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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March and July 2017

Scheduling medicines and poisons

15 September 2017

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2.7 Epidermal growth factor

An application was submitted to amend the Schedule 7 entry for epidermal growth factor (EGF) to exempt topical cosmetic preparations containing low concentrations of transgenic plant EGF.

Scheduling application

This was a general application. The applicant's proposed amendments to the Poisons Standard are:

Schedule 7 – Amend Entry

EPIDERMAL GROWTH FACTOR except in preparations for therapeutic use.:

  1. in preparations for human therapeutic use; or
  2. in topical cosmetic preparations containing 0.0002% or less of transgenic, plant-made epidermal growth factor.

This is a re-scheduling proposal for epidermal growth factor (EGF) that was considered by the joint ACCS-ACMS at the November 2016 meeting. The advice at that time was that the current Schedule 7 not be amended.

In support of the application, the applicant has provided additional information and consideration of an alternative proposal to move the parent entry for EGF to Schedule 4. The applicant suggests that this would align EGF to a consistent scheduling classification with other growth factors. The applicant contends this would enable cosmetic use at very low concentrations to be exempt from scheduling.

The initial reasons for the request provided to the committee in November 2016 were:

  • The wording of the current Schedule 7 entry for EGF captures any use of EGF other than for human therapeutic use. This is despite the original scheduling submission relating to injectable u-hEGF (urinary human EGF).
  • Since the addition of EGF into the Poisons Standard after the November 1996 advisory committee meeting, there have been significant technological developments in cosmetic product innovation, such as the development of recombinant chemicals in plants for cosmetic use. These substances are commonly used topically in very low concentrations in cosmetic products, having acceptable safety profiles and meeting international regulatory requirements for cosmetic use.
  • By amending the Schedule 7 entry, the applicant proposes that this would allow supply of their cosmetic products to Australian consumers within the provisions of Australian consumer protection laws. Therefore, the product will be able to compete with similar cosmetic products available to purchase online via overseas websites.
  • The original 1996 National Drugs and Poisons Scheduling Committee (NDPSC) decision on EGF considered a veterinary application for injectable EGF. The consequent Schedule 7 entry was valid for veterinary use, and the Schedule 7 entry only exempts EGF for human therapeutic use. The decision by the NDPSC to include EGF in both Schedule 7 and Appendix J indicates that the committee's scheduling decision was focussed on veterinary use of the substance. This was further demonstrated by the Appendix J entry, confining its use to authorised or licensed persons.

New information provided by the applicant on the toxicity and safety of the substance:

(A) Risks and Benefits associated with the use of a substance

The absence of any cosmetic regulatory controls by any regulatory agency of EGF, other growth factors or cytokines in cosmetic products internationally, confirms that there has been no hazard to public safety associated with this substance when used in cosmetic products, i.e. topical use at low concentrations. This supports unrestricted public availability for this usage pattern, which is significantly different to the hazard associated with systemic application of EGF in veterinary use, which prompted the original Schedule 7 entry.

(B) Purposes for which a substance is to be used and the extend of use of that substance

No new information was provided.

(C) Toxicity and safety of the substance

Cosmetic ingredients are subject to a different set of criteria for safety assessment compared to medicinal substances due to their vastly different intended uses and dosages. There are limited specific studies available with endpoints to assess the toxicity and safety of cosmetic products. To address the concerns expressed by the ACCS-ACMS meeting #14, it is necessary to cross refer to studies undertaken with EGF in the context of its therapeutic function in wound healing. The intended scheduling exemption is for very low concentrations of topical use of EGF in cosmetic products, and the usage profile of EGF for cosmetic purposes is very different to that used in the context of wound healing studies.

EGF has been used since 1989 to accelerate healing of open human skin wounds, such as chronic ulcers and burns, without observed increased incidence of serious adverse effects.

A 2014 publication provides a systemic review and meta-analysis of 12 randomised clinical trials, in which growth factors were used in therapeutic dosages for treatment of burns. Of these 12 studies, 4 used EGF as the treatment. 476 patients were enrolled in the EGF studies, of which 240 patients used EGF and standard would care, whilst 236 were in the control group and used standard would care alone. The concentration of EGF used in these studies ranged from 80,000 pg/cm2 to 1200000 pg/cm2. The results showed a dose dependent acceleration in wound healing.[12]

No allergic, toxicity or systemic adverse reactions were reported from these studies. The concentrations of EGF used in these studies in injured skin, enabling systemic absorption, has been calculated by the applicant to be 800 times greater than the EGF concentrations proposed for exemption from scheduling for cosmetic use on intact skin.

These results are consistent with the safety profile reported in the review published by Berlanga-Acosta (International Wound Journal, Vol 6, No 5. 2009) presented in the original submission to ACCS-ACMS.

Further to this clinical experience, the applicant's supply of EGF and the company quality managements system confirms that there have been no serious undesirable effects, or undesirable effects reported. Only limited numbers of minor or mild reported effects including mild irritation, itching, and small pimples have been reported, all of which are classified as minor or mild.

New information provided by the applicant related to the Hebermin clinical study.[13]

New information provided by the applicant related to the Heberprot-P clinical study.[14]

(D) Dosage, formulation, labelling, packaging and presentation of a substance

The ACCS-ACMS meeting #14 expressed concern about the therapeutic intent of cosmetic products containing very low concentrations of EGF. This was one of the reasons for retaining the current scheduling of EGF in Schedule 7.

The intended purpose of the plant-made EGF proposed for exemption from scheduling is as a skin conditioning cosmetic ingredient in formulated topical cosmetic products, at concentrations of 0.0002% or less. Cosmetic products containing this ingredient for this intended purpose are able to be purchased without restriction by consumers in the EU, USA, Canada, Japan, South Africa, China and South America.

Cosmetic products are prohibited from making any representations for therapeutic use in labelling, packaging or advertising. Concerns of therapeutic intent are adequately and appropriately controlled through the legislative provisions of the Australian Consumer Law, as set out in Schedule 2 of the Competition and Consumer Act 2010.

(E) Potential for misuse/abuse

No new information was provided.

(F) Any other matter that may be relevant to the scheduling of a substance

A review by Zhang et al., includes clinical studies using other growth factors.12 There are no scheduling controls that apply to cosmetic products supplied in Australia that use other growth factors. For example:

  • Product 1: has been subject to published reviews that identify a mixture of growth factors, cytokines, and soluble matrix proteins secreted by cultured neonatal human dermal fibroblasts during production of extracellular matrix in an oil-free gel formulation.[15]
  • Product 2: see attached screen shot from Australian website[16]
  • Product 3: one of many new cosmetic serums available in Australia that use the secretions of the snail Cryptomphalus aspersa (SCA), which contains a mixture of growth factors and peptides for the improvement of facial wrinkles.[17]

It is understood that this is because the parent schedule entry for the growth factors present in these other products are in Schedule 4, and the low concentrations present in cosmetic preparations enable the products to use the exemption from scheduling that apply to very low concentrations (Ref Poisons Standard Part 1 Interpretations 2 (j)) but does not include:

'any other substance included in Schedules 1 to 6, at a concentration not exceeding 10 mg per litre or 10 mg per kilogram, unless that substance is also included in Schedule 7 or 8.'

Alternatively, consideration is requested for moving the parent entry for EGF to Schedule 4. This would align EGF to a consistent scheduling classification with other growth factors. This would enable cosmetic use at very low concentrations to be exempt from scheduling.

Current scheduling status and relevant scheduling history

Epidermal growth factor is currently listed in Schedule 7 of the Poisons Standard as follows:

Schedule 7

EPIDERMAL GROWTH FACTOR except in preparations for human therapeutic use.

It is also included under the entry EPIDERMAL GROWTH FACTOR in Appendix J, Part 2 with the following statements:

Appendix J – Part 2

EPIDERMAL GROWTH FACTOR

Standard Statement: 1 (Not to be available except to authorised or licensed persons).

In November 1996, the National Drugs and Poisons Schedule Committee (NDPSC) considered an application for a recombinant epidermal growth factor for use in sheep. It was listed in the Poisons Standard in Schedule 7 and Appendix J, Condition 1.

In June 2008, the NDPSC considered a minor editorial amendment to the Schedule 7 entry of epidermal growth factor, changing the entry from "other than for" to "except for" in reference to "preparations for human therapeutic use".

In November 2016, the Joint Advisory Committee on Chemicals and Medicines Scheduling (ACCS-ACMS meeting #14) considered a proposal to amend the wording of the Schedule 7 entry for EGF to exempt topical cosmetic preparations containing low concentrations of transgenic plant-made epidermal growth factor from the scope of the Schedule 7 entry. The committee recommended that the current scheduling of epidermal growth factor in Schedule 7 remained appropriate, and the scheduling delegate concurred. The scheduling delegate's final decision can be found on the TGA website at Scheduling delegate's final decisions, March 2017 - 2.4 Epidermal Growth Factor.

Australian regulatory information

According to the TGA Ingredient Database, EGF is available for use as an:

  • Active and excipient ingredient in biologicals and prescription medicines.

EGF is used in one PI formulation and it is present in one product on the ARTG at 15% v/v. The concentration of EGF in the PI is unknown.

Epidermal growth factor is not listed in Therapeutic Goods (Permissible Ingredients) Determination No. 3 of 2017.

International regulations

There is limited information on the clinical use of EGF internationally. However, EGF has been used experimentally to treat diabetic foot ulcers[18] and mucositis in patients undergoing radiotherapy.[19] A collation of published papers (through Pubmed and Bioline International) related to the clinical use of EGF was published in 2009.[20]

There are no cosmetic regulatory controls of EGF, or other growth factors or cytokines in cosmetic products internationally. Cosmetic products containing EGF at concentrations of 0.0002% or less are able to be purchased without restriction by consumers in the EU, USA, Canada, Japan, South Africa, China and South America.
EGF is unclassified in NZ, the EU and the USA.

Canada

EGF is listed on the Health Canada website as being a ‘Substances in Cosmetics and Personal Care Products Regulated Under the Food and Drugs Act (F&DA) That Were In Commerce between January 1, 1987 and September 13, 2001.' EGF is classified as a medicinal ingredient in Canada according to an April 2017 document titled, ‘Guidance Document on Classification of Veterinary Drugs and Animals Feeds.'

Substance summary

Human EGF is a short 53 amino acid polypeptide. It is secreted by cells and acts as a mitogen, stimulating cellular proliferation, differentiation and survival primarily through the epidermal growth factor receptor (EGFR).

Abcam image - EGF Signalling

Figure 2.7.1: EGF stimulation cell signal pathway diagram

Barley sh-Oligopeptide-1(CAS 1807528-51-3) is a plant produced peptide expressed from an in vitro synthesised gene with a barley (Hordeum Vulgare) codon optimization.

Barley sh-Oligopeptide-1 is a single chain recombinant human-like growth factor, produced by the barley plant (Hordeum Vulgare) after insertion of a copy of a human gene into the barley DNA.

Barley sh-Oligopeptide-1 contains 53 amino acids (aa) and an N-terminal 6 aa histidine tag for a total length of 59 aa and has a predicted molecular mass of 7 kDa. The recombinant protein migrates with an apparent molecular mass of 9.5 kDa in SDS-PAGE. The starting gene that is inserted into the barley DNA is synthesised in vitro to be identical to the sequence of the human gene that codes the Epidermal Growth Factor (rhEGF; NP_001954.2). The synthesised gene is later modified with both (1) codon optimization to adjust the synthesised DNA sequence to the natural barley genomic codon frequency and (2) with histidine-based oligopeptide as His-tag for purification.

The applicant claims that by using barley as a production host, bypassing the use of bacterial or animal cell systems, the peptide is animal-free and endotoxin-free. Testing by a third party research service organization (Charles River Laboratories, France) confirms that barley produced proteins typically contain more than 200 times lower levels of endotoxins than are allowed in most other commercially available product.

Pre-meeting public submissions

Two (2) submissions were received, one (1) in support and one (1) opposed.

Main points in support:

  • The submission supports the consideration of the ingredient to align Australian regulatory controls with comparable overseas jurisdictions.
  • The submission also notes that they are unaware of any specific safety concerns in Australia or overseas for this substance when used in cosmetics at very low concentrations.

Main points opposed:

  • EGF is a common name for human single chain recombinant human peptides derived from various sources and these ingredients are not commonly used in cosmetics in the USA.
  • The submission notes that the proposed concentration of 0.0002% does not harmonise with current known practices for cosmetics, as the current international limit is 0.001% for some cosmetic uses.
  • The submission recommends that the Joint ACCS-ACMS committee allow for current usage of these ingredients for topical preparations and restrict its availability to only authorised or licensed persons.

The public submissions will be made available on the TGA website.

Summary of ACCS-ACMS advice to the delegate

The committee recommended that new Appendix G entry and index cross reference for epidermal growth factor be created in the Poisons Standard as follows:

Appendix G – New Entry

EPIDERMAL GROWTH FACTOR

Column 1 – Poison: EPIDERMAL GROWTH FACTOR
Column 2 – Concentration (quantity per litre or kilogram): 10 micrograms

Index – Amend Entry

EPIDERMAL GROWTH FACTOR
cross reference: SH-OLIGOPEPTIDE-1, RH-OLIGOPEPTIDE-1

Schedule 7
Appendix G
Appendix J, Part 2

The committee also recommended an implementation date of 1 February 2018.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice were:

  • The safety data indicates a low level of risk associated with the use of EGF.
  • The absence of regulatory controls internationally on EGF or other growth factors and cytokines, in cosmetic products by any regulatory agency confirms there has not been any hazard to public safety when this substance is used in cosmetic products (e.g. topical use at low concentrations).
  • Although EGF meets international standards for cosmetics, its benefits are unknown.
  • The proposal is for the use of EGF as a skin conditioning cosmetic ingredient in topical cosmetic products, at concentrations of 0.0001% or less. Likely to be used in cosmetics only as an anti-ageing cosmetic.
  • There is no evidence of allergic, toxicity or systemic adverse events in human studies with doses significantly higher than the proposed cut off and when used on wounds with broken skin. Dermal penetration is limited. No toxicity noted in studies where EGF has been used on burns to assist in wound healing.
  • There are no maximum limits imposed on concentrations of EGF by any international cosmetic regulatory jurisdictions. Packaged as cosmetic for topical use only.
  • Amending the scheduling will align with overseas jurisdictions and provide consistency with cosmetics available overseas.

Delegate's considerations

The delegate considered the following regarding this proposal:

  • Scheduling proposal
  • ACCS-ACMS advice
  • Public Submissions received
  • Section 52E of the Therapeutic Goods Act 1989
  • Scheduling Policy Framework (SPF 2015)
  • Other relevant information

Delegate's interim decision

The delegate's interim decision is to create new Appendix G entry and index cross reference for epidermal growth factor in the Poisons Standard. The proposed Schedule entry is as follows:

Appendix G – New Entry

Column 1 – Poison: EPIDERMAL GROWTH FACTOR
Column 2 – Concentration (quantity per litre or kilogram): 10 micrograms

Index – Amend Entry

EPIDERMAL GROWTH FACTOR
cross reference: SH-OLIGOPEPTIDE-1, RH-OLIGOPEPTIDE-1

Schedule 7
Appendix G
Appendix J, Part 2

The proposed implementation date is 1 February 2018, as this is the earliest possible implementation date.

The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the interim decision are:

  1. the risks and benefits of the use of a substance:
    • The safety data indicates a low level of risk associated with the use of EGF.
    • The absence of regulatory controls internationally on EGF or other growth factors and cytokines, in cosmetic products by any regulatory agency confirms there has not been any hazard to public safety when this substance is used in cosmetic products (e.g. topical use at low concentrations).
    • Although EGF meets international standards for cosmetics, its benefits are unknown.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • The proposal is for the use of EGF as a skin conditioning cosmetic ingredient in topical cosmetic products, at concentrations of 0.0001% or less. Likely to be used in cosmetics only as an anti-ageing cosmetic.
  3. the toxicity of a substance:
    • There is no evidence of allergic, toxicity or systemic adverse events in human studies with doses significantly higher than the proposed cut off and when used on wounds with broken skin. Dermal penetration is limited. No toxicity noted in studies where EGF has been used on burns to assist in wound healing.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Packaged as cosmetic for topical use only.
    • There are no maximum limits imposed on concentrations of EGF by any international cosmetic regulatory jurisdictions.
  5. any other matters that the Secretary considers necessary to protect public health.
    • Amending the scheduling will align with overseas jurisdictions and provide consistency with cosmetics available overseas.

Footnotes

  1. Zhang, Y et al., (2016), Growth factor therapy in patients with partial-thickness burns: a systemic review and meta-analysis International Wound Journal, 13(3):356-66.
  2. The HEBERMIN epidermal growth factor studies were conducted in burns patients, where skin integrity is damaged, and these studies did not demonstrate systemic absorption (Hebermin Clinical results). The study results state "the detected EGF corresponded to the endogenous human EGF, and there was very little or no protein absorption as a result of the topical application of the EGF as a cream." These results are important since the little penetrability revealed suggests that the molecule is captured by the receptors in the cutaneous epithelium cells, and by the dermis fibroblasts, which contributes to the safety of the product by reducing the possibility of adverse systemic or long term effects.
  3. A further study on parenteral Heberprot-P injection for treating advanced diabetic foot ulcers demonstrated a dose-effect relationship for adverse effects. There were reported adverse effects of mild to moderate pain and burning at administration site as being the most frequently reported effect. Pain reported was mild to moderate in intensity and was not associated with treatment. (J.Berlanga MEDDDIC review , Jan 2013, 15(1) (Heberprot-P A novel product for treating advanced diabetic foot ulcer MEDDIC Review Jan 2013)
  4. Mehta et al., (2008), Reduction in facial photodamage by a topical growth factor product. Journal of Drugs in Dermatology, 7(9):864-71.
  5. Environ Intensive Colostrum Gel- Au website
  6. Fabi et al., (2013), The effects of filtrate of the secretion of the <EM>Cryptomphalus aspersa</EM> on photoaged skin. Journal of Drugs in Dermatology, 12(4):453-7.
  7. Berlanga et al,. 2013 Heberprot-P: a novel product for treating advanced diabetic foot ulcer, MEDICC Rev. Jan;15(1):11-5.
  8. Wu et al., 2009 Therapeutic effect of recombinant human epidermal growth factor (RhEGF) on mucositis in patients undergoing radiotherapy, with or without chemotherapy, for head and neck cancer: a double-blind placebo-controlled prospective phase 2 multi-institutional clinical trial, Cancer. Aug 15;115(16):3699-708. doi: 10.1002/cncr.24414
  9. Berlanga-Acosta et al., 2009Epidermal growth factor in clinical practice – a review of its biological actions, clinical indications and safety implications, IWJ, 6(5):331-346.

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