likert scale employed in this study, while 70

(97.2%) indicated that they would recommend the treatment to others. In summary, this 24-

month prospective, observational study provides long-term results after Juvéderm Voluma

treatment. Performance of Juvéderm Voluma in correction of midface volume deficiency could

be conclusively demonstrated (Callan, Goodman et al. 2013).

Humphrey et al conducted a retrospective chart review of patients who received Juvéderm

Voluma for facial augmentation between February 1, 2009, and October 1, 2014. Clinical

results were assessed 2 weeks after initial treatment, with touch-ups performed as necessary.

Color photographs were taken before and after treatment, and adverse events were documented.

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Over 68 months, the authors treated 2,342 patients with 11,460 mL of Juvéderm Voluma.

Aesthetic results lasted upwards of 12 months, and most side effects were transient and mild.

Three patients developed signs of vascular compromise that was promptly treated and resolved

within 2 months. Twenty-one patients (<0.5%) experienced late-onset, temporary, nontender

nodules that were successfully managed with conservative measures. The authors concluded

that Juvéderm Voluma is an ideally formulated dermal filler for soft-tissue augmentation in the

face (Humphrey, Carruthers et al. 2015).

Restylane SubQ

DeLorenzi et al investigated patients in a multicentre, open-label, clinical trial. 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

(Restylane SubQ) (20mg/mL). Efficacy was assessed subjectively using the Global Aesthetic

Improvement Scale at intervals up to 12 months after treatment. After treatment, patients and

investigators independently considered treatment sites to be at least somewhat improved in 91%

and 96 % (6 months), 68 % and 77 % (9 months), and 58 % and 52 % (12 months) of cases,

respectively. Patient- and investigator-assessed treatment response rates (the proportion of

patients showing at least moderate improvement) were 72 % and 81 % (6 months), 42 % and

40 % (9 months), and 21 % and 15 % (12 months), respectively. Most commonly reported

adverse events were local injection-site reactions, skin indurations, and implant mobility. The

authors came to the conclusion, that this large-particle stabilised hyaluronic acid–based gel is

well tolerated and provides relatively long-lasting aesthetic correction of the cheeks and chin

after subcutaneous or supraperiosteal injection (DeLorenzi, Weinberg et al. 2009).

Skeie et al investigated Restylane SubQ for the treatment of facial lipoatrophy in HIV-positive

patients. Twenty patients received injections of Restylane SubQ. Refill treatment was offered

at 12 and 24 months. Treatment effects were evaluated using ultrasound, the Global Aesthetic

Improvement Scale, visual analogue scale (VAS) and the Rosenberg self-esteem scale.

Seventeen patients remained at 36 months. Mean (+/- standard deviation) total cutaneous

thickness increased from 6 +/- 1mm at baseline to 12 +/- 1mm (P<0.001) at 36 months.

Response rate was 70%. Fifteen patients classified their facial appearance as very much or

moderately improved. VAS increased from 39 +/- 25 to 70 +/- 20 (P<0.05) and higher self-

esteem scores were reported. Local swelling and tenderness after treatment was common.

Persistent papules found in several patients after treatment were removed effectively with

hyaluronidase injections. Three patients, treated only at baseline, still had higher total cutaneous

thickness scores at 36 months. The results indicate that a large particle hyaluronic acid

formulation represents a durable and well-tolerated dermal filler for treating HIV-positive

patients with facial lipoatrophy (Skeie, Bugge et al. 2010).

Restylane

The key active comparator study of Restylane versus Zyplast (bovine collagen; Inamed Aesthet-

ics, Inc., Santa Barbara, Calif.), reported in 2003, provided the basis for the approval of

Restylane use in the United States. The randomised patient- and evaluator-blinded study was

conducted at six centres in the United States, and subjects seeking soft tissue augmentation

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treatment for correction of bilateral nasolabial folds were recruited. Each patient received

Restylane in one nasolabial fold and Zyplast on the contra-lateral side of the face. Of 152

subjects who were initially screened, 138 were randomised to study treatment and treated with

both study products (safety population). The intent-to-treat population comprised 137 patients

(128 women and 9 men). Patients ranged in age from 27 to 78 years (mean 54.3) and were

predominantly White (89 %); 59 patients (43.1 %) had previously received collagen injections.

Of this population, 134 patients completed 6 months of follow-up, whereas 4 patients withdrew

from the study prematurely because of consent withdrawal (2), protocol violation (1), or loss to

follow-up (1). Restylane was superior to Zyplast in 56.9 % of patients, whereas Zyplast was

superior to Restylane in 9.5 % of patients (P<0.0001). By this time, 67.2 % of Zyplast-treated

folds had returned to their pre-treatment condition compared with only 29.9 % of Restylane-

treated folds. Likewise, Restylane produced a significantly better (P<0.0001) Global Aesthetic

Improvement Scale (GAIS) rating than Zyplast at all time points after baseline. At 6 months

after baseline, Restylane proved superior to Zyplast in this regard in 62.0 % of patients, whereas

Zyplast was superior to Restylane in 8.0 % of patients (P<0.0001). Patient evaluations of

treatment efficacy were consistent with those of the investigators. After the initial treatment

session, local injection-site reactions (as recorded in patients’ diaries) occurred at 93.5 % of

Restylane- and 90.6 % of Zyplast-treated sites, but these were predominantly mild or moderate

in intensity and short lasting (7 days or less). All delayed-onset reactions (redness was the most

common) were mild or moderate in intensity and resolved within 2 to 3 months without

treatment (Narins, Brandt et al. 2003).

Morris et al retrospectively reviewed the records of 145 consecutive patients who underwent

intradermal and subcutaneous injection of the face with Restylane (0.4 ml or 1 ml) for volume

augmentation and/or to improve rhytid appearance. Patients were treated at Duke University

Eye Centre between February 2005 and March 2006. IRB approval was obtained From

February 2005 to March 2006, 309 Restylane injections were performed on 145 patients (mean,

2.14 injections/ patient). Gender distribution was 139 female and 6 male, and median age was

53 years (mean, 54 years). There was a median follow-up time of 8 months (mean, 10.4 months;

range, 1–37 months) for all returning patients. Median follow-up time was 11 months (mean, 12

months; range, 1–37 months) for the 75 patients (52 %) who underwent reinjection. Thirty-

seven of 140 patients (26 %) received adjunctive anaesthesia. Injection locations were as

follows: nasolabial folds [72 % (104/145)], melolabial folds [70 % (102/145)], lips [51 %

(74/145)], infraorbital rims [24 % (35/145)], perioral rhytids [24 % (35/145)], glabella [23 %

(34/145)], malar hollows [10 % (14/145)], chin [8 % (12/145)], and other [8 % (12/145)]. The

excellent safety profile of Restylane reported in this study is consistent with its favourable

status when compared with other soft-tissue fillers. Unlike other soft-tissue fillers, its

reversibility with hyaluronidase can help mitigate overcorrection or hypersensitivity. Its

biodegradability and shorter duration compared with more permanent fillers are also favourable

in the setting of an adverse reaction (Morris, Stinnett et al. 2008).

Glogau et al investigated 180 patients in a randomised controlled trial within the indication lip

augmentation. Of 180 patients randomised, 135 received Restylane, and 45 received no

treatment and were included in the ITT population. Eighty patients in the Restylane group

received a touch-up 2 weeks after the first treatment session. One hundred sixteen (86 %) in the

Restylane group and 39 (87 %) in the no-treatment group completed the study. The results of

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the current study clearly demonstrated the durability of the augmentation provided by

Restylane. All of the pivotal assessments (live blinded evaluations, unblinded evaluator scoring,

and IPR) showed statistically significant differences in MLFS response between the treatment

group and the control group through 6 months (week 24). The data from the GAIS scoring, on

which patients and physicians noted significant differences at all time points, further

corroborated the persistence of effect. This durability compares favorably with collagen

products (animal and human, no longer available in the United States), which produce results

that last an average of approximately 3 months. Restylane treatment for lip augmentation was

well tolerated. The majority of reported AEs were mild to moderate in severity, anticipated in

their nature (swelling, contusion, pain), and generally resolved promptly. No persistent nodules,

masses, or significant asymmetry were noted during the study. Nearly all (96 %) patients

enrolled in the present study received an anaesthetic during the first Restylane treatment,

including topical, regional, or a combination of both types of anaesthesia. Injecting local

anaesthetic for an infraorbital or submental nerve block can distort anatomic features and

complicate the augmentation procedure (Glogau, Bank et al. 2012).

