Easing the Pathway for Combination Products: An Australian Regulatory Perspective

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Combination-product growth has surged globally as both physicians and patients request fewer invasive procedures in favor of user-friendly treatment delivery options (1). Driven in part by the push for an integrated approach to patient care, the biopharmaceutical industry also has been buoyed by advances in technology. Although drug–device combinations have been marketed around the world for many years, they are playing increasingly crucial roles in patient safety and medicinal usability, with simple drug-release delivery systems such as drug-eluting stents paving the way for products that could reshape medicine (2). The market for combination products was worth US$127.8 billion in 2022, and by 2030, analysts expect that value to increase by a compound annual growth rate (CAGR) of 8.9%. (3). Sponsors and manufacturers of such products need clarity to navigate different regulatory pathways and determine how local regulations can be leveraged to accelerate approval in new markets.

Australian Regulatory Updates

As of its 2023 guidance on combination and boundary products, the Australian Therapeutic Goods Administration (TGA) has provided context around key regulated product categories: Combination products consist of components with more than one therapeutic effect (such as medicine–device combinations and devices that include or are used to administer a medicine), and boundary products have characteristics from two or more categories for which the proper regulatory pathways are ambiguous.

The TGA updated its guidelines in April 2023, providing examples of such products to increase understanding of how the agency is likely to regulate them (5). The list will be updated as the TGA makes further determinations.

In Australia, boundary products are regulated based on their principal therapeutic effects, therapeutic claims, and stated intended uses. Such products could include alcohol swabs, disinfectants, nasal decongestant sprays, and eye lubricants that could be considered either medical devices or medicinal products.

The TGA regulates combination products depending on primary modes of action (PMoAs) for achieving therapeutic effects as well as primary intended purposes, as shown by the following criteria:

• Products that administer or incorporate a medicine in which the action is secondary, such as heparin-coated catheters, are regulated as medical devices.

• Integral combination products in which the device and medicine form a single, nonreusable unit (e.g., prefilled inhalers) and copackaged medicines with devices in which the medicine is the main component and the device is used to measure or administer that medicine are regulated as medicinal products.

The focus of classifying combination products should be to determine whether they should be regulated as medicines or medical devices (6).

Comparing Key Regulatory Views

In the United States, integral drug–device products and single-entity combination products also are regulated according to the PMoA (7), which is defined by the Federal Food, Drug, and Cosmetic Act as “the single mode of action that provides the most important therapeutic action of the combination product” (8). If a PMoA is attributable to a drug’s actions, then the US Food and Drug Administration's (FDA's) Center for Drug Evaluation and Research (CDER) has primary jurisdiction over product approval. If the PMoA is driven by a device component’s actions, then the Center for Devices and Radiological Health (CDRH) controls product approval. If the most important therapeutic action cannot be identified, the FDA will assign primary jurisdiction based on two criteria: which center regulates other combination products with similar questions of safety and effectiveness, and which center has more expertise related to safety and effectiveness questions surrounding product use (9). Regardless of which center is assigned primary jurisdiction, a review team typically includes the nonprimary center for consultation during product approval.

In the European Union (EU), a combination medicinal product is regulated as such if it is composed of a drug and a device, marketed as a single integral product, intended for use in the given combination and not reusable (refillable), and has the PMoA (10). Those criteria also apply to single integral products for which the device is intended to administer the drug, such as with prefilled syringes (11).

The device portion of a combination product must comply with general safety and performance requirements (GSPRs) outlined in medical device regulations (MDRs) (10). For high-risk products, compliance with GSPRs must be verified by a notified body (NB) — a third-party entity appointed by relevant authorities to assess medical devices — either through European conformity (CE) markings or an NB opinion for the specific combination (10). If significant changes are made to the device portion of a combination product and no CE mark is available for the device, the EU MDR requires NB opinions on the device to support new medicine applications. The developer or marketing authorization holder (MAH) of a drug–device combination must apply for NB assessment and obtain the opinion before submitting a drug application. If the PMoA is from the medical device (nonchemical/pharmacological), the whole product is regulated as a medical device, with additional assessment for the ancillary medicinal substance (12).

Speeding Up Approvals in Australia

In Australia, companies must list their medical devices in the Australian Register of Therapeutic Goods (ARTG) unless the product is exempt. The TGA has proposed changes to the regulation of exempt devices aimed at removing barriers to supply where appropriate (13). A device that is a component of a medicinal product does not require a separate ARTG entry, but it must adhere to the Essential Principles of the Therapeutic Goods (Medical Devices) Regulations (14). Those requirements ensure that products are designed according to safety principles and follow risk-management processes (15). Manufacturers also must assess relevant TGA requirements to evaluate the safety, quality, and efficacy of medicinal components within combination products.

Certain circumstances can allow overseas manufacturers to by-pass the TGA’s extensive — and expensive — assessment process for full conformity. Abridged pathways for drug–device combinations enable innovative combination products that have been approved in some major markets to be expedited into Australia (16).

Devices incorporating medicine can leverage certification through the EU MDR or medical device directive (MDD) for ARTG applications (17). Such combination products are regarded as class III medical devices in Australia. Unless overseas evidence is leveraged, the TGA process includes an in-depth compliance assessment with quality-management system (QMS) requirements, as well as a review of the technical documentation to determine adherence to essential principles.

The TGA requires companies to provide extensive documentation, including device verification and validation information, supplier agreements, storage and packaging details, sterilization requirements, and other device documents as part of its certification process. Manufacturers also may be subject to onsite audits (18).

To expedite approvals for medicinal products, the TGA can use assessments from comparable overseas regulators (CORs) if there is enough similarity between the TGA and a COR (as is the case with the European Medicines Agency, EMA) and when other key criteria are met (19).

Although the TGA recognizes overseas evidence for medical devices from several countries, the agency only makes exemptions for devices incorporating medicines from the European Union because of similarities between the TGA’s conformity assessment and that conducted by an EU NB — a requirement for the assessment and certification (or recertification) of most medical devices and in vitro diagnostic devices on the EU market (20).

The EMA offers two guidances for applicants regarding device information in the drug dossier: a document that explains the different types of drug–device combinations (DDC) and MDR impacts on drug dossiers (10), and a guideline of quality documentation for medicinal products when used with a medical device (21). Further guidance on the content and format of documentation for an NB opinion dossier and the management of changes is available from the European Association of Notified Bodies (Team NB) (22).

The FDA issued a final rule amending the current good manufacturing practice (CGMP) requirements of its Quality System Regulation (QSR) and harmonizing device quality system requirements with ISO 13485 to promote consistency in device regulation, effective February 2026. The FDA already has updated

21 CFR 4.4 to address CGMP requirements for copackaged and single-entity combination products under the final rule, including incorporation of general requirements (clause 4.1) under ISO 13485, analysis of data, improvement, complaint handling, and installation and/or servicing activities. Those amendments are in addition to preexisting FDA guidances on pathways for combination products, aimed at improving transparency, efficiency, and regulatory consistency (7, 23–24).

Bridging the Gap for Patients

The rise of chronic illnesses such as cardiovascular diseases and cancers has spurred regulators to streamline approval processes for products that not only save lives, but also give patients some control over their conditions. Patients (especially those who are most vulnerable) increasingly want products that combine drugs and devices to target the release of medicine and deliver less invasive treatments. Physicians also are looking for integrated, effective approaches to the care that they often provide, simplifying healthcare delivery and ensuring improved outcomes for their patients (3).

By clarifying guidelines and working closely with comparable overseas regulators to enable abridged pathways for combination products, regulatory agencies can help to ensure that effective treatments reach those who need them as quickly as possible. Such efforts must not infringe on regulators' ability to hold sponsors and manufacturers to the highest standards of safety, quality, and efficacy. A collaborative, streamlined approach is crucial as innovative technologies continue to develop. The global growth of combination products comes with an increased responsibility for all stakeholders to deliver on their promises.

Disclaimer

The information provided in this article does not constitute legal advice. PharmaLex Australia and its parent Cencora, Inc. strongly encourage readers to review available information related to the topics discussed herein and to rely on their own experiences and expertise in making decisions related thereto.

References

1 Decoding the Drug–Device Combination Products Market: A Deep Dive into the Latest Market Trends, Market Segmentation, and Competitive Analysis. Global Market Report Insights: 29 September 2023; https://www.linkedin.com/pulse/decoding-drugndashdevice-combination-products.

2 Liu Z, Shi Y, Liu C. Emerging Trends in Drug–Device Combination for Advanced Disease Diagnosis and Therapy. Nano Today 50, 2023: 101853; https://doi.org/10.1016/j.nantod.2023.101853.

3 Drug Device Combination Products Market Size, Share & Trends Analysis Report by Product, By Region, and Segment Forecasts, 2024—2030. Grand View Research, https://www.grandviewresearch.com/industry-analysis/drug-device-combination-market.

4 Guidance on Boundary and Combination Products: Medicines, Medical Devices, and Biologicals. Therapeutic Goods Administration: Woden Act, Australia, 2023; https://www.tga.gov.au/sites/default/files/2023-12/guidance-boundary-combination-products.pdf.

5 Examples of Boundary and Combination Products and Their Product Category. Therapeutic Goods Administration: Woden Act, Australia, 2023; https://www.tga.gov.au/sites/default/files/2024-05/examples-boundary-combination-products-and-product-category.pdf.

6 Reis ME, Bettencourt A, Ribiero HM. The Regulatory Challenges of Innovative Customized Combination Products. Front. Med. (Lausanne) 9, 2022: 821094; https://doi.org/10.3389/fmed.2022.821094.

