Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, November 2016
Scheduling medicines and poisons
2.4 Epidermal Growth Factor
Part A - Interim decisions on matters referred to an expert advisory committee (November 2016)
2. Joint meeting of the Advisory Committee on Chemicals and Medicines Scheduling (ACCS-ACMS #14)
2.4 Epidermal Growth Factor
Referred scheduling proposal
An applicant has proposed to amend the wording of the Schedule 7 entry for Epidermal Growth Factor (EGF), to exempt topical cosmetic preparations containing low concentrations of transgenic plant made epidermal growth factor from the scope of the Schedule 7 entry.
Current scheduling status
Epidermal Growth Factor is currently in Schedule 7 and Appendix J of the Poisons Standard as follows:
EPIDERMAL GROWTH FACTOR except in preparations for human therapeutic use.
EPIDERMAL GROWTH FACTOR, Condition 1 (Not to be available except to authorised or licensed persons).
Relevant scheduling history
In November 1996, the NDPSC considered an application for a recombinant epidermal growth factor for use in sheep. It was listed in the SUSMP 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".
This was a general application. The applicant's proposed amendments to the Poisons Standard are as follows:
Schedule 7 - Proposed amended Entry
EPIDERMAL GROWTH FACTOR except:
- in preparations for human therapeutic use; or
- in topical cosmetic preparations containing 0.0002 % or less of transgenic, plant-made epidermal growth factor.
The applicant's reasons for the proposal are:
- 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 SUSMP 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 and therefore be able to compete with similar cosmetic products available to purchase online via overseas websites.
Australian and international regulatory information
No information was found on the clinical use of EGF in Australia, the USA or EU. It has been used experimentally to treat diabetic foot ulcers (Heberprot-P: a novel product for treating advanced diabetic foot ulcer.) and mucositis in patients undergoing radiotherapy (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.). A collation of published papers (through PubMed and Bioline International) related to the clinical use of EGF was published in 2009 (Epidermal growth factor in clinical practice - a review of its biological actions, clinical indications and safety implications.
Human epidermal growth factor (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).
Figure 2.4: Signal transduction activity resulting from EGF binding to its receptor.
The applicant summarises the plant-made EGF as follows:
- Barley sh-Oligopeptide-1 (CAS # 1807528-51-3) is a plant-produced peptide expressed from an in vitro synthesized 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 starting gene that is inserted into the barley DNA is synthesized in vitro to be identical to the sequence of the human gene that codes EGF (rhEGF; NP_001954.2). The synthesized gene is later modified with both (1) codon optimization to adjust the synthesized 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 (Magnusdottir A, et al.).
Pre-meeting public submissions
One (1) pre-meeting submission was received which supported the proposal on the basis that it will align Australian regulatory controls with comparable overseas jurisdictions.
Summary of Joint ACCS-ACMS advice to the delegates
The committee advised that the current scheduling of epidermal growth factor remains appropriate.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee 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; e) the potential for abuse of a substance; f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the advice comprised the following:
- Low risk of systemic absorption at low dermal concentration as demonstrated by the limited evidence presented by the applicant does not inform risk/benefit profile sufficiently.
- Cosmetic use of peptides and growth factors has increased since original consideration, which was for a broad administration and use of EGF.
- Danger of toxicity minimised by lack of transdermal absorption. Topical product only with no potential for abuse.
- Dependant on concentration in substance, application is for very low concentration.
- Lack of information associated with local toxicological effects.
- There is a lack of data showing safety and no information provided of local effect and concern of therapeutic intent.
The delegates considered the following in regards to this proposal:
- Scheduling proposal
- Joint ACCS-ACMS advice
- Public submissions received
- Section 52E of the Therapeutic Goods Act 1989;
- Scheduling Policy Framework (SPF 2015)
- Other relevant information.
Delegates' interim decision
The delegates' interim decision is that the current scheduling of epidermal growth factor remains appropriate.
The delegates considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: 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; e) the potential for abuse of a substance; f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the interim decision are the following:
- The delegates acknowledge and agree with the committee's advice.
- Limited evidence was presented by the applicant to demonstrate that there is a low risk of systemic absorption at low dermal concentrations. Lack of information on potential local toxicity.
- Danger of toxicity minimised by low transdermal absorption. Topical product only with no potential for abuse. However, there is a lack of safety data and no information was provided on local effect.
- Concern around therapeutic intent. Cosmetic use of peptides and growth factors has increased since original EGF scheduling.