Schweiger et al reported on a 21-year-old female was seen in dermatology clinic with the

complaint of lip asymmetry. She reported being born with a unilateral left-sided cleft lip and

cleft palate. From the age of 12 weeks to 20 years, she had received an estimated 12

reconstructive procedures by craniofacial surgeons. She also had received specialized care from

dentists, oral surgeons, and speech pathologists in the past. The patient was successfully treated

with injection of HA (Restylane, Medicis Aesthetics, Scottsdale, AZ). She first underwent an

intraoral miniblock with 0.5 mL of 1 % lidocaine with 1:100,000 epinephrine injected above

each canine in the buccal mucosal groove. A quantity of 0.5 mL of HA was then placed into the

left mucosal body and vermilion. Additional filler was placed at both areas of dimpled

retraction. After the mucosal lip was treated with a goal of 100 % correction, an additional

0.2mL of HA was injected under the left cutaneous upper lip line scar. Clinical improvement

was noted immediately, as was mild bruising. She returned to clinic 10 days after treatment for

follow-up and was felt to have an excellent cosmetic result. The results lasted approximately 4

months with a gradual decline to baseline. The authors concluded that soft tissue augmentation

using injectable fillers can also be used to address the aesthetic considerations of decreased

upper lip volume and asymmetry (Schweiger, Riddle et al. 2008).

Solish et al describe a prospective pilot study conducted a two centres in Canada with Restylane

hyaluronic acid. 21 adults were enrolled in this study seeking lip augmentation. The finding of

this study suggests the treatment resulted in a clinically significant change in patients’

appearance. Adverse events were reported in five patients during the study, but all of them were

considered to be not related to the study treatment (Solish and Swift 2011).

Wu et al performed a clinical trial in order to compare Restylane with a new HA dermal filler

(BioHyalux). This was a multicenter, double-blinded, randomised, controlled, non-inferiority

clinical trial involving 88 subjects with moderate to severe nasolabial folds. Subjects were

randomised to receive an injection of Restylane in one nasolabial fold and BioHyalux in the

opposite nasolabial fold. The total amount of filler was 0.99 ± 0.27 mL on the BioHyalux side,

and 0.94 ± 0.27 mL on the Restylane side. The outcome was assessed before and right after

injection, and at 1 week, 1, 3, and 6 months. Patients were followed up for 13–15 months to

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evaluate the durability and long-term safety. A clinically meaningful response was predefined

as at least one-point improvement on the Wrinkle Severity Rating Scale, which is a five-point

scale. At 6 months, the response rate of BioHyalux was not significantly different to that of

Restylane. At the 13–15 months follow-up, the response rate by investigators was 58.0 % on the

BioHyalux side versus 63.8 % on the Restylane side. The response rate by subjects showed

similar results, which was 56.5 % on the BioHyalux side versus 60.9 % on the Restylane side at

13–15 months. The subjects’ Global Aesthetic Improvement Scale (GAIS) showed that most

subjects felt improvements on both sides of the nasolabial folds at all time points. At 6 months,

100 % reported improvements on both side; at 13–15 months, 60 % of subjects reported

improvements with BioHyalux versus 64 % with Restylane. Adverse events were transient and

predominantly mild or moderate in severity including injection site swelling, pain, itching,

bruising, and tenderness. It can be concluded that both products showed an adequate

performance in this study, with reliable safety (Wu, Sun et al. 2016).

