Registration trials for specific immunotherapy in Europe: advanced guidance from the new European Medical Agency guideline


  • Edited by: Thomas Bieber

Viola Gödicke, Faculty of Medicine, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany.
Tel.: +49 321 212 69 252
Fax: +49 321 212 69 252


To cite this article: Gödicke V, Hundt F. Registration trials for specific immunotherapy in Europe: advanced guidance from the new European Medical Agency guideline. Allergy 2010; 65: 1499–1505.


Marketing authorization of medicinal products is granted based on results of registration trials. The European Medical Agency (EMA) has issued general and disease state-specific guidelines for the conduct of such trials. In the area of allergic diseases, there are basically two general therapeutic approaches: Drugs that mitigate the symptoms and an approach that is targeted to the root cause of the disease, the allergen-specific immunotherapy (SIT). While the ‘Guideline on the Clinical Development of Medicinal Products for the Treatment of Allergic Rhino-Conjunctivitis’ (CHMP/EWP/2455/02) and the ‘Note for Guidance on the Clinical Investigation of Medicinal Products in the Treatment of Asthma’ (CPMP/EWP/2922/01) focuses exclusively on the development of medicinal products to treat allergic symptoms, there was no guideline for SIT in the past. In consequence, the conduct of clinical trials for SIT was widely lacking a standardized approach. This created difficulties when comparing drugs and outcomes and also uncertainty to predict marketing authorization. In 2009, the EMA has issued a new guideline on the clinical development of products for SIT. Despite some white spots in some areas, the new guideline constitutes a breakthrough with regard to guidance, harmonization and transparency in the conduct of clinical trials in SIT.


American Academy of Allergy, Asthma and Immunology


American College of Allergy, Asthma and Immunology


Allergic Rhinitis and its Impact on Asthma


Biological Units


Committee for Medicinal Products for Human use


Committee for Proprietary Medicinal Products


Deoxyribonucleic Acid


Academy of Allergy and Clinical Immunology


European Medical Agency


European Union


Efficacy Working Party


Food and Drug Administration


Immunoglobulin E


Immunoglobulin G


Interleukin 10


Medical Dictionary for Regulatory Activities


new drug application


named patient product


primary endpoint


specific immunotherapy


Symptom Medication Score


T helper cell type 1


T helper cell type 2


World Allergy Organization


World Health Organization

While there is general agreement about the values of evidence-based medicine, both with regard to marketing authorization and subsequent guideline compliant routