Clinical Evaluation - Genefill - hyacorp.fr · - Have a tendency to hypertrophic and keloid scarring - Have an intolerance towards gram-positive bacteria - Are prone to active inflammatory

Clinical Evaluation

Dermal Filler 16/2

CRM Gel/CRM Dur/GeneFill Soft Touch/

Hyacorp Lips

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 ..................................................... 10

5. Summary of the clinical data and appraisal ........................................................................... 13

6. Data analysis ......................................................................................................................... 21

6.1. State-of-the-Art ............................................................................................................................................. 21

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

6.3. Safety .......................................................................................................................................................... 30

6.4. Risk analysis ................................................................................................................................................. 35

7. Post-marked data .................................................................................................................. 36

8. Conclusion ............................................................................................................................ 36

9. References ............................................................................................................................. 37

10. Attachments .......................................................................................................................... 40

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1. General Details

Manufacturer: BioScience GmbH

Walsmühler Straße 18

19073 Dümmer

Germany

Medical Devices: CRM Gel

CRM Dur

GeneFill Soft Touch

Hyacorp Lips

GMDN-Code: 17876

2. Description of the device and its intended application

Four products with identical composition are marketed by the manufacturer BioScience GmbH

under four different names – CRM Gel, CRM Dur, GeneFill Soft Touch, and Hyacorp Lips.

There are differences between the products under discussion regarding their indications. CRM

Gel, CRM Dur, and GeneFill Soft Touch are indicated for replacement of volume and lost

hyaluronic acid in the facial skin. Hyacorp Lips is specifically indicated for restoration of

volume and contour of the lips.

The products under discussion are clear and viscous gel and are provided in a sterile form. The

products are for single use only and supplied in a syringe with a Luer lock port. 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. CRM Gel, CRM Dur, GeneFill Soft Touch,

and Hyacorp Lips 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.

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:

CRM Gel: since 2003

CRM Dur: since 2003

GeneFill Soft Touch: since 2009

Hyacorp Lips: since 2009

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Composition

The products under discussion are composed identically.

1 mL CRM Gel contains:

Hyaluronic acid sodium salt 2.0 mg

Cross-linked Hylan gel 16.0 mg

Sodium chloride 6.9 mg

Water for injection ad 1.0 mL

1 mL CRM Dur contains:





1 mL GeneFill Soft Touch contains:





1 mL Hyacorp Lips 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

CRM Gel 15.000-

21.000

7.0 – 7.2 280-360

80 – 150 0 – 20 1 mL

CRM Dur 12.000-

18.000

7.0 – 7.2 280-360

80 – 150 0 – 20 1 mL

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GeneFill

Soft Touch

15.000-

21.000

7.0 – 7.2 280-360

80 – 150 0 – 20 1 mL

Hyacorp

Lips

15.000-

21.000

7.0 – 7.2 280-360

80 – 150 0 – 20 1 mL

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 instruction and techniques

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

CRM Dur

Replaces lost hyaluronic acid in the skin, is used for volume replacement

(filling of folds), superficial folds, periorbital lines, perioral lines.

CRM Gel

CRM Gel 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 folds, nasolabial folds, cheek

area, lip augmentation, glabella folds.

Do not inject CRM Gel in the periorbital region (eyelid, crow’s feet,

circles under the eyes)

Genefill Soft Touch

Replaces lost hyaluronic acid in the skin, is used for volume replacement

(filling of folds), superficial folds, periorbital lines, perioral lines.

Hyacorp Lips HYAcorp Lips is intended for the restoration of volume and contour of

the lips.

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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.

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,

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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 CRM Gel, CRM Dur, GeneFill Soft Touch, and Hyacorp Lips

can be demonstrated based on equivalence to other products and established-use of hyaluronic

acid dermal fillers.