7 Guidance for Industry and FDA Staff: Principles of Premarket Pathways for Combination Products. US Food and Drug Administration: Silver Spring, MD, 2022; https://www.fda.gov/regulatory-information/search-fda-guidance-documents/principles-premarket-pathways-combination-products.

8 21 CFR 3. Definition of Primary Mode of Action of a Combination Product. US Food and Drug Administration: Silver Spring, MD, 2005; https://www.federalregister.gov/documents/2005/08/25/05-16527/definition-of-primary-mode-of-action-of-a-combination-product.

9 Frequently Asked Questions About Combination Products. US Food and Drug Administration: Silver Spring, MD, 2022; https://www.fda.gov/combination-products/about-combination-products/frequently-asked-questions-about-combination-products.

10 EMA 37991. Questions & Answers for Applicants, Marketing Authorisation Holders of Medicinal Products and Notified Bodies with Respect to the Implementation of the Regulations on Medical Devices and In Vitro Diagnostic Medical Devices. European Medicines Agency: Amsterdam, the Netherlands, 2024; https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/questions-answers-implementation-medical-devices-vitro-diagnostic-medical-devices-regulations-eu-2017-745-eu-2017-746_en.pdf.

11 Medical Devices. European Medicines Agency: Amsterdam, the Netherlands, 2024; https://www.ema.europa.eu/en/human-regulatory-overview/medical-devices.

12 MDCG 2022 — 5. Guidance on Borderline Between Medical Devices and Medicinal Products Under Regulation (EU) 2017/745 on Medical Devices. Medical Device Coordination Group: Brussels, Belgium, 2022; https://health.ec.europa.eu/system/files/2023-06/mdcg_2022-5_en.pdf.

13 Proposed Changes to the Regulation of Exempt Medical Devices and Exempt Other Therapeutic Goods. Therapeutic Goods Administration: Woden Act, Australia, 2024; https://consultations.tga.gov.au/tga/proposed-changes-to-exempt-devices-and-otgs.

14 Therapeutic Goods Act 1989. Therapeutic Goods Administration: Woden Act, Australia, 2024; https://www.legislation.gov.au/F2002B00237/latest/versions.

15 Quality, Safety, and Performance Requirements for Medical Devices. Therapeutic Goods Administration: Woden Act, Australia, 2024; https://www.tga.gov.au/how-we-regulate/manufacturing/manufacture-medical-device/quality-safety-and-performance-requirements-medical-devices.

16 Fast Track Approval Pathways. Therapeutic Goods Administration: Woden Act, Australia, 2023; https://www.tga.gov.au/fast-track-approval-pathways.

17 Use of Market Authorisation Evidence from Comparable Overseas Regulators/Assessment Bodies for Medical Devices (Including IVDs). Therapeutic Goods Administration: Woden Act, Australia, 2023; https://www.tga.gov.au/sites/default/files/use-market-authorisation-evidence-comparable-overseas-regulators-assessment-bodies-medical-devices-including-ivds.pdf.

18 Conformity Assessment Overview. Therapeutic Goods Administration: Woden Act, Australia, 2024; https://www.tga.gov.au/how-we-regulate/manufacturing/medical-devices/conformity-assessment/conformity-assessment-bodies/tga-conformity-assessment-certification/conformity-assessment-overview.

19 Comparable Overseas Regulators. Therapeutic Goods Administration: Woden Act, Australia, 2024; https://www.tga.gov.au/resources/resource/guidance/comparable-overseas-regulators-cors-prescription-medicines.

20 Notified Bodies. European Commission: Brussels, Belgium, 2024; https://single-market-economy.ec.europa.eu/single-market/goods/building-blocks/notified-bodies_en.

21 Quality Documentation for Medicinal Products When Used with a Medical Device — Scientific Guideline. European Medicines Agency: Amsterdam, the Netherlands, 2022; https://www.ema.europa.eu/en/quality-documentation-medicinal-products-when-used-medical-device-scientific-guideline.

22 The European Association of Medical Devices Notified Bodies. European Commission: Brussels, Belgium, 2024; https://www.team-nb.org.

23 Guidance for Industry and FDA Staff: Classification of Products as Drugs and Devices and Additional Product Classification Issues. US Food and Drug Administration: Silver Spring, MD, 2017; https://www.fda.gov/regulatory-information/search-fda-guidance-documents/classification-products-drugs-and-devices-and-additional-product-classification-issues.

24 Guidance for Industry and FDA Staff: Current Good Manufacturing Practice Requirements for Combination Products. US Food and Drug Administration: Silver Spring, MD, 2017; https://www.fda.gov/regulatory-information/search-fda-guidance-documents/current-good-manufacturing-practice-requirements-combination-products.

Piety Rocha is director, head of regulatory affairs, and country VDC head at PharmaLex Australia, and Heyam Kalla is associate director and team lead for medical devices/IVD at Cencora, Inc.; Suite 4, Level 10, 1 Chandos Street, St. Leonards NSW 2065, Australia; https://www.pharmalex.com/contact-us/.