European Medicines Agency (EMA) commentary on EMA/CHMP Guideline on allergen products development for immunotherapy and allergy diagnosis in moderate to low-sized study populations

The European Medicines Agency (EMA) promotes regulatory science and innovation by providing state-of-the-art recommendations to medicines developers. Guidelines developed by EMA's committees and working parties support evidence generation and encourage appropriate methodology, enabling the evaluation of medicinal products. The newly developed Guideline on allergen products development for immunotherapy and allergy diagnosis in moderate-to-low-sized study populations provides regulatory and scientific guidance on the development of medicinal products for the diagnosis and immunotherapy of allergies.

The guideline is addressed to all stakeholders involved in developing medicinal products for in vivo diagnosis of allergies and allergen immunotherapy (AIT).

In this commentary, we outline the historical and regulatory background, as well as the anticipated benefits of the new guideline for the development of allergen products for immunotherapy and the diagnosis of allergies when only moderate- to low-sized study populations are available. The guideline is anticipated to be published in the coming months.

The guideline considers a moderate- to low-sized study population as a population for which a standard development programme with the usual statistical rigor on a clinically relevant endpoint is not feasible, necessitating alternative strategies to collect data required for regulatory decision-making. Guidance is provided on quality, nonclinical and clinical aspects of allergen product development for in vivo diagnosis of type I allergy (prick test, provocation test) and type IV allergy (epicutaneous patch test) as well as for allergen immunotherapy.

The guideline is not applicable to any common clinically relevant allergen of type I allergy (diagnostic or allergen immunotherapy), defined in Annex 1 of the recommendations on common regulatory approaches for allergen products (CMDh/399/2019).¹

Further, the guideline does not cover medicinal allergen products manufactured using recombinant DNA technology, synthetic peptides, DNA or RNA constructs and/or cell preparations, as these differ substantially from the allergen products.

According to the European Union Directive for medicinal products currently in force (Directive 2001/83/EC), allergen products (for therapy and diagnosis) are defined as medicinal products throughout the EU, and a marketing authorization is therefore required for their distribution. There are several guidelines for the development and evaluation of allergen products in the EU, all of which aim to define how to develop allergen products according to current scientific knowledge. However, none of these guidelines provide specific advice on the clinical development of allergen products intended for use in small populations.

For example, requirements according to the Guideline on clinical evaluation of diagnostic agents (CPMP/EWP/1119/98/Rev. 1)² and the Guideline on the clinical development of products for specific immunotherapy for the treatment of allergic diseases (CHMP/EWP/18504/2006)³ may not be fully adequate for products intended to diagnose or treat allergies in a limited number of patients due to, for instance, low prevalence, co-sensitizations or overlapping seasons. In such cases, the clinical development programme cannot be conducted in the number of patients as recommended in existing guidelines.

As a consequence, the regulatory status of allergen products across the EU remains very heterogeneous with regard to their marketing authorization status or application as a named-patient product, as described below.

Currently, a very high number of allergen products are available on the market on a named-patient products-basis, in accordance with Article 5 of Directive 2001/83/EC. This provides the possibility of accessing medicines for individual patients without a marketing authorization. This means that in most member states there is no regulatory assessment with regard to their quality, safety and efficacy. As a result, these medicinal products are made available to patients with lower standards in terms of regulatory requirements than what would be requested for a marketing authorization application.

Therefore, there is a high need to support the development of new allergen products or to further develop products that are currently distributed as named patient product to become suitable for a marketing authorization.

To this end, an important step forward was the publication of the scientific and regulatory guideline Recommendations on common regulatory approaches for allergen products (CMDh/399/2019)¹ that provides principles and guidance for the regulation of medicinal allergen products throughout the European Union. Further, the EMA Committee for Human Medicinal Products (CHMP) published the Concept paper on a Guideline for allergen products development in moderate to low-sized study populations on 13 December 2018,⁴ which formed the basis for the development of the guideline discussed here.

In February 2024, EMA published the draft guideline for allergen products development for immunotherapy and allergy in moderate- to low-sized study populations for public consultation. This is a routine step to invite stakeholders' views on EMA's scientific guidelines before their finalization. The objective of the public consultation is to invite interested parties to comment on the draft guideline. A total of 115 comments were received and are currently under review. They will all be considered for the finalization of the guideline planned in the coming months. The outcome of how reviewer comments were addressed will be made public together with the final guideline, as per usual EMA practice.

Allergic diseases are immune-mediated reactions to innocuous exogenous stimuli. Type I allergic reactions are immediate reactions mediated by immunoglobulin E (IgE) antibodies (e.g., hay fever), whereas type IV allergic reactions are based on a cellular immune response (e.g., contact dermatitis). In addition to medical history and physical examination, allergen products are needed for in vivo diagnosis. Management of allergic diseases involves allergen avoidance, symptom treatment and, for some IgE-mediated diseases, administration of allergen immunotherapy.

