Harmonising Regulation of Medicinal Allergen Products Throughout the European Union – the Historic Situation and Subsequent CMDh Guidance

Abstract

Allergen products in the EU are defined as goods ‘intended to identify or induce a specific acquired alteration in the immunological response to an allergizing agent’. Historically, allergens were authorised under the national frameworks of member states (MS) with some legislation pre-dating the Treaty of Rome in 1957. This led to regulatory problems, such as pharmacovigilance monitoring standards. The Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) addressed these authorisation issues and published a document on recommendations to common regulatory approaches for medicinal allergen products. This article provides an overview of the CMDh guidance, including a summary of some of the responses received during its consultation phase.

Introduction and background

Allergic diseases constitute one of the most prevalent diseases in Europe¹ and arise from immune responses – type I hypersensitivity or immediate reaction – to agents which are often harmless, such as inhaled pollen particles or certain foods including nuts and soy.²

Where a subject becomes sensitised to such an agent or allergen, subsequent exposure results in interaction of the allergen with specific immunoglobulin E antibodies and triggers the release of inflammatory mediators such as histamine, leukotrienes and cytokines. This culminates in a harmful immune response, which may manifest as rhinitis, bronchospasm and abdominal cramping – indeed a severe allergic reaction can trigger life-threatening anaphylaxis. One long-term therapeutic strategy to treat such allergic diseases is specific immunotherapy with allergen products.³

An allergen product, according to the definition provided under Article 1, paragraph 4 (b) of Directive 2001/83/EC (as amended)⁴, is:

‘…any medicinal product which is intended to identify or induce a specific acquired alteration in the immunological response to an allergizing agent.’

It covers medicinal products containing allergens, or derivatives of allergens, used for in vivo diagnosis or treatment of allergic disease. However, the legal basis for authorisation of allergen products varies considerably across the EU; for example, prior to 1993, allergen diagnostics and therapeutics in the Netherlands were not regulated as medicinal products.^5,6 Moreover, in some MS, such as Italy and Spain, the majority of such products were distributed under the named-patient product (NPP) provision of Article 5 of Directive 2001/83/EC; where a medicinal product is supplied in response to an unsolicited order from an authorised healthcare professional for use by an individual patient under their direct responsibility.⁶ The heterogenous authorisation status of allergen products therefore precludes the creation of unique and specific entries in the database of all medicines authorised in the European Economic Area (Article 57 database); and may result in use of products by patients where the quality and efficacy are unknown.^5,7

In response to these concerns, during 2019-2020, the allergen working party of the CMDh developed a new guideline for the regulation of allergen products, which aims to harmonise the authorisation of these products across the EU by detailing common regulatory approaches and procedures.⁵ The guideline also provides, as an annex, a list of allergen sources where submission of a full marketing authorisation application (MAA) according to Article 8(3) of Directive 2001/83/EC is considered to be mandatory. A summary of comments received during public consultation on a draft version of the guideline was released together with the final document.⁸

Scope of guidance

The CMDh guideline is applicable to products falling under the definition given in Directive 2001/83/EC as quoted above, and therefore concerns human medicinal products that are either prepared industrially or manufactured by a method involving an industrial process. All such products are affected, irrespective of marketing authorisation (MA) status (ie, products where an MA is planned, or currently marketed with or without an MA). However, the guidance does not cover any allergen products manufactured by recombinant DNA technology, or those that consist of synthetic peptides, nucleotide constructs or cell preparations.

In the past, allergen products may have been authorised by MS as a single MA for an individual product, or grouped into a single MA according to allergen group/pharmaceutical form, or through control of industrially manufactured bulks. The recommended approach for MAA, for those allergen products detailed in Annex I to the guideline, is a full application (ie, complete quality, nonclinical and clinical data sets) as noted above. This encompasses products intended for allergen immunotherapy (AIT), or in vivo diagnosis, containing allergens derived from the sources listed in Table 1.

Table 1: Allergen sources specified in Annex I of CMDh/399/2019

An alternative legal basis could be explored where obtaining a full clinical data set may not be feasible, owing to a very restricted patient population. This would need to be justified on a product-specific basis; however, a full quality data set is always expected. Of note, a therapy or diagnostic product that contains a mixture of extracts from different sources would be defined by its formulation and considered to be an individual product.

Where MS have issued so called ‘umbrella’ authorisations for groups of allergen products, the guidance notes that there must be an MA for each product on the market; and encourages MS to provide MA holders with options to transfer such authorisations to an individual MA, with minimal requirements for dossier content and avoiding scientific reassessment of documentation.

General approaches for authorisation

For a standalone allergen product application, a dossier should include, besides regional administrative information (Module 1) and overviews/summaries (Module 2), a complete Module 3 in line with current guidance – including the ‘Guideline on Allergen Products: Production and Quality Issues’¹ and applicable monographs of the European Pharmacopoeia. Modules 4 and 5 would be completed in accordance with relevant guidelines – such as the ‘Guideline on the clinical development of products for specific immunotherapy for the treatment of allergic diseases’³, or the December 2018 ‘Concept paper on a guideline for allergen products development in moderate to low-sized study populations.’⁹ A ‘mixed’ MAA, where Modules 4 and/or 5 consist of a combination of study reports and published scientific literature – Part II, section 7 of Annex I to 2001/83/EC – may be acceptable where provision of full clinical data is not feasible. As noted above, bridging data should be provided to justify the relevance of bibliographical data to the allergen product. A paediatric investigation plan would also be required for a full application, although options for waiver, deferral or fulfilment of requirements using bibliographic data could be discussed with the Paediatric Committee.

The CMDh guidance discourages bibliographic (well-established use) applications (Article 10a of Directive 2001/83/EC) for allergen products, owing to the complexity of characterisation and difficulty in demonstrating safety and efficacy from literature. There may be, however, exceptions on a case-by-case basis which should be discussed in advance with the national competent authorities concerned. A bibliographic application might be acceptable in situations of unmet medical need for a product with at least ten years’ history of medicinal use in the EU, and where limited patient numbers preclude generation of a full clinical data set. In the context of multiple allergen products for diagnosis, the guidance also notes that ‘fixed combination’ (Article 10b of Directive 2001/83/EC) cannot be considered appropriate to allow presentation of drug substances in separate pharmaceutical forms in a combination pack, except in exceptional circumstances and for reasons related to public health.

In terms of the application procedure, a decentralised procedure should be used for a MAA for a new allergen product for allergen immunotherapy or in vivo diagnosis, although the former may fall within the scope of the centralised procedure – new drug substance for the treatment of auto-immune diseases and other immune dysfunctions. Where a product is already authorised in one or more MS, then the mutual recognition procedure (MRP) is used to authorise the product in additional MS. The reference MS (RMS) and concerned MS (CMS) are advised to agree on the appropriate legal basis for the product(s) prior to start of the procedure and to consider options for multiple products such as a lead procedure to give a framework for additional products, or parallel MRP(s) with the same timetable. The CMDh Group on Allergen Products can provide advice to support such approaches where previously requested by the MS involved. Where available quality data are comparatively old, and not necessarily in full compliance with current requirements, the RMS and CMS may also agree, on a case-by-case basis. It may also be justified to allow a commitment for additional data from subsequent batches to be included post-authorisation, for example in the context of a product where batches are not produced regularly, and this is deemed plausible.

Product-specific consideration

Medicinal products for AIT represent disease-modifying treatment – as opposed to symptomatic relief of allergic symptoms – and such efficacy is product-dependent even where multiple products may be derived from the same source material (owing to, for example, composition, formulation, administration, and posology). As such, the CMDh guidance states that each product must be evaluated individually to demonstrate quality, safety and efficacy, and (as discussed above) a full application is mandated for AIT products derived from the sources in Table 1. Where not mandatory, full data should be presented, as discussed above, where possible; however, the concept of a ‘mixed’ MAA may be applied if considered reasonable. Bibliographic applications for AIT products should only be accepted in exceptional cases, as detailed above.

For allergen in vivo diagnosis products, the requirement for full data to be provided generally applies and is mandatory for those containing allergens derived from the sources in Table 1. It is noted, however, that different types of products are available, including skin prick tests, provocation tests, intracutaneous tests and percutaneous tests. The levels of evidence available and the risk of adverse events for these may differ, and so an alternative legal basis may need to be considered where a full application is not mandatory. Where full data are to be provided, the content described above for a standalone application should be included, and the (non)clinical information is expected to be in line with the ‘Guideline on Clinical Evaluation of Diagnostic Agents.’¹⁰ Regarding mixed MAAs, the same considerations as discussed above apply, which may be relevant in particular to products where severely limited numbers of patients may restrict the feasibility of obtaining complete clinical data. In cases where there is a clinical need to have the allergen products available for diagnosis and no complete clinical data are available due to the difficulty of recruiting an adequate number of sensitised patients, submission of a bibliographic MAA may be considered, providing that the requirements for demonstration of well-established medicinal use can be fulfilled.

The CMDh guideline also discusses medicinal products for the diagnosis of type IV allergies, which are mainly derived from chemical substances or mixtures thereof – such as synthetic substances, or metals such as nickel. The considerations as stated above apply but the starting materials are often derived from chemical industries outside of pharmaceutical legislation – known as ‘atypical active substances’ – and so the quality requirements should consider this accordingly, as good manufacturing practice requirements may not be fully applicable to these substances.⁵

The preparation and use of NPPs should be considered only in exceptional cases when no alternative authorised allergen products for the treatment of the same allergy are available on the EU market. Where alternative authorised allergen products are available on the EU market, the use of the MRP should be encouraged and supported in order to make these products available in the individual MS, and if products are authorised in one MS, they should not be routinely imported and used as NPPs in another MS. Additionally, the use of NPP provisions is not considered to be justified for preparations containing allergens derived from the sources listed in Table 1, whether alone, or in combination, with other non-listed allergens. Companies that currently market allergens as NPPs should consider applying for an MA, as detailed above, with temporary use of NPPs according to nationally implemented transitional periods. Where possible, such NPPs should only be used to complete ongoing therapies, and initiation of new therapies should be avoided where alternative and authorised products are available. Where respective data are available and upon agreement by the concerned national competent authorities, a well-established use procedure may be considered to be applicable.

Implementation aspects

The CMDh guideline and its recommendations on applicable regulatory procedures were required to be followed for new MAAs from the time the guideline was adopted. For allergen products that were already on the market in the MS at that time, it was recommended that policies that clarified procedures and transition periods to implement the recommendations be devised by the respective MS within three years. After the respective procedures were developed, the applicable transition periods were not to exceed a timeframe of eight years.

Public consultation

A summary of comments received from 13 stakeholders during public consultation on a draft version of the guideline was released together with the final guideline.⁸ It was commented that the CMDh initiative which aims at common regulatory approaches for allergen products within the EU was welcomed, and some stakeholders appreciated the opportunity to comment. While not all comments were considered to be valid, a number were accepted and amendments to the draft version were made, including:

• Guidance on implementation of recommended regulatory harmonisation timelines and transition periods.
• Specific allergens originally listed in two annexes were updated and the annexes combined.
• Amendment of references to the December 2018 concept paper on a guideline for allergen product development in moderate to low-sized study populations.⁹
• Addition of specific information regarding allergen mixtures.
• Addition of a statement that it will still be possible to evaluate products by homologous group.

Summary and conclusions

The new CMDh guideline aimed to pave the way to a harmonisation of the regulation of medicinal allergen products throughout the EU that were historically authorised by national frameworks of MS. The guideline is applicable to allergen products falling under the definition given in Directive 2001/83/EC and all such products are affected, irrespective of MA status. The guideline summarises the general approaches for MA, including the content requirement for MAAs submitted under different legal bases, and Annex I of the specifies allergen products for which a full application is mandatory. Product-specific considerations are detailed, covering medicinal products for AIT, allergen in vivo diagnosis products – including those for the diagnosis of type IV allergies – and NPPs. Implementation aspects, in terms of the coming into effect of the guideline and transition period timelines are defined. Thirteen stakeholders supplied comments the during public consultation on a draft version of the guideline; many of the comments were positive and some resulted in amendments to the draft version being made.

References

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