Juvéderm Ultra

Pinsky et al investigated the safety and effectiveness of Juvederm dermal fillers compared to

Zyplast® bovine collagen for the correction of nasolabial folds in a multicentre, double-blind,

randomised, within-subject controlled trial. 292 subjects were randomly treated with Juvederm

Ultra or Juvederm Ultra Plus in one nasolabial fold and Zyplast bovine collagen in the other

nasolabial fold. The treating investigators were instructed to fill each nasolabial fold to full

correction (100 % of the defect), but not to overcorrect. A maximum of 3 treatments – first

treatment and up to 2 touch-ups at roughly 2-week intervals – were allowed to achieve optimal

correction. An average injection volume of 1.5 mL (2 syringes) of Juvederm dermal filler was

used for initial treatment and 0.7 mL (1 syringe) for repeat treatment. Nasolabial fold severity

was assessed using the 5-point Wrinkle Assessment Scale (WAS), and a validated photographic

guide. After 6 months subjects showed a clinically significant mean level of improvement for

the nasolabial folds treated with Juvederm Ultra or Juvederm Ultra Plus, but not for nasolabial

folds treated with Zyplast, supporting the above stated findings by showing a longer longevity

for Juvederm Ultra and Ultra Plus than for Zyplast. The mean level of improvement was still

clinically significant for subjects who returned for a follow-up treatment beyond 9 months, with

the proportion of nasolabial folds still showing clinically significant improvement in 75 % with

Juvederm Ultra and 81 % with Juvederm Ultra Plus. Juvederm Ultra Plus was shown to last

even 12 months or longer. Again, the frequency and severity of treatment site reactions (e.g.,

erythema, indurations, pain, edema, nodule formation, bruising, pruritus, and discoloration)

were mild or moderate and were similar for all fillers. The authors concluded, that due to its

superior longevity, individuals treated with these Juvederm™ dermal fillers may require to

repeat treatments less frequently than those treated with bovine collagen fillers, and that less

product will be needed at repeat treatments (Pinsky, Thomas et al. 2008).

Upon completion of the pivotal IDE clinical trial for Juvederm, Juvederm Ultra, and Juvederm

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

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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. At the end of the pivotal study, subjects were asked which

treatment they preferred and were subsequently un-blinded. Subjects were offered repeat

treatment of both NLFs with the original Juvederm formulation after the 24-week visit. For this

follow-up study, subjects remained non-randomised and un-blinded. 80 individuals signed

consent forms and enrolled in the follow- up study. The mean improvement in NLF severity

remained clinically significant from 4 weeks after initial treatment through 48 weeks after

repeat treatment. Thus, subjects sustained a total of 18–21 months of wrinkle correction with a

repeat treatment at 6–9 months. Furthermore, a full 78–90% of subjects were responders at 48

weeks post-repeat treatment, and the long-term results showed a smooth, natural looking

wrinkle correction. No serious or unanticipated adverse events were reported. One subject had

positive serum IgG antibody titers at 24 weeks after initial and 4 weeks after repeat treatment,

but no clinical signs or symptoms of hypersensitivity (Smith, Jones et al. 2010).

6.3. Safety

Hyaluronic acid

Since HA occurs naturally in the human body, the risk of allergic reactions is very low and thus,

the manufacturers suggest that there is no need for skin testing before. The differences in chain

length molecular weight do not appear to have any clinical significance. Adverse effects related

to HA injection are most commonly localized, immediate, and non-allergic, and include pain,

edema, and ecchymoses. Additional side effects to consider are an angioedema-like swelling

and hypersensitivity as well as the rare rapidly developing bacterial infection acquired

transdermally while injecting (Gilbert, Hui et al. 2012).

Since HA occurs naturally in the human body, the risk of allergic reactions is very low and thus,

the manufacturers suggest that there is no need for skin testing before. The differences in chain

length molecular weight do not appear to have any clinical significance. Adverse effects related

to HA injection are most commonly localized, immediate, and non-allergic, and include pain,

edema, and ecchymoses. Additional side effects to consider are an angioedema-like swelling

and hypersensitivity as well as the rare rapidly developing bacterial infection acquired

transdermally while injecting (Gilbert, Hui et al. 2012).

In fact, there is a very small amount of proteins which can lead to some hypersensitivity

reactions. Anti-HA antibodies have been demonstrated but the clinical significance is not

exactly known. A retrospective European survey has evaluated the risk of important adverse

reactions with the HA from Q-Med from 1997 to 2001. A total of 4,320 patients were evaluated

and 12,344 syringes were injected. From 1997 to 2001, 34 cases of hypersensitivity are

reported: 16 cases of immediate hypersensitivity and 18 cases of delayed reactions. Global risk

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is 0.8 %. Since 2000, the load of proteins of the Q-Med product has decreased, and the

incidence of hypersensitivity reactions has become around 0.6 %. As 50 % of these reactions

are immediate and resolved within less than three weeks, the risk of transient delayed reactions

was around 0.3 % with the old formulations. These are now significantly less frequent (less than

1 in 2000 treatments) with the current Q-Med products. These remain the most used products in

the UK and are very predictable. Sterile abscess and lividoid pattern after intra vascular

injection has been reported. No systemic reactions have been reported. Non-animal HA from

the Q-Med company does not need skin testing. In cases of ‘‘inflammatory’’ reactions, the

histological aspects can be either a moderate lymphocytic infiltrate with some plasma cells in

the dermis and the hypodermis or a lymphocytic infiltrate with macrophages and presence of

foreign body giant cells (Andre, Lowe et al. 2005).

HA dermal fillers as a group are very well tolerated. Infection can occur but is rare.

Hypersensitivity reactions are also uncommon, and may result from reaction to the cross-

linking agent used to stabilize the HA. Occasionally HA can be palpated, or a blue-gray tinge

can be seen in the area of injection. This can be the result of superficial injection allowing more

water binding in the dermis which selectively reflects blue wavelength of light making it appear

darker than the surrounding skin. Solutions to this problem can be addressed by camouflage

with makeup, needle puncture, and massage of excess gel from the dermis or injection of

hyaluronidase. Injection technique can lead to clumping of HA especially in the lips. Massaging

the area immediately following injection is the best way to prevent lumps from persisting. It is

important to have patients understand the expected clinical course of swelling, firmness, and

then softening which typically occurs over the course of 1 week. One of the benefits of using

HA for the less experienced user is the fact that they can be readily broken down by the

hyaluronidase (Newman 2009).

The most frequent types of reactions are needle marks at the site of injection, erythema,

swelling, tenderness, mild pruritus, bruising, and small lumps/bumps. These are generally mild

and are usually transient. These reactions should be discussed in detail with the patient before

treatment so that they are considered expected rather than true complications (Beasley, Weiss et

al. 2009).

True complications are rarely seen when injecting HAs, but many of these complications

directly correlate with the skill and experience of the physician-injector. These true

complications include injection into or compression of vascular supply, tissue necrosis,

persistent nodule formation, granuloma formation, allergic reaction, infection, and visible blue

hue (Tyndall effect). It has been well documented that nitropaste and hyaluronidase must be

readily available in the physician´s office for the immediate treatment of any vascular

compromise. Hyaluronidase and extrusion techniques are also helpful for treating persistent

nodules and the Tyndall effect (Beasley, Weiss et al. 2009).

The management of dermal filler complications is summarised in an article of C. Winslow.

Bruising is a potential complication to all fillers. The potential to bruise can be affected by

needle size, location of infection, and type of filler. Medication such as aspirin, ibuprofen, or

other anticoagulants may make the patient more susceptible to bruises. Herbal supplements

such as fish oil, glucosamine, or chondroitin can also adversely impact bruising. Swelling is the

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most common and ubiquitous complication experienced with fillers. HA fillers are sugar

molecules that bind and hold water and should be expected to cause more swelling than do

other classes of fillers. Post-treatment ice application and elevation of there head may help.

Patient troubled by swelling may benefit from short prednisone taper or antihistamines.

Formation of lumps under the skin can occur due to the consistency of the filler, reaction to the

product, or poor technique. Small lumps resulting from HA injection can easily be treated with

hyaluronidase. Improvement can be seen within hours. The ability to contour the injection site

after injection is unique to HA class and is attractive to many patients. Erythema after injection

is common, especially if massage is performed immediately after filler placement. Some

amount of pain during and after injection is common and can be prevented with topical

numbing and/or nerve blocks administered before injecting the filler. Skin necrosis is a well

known complication that has a predilection for certain “danger zone”. The dorsal nasal artery

may cause compromise of skin at the alar region. Collagen and hyaluronic acid are commonly

injected in the lips. Filler injections in the perioral area can induce cold sore formation by

reactivation of the latent virus. Stress, swelling, and massage may also contribute. Patients with

a strong history of cold sore activation or those who had cold sores with prior injections should

be treated with an antiviral such as acyclovir. Infection is fortunately quite rare after filler

injection in an acutely inflamed area, such as skin with active acneic breakout. Focal or

systemic infections should be considered a contraindication to injection. True allergic reactions

are quite rare with HA. Immediate allergic reactions are manifested by significant swelling,

itching, and pain. Swelling may involve the oral cavity, lips, and tongue, depending on the

severity of reaction and location of injection. Skin testing for HA is not standard or required but

should be considered in atopic individuals. Despite its rare nature, hypersensitivity to HA or its

derivatives of its preparation may still be seen in < 1 % of patients injected. Granulomas

typically appear late, months or years after injection, and remain localized to the injection site.

They are typically soft and dark red or purple. Intralesional steroids remain the mainstay of

granuloma treatment. The most dreaded complication because of its unsightly nature and

permanence, a scar can result from injection or a complication thereof. Treatment of scares

includes intralesional steroid, pulsed dye laser or pulsed light treatments, pressure, and silicone

(Winslow 2009).

Whilst it is true that HA is tolerated extremely well, it is not uncommon (12 %) to observe

transient erythema and mild swelling. Other documented complications include a case report of

a clinical picture similar to a sterile abscess over injection sites and injections of any form may

trigger sarcoidosis at the injection site, and HA has not escaped. A recent review also quoted an

overall significant complication rate of 1 in 1600 applications. The mild tissue reaction seen

with many injections may, on occasion, be so profound as to elicit a formal inflammatory

response and a range of reactions has been documented, varying from simple hypersensitivity,

to angioedema with positive titres of anti-HA immunoglobulin G and E (Price, Berry et al.

2007).

Depth of dermal filler placement is particularly important in preventing discoloration. Novice

injectors occasionally inject too superficially causing a blue-gray discoloration known as the

Tyndall effect. The Tyndall effect refers to the fact that different wavelengths of light scatter

depending on the size of substances they encounter. According to Rayleigh scattering, for

sufficiently small particles, the amount of light scattered is inversely proportional to the fourth

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power of wavelength. For example, blue light is scattered more than red light by a factor of

(700/400) = ~ 10. Thus, within the skin, long red wavelengths penetrate deeper into the tissue

while shorter blue wavelengths are more easily scattered and reflected outwards. The incidence

of the Tyndall effect is most likely to occur if filler meant to be injected deeply is injected too

superficially in the skin. The high-risk areas include the so-called I zone of the central face, (the

nasojugal folds, nasal dorsum, and lip), the infraorbital troughs, and fine superficial lines such

as periorbital and perioral rhytids ("crow's feet" and "pucker lines") (Hirsch and Stier 2008).

A more recent review article also discussed potential complications associated with the use of

dermal fillers. The authors concluded the following: The past decade has seen the arrival of a

host of new soft tissue fillers for facial rejuvenation, which not only remove wrinkles but also

have the ability to restore facial volume to create a balanced, more natural rejuvenated look. To

achieve cosmetically pleasing results, it is essential that those practicing facial rejuvenation

have a thorough understanding of the individual characteristics of available fillers, their

indications, contraindications, benefits and drawbacks, and ways to prevent and avoid potential

complications. Side effects can occur with any dermal filler, but knowledge of the frequency

and potential risk factors is limited. A report from the Injectable Filler Safety Study, which

obtained population-based data on the type and frequency of adverse reactions to injectable

filler substances from dermatologists and plastic surgeons practicing in Berlin, Germany,

confirmed that while adverse reactions are documented with all injectable fillers, time until

reaction and the type of adverse reaction varied between the different fillers. For example,

adverse reactions to biodegradable fillers occurred after a mean (standard deviation) of 4.9 ± 5.8

months, and reactions to nonbiodegradable fillers after 18.3 ± 19.0 months. Adverse events in

patients treated with HA-based fillers (mostly Restylane) were mainly swelling, erythema, and

nodules. Furthermore, as with any procedure that breaks the surface of the skin, dermal filler

injections are associated with a risk of infection. To minimize this risk, sterilising the injection

site with an effective topical disinfectant, carefully removing the needle and syringe from

sterilized individual packaging, wearing gloves throughout the procedure, and ensuring that the

needle is not contaminated during the procedure is important (Funt and Pavicic 2015).