The products under discussion can be regarded as similar to the dermal filler Juvéderm Voluma

(Allergan, Santa Barbara, California USA) regarding their physic-chemical parameters:

Criterion CRM Dur/CRM Gel/GeneFill Soft

Touch/Hyacorp Lips Product Specification

Juvéderm Voluma® VB20A4001

Sterilisation Moist heat Moist heat

Osmolarity 280-360 mosmol/kg 352 mosmol/kg

Viscosity 12.000 - 18.000 mPas

15.000 – 21.000 mPas

21.580 mPas

pH value 7.0 – 7.5 7.2

Quantity of cross-linked HA 16 mg/mL 20 mg/mL

Source HA Fermentation Fermentation

Cross-linker BDDE BDDE

BDDE residuals <0.001 mg/mL (<1ppm) <0.001 mg/mL

Degree of cross-linking 0 – 20% 10.1%

Particle size 80 – 150 µm 149 µm

Slight differences in cross-linked HA content and viscosity are considered to have only minor

influence on the clinical outcome after administration. 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. Juvéderm Voluma® is intended for deep

(subcutaneous and/or supraperiosteal) injection (see IFU of Juvéderm Voluma®). Therefore,

the following can be concluded: Technical, and biological equivalence of Juvéderm Voluma

and the products under discussion is demonstrated. Since the intended use differs – intradermal

versus subcutaneous/supraperiosteal injection – there is clinical similarity but no equivalence.

However, two important rheological properties of a soft tissue filler gel that can be quantified

are its complex viscosity and its elastic modulus. The elastic modulus of Juvéderm Voluma has

been determined at 499 Pa (data provided by the manufacturer). Sundaram et al analysed the

complex viscosity and elastic moduli of different hyaluronic acid dermal fillers and a calcium

hydroxylapatite filler (Sundaram, Voigts et al. 2010):

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(Sundaram, Voigts et al. 2010)

It can be deduced from the results presented in Sundaram et al that the rheological properties of

Juvéderm Voluma are within the range of other well-established products (Juvéderm Ultra,

Juvéderm Ultra Plus, Restylane, Perlane, and Restylane SubQ).

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, as Juvéderm Voluma, clinical

equivalence of Restylane SubQ to the products under discussion is not given.

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

dermal implantation for the correction of moderate to severe facial wrinkles and folds, such as

nasolabial folds (see IFU Restylane). The indications of Restylane are equivalent to CRM Gel,

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CRM Dur, and GeneFill Soft Touch, and partly (lip augmentation) to Hyacorp Lips. Thus,

Restylane is considered to be an equivalent product to the products under discussion.

Juvéderm Ultra and Juvéderm Ultra Plus injectable gels are sterile, biodegradable,

nonpyrogenic, viscoelastic, clear, colorless, homogenised gel implants. Juvéderm Ultra (Plus)

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 (Plus) 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 higher in Juvéderm Ultra and Juvéderm Ultra Plus

compared with CRM Gel, CRM Dur, and GeneFill Soft Touch, it is regarded as essentially

similar and is therefore taken into consideration as well.

Perlane is a sterile gel of hyaluronic acid generated by Streptococcus species of bacteria,

chemically cross-linked with BDDE, stabilised, and suspended in phosphate buffered saline at

pH 7 and a concentration of 20 mg/mL. This product significantly differs with regard to its

particle size, since is contains the biggest particle size of the presented proucts (the largest

fraction of gel particle size is between 940 and 1090 microns). The particle size is markedly

larger than in the products under discussion, and it is therefore excluded from the evaluation.

Moreover one product is available (Juvéderm Volbella) that is indicated for the treatment of any

fine lines and medium-sized skin depressions due to conditions such as premature aging as well

as for enhancement and pouting of the lips via superficial or middermis injection or lips mucosa

injection. Juvéderm Volbella contains 15 mg/mL BDDE-crosslinked hyaluronic acid (according

to its IFU). Regarding lip augmentation, Juvéderm Volbella is considered equivalent to Hyacorp

Lips.

According to MEDDEV 2.7/1 rev3 evaluation of performance and safety of the products under

discussion based on published data regarding Restylane, Juvéderm Ultra, Juvéderm Ultra Plus,

and Juvéderm Volbella is feasible. Details on the equivalence analysis are provided in

attachment 2.

Therefore, a thorough literature search in established databases is performed to demonstrate the

performance and safety of CRM Gel, CRM Dur, GeneFill Soft Touch, and Hyacorp Lips by

taking products that are regarded as equivalent and the state-of-the-art of dermal fillers into

consideration.

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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 Restylane, Juvéderm Ultra, Juvéderm Ultra Plus, and Juvéderm Volbella 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:

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

D2

A1

P1

R2

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provisions of the Helsinki Declaration for studies in

humans. Written informed consent was obtained from

the patients.

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 substances.

D2

A2

P2

R1

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

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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 and

describes how the physical properties of hyaluronic

dermal fillers may influence clinical outcomes.

D2

A1

P1

R1

Performance

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.

The objective of this study was to compare the

effectiveness and safety of smooth-gel HA dermal

fillers with bovine collagen for nasolabial fold

(NLF) correction. Therefore, a total of 439 subjects

with moderate or severe NLFs received one of

three types of smooth-gel HA dermal filler (in one

NLF) and cross-linked bovine collagen (in the

other NLF) and were evaluated for 24 weeks. All

three HA dermal fillers achieved considerably

longer-lasting clinical correction than bovine

collagen; 81 % to 90 % of HA dermal filler-treated

NLFs maintained a clinically significant

improvement from baseline for 6 months. Up to

88 % of subjects preferred the HA dermal fillers

over bovine collagen. All fillers were similarly well

tolerated. In summary, the smooth-gel HA dermal

fillers offer longer-lasting correction than bovine

collagen-which may lessen the frequency that

repeat treatments are needed. Also, they were

preferred by the vast majority of subjects-which

should promote patient satisfaction.

D2,

A1,

P1,

R1

Bogdan Allemann, I. and L.

Baumann (2008). "Hyaluronic

Review article summarising the results of two large

controlled trials performed by Baumann et al

D2,

A1,

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acid gel (Juvederm) preparations

in the treatment of facial

wrinkles and folds." Clin Interv

Aging 3(4): 629-634.

(2007) and Pinsky et al (2007). In summary, the

performance and safety of Juvederm compared to

Zyplast was investigated on 731 subjects.

P1,

R2

Eccleston, D. and D. K. Murphy

(2012). "Juvederm((R)) Volbella

in the perioral area: a 12-month

prospective, multicenter, open-

label study." Clin Cosmet

Investig Dermatol 5: 167-172.

The objective of this prospective, multicenter,

open-label, post market study was to demonstrate

the safety and effectiveness of Juvéderm Volbella

injectable gel for lip enhancement. Ethics

Committee approval was obtained from Sheffield

Research Ethics Committee (Leeds, UK), and the

study was conducted at four European sites (three

in the UK and one in Northern Ireland). The study

was registered at http://www.clinicaltrials.gov

(NCT 01176773), and all subjects provided written

informed consent.

D2

A1

P1

R2

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.

D2

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P1

R1

Lupo, M. P., S. R. Smith, et al.

(2008). "Effectiveness of

Juvederm Ultra Plus dermal filler

in the treatment of severe

nasolabial folds." Plast Reconstr

Surg 121(1): 289-297.

A multicentre, double-blind, randomised, within-

subject, controlled study was conducted as part of a

submission for approval by the U.S. Food and Drug

Administration. This study compared three

different formulations of Juvederm against bovine

collagen (Zyplast; Allergan). One-third of subjects

were randomly assigned to receive treatment with

Juvederm Ultra Plus, containing 24 mg/ml of cross-

linked hyaluronic acid, in one nasolabial fold and

Zyplast in the other. Results presented here are

limited to those subjects who received Juvederm

Ultra Plus and had severe folds at baseline.

Because of the differences in appearance between

the two products, each study site had two

investigators: a treating investigator who was not

blinded and an evaluating investigator who was. To

maintain this blinding, the evaluating investigator

was not present during treatment every 4 weeks for

up to 24 weeks after the last treatment, subjects

were followed for assessment of nasolabial fold

severity. Follow-up visits for effectiveness

assessments after repeated treatment occurred at 4,

12, and 24 weeks after repeated treatment, and an

amendment to the extended study protocol allowed

even further evaluations at 36 and 48 weeks after

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repeated treatment. The protocols and amendments

were approved by the applicable institutional

review boards, and subjects provided written

informed consent for each study in which they

participated.



"Consensus recommendations for

soft-tissue augmentation with

nonanimal stabilised hyaluronic

acid." Plast Reconstr Surg 117(3

Suppl): 3S-34S; discussion 35S-

43S.


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

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.

D2

A1

P1

R2

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.

D2

A1

P1

R1

Philipp-Dormston, W. G., S.

Hilton and M. Nathan (2014). "A

prospective, open-label,

multicenter, observational,

postmarket study of the use of a

15 mg/mL hyaluronic acid

dermal filler in the lips." J

Cosmet Dermatol 13(2): 125-

134.

This one-month, prospective, open-label,

multicenter, observational postmarket study

(clinicaltrials.gov identifier: NCT01629134) was

conducted in two German sites. Eligible subjects

were aged 18 years and older, expressed a desire

and willingness for correction of asymmetry or

enhancement of their lips and could comply with

the study requirements. Each subject signed an

informed consent form and underwent treatment

with the product.

D2

A1

P1

R2

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

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additional poststudy visit provided long-term

effectiveness data. Safety was evaluated through

subjects’ daily diaries for 14 days after treatment.

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

al. (2008). "Successful treatment

with injected hyaluronic acid in a

patient with lip asymmetry after

surgical correction of cleft lip."


Surgical repair of cleft lip, while correcting

deformity and dysfunction, may leave residual

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.

D2

A1

P2

R2

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.

D2,

A1,

P1,

R2

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.

D2

A1

P1

R2

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

D2

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investigators) were recruited in this study. The

study was approved by a central institutional

review board and conducted at two Chinese

hospitals, in full accordance with the Good Clinical

Practice regulations and guidelines. All subjects

provided a written informed consent.

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

D2

A2

P1

R1

Artzi, O., et al. (2016). "Resistant

and Recurrent Late Reaction to

Hyaluronic Acid-Based Gel."


Medical records of 400 patients (360 women and

40 men; average age = 49.6 years) were examined

in this retrospective study. Juvederm Volbellafiller

was injected only into the tear trough area or lips.

Other HA-based products were used in other areas

of the face. Four centers in Israel participated in the

study. Data were collected from patient charts and

through phone call interviews.

D2

A1

P1

R2

Brandt, F., B. Bassichis, et al.

(2011). "Safety and effectiveness

of small and large gel-particle

hyaluronic acid in the correction

of perioral wrinkles." J Drugs

Dermatol 10(9): 982-987.

This open-label, 4-week study at two US centres

evaluated patients who intended to undergo

intradermal injection for correction of perioral

wrinkles and folds. At screening, a 5-grade Wrinkle

Severity Rating Scale (WSRS) was used to

evaluate the baseline appearance of bilateral NLFs,

and a 6-grade Wrinkle Severity (WS) scale was

used to evaluate the appearance of bilateral oral

commissures, marionette lines and upper perioral

rhytides. To qualify, each patient must have had

moderate-to-severe wrinkles at one pair of

marionette lines and upper perioral rhytides. Each

wrinkle was treated to optimal correction with

either SGP-HA or LGP-HA at the discretion of the

treating investigator. All reported local and

systemic adverse events (AEs) were recorded. At

two weeks after treatment or touch-up, the treating

investigator and the patient assessed appearance

using the Global Aesthetic Improvement Scale

(GAIS).

D2

A1

P1

R2

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.

D2,

A1,

P2,

R1

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Eccleston, D. and D. K. Murphy

(2012). "Juvederm((R)) Volbella

in the perioral area: a 12-month

prospective, multicenter, open-

label study." Clin Cosmet

Investig Dermatol 5: 167-172.

The objective of this prospective, multicenter,

open-label, post market study was to demonstrate

the safety and effectiveness of Juvéderm Volbella

injectable gel for lip enhancement. Ethics

Committee approval was obtained from Sheffield

Research Ethics Committee (Leeds, UK), and the

study was conducted at four European sites (three

in the UK and one in Northern Ireland). The study

was registered at http://www.clinicaltrials.gov

(NCT 01176773), and all subjects provided written

informed consent.

D2

A1

P1

R2

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.

D2

A1

P1

R1

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.

D2,

A1,

P2,

R2

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.

D2,

A1,

P2,

R2



"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.


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

Review article covering the time period from 2000

to 2008. This article compared the current options

D2,

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face." Clin Cosmet Investig

Dermatol 2: 141-150. of tissue augmentation and discussed the

composition and characteristics of available dermal

fillers.

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

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.

D2,

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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

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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-

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

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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

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,

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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

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.

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6.2. Performance

Restylane

Early clinical and efficacy studies of Restylane were reported from Italy and Sweden. In

Sweden, 100 patients were fully assessed following treatment in 285 locations (lips, wrinkles,

folds). The Swedish study reported that, based on physician evaluations, treatment sites

maintained an average of 82 % and 69 % correction (using a visual analogue scale of 0 to

100 %) at 12 and 26 weeks, respectively. In Italy, 158 patients were treated for augmentation

therapy of wrinkles and folds. The Italian study reported that 78 percent of patients maintained

moderate to marked improvement after 8 months, with nasolabial folds and lips sustaining the

best results (Matarasso, Carruthers et al. 2006).

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

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,

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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

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

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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

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/Juvéderm Ultra Plus

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

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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).

In the pivotal trial that led to FDA approval of Juvederm, Baumann et al (2007) compared the

safety and effectiveness of 3 types of smooth-gel HA dermal fillers vs. cross-linked collagen in

the treatment of NLF in 439 subjects in a multicentre, double-masked, randomised, within-

subject study. The subjects randomly received one of three types of smooth-gel HA dermal

filler in one NLF and cross-linked bovine collagen in the other. The three different smooth-gel

HAs used were Juvederm, Juvederm Ultra, or Juvederm Ultra Plus. The cross-linked bovine

collagen filler used was Zyplast (Allergan, formerly Inamed). The NLFs were to be filled to full

correction (100 % of the defect), and not overcorrected, and a maximum of 3 treatments – first

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

correction. NLF severity was assessed using the 5-point Wrinkle Assessment Scale (WAS),

with 0 = none (no wrinkle); 1 = mild (shallow, just perceptible wrinkle); 2 = moderate

(moderately deep wrinkle); 3 = severe (deep wrinkle, well defined edges but not overlapping); 4

= extreme (very deep wrinkle, redundant fold with overlapping skin). The results showed that

all three dermal fillers proved longer-lasting clinical corrections than bovine collagen. Twenty-

four weeks after the last treatment, 90 % of subjects treated with Juvederm Ultra Plus dermal

filler retained a clinically significant improvement, 88 % treated with Juvederm Ultra and 81 %

with dermal filler. The bovine collagen–treated NLFs showed clearly shorter longevity with

lasting improvement after 24 weeks ranging from 36 % to 45 %. In addition to its superior

longevity, the injection volume for HA dermal fillers proved to be lower (median, 1.6 mL)

compared with bovine collagen (median, 2.0 mL), representing an additional important

advantage for the patient in treatment costs and comfort. The only treatment-related adverse

events observed were localized site reactions in the area of injection, which were mild to

moderate in severity and did not differ between any filler type. In decreasing percentage those

were injection site induration, erythema, edema, pain, nodule formation, bruising, discoloration,

and pruritus; they lasted no more than 7 days. The preferred filler by the patients used was

Juvederm Ultra with 88 %, followed by 84 % for Juvederm Ultra Plus and 78 % for Juvederm;

the majority of subjects preferred HA fillers to the collagen fillers (Baumann, Shamban et al.

2007, Bogdan Allemann and Baumann 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).

The results of the above mentioned studies are supported by a recent study by Lupo et al which

compared Juvederm Ultra Plus HA filler with Zyplast bovine collagen in a multicentre, double-

blind, randomised, within-subject, controlled study (Lupo et al 2008). In a split-face mode,

severe NLFs of 87 subjects were treated one side with Juvederm Ultra Plus and the other side

with Zyplast. In the study population all Fitzpatrick skin types were represented, 36% having

darker skin types (Fitzpatrick types IV through VI). Up to two touch-up treatments were

allowed at 2-week intervals. Effectiveness was assessed using the validated, static, 5-point

Wrinkle Assessment Scale (WAS) with a photographic guide. The Juvederm Ultra Plus filler

showed significantly better NLF severity scores compared to Zyplast at each follow-up time

point from 4 to 24 weeks. At 24-week follow-up clinically significant correction of NLF treated

with Juvederm were shown in 96% compared with 41 % Zyderm. The clinical correction with

Juvederm Ultra Plus remained high, whereas the scores for Zyplast nearly returned to baseline

over the period of 24 weeks. At 24 weeks, the mean improvement was still 1.7 with the

Juvederm Ultra Plus product but only 0.5 with bovine collagen. Longevity was shown by

maintenance of the clinical correction for 1 year or more in 81 % of NLFs treated with

Juvederm. The median volume of Juvederm required was 0.7 mL (one syringe), significantly

less than for Zyplast (1.6 mL). For the initial treatment, the median volume of Juvederm Ultra

Plus injected was 2 syringes (1.6 mL), and less than 1 syringe (0.7 mL) for the retreatment at

after 6–9 months. Treatment site reactions were similar for Juvederm Ultra Plus and Zyplast

and were similar to those in the abovementioned trials. As for patient satisfaction, most subjects

preferred Juvederm Ultra Plus (85 %) versus collagen (10 %); 5% showed no preference (Lupo,

Smith et al. 2008).

Juvéderm Volbella

The objective of the prospective, multicenter, open-label, post market study of Ecclestone et al

was to demonstrate the safety and effectiveness of Juvéderm Volbella injectable gel for lip

enhancement. The four investigators enrolled and treated 60 subjects between October 2010 and

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January 2011, and 59 of these subjects (98.3%) completed the study. All of the subjects were

women, and the mean age was 50 years (range, 21–74). Following treatment with Juvéderm

Volbella injectable gel, subjects returned to the clinic for follow-up at 1, 3, 6, 9, and 12 months

after initial treatment. An optional top-up treatment was allowed at 2 weeks. The mean injection

volume was 1.2 mL (range, 0.5–2 mL) for initial treatment and 0.55 mL (range, 0.3–1 mL) for

touch-up treatment. The Month 3 Lip Fullness Score responder rate based on investigator

assessments was 93.2% (P <0.0001). The responder rate over time showed that more than three-

quarters of subjects still had improved lip fullness at month 9 and almost half had improved

fullness at month 12. After treatment, the Lip Fullness Score improved from 1.8 (mild) to 3.0

(moderate). On the 11-point look and feel questionnaire where 0 is lumpy and 10 is smooth,

81.0% of subjects had ratings of 7–10 at Month 1, indicating that they thought their lips felt

smooth. On similar questions at Month 1, 67.2% of subjects reported that their lips felt soft,

91.4% reported their lips felt natural, 91.4% reported their lips looked natural, and 84.5%

reported their lips looked even. High ratings on all of these outcomes were maintained

throughout the course of the study. In terms of overall satisfaction with the effects of treatment,

96.6% of subjects reported being satisfied (scores of 7–10 on the 11-point scale) at Month 1,

and by Month 12 more than 80% of subjects were still satisfied. The mean satisfaction score at

Month 1 was 9.3, and it remained at 9.0 or better at every subsequent visit. The performance of

Juvéderm Volbella for lip augmentation was conclusively demonstrated in this clinical study

(Eccleston and Murphy 2012).

