EU pharma package: combination products

The proposed revision of the EU medicines regulatory framework aims at strengthening the development of new therapies involving medicines and increasing availability for patients.

The proposed medicines framework provides rules for novel combinations of active substances offered as a single product or exclusive combinations involving other active substances, technologies or products.

In particular the proposed Directive introduces the option to obtain market authorisations for multi-medicinal packages and platform technology. Furthermore, in addition to medical devices combined with medicines, the proposed Directive will also govern any other combinations involving medicines with something else.

Combination medicinal products come in various shapes and forms

An increasing number of innovative medicinal products combine medicinal properties with other technologies or products, leading to an ever increasing offer of novel treatments.

The following products combining active substances will be eligible for marketing authorisation under the proposed regime applicable to medicinal products:

Medicines – Medicines combinations

Justified for therapeutic purposes:

• fixed dose combination: a combination of active substances intended to be placed on the market as a single pharmaceutical form (article 4(16)).
• platform technology: a medicinal product comprised of a fixed component and a variable component (article 15(2)).

Justified for public health reasons:

• multi-medicinal product package: a package that contains more than one medicinal product under a single invented name intended to be used in a medical treatment, and where the individual medicinal products in the package are for medical purposes simultaneously or sequentially administered (article 4(17)).
• combined advanced therapy medicinal products: a product as defined in Article 2 of Regulation (EC) No 1394/2007, including when a gene therapy medicinal product is part of the combined advanced therapy medicinal product.

Medicines – medical devices combinations

• an integral combination of a medicinal product with a medical device (article 4(23), where:
  • the two form an integral product and where the action of the medicinal product is principal and not ancillary to that of the medical device¹ , or
  • the medicinal product is intended to be administered by the medical device and the two are placed on the market forming a single integral product intended exclusively for use in the given combination where the medical device is not reusable.
• medicinal products in exclusive use with a medical device² (article 4(25)), meaning:
  • a medicinal product presented in a package with a medical device, or
  • to be used with a specific medical device referenced in the SmPC.

Medicines - other products combinations

• combinations of medical products and products other than medical devices, intended for use in the given combination³ in accordance with the summary of product characteristics (article 4(26)).

Medical Devices Regulation

The EU regulatory framework for medical devices (MDR)⁴ remains to be relevant, in relation to medical devices combined with medicines, where the medicine is ancillary to the medical device.⁵

As a general rule, a product is regulated either by the MDR or the proposed Directive. The procedures of both regulatory regimes do not apply cumulatively but might apply in conjunction. Cross-references remain needed between the legal regimes.⁶

The proposed Directive for instance clarifies that a medical device that is part of an integral combination has to comply with the general safety and performance requirements set out in Annex I of the MDR. Also a medicinal product in exclusive use with a medical device must comply with the proposed Directive taking into account its use with the medical device, without prejudice to the specific requirements of the MDR that apply to the medical device.

Demarcation issues

Typically, questions may arise as to which legal regime applies, particularly in case of products combining medicines with medical devices.

Decision on regulatory status borderline products

The proposed Regulation introduces the option⁷ for developers, competent authorities or a Member State to submit a duly substantiated request to the EMA to adopt a scientific recommendation on the regulatory product status of a medicinal product under development, including ATMP products. The EMA must consult other advisory or regulatory bodies established in the EU.

In this context the Medical Device Coordination Group has published guidance to support uniform application of legislation which will remain relevant.

Ultimately, the European Commission would decide in case a Member State has duly substantiated its disagreement with the EMA’s recommendation.⁸

Principal or Ancillary action

A factor that is determinative for the application of the medical devices legal regime or the medicines legal regime depends on the answer to the question whether or not a medicinal product is ancillary to the mode of action of a medical device. The manufacturer must demonstrate whether or not a substance has an action considered as ‘ancillary’⁹ to that of a device based on state of the art scientific data. This is of particular relevance if the manufacturer prefers to be regulated under the MDR solely.

Increased burden to demonstrate compliance with the proposed Directive

The MDD introduces a general responsibility and liability upon the marketing authorisation holder of integral combination of a medicinal product with a medical device and for combinations of a medicinal product with a product other than a medical device, covering the product as a whole.¹⁰

The marketing authorisation holder should also ensure coordination of the information flow between the sectors throughout the assessment procedure and the lifecycle of the medicinal product.

The competent authority should assess the benefit-risk balance of the integral combination taking into account the suitability of the use of the medicinal product together with the medical device or the other product.

Sufficient information for safe use to those who prescribe ór administer medicinal products

Because combination products may be complex in use, information aimed at understanding the characteristics of such products and how to safely administer them, should be clearly stated¹¹ notably as individuals qualified to administer such products are not necessarily the one prescribing these medicines.

Conclusion

As technology progresses, ever more much needed novel combination products involving medicinal products will be developed, leading to new questions of demarcation. It seems though that the proposed revisions will offer a more clearly defined and aligned legal framework with the future in mind, aiming for legal clarity and above all, safety in using these often complex products.

¹ Examples: syringes prefilled with a medicinal product, patches for transdermal drug delivery, implantable plastic beads containing antibiotic for treating bone infections, tablets containing a medicinal product with embedded sensor to monitor adherence to treatment.

² Examples: drug delivery pumps, syringes, jet injectors, spacer devices for use with metered dose inhalers.

³ Examples: sirup with a prepacked spoon, sand glass to measure time, hand cream with protective glove.

⁴ Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices.

⁵ Examples: Wound dressings with antimicrobial agents, drug eluting coronary stents.

⁶ The cross reference defining the scope of the MDR in relation to the Medicines Directive/Regulation sit in article 1(8) and (9) of the MDR.

⁷ Article 61 of the proposed Directive.

⁸ Article 62 of the proposed Directive.

⁹ Whereas the term ‘ancillary’ is used in both the proposed Directive as well as the MDR, neither pieces of legislation offer a proper definition. It generally means ‘providing necessary support to the primary activities or operation of a system.

¹⁰ Article 56(5) of the proposed Directive.

¹¹ Recital 140 of the proposed Directive and further detailed in chapter XIII.