Proposed refinements to the Regulation of medical devices that are substances introduced into the human body via a body orifice or applied to the skin

The intended outcome of the proposed changes to the classification rule, that of not allowing for systemic absorption of the device or of its products of metabolism either:
• in order to achieve the intended purpose of the device or
• where the device achieves its intended purpose in the stomach or lower
gastrointestinal tract,
appears to have quite significant implications from the examples provided in the consultation. Devices which match some of these classifications that are already included in the ARTG and are currently classified as say a Class IIa and were to be reclassified as Class III medical device under the new rule, would now be defined as a medicine. So while these products being imported from Europe, would have been supported to transition to the increased classification of the EU MDR’s Rule 21, this does not translate similarly if the product will now be determined to be a medicine in Australia. The Australian sponsor would now need to determine if that manufacturer could also support that medical device product with a medicine common technical dossier and could manufacture the product compliant with medicinal GMP, as well as provide ongoing support to maintain the product in compliance as a medicine, and ideally at no additional cost. If these requirements are not able to be supported, the sponsor would need to either:

• seek to develop or licence an equivalent replacement medicinal source of a similar design of product (noting a change of formulation is always noted and may impact market share) or
• discontinue the product in the Australian market.

We note that should some of these medical devices now be determined to be regulated as medicines, several of the example products provided in the consultation do not contain a substance approved for use as an active ingredient in a medicine. Therefore, further to the complexities described, the sponsor may need to apply for approval of one or more new active ingredients, either prior to or as part of the medicine application.

This new rule is due to take effect from 25 November 2021 for all new applications. Submissions for included devices requiring reclassification are required to be made before 1 November 2024. However, the transition arrangements made in December 2019 did not factor in that some products would be required to reapply for their device as a medicine along with the added complexity that would entail. It is critical that suitable timeframes be provided to allow sponsors to plan for a replacement product to be registered as a medicine. With these complexities, it is hard to see how TGA might facilitate a change of regulatory pathway to reduce the regulatory burden.

Members have advised that as part of pre-submission meetings with the Medical Devices Branch they have for some time been receiving questions on any perceived chemical means of action in or on the human body, with requests to justify why the means stated is not a chemical action. However, we note that there is nothing in the definition of a medical device in the Therapeutic Goods Act 1989, which precludes a device from having a chemical means of action. With the benefit of hindsight, and on reading some of the example devices and the proposed revised classifications, provision of definitions of each of the ‘means of action’ of a device would be beneficial. This is particularly important within the Australian regulatory framework where a chemical means can be both a medicine and device mode of action. Some of the actions in the provided example device products are described as being a chemical action, where that action might equally be justified as a being a physical action e.g. changing surface tension.

Operating without an agreed definition of these means of action results in the case by case requirement for the manufacturer to technically justify the ‘means of action’ of the device in achieving its ‘intended purpose’. Certainty of requirement before embarking on preparing a submission will ensure that resources are not wasted.

Losing this alignment with the EU MDR around the invasive application of substance based devices, in effect cuts off a key source of supply of medical device products for the Australian market. Where this can be avoided it should be.

However, the examples provided in the paper tend to demonstrate a lack of consideration of the risk continuum across the medicine/medical device interface – refer to Appendix 1 - Review of Examples of devices, comparisons of old and new classifications, and clarification of regulatory pathways - provided in the emailed response due to difficulty of inclusion in this format.

CHP Australia are concerned that the proposed amendments, of simply deleting Parts (c) and (d) of the classification rule, appears to be somewhat ill considered. This approach appears to leave the remains of the rule wide open to misinterpretation and hence does not actually address the expressed concern. The amended rule now reads

(4) If a device is composed of substances, or combinations of substances, that are:
(a) intended to be:
(i) introduced into the human body through a body orifice; or
(ii) applied to the skin; and
(b) absorbed by, or locally dispersed, in the human body after introduction or
application;
the device is classified as follows:
(e now c) if the device is applied to the skin, or in the nasal or oral cavity as far as the
pharynx, and achieves its intended purpose on those cavities – Class IIa;
(f now d) in any other case – Class IIb.

So the rule may now be read, that if the device, composed of substances, is intended to be introduced into the human body through, say the mouth and into the gastrointestinal tract, “(e now c)” doesn’t apply and therefore “(f now d) in any other case” applies, classifying the product as Class IIb.

This proposal appears to assume the reader is aware of the disallowance of the deleted clauses.