As mentioned above, the guideline concerns allergen products for the diagnosis of type I and type IV allergies, as well as allergen products for immunotherapy with inhalant allergens, insect venom allergens and food allergens.

The guideline presents recommendations for clinical development, potential study designs and criteria and standards for patient selection. Considerations related to the available study population are provided. Possible indications for products for allergen immunotherapy are also addressed.

For allergen products, submission of a full set of data on medicine quality is required⁵ for a marketing authorization application. This should describe all relevant and specific manufacturing and quality control aspects of the product and its intermediates. For particularly uncommon allergies, alternative approaches are proposed. The general concept of homologous groups and the adjusted expectations of information to be provided for type IV patch test preparations are also discussed.

For natural allergen extracts, nonclinical bibliographic data could be sufficient, while for modified extracts used for allergen immunotherapy, a minimum set of nonclinical data will be necessary (e.g., repeat-dose toxicity, including local tolerance, genotoxicity in vitro, etc.). For epicutaneous test products, submission of predominantly bibliographic data is considered acceptable.

Regarding allergen immunotherapy, a key message is that the available guideline CHMP/EWP/18504/2006³ should be followed wherever possible. Yet alternative approaches are described but are subject to case-by-case justifications and acceptability. Where such approaches are intended, the applicant is recommended to discuss their plan with regulatory authorities in a scientific advice meeting to ensure the regulatory acceptability of the planned development programme.

The guideline also provides potential alternative solutions that allow meaningful clinical development while considering the challenges of typical phase II and III clinical trials with a mandatory placebo-controlled setting. Since the low number of patients available for clinical development is one of the main challenges, ways to improve patient selection and endpoint choice are discussed (e.g., in exceptional cases, environmental exposure chambers or provocation tests for inhalant allergens as potentially acceptable approaches for endpoints in phase III studies). Trials for allergen immunotherapy extracts of inhalant allergens within the scope of this guideline are expected to target allergic rhinitis/rhinoconjunctivitis with or without controlled asthma, mainly for the treatment of allergic symptoms.

Regarding the limited availability of test substances, alternative approaches are proposed to the existing guideline CPMP/EWP/1119/98/Rev. 1² for testing and analysing test substances. While biologic standardization is the starting point for allergen extracts, alternative sources of data could also be used for dose-finding of test allergens (major allergen content, named-patient product, etc.). Moreover, for test allergens, the new guideline suggests the possibility of combining several allergens in the same phase III study, with patients allergic to different allergens as negative controls. Further, besides sensitivity and specificity, which often cannot be determined for epicutaneous test allergens, data on the positivity ratio and the reaction index could also be submitted for clinical assessment.

Safety of investigational medicinal products is an important aspect to consider for clinical developmental programmes. Safety and tolerability must be shown in a target population before the selected dose can be tested in a larger (Phase III) population. The new guideline also discusses the possibility of providing safety data from different sources, including bibliographic data, acknowledging that many adverse drug reactions, warnings or contraindications are considered to be class effects of immunotherapy or diagnostic test products.

Clinical trials, according to current European guidelines, are feasible only for the most common allergies (e.g., against birch or grass pollen, house dust mites or bee/wasp venoms) where a sufficient number of patients are available as required.

This new guideline should raise awareness that, for distinct allergies, it will not be possible to gain sufficient scientific data according to existing guidelines to support a marketing authorization for medicinal products for in vivo diagnosis or allergen immunotherapy.

The new guideline will propose alternative, simplified development programmes for these situations. Thereby, as development programmes will now become more feasible for allergens in moderate- to low-sized populations, pharmaceutical companies should be encouraged to seek marketing authorization.

The guideline will also enable pharmaceutical companies to suggest and discuss new alternative development programmes for small populations. Consequently, new options are created to support and foster innovation, aiming at increasing the number of allergen products available to patients.

Recent regulatory experience on regulatory submissions related to allergen products has shown that, for some allergen products, there is a gap between the regulatory and scientific data requirements and the evidence that can feasibly be collected in developmental programmes in clinical practice. For allergen products where only very limited numbers of patients are available for clinical trials, for reasons beyond the control of the applicant, existing scientific and regulatory guidelines were not fully adequate and a new guideline was needed to inform developers of such medicines.

The new guideline described here will provide a structured framework for developing allergen products in moderate- to low-sized study populations. It will provide recommendations for the development of medicines meeting the highest standards of quality control, efficacy and safety, taking into account feasibility aspects. With the guideline, new opportunities and approaches will be available to improve the development of controlled, effective allergen products and reduce reliance on named-patient products.

This will ultimately facilitate innovation and speed up medicine access for patients suffering from such allergies.

Catherine Drai: Conceptualisation of the work. Andreas Bonertz, Catherine Drai, Diana Hartenstein, Susanne Kaul, Milica Mitrevski, Jose M Zubeldia: Drafting and reviewing of the article. All authors read and approved the final version of the article.

The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the regulatory agency/agencies or organisations with which the authors is/are employed/affiliated.