Recently, the performance and safety of Juvéderm Volbella containing lidocaine have been

investigated in 62 patients. In total, 83.6% of the subjects were “Extremely Satisfied”, “Very

Satisfied” or “Satisfied” with the improvement in their lips after the first injection, and the

physicians being “Extremely Satisfied” or “Very Satisfied” with lip improvement in 100% of

the subjects. The high levels of satisfaction may be explained by the natural effect produced by

the treatment: 61.7% of subjects rated the look and feel of their lips as “Extremely Natural” or

“Very Natural” after the first injection, and no subject considered the look and feel to be “Not

Natural” at the follow-up visit. These results are particularly relevant when it is considered that

the majority of subjects (77.4%) had pre-treatment concerns about the possible unnatural look

of their lips following injection. In summary, BDDE-crosslinked HA in an amount of 15

mg/mL has been shown to be effective in lip augmentation (Philipp-Dormston, Hilton et al.

2014).

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).

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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

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).

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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

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).

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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

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).

Restylane

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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, localised 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–

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).

Small gel-particle hyaluronic acid (Restylane) and large gel-particle hyaluronic acid (Perlane)

were studied to evaluate their safety for the correction of oral commissures, marionette lines,

upper perioral rhytides and nasolabial folds (NLFs). Twenty patients with a mean age of 59.6

years (range 49 to 65 years) were treated with an average of 5.58 +/-1.15 mL of HA for the

entire perioral area. Treatment areas included NLFs, marionette lines, oral commissures and

perioral rhytides. Eighteen of 20 patients received Restylane and Perlane. The products were

injected into the mid or deep dermis using primarily linear threading and multiple punctate

pools. Patients experienced a total of 66 treatment-emergent adverse events. The reported

events in decreasing order of occurrence were bruising, tenderness, swelling, redness, headache

and discomfort. Bruising was more common in the NLFs and marionette lines than in the oral

commissures and perioral rhytides. Tenderness occurred more often in the perioral rhytides than

in the other areas. The maximum intensity of all adverse events was considered mild. Most

adverse events resolved within seven days, with an average duration of four days. No serious

adverse events occurred during the study. One hundred percent of GAIS evaluations by both

investigators and patients indicated improvement, regardless of filler used or area treated

(Brandt, Bassichis et al. 2011).

Juvéderm Volbella

In the study of Ecclestone et al, Juvéderm Volbella has been revealed to be safe when used for

lip augmentation as intended. There were 34 subjects with 72 adverse events related to the study

injection or device, and the most frequent was injection site bruising (51.7%, 31/60 subjects).

Injection site swelling and lumps each occurred at much lower rates (8.3%, 5/60 subjects), and

all other adverse events occurred in less than 4% of subjects. Three-quarters of the events

(75.0%) were mild, and the remainder (25.0%) were of moderate severity. Two-thirds of the

events (66.7%) resolved within 1 week, and the vast majority resolved without sequelae

(98.6%) and did not require treatment (97.2%). One event of an injection site mass (lump) was

ongoing. There were no severe or serious events related to treatment (Eccleston and Murphy

2012).

Artzi et al reported on a cohort of 400 patients (360 women, average age 49.6 years) who

received Juvéderm Volbella in the tear through area and lips. All patients were injected with

additional HA-based products into other facial areas. The average number of different products

injected to the same patient, in two consecutive sessions, was 2.6. The average amount of fillers

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injected to the same patient in two consecutive sessions was 3.2 mL. The interval between two

sessions ranged from 6 weeks to 6 months. To follow-up the patients after treatment, data were

collected from patient charts and through phone call interviews. Of 400 patients, 17 (4.25%)

developed a cutaneous reaction to the examined filler. In addition to Juvéderm Volbella, 8 of 17

patients (47%) were treated with 1 additional product, 4 (23%) were treated with 2 additional

products, and 5 (29%)with 3 additional products. The cutaneous reaction was observed 8.41

weeks after the injection of Juvéderm Volbella (range: 5–12) and initially manifested with

purplish to brownish discoloration of the skin surrounding the injection site. All affected

individuals were first treated with oral ciprofloxacin for a period of 3 to 4 weeks. In 6 of these

patients, all symptoms and signs receded and did not recur. The 11 remaining patients

developed recurrent episodes of inflammatory reactions. Three patients had only 1 recurrence, 2

patients had 2 recurrences, 2 patients had 3 recurrences, 1 patient had 4 recurrences, 1 patient

had 5 recurrences, and 2 patients had 8 recurrences. Relapses were not always seen at the initial

reaction site. They resolved and recurred in different facial areas, where otherHAfillerswere

previously injected. During analysis of the data, a strong positive association was found

between the number of products injected and the time of full resolution. Furthermore, the total

volume of injected material also correlated with time until resolution. When more than 1 mL of

filler was injected during a session, the median time until resolution was 4.75 months when

compared with 1.5 months, when only 1 mL was injected. The incidence of late-onset adverse

reaction in this study was higher than reported in other studies (Artzi, Loizides et al. 2016). The

reasons are unclear. Importantly, this study revealed that late-onset adverse reactions are of less

severity and duration if the amount of injected HA material is below 1 mL. Thus, for use of

dermal fillers in the facial area, it should be attempted to decrease the amount of injected

material as far as possible.

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 CRM Gel, CRM Dur, GeneFill Soft Touch, and Hyacorp Lips is tolerable after

implementation of risk-minimising measures. There are no inacceptable risks associated with

CRM Gel, CRM Dur, GeneFill Soft Touch, and Hyacorp Lips.

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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

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

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

CRM Gel, CRM Dur, GeneFill Soft Touch, and Hyacorp Lips are regarded to be equivalent to

the currently used and well established products Restylane, Juvéderm Ultra, Juvéderm Ultra

Plus, and Juvéderm Volbella from a technical, biological, and clinical point of view. Therefore

the scientific literature discussing these products was analysed. Restylane, Juvéderm Ultra,

Juvéderm Ultra Plus, and Juvéderm Volbella 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 Restylane, Juvéderm Ultra, Juvéderm Ultra Plus, and Juvéderm

Volbella has been proven. According to MEDDEV 2.7/1 rev3 and based on the principle of

equivalence, performance of CRM Gel, CRM Dur, GeneFill Soft Touch, and Hyacorp Lips can

be regarded as demonstrated.

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

Volbella 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.

Product Certified since Units sold in

EU

(until July

2014)

Units sold

outside EU

Serious

adverse events

or incidents

reported

CRM Gel 2003 34614 28232 -

CRM Dur 2003 14052 13134 -

GeneFill Soft

Touch

2009 444 1771 -

Hyacorp Lips 2009 18466 17565 -

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The post market surveillance of CRM Gel, CRM Dur, GeneFill Soft Touch, and Hyacorp Lips

reflect their status of safety reported in scientific literature for the equivalent products

Restylane, Juvéderm Ultra, Juvéderm Ultra Plus, and Juvéderm Volbella. 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. CRM Gel, CRM Dur, GeneFill Soft Touch, and Hyacorp Lips are equivalent to the

well established products Restylane, Juvéderm Ultra, Juvéderm Ultra Plus, and Juvéderm

Volbella. Performance and safety can be demonstrated by these products and by post-market

data on the products under discussion. 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, 2016-03-10 BioScience GmbH, 2016-03-10

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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Clinical Evaluation - Genefill - hyacorp.fr · - Have a tendency to hypertrophic and keloid scarring - Have an intolerance towards gram-positive bacteria - Are prone to active inflammatory

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