REVIEW ARTICLE. I. Eichler & E. Sala Soriano. Abstract

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1 Allergy REVIEW ARTICLE Close collaboration between academia, industry and drug regulators is required in the development of allergen products for specific immunotherapy in children I. Eichler & E. Sala Soriano European Medicines Agency, London, UK To cite this article: Eichler I, Sala Soriano E. Close collaboration between academia, industry and drug regulators is required in the development of allergen products for specific immunotherapy in children. Allergy 2011; 66: Keywords allergens; allergic rhinitis; children; specific immunotherapy. Correspondence Dr. Irmgard Eichler, European Medicines Agency, 7 Westferry Circus, London E144HB, UK. Tel.: + 44 (0) Fax: + 44 (0) irmgard.eichler@ema.europa.eu Accepted for publication 19 February 2011 DOI: /j x Edited by: Thomas Bieber Abstract Modification of the response to allergens at an early stage and thereby of the natural history of a respiratory allergic disease by preventing disease progression would constitute the key benefit of specific immunotherapy (SIT) in children. However, although allergen products for SIT have been on the market on a named-patient basis for many years, long-term efficacy, the optimal duration of the treatment and the optimal dosage have not been sufficiently elaborated until now. The enactment of the Therapy Allergen Ordinance in Germany mandates that allergen products for SIT of the most prevalent allergies must submit an application for marketing authorization to the German authorities. In line with the European Paediatric Regulation, decisions by the European Medicines Agency on agreed paediatric investigation plans must be included in these applications. These regulatory requirements provide a unique opportunity to fill the gap in knowledge concerning the benefits of SIT for children and to obtain the data needed to support evidence-based authorization of allergen products for immunotherapy. This goal can only be achieved through close cooperation between academia, drug regulators and industry as well as parent/ patient organizations. The prevalence of allergic rhinoconjunctivitis in children is increasing, and its burden is substantial (1, 2). It can begin at any age, and there is wide variation in prevalence, from 0.8% to 14.9% in 6- to 7-year-old and from 1.4% to 39.7% in 13- to 14-year-old (3). Allergic rhinitis is an independent risk factor for the development of asthma (4). At present, allergenspecific immunotherapy (SIT) is the only treatment for allergic rhinitis with the potential to modify the natural history of the disease and to reduce the development of new sensitisations (5) and the progression of allergic rhinitis to asthma (4, 6). This disease-modifying effect would constitute the key benefit of SIT in children. However, although SIT was already introduced 100 years ago (7, 8) and despite many recent advances, evidence for such long-term efficacy and disease-modifying effect in children is still very limited (9). In addition, most children in Europe are treated with allergen products that have not obtained a marketing authorization (MA) according to the Directive 2001/83/EC as amended (10). This directive mandates that all medicinal products manufactured by an industrial process require a MA based on results of clinical trials, demonstrating the quality, efficacy and safety of the medicinal product. Although allergen products are defined as immunological medicinal products (11) and the production of nearly all allergen products in Europe involves an industrial step, to date only a few allergen products obtained a MA according to this Directive. In many, though not all, European countries, it is still common practice to manufacture allergen products for an individual patient on the basis of an individual prescription (12, 13). Those so-called namedpatient products (NPPs) are marketed without a MA owing to national exemptions introduced by several EU member states. Consequently, quality, efficacy and safety of NPPs have not been independently evaluated according to Directive 2001/83/EC (10). The use of those products is mainly based on expert opinions rather than on scientific evidence. In the United States, the manufacture of allergen products is regulated by the Food and Drug Administration s (FDA s) Center for Biologics Evaluation and Research (CBER) (12, 14). Allergen products for SIT are marketed as standardized and unstandardized extracts. Standardized allergenic extracts are compared to US reference standards for potency. CBER maintains these reference standards and distributes them to Allergy 66 (2011) ª 2011 John Wiley & Sons A/S 999

2 manufacturers. Extracts for which there are no US reference standards are called unstandardized extracts (15). In contrast to Europe, more than 95% of the final allergen extracts used in the United States are prepared in the physician s office and contain multiple allergens (9, 12, 14). CBER provides a list of standardized allergen extracts licensed for distribution in the United States (15). While sublingual immunotherapy (SLIT) represents a significant percentage of SIT treatment in Europe (approximately 45%), only a small percentage of US allergists (approximately 5.9%) prescribe SLIT (12). At present, no SLIT product has obtained FDA approval (16). According to the International Congress of Harmonization (ICH) guideline on clinical investigation into medicinal products in the paediatric population (17), children should be given medicines appropriately evaluated for their use. In the United States, a series of government actions have evolved since the 1990s to facilitate the development of medicinal products for children using a combination of incentives and mandates. At present, two partially unified, but separate, processes are in place with a sunset provision for 2012: the Pediatric Research Equity Act (PREA, requirement) and the Best Pharmaceuticals for Children Act (BPCA, incentive) (18). PREA assures that, regardless of the level of use of a product or market protection status, paediatric studies must be considered and conducted if the core indication developed is relevant to paediatrics. Allergen products for immunotherapy fall under the scope of PREA. Under BPCA, FDA has the opportunity to request studies in conditions and ages for paediatric indications that are not directly linked to the adult indication. These studies are voluntary but, if completed in compliance with FDA s written request, result in the 6-month marketing exclusivity incentive (18). In Europe, the Regulation (EC) No 1901/2006 on medicines for paediatric use (the Paediatric Regulation) (19) entered into force in 2007 with the purpose to generate data on the safety and efficacy of medicinal products when used in children and to promote the development of paediatric medicinal products. Under this law, companies are obliged to conduct studies in children under the age of 18 in accordance with an agreed Paediatric Investigation Plan (PIP), unless a formal waiver has been agreed. A Paediatric Committee (PDCO), including patient representatives, was established at the European Medicines Agency (EMA) with the task to evaluate PIPs proposed by industry. Germany, where approximately 60% of allergen products for SIT are used under a Named-Patient basis, recently enacted the Therapy Allergen Ordinance (20, 21). This ordinance was introduced to prevent the marketing of unauthorized products for the treatment of highly prevalent allergies in order to avoid a potential serious risk to public health. It mandates that all NPPs derived from grass pollen, earlyflowering trees pollen, house dust mites, and bee and wasp venom, regardless if produced as single allergen preparation or included in mixtures, must have an application for MA submitted by 1 December 2010 to the German authorities (22). In line with the European Paediatric Regulation (19), EMA decisions on agreed PIPs must be included in these applications. According to this regulation, PIP applications shall be submitted following the completion of adult human PK studies. For allergen extracts, PK studies are not possible because of the nature of the products. Therefore, this requirement cannot easily be applied. Nevertheless, a PIP has still to be submitted at an early development stage of the allergen product. Pursuant to Article 20(1) of the Paediatric Regulation, a request may be made for deferral of the initiation or completion of some or all of the studies set out in the plan. However, this does not mean that it is a deferral for proposing studies. Consequently, a PIP with an outline of the paediatric studies must be submitted. From December 2009 until July 2010, 118 PIP applications for immunotherapy products from eight different applicants were submitted to the EMA. The EMA Guideline on Allergen Products: Production and Quality Issues (23) introduced the concept of homologous groups: the grouping is based on comparable physicochemical and biological properties of the source material, cross-reactivity/structural homology of allergens, identical formulation of the finished product and identical production process of the allergen extract and of the finished product. One member of a homologous group can be selected as the representative allergen. Clinical studies would be required for the selected representative allergen only. These data can then be used for all allergen products belonging to the same homologous group, but not across groups. Applying this concept to the 118 PIP applications under evaluation reduced the number to 58 reference applications. Each reference PIP application had to propose details of the timing and the studies to demonstrate quality, safety and efficacy in children aged 5 years and older and adolescents. The homologous group concept only reduced the number of proposed studies in children and adolescents, not the number of products aiming to gain MA. A summary of the applications under evaluation is shown in Table 1. In January 2010, the EMA organized a meeting involving experts from the European Academy of Allergy and Clinical Immunology Paediatrics Section and the PDCO to elaborate a set of requirements considered necessary for the development of allergen products for SIT in children. At present, only two sublingual grass pollen products have obtained MA for children according to Directive 2001/83/EC (10) with demonstrated short-term efficacy, but no single product is approved for long-term efficacy. This meeting aimed at balancing the need to develop a paediatric development program which can be fulfilled by several applicants in parallel, with the requirement of the Paediatric Regulation to ensure that medicinal products for use in children are subject to research of high ethical quality and are appropriately authorized without subjecting the paediatric population to unnecessary trials. To this end, the Committee prepared a standard PIP (24) identifying ahead of submissions the requirements for any such allergen product. This standard PIP provides a detailed standard study design based on the requirements of the new EMA guideline on the conduct of clinical trials with allergen products for SIT (25), taking into account the specific 1000 Allergy 66 (2011) ª 2011 John Wiley & Sons A/S

3 Table 1 Summary of all PIP applications for immunotherapy products under evaluation until July (A) The total number of applications under evaluation, the final reference applications after applying the homologous group concept (after HG) as well as the number of PIP applications divided into the different routes of administration: sublingual (SLIT) and subcutaneous (SCIT). (B) The number of PIP applications under evaluation for allergen products belonging to different homologous groups, including mixtures of allergens belonging to two different homologous groups. (C) The number of PIP applications divided into the different routes of administration (SLIT and SCIT) for products of the homologous group of sweet grasses of the Poaceae (Gramineae) family, the birch group and the group of house dust mites of the Dermatophagoides genus Total SCIT SLIT (A) PIP applications After HG (B) Grass Birch Mite PIP applications After HG (C) SLIT SCIT SLIT after HG SCIT after HG Mixtures 2 different homologous groups requirements of the paediatric population and emphasizing the need to demonstrate long-term efficacy. Several problems and open scientific questions were identified: Although on the market for many years, allergen products manufactured for individual persons did not have a MA as therapy allergens and consequently no evaluation of quality, safety and efficacy and benefit/risk-assessment through a regulatory body under the German law. Long-term efficacy, clinical relevance, the optimal duration of the treatment and the optimal dosage have not been sufficiently elaborated until now, particularly in children (14, 26 28). This information and data still need to be obtained. The difficulty to compare SIT products of different companies regarding the content of major allergen owing to the lack of common international standards for purified natural or recombinant allergens with verifiable allergen content: There is a need for a validated assay to measure the concentration of the allergen. Until such a validated assay is universally available, the information on companies internal allergen standardization has to be assessed case by case. Companies should follow the requirements outlined in the EMA Guideline on Allergen Products: Production and Quality Issues (23). The lack of validated endpoints on which to base the outcome of clinical trials: The EMA Guideline on the clinical development of allergen products for SIT (25) requires that the primary endpoint reflects both symptom severity and the use of rescue medication. Patient self-rated symptom scores are often used as primary measures of efficacy. While at present no universally accepted symptom score is available, the most frequently used approach in SIT clinical trials is a 4-point rating scale (from 0 = absent to 3 = severe) applied to each symptom. Nasal itching, sneezing, rhinorrhoea, nasal obstruction, ocular itching/grittiness/redness and ocular tearing are mandatory symptoms to be scored for rhinoconjunctivitis (29). The PDCO is taking the initiative to obtain the information needed to establish a validated scoring system: in the standard PIP, companies are requested to implement the above symptom score as either primary or secondary endpoint. Similarly, no validated and universally agreed medication score is currently available although SIT has been used for decades. The EMA Guideline on the clinical development of allergen products for SIT requires defining a medication score and justifying that the rating mirrors the clinical impact on symptoms of the respective rescue medication. A medication score recently proposed by the World Allergy Organization (29) attributes one point to each dose of a nasal, ocular and/ or oral antihistamine; a score of 2 and 3 for nasal/inhaled corticosteroids and oral corticosteroid, respectively, without providing justifications as to why the medications should have such an impact. It is not easily understood why ocular, nasal and oral antihistamines are all scored 1 although an oral antihistamine has an impact on all symptom categories, while an ocular antihistamine has only an impact on ocular symptoms. Companies are now proposing the abovementioned score in their paediatric investigation plans by adding 1, 2 or 3 points to the symptom score, without further justification. The use of any score will require convincing regulatory authorities that the score points truly mirror the impact on symptoms. In addition to the need to demonstrate clinical efficacy in terms of a reduction in symptoms and the use of additional medication, the standard PIP (24) also requires documentation of the allergen product s effect on quality of life. Changes in organ-related Quality of Life scores, validated in the paediatric population, e.g. Juniper Paediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) (30) for children <12 years old and Adolescent Juniper RQLQ (AdolRQLQ) (31) for children above 12 years old must be included as secondary outcome measures. Need to demonstrate long-term efficacy in children: There is limited evidence from controlled, but unfortunately open, studies for a disease-modifying effect of SIT in children (6, 32 34). The potential to modify the response to allergens at an early stage and thereby to modify the natural history of a respiratory allergic disease would constitute the key benefit of SIT over symptomatic treatment. To achieve this beneficial effect, long-term treatment over several years is required; however, the optimal treatment duration for SIT, particularly for SLIT, has not been established (14, 26, 35). SIT is Allergy 66 (2011) ª 2011 John Wiley & Sons A/S 1001

4 associated with discomfort and/or pain for the children. SLIT requires daily oral intake and has high frequency of local adverse events; SCIT requires regular subcutaneous injections and has a risk of serious adverse events including anaphylactic shock. To compensate for the discomfort and the risks and to provide evidence to support a positive benefit risk balance, the PDCO concluded that long-term efficacy must be demonstrated in children. Can long-term efficacy in children be extrapolated from adults? The basic pathophysiologic mechanism of type I allergies, be they seasonal or perennial, is not fully understood but is assumed to be identical in adult and paediatric populations. However, while SIT is expected to act in the same way in children and adults, the magnitude of the effect and the safety profile could differ. In addition, as a result of the plastic nature of the paediatric immune system (36), the longterm benefit in children might be expected to be even better than in adults. The expert meeting held at the EMA unanimously concluded that, at present, evidence is lacking to support a conclusion as to whether long-term efficacy and the disease-modifying effect of immunotherapy in children might be extrapolated from adult data. Until such evidence is available, long-term studies have to be performed in the paediatric population. This requirement should be revised with the evolution of knowledge and increased availability of long-term data. Is there a need to conduct placebo-controlled studies in children? Children, requiring particular protection as vulnerable research participants, should only be involved in trials able to generate reliable results (37). At present, there is insufficient evidence that immunotherapy in any administration form has a positive long-term effect on symptoms and/or medication use in children and adolescents with allergic rhinoconjunctivitis (38). Authorization of products for immunotherapy must be based on evidence and not on the fact that a product has been prescribed for years. Because of the variability in individual clinical responses, the unpredictability and variability of allergen exposure and the subjective nature of symptom assessment, double-blind comparison to placebo is the only valid design able to prove efficacy for allergen products (39). At present, no allergen product with demonstrated long-term efficacy is authorized for children, precluding the use of an active comparator instead of placebo. The question of whether it is ethical to conduct a 3-year placebo-controlled trial in children must be weighed against the question of whether the prescription of medicines without appropriate data on safety and efficacy is ethical. Conducting a clinical trial aiming to define the risks and benefits of allergen medicines with all available and necessary precautions and measures in place to prevent and minimize the risks for participating subjects, as laid down in Directive 2001/20/EC (40), might represent greater protection for the children (41). Achieving this goal, however, will require continuous education of parents/patients and also ethics committees. Conclusion The European Paediatric Regulation and the enactment of the Therapy Allergens Ordinance in Germany provide a unique opportunity to fill the gap in knowledge concerning the benefits of SIT for children and to obtain the data needed to support evidence-based authorization of allergen products for immunotherapy for the paediatric population. This goal can only be achieved through close cooperation between academia, regulators and industry as well as parent/patient organizations. A first step towards closer cooperation was undertaken by EMA by organizing the expert group meeting mentioned in this article, which resulted in identifying gaps in knowledge in need to be addressed and the elaboration of a standard paediatric investigation plan providing guidance on the design of paediatric trials in SIT. The European paediatric research network at the EMA (Enpr-EMA) (42) could be an appropriate platform for close interactions of all stakeholders necessary to facilitate the conduct of large long-term multi-centre studies in children to increase the availability of high-quality data in the field of SIT for the treatment of allergic rhinoconjunctivitis. This eventually will enable both patients and physicians to take evidence-based treatment decisions. Acknowledgments We thank Beatrice Bilo, Susanne Kaul, Susanne Lau, Marek Migdal, Graham Roberts, Odilija Rudzeviciene, Franziska Rueff, Zsolt Szepfalusi and Stefan Vieths for their participation at and contributions to the expert group meeting. We thank all members of the PDCO and the EMA paediatric team for their contribution to the standard PIP for allergen products for specific immunotherapy. The authors are grateful for the review of the manuscript by Agnes Saint Raymond. 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