Juvéderm Voluma

Callan et al evaluated the long-term outcome of Juvéderm Voluma injection into the midface

area. In this study, 103 patients were enrolled. Juvéderm Voluma was well tolerated, with the

majority of treatment-related adverse events being transient, of mild to moderate severity, and

localized to the injection sites; principally bruising and swelling. For more detailed analysis, the

study period was divided into two observation periods: weeks 0–8 and weeks 78–108. Any

adverse events occurring after week 8 were documented during this second observational

period. The incidences of adverse events recorded are presented in table 6.3.2-1. There was a

single case of swelling in the left tear trough area which became more severe and generalized

over time. This event occurred approximately 17 weeks after the week 4 treatment with the

study product. Bilateral hardening of the Juvéderm Voluma implant occurred. Oral

prednisolone 5 mg/day was administered over 5 days and hyaluronidase (100–150U) was

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injected three times over a 3-week period. The swelling completely resolved approximately one

month after the third hyalase session.

Event N (%) N (%)

Weeks 0 – 8 Weeks 78 - 108

Brusing 42 (40.8) 2 (1.9)

Swelling 15 (14.6) 5 (4.9)

Pain/tenderness 8 (7.8) 1 (1.0)

Erythema 2 (1.9) 0 (0.0)

Eyelid oedema 1 (1.0) 0 (0.0)

Vasovagal syncope 1 (1.0) 0 (0.0) Table 6.3.2-1: icidences of injection site reactions following the the two observational periods (Callan,

Goodman et al. 2013)

The predominant number of adverse events in this study were within the expected range in

regard with incidence and severity. The unexpected occurrence of eyelid oedema was

completely resolved. Thus, in this study, Juvéderm Voluma is considered to be a safe injectable

filler.

In another prospective open-label nonrandomised study, Juvéderm Voluma was evaluated

within its indended use and indication. Fifteen physicians treated 70 patients (91% female;

mean age 50 years). The majority (66%) of the 70 patients experienced no adverse events. A

total of 24 patients experienced injection-site reactions. The mean duration of these events was

5.5 days (range: 2–15 days). Bruising (n = 7) occurred most frequently, followed by pain and

bruising (n = 4), swelling (n = 3), and bruising and swelling (n = 3). Infection occurred in one

patient. Seven of the AEs were rated as severe (bruising and swelling, n = 2; pain and swelling,

n = 2, pain, n = 1; infection and swelling, n = 1, pain and bruising, n = 1). For the patient who

experienced posttreatment infection, previous aesthetic treatments included onabotulinumtoxin

type A (BOTOX®), synthetic polyacrylamide gel polymer filler (Bio-Alcamid™; Rofil), and

lip augmentation with synthetic polyacrylamide gel polymer filler (Beautical 2®; Rofil). Prior

polyacrylamide treatments were not disclosed to the treating physician. Four months after

injection with 2 mL of the 20-mg/mL smooth, highly cohesive, viscous HA volumising filler

into the malar area and chin; a biofilm and abscess developed. The event was determined to be

unrelated to treatment with the 20-mg/mL smooth, highly cohesive, viscous HA volumising

filler. The patient was treated with amoxicillin/clavulanic potassium (Augmentin®) 3 times

daily for 10 days, and with ibuprofen 600 mg, 3 times daily for 7 days. The site was evacuated

and cleansed, and the symptoms fully resolved without further sequelae. Thus in this study,

Juvéderm Voluma can be regarded as safe (Hoffmann 2009).

Restylane

Studies reported injection-related reactions, including redness, swelling, darkening of the

treatment site, and slight pain in about 12 % of patients. Ongoing analysis of the adverse event

databases indicated that in 1999, with an estimated 144,000 patients treated with Restylane,

only one of every 650 (0.15 %) reported redness, swelling, localized granulomatous reactions,

bacterial infection, or acneiform lesions. Delayed implant hypersensitivity reactions were

reported in several case series at low incidences (0.4 to 3.7 %) in early (before mid-1999) non–

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United States use of Restylane. In mid 1999, a hyaluronic acid raw material with trace amounts

of protein six times lower than the raw material previously used was introduced. The amount of

protein in the more purified product was reported to be in the range of 13 to 17 mg/ml of

product. In contrast to 1999, reported adverse events were reduced to 0.06 % and

hypersensitivity reactions were reduced to 0.02 % (Matarasso, Carruthers et al. 2006).

6.4. Risk analysis

A comprehensive risk analysis for the products under discussion has been performed. Thereby,

potential risks have been addressed and discussed. In the risk analysis, hazards and their clinical

consequences have been characterised according to the putative harm for patients and

probability of occurrence. Risk-diminishing measures have been taken. For more detailed

information, reference is made to the risk management file, which is part of the technical

documentation. From a technical, biological, and clinical point of view, the residual risk for

clinical use of Hyacorp Face, GeneFill Soft Fill, Hyacorp Face II Voluma, or SMS Solution is

tolerable after implementation of risk-minimising measures. There are no inacceptable risks

associated with the products under evaluation.

7. Post-marked data

8. Conclusion

Procedures for facial volume replacement become more and more predominant during the last

two decades.

Cross-linked hyaluronic acid products offer several distinct advantages over permanent filler.

Because HA oocurrs naturally in the human body, its biocompatibility is excellent. Multiple

clinical records confirm the high overall safety profile of BDDE-cross-linked HA fillers. One

great advantage is the possibility to reverse the effects either by hyaluronidase injection or by

Product Certified since Units sold in

EU

(until July

2014)

Units sold

outside EU

Serious

adverse events

or incidents

reported

Hyacorp Face 2009 12931 24396 -

GeneFill Soft

Fill

2009 1043 5095 -

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removing the HA from the implant site through aspiration. Furthermore, its administration is

minimally-invasive and its performance is well-established for decades.

The products under evaluation are regarded to be equivalent to the currently used and well

established products Juvéderm Voluma, Restylane SubQ, Restylane, and Juvéderm Ultra from a

technical, biological, and clinical point of view. Therefore the scientific literature discussing

these products was analysed. Juvéderm Voluma, Restylane SubQ, Restylane, and Juvéderm

Ultra were investigated in several prospective studies and case studies. The trials were

performed during 2003 to 2014. The performance of of these products can be assessed as

appropriate leading to high satisfaction in patients and physicians. In summary, performance of

Juvéderm Voluma, Restylane SubQ, Restylane, and Juvéderm Ultra has been proven.

According to MEDDEV 2.7/1 rev3 and based on the principle of equivalence, performance of

the products under evaluation can be regarded as demonstrated.

Articles related to the safety of hyaluronic acid in general, and especially to the Juvéderm

Voluma and Restylane report only a very low rate of side effects and complications. No

unexpected side effects, complication, or incidents related to these products were reported.

Based on the data provided there are no concerns related to the safety of these products.

Performance and safety of hyaluronic acid have been well supported by additional review

articles issued during the last years.

The post market surveillance of Hyacorp Face and GeneFill Soft Fill reflect their status of

safety reported in scientific literature for the equivalent products Juvéderm Voluma, Restylane

SubQ, Restylane, and Juvéderm Ultra. No harm to patients has been reported during the last

years.

In summary hyaluronic acid as filling agent provides a suitable performance and a high safety

in patients. Hyacorp Face, GeneFill Soft Fill, Hyacorp Face II Voluma, and SMS Solution are

equivalent to the well established products Juvéderm Voluma, Restylane SubQ, Restylane, and

Juvéderm Ultra. Performance and safety can be demonstrated by these products. The benefit-to-

risk ratio for clinical use of the products under discussion within their indications is considered

to be positive.

Compiled by Reviewed and approved by

i.DRAS GmbH, 2016-03-11 BioScience GmbH, 2016-03-11

Dr. med. Christian Schübel Kirsten Krollmann

Head Clinical Affairs Product Management

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10. Attachments

Attachment 1 - Literature Search and Outcome

Attachment 2 – Equivalence Analysis

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