Additionally the removal of the clauses (c) and (d) from Subclause 3.1(4) of Schedule 2 removes the EU MDR intended increased risk based classification for these products.

We suggest that some of these terminologies describing means of action need to be defined. For example, in this rule what is the difference in meaning between systemically absorbed by in clauses (c) and (d) compared with the term absorbed by in clause (b).

This proposed amendment alone, will clearly not address the concerns expressed in the consultation paper, which are:

"that the new classification rule may result in a number of products meeting the definition of both a medical device and a medicine, which creates regulatory inconsistencies due to the different frameworks that might be applied to a given product."

And:

"Therefore, it is proposed that the new classification rule be amended to remove references to products that are systemically absorbed by the body, as these products meet the definition of a medicine."

We note that since the Australian regulatory framework moved to align with the EU framework as far as possible, the definitions of medicine and medical device under the Therapeutic Goods Act 1989 since 3 July 2002 have not dove-tailed, to provide a clear divide. The definition of a "medicine" describes:

• "their principal intended action by pharmacological, chemical, immunological or metabolic means in or on the body"
while the definition of a "medical device" notably omits reference to chemical means as follows:
• "does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means. "

It should be noted that a chemical means of action was deliberately omitted from this definition, in effect allowing medical devices to act in or on the human body via such means since that time.
In contrast the:
• EU definitions of medicinal product and medical device do not reference a chemical means of action with:
o A medicinal product’s mode of action being - "by exerting a pharmacological, immunological or metabolic means in or on the body"
o A medical device means of action limited by the wording - "and which does not achieve its principal intended action by pharmacological, immunological or metabolic means, in or on the human body, but which may be assisted in its function by such means."

• Canadian definition of a drug does not make reference to a ‘means of action’ however the definition of a device advises it does not include…..that achieves any of the actions listed in the definition:
o "solely by pharmacological, immunological or metabolic means or solely by chemical means in or on the body."

• US definitions of a drug does not make reference to a ‘means of action’ however the definition of a device clarifies:
o "which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes."

This misalignment of the Australian definitions of a medicine and a medical device was clearly deliberate to position Australia, as a nation with a small population, with a level of flexibility to access products from larger comparable regulators, not just from North America but also the EU (and the UK).

As such, this issue described in the consultation paper has existed prior to the adoption of the EU MDR Rule 21 into the Therapeutic Goods (Medical Device) Regulations 2002 as Subclause 3.1(4) of Schedule 2, back in December 2019. This also means that there have already been formulated medical device products included in the ARTG for many years now. This consultation provides no certainty, other than via the examples provided, indicating circumstances where these products would now be required to be regulated as medicines. See responses to survey question 1.

Additionally, to provide complete clarity around the classification of substance-based devices, guidance is still needed around the impact of microbially derived substances on classification. Until this is addressed consistently with the EU MDR, devices composed of a substance of microbial origin (like Xanthan Gum – produced by bacterial fermentation, and commonly used in cosmetics, foods and some OTC medicines), will be classified Class III in Australia but Class IIa or Class IIb in the EU. There can be no risk-based justification for this position. The implication of this inconsistency translates to a need for an Australian specific Class III data package for the device, however in reality the expense of undertaking this exercise is unlikely to be justified for the Australian market. This needs to be clarified before sponsors are required to transition their products, and there is already little time to plan with certainty.

We note that there is regulatory action taking place in key comparable regulators with respect to the medicines/medical device interface.

• Health Canada on 22 July 2021, published an update to the Classification of Products at the Drug: Medical Device interface guidance (ref 1) . This update reflects new authorities that allow the Minister to determine a single set of regulations that would apply to a health product that simultaneously meets more than one of the definitions outlined in the Act (i.e., drug, food, device, or cosmetic). The new Schedule is intended to improve consistency, predictability, and transparency of classification decisions for industry stakeholders.
• We understand the European Commission have recently undertaken two rounds of consultation with industry on updated Guidance - "Borderline with medicinal products (including general guidance, definitions of pharmacological, immunological and metabolic means of action and diagnosis)".
• The US FDA invited stakeholders (ref 2) on 9th August 2021, to submit comments regarding categories of products currently regulated as drugs that may be required to transition to device status. This comes after a decision of the US Court of Appeals with regard to certain barium sulfate contrast imaging agents which are currently regulated as drugs although they also meet the definition of a device. The Court of Appeals determined that the FDA cannot classify as a drug any product that meets the definition of device, stating ‘‘[e]xcepting combination products, . . . devices must be regulated as devices and drugs—if they do not also satisfy the device definition—must be regulated as drugs.’’
o “FDA intends to regulate products that meet both the device and drug definition as devices, except where the statute indicates that Congress intended a different classification, and we further intend to bring previously classified products into line with the Court’s decision.”
o “FDA intend to re-examine other product categories as well and will aim to effect necessary product transitions in a way that does not disrupt the supply of these important medical products or place undue burden on manufacturers or on the healthcare delivery system.”

Both the EU (ref 3) and Canada’s (ref 1) regulatory frameworks have been supported by a guidance on borderline products (ref 4). Australia previously had a Device-medicine boundary products guidance but this document remains marked as under review. We note that the November 2005 webpage for this guidance stated –

"In developing the list, the status of each product as determined by the USA FDA and European Union was considered with the desire that 'internationally' recognised distinctions be adopted as far as possible."

We believe the sentiment expressed remains important. We need where possible to be flexible to reflect other major markets. While the TGA is recognised as a leading regulator internationally, the size of the Australian market does not compare to the market sizes of those of other internationally recognised regulators.

CHP Australia believe this should remain an important aim of the Regulation and recommend that rather than amend this rule removing alignment with the EU MDR, and/or make other changes to the legislation around the medicine-medical device interface, that it would be preferable to work with industry members to re-establish a borderline guidance. This guidance should provide clear expectation of how to classify products within the Australian regulatory framework. This should also give consideration of how those products are regulated by other equivalent regulators. This would allow the TGA to determine when a product may be safely considered medical device, a medicine or may be regulated as either a medicine or a medical device without risk to consumers. Where necessary, determinations could be made under section 41 BD (3) of the Act to establish a firm borderline.

Ref 1 - https://www.canada.ca/en/health-canada/services/drugs-health-products/classification-health-products-device-drug-interface/guidance-document-factors-influencing-classification-products-device-drug-interface.html

Ref 2 - https://www.govinfo.gov/content/pkg/FR-2021-08-09/pdf/2021-16944.pdf

Ref 3 - https://ec.europa.eu/docsroom/documents/10328/attachments/1/translations

Ref 4 - https://www.tga.gov.au/publication/device-medicine-boundary-products

While we can think of no other impacts the following is a summary of the impacts identified:

• It is clear that this refinement alone, will not address all aspects of the TGA’s stated or implied concerns as presented in the consultation paper.

• The revised wording of the proposed amendment to Subclause 3.1(4) of Schedule 2 would both leave the rule open to misinterpretation and remove the EU MDR intended increased risk based classification for these products.

• The proposal fails to address the point of difference in definitions between medicine and medical device in that a medical device does not achieve its principal intended action by pharmacological, immunological or metabolic means, but that may be assisted in its function by such means.

• The finalisation of the EC’s updated Guidance - Borderline with medicinal products (including general guidance, definitions of pharmacological, immunological and metabolic means of action and diagnosis) will be essential in setting the principal rules by which products can be considered devices versus medicines in the EU.

• If TGA progress this refinement in advance of a clear understanding of the European framework interpretation, it will result in divergence of requirements and a shift from a harmonised approach to classification of substance-based devices.

• The impact of this will be that some existing products classified as devices and supplied in the Australian market will cease to be compliant with the new requirements post deadline for implementation and will no longer be suitable for supply without the alternative reclassification and submission as a medicine. For many device manufacturers, the lack of expertise in medicinal product requirements and applications likely to result in those devices being unable to be supported and therefore would need to be discontinued.

• The proposed amendment to the rule will also limit the availability of new and innovative products in the Australian market.

• CHP Australia would recommend TGA take an alternative approach to the proposed refinement, to allow the rule to remain aligned with the EU but manage product areas of significant safety risk utilising the legislative tool and with the support of a Medicine/Medical device interface guidance.

• It would be CHP Australia’s preference to have a clear understanding of the concerns and options of the range of measures necessary to address the extent of the concern. Responding to separate consultations addressing each proposed measure in isolation and without an opportunity of understanding the implications of the sum of the parts can result in unforeseen issues.

• From a transition perspective the TGA should endeavour to maintain continuity with respect to products currently entered on the ARTG as medicines, whilst also ensuring that products meeting the definition of a medical device are able to be reclassified and remain included on the ARTG as such. Where continuity of a medical device will not be achieved it will be critical that suitable timeframes be provided to allow sponsors to achieve a replacement product to be registered as a medicine, with all the complexities that will involve, and without disrupting continuity of supply of their product in the Australian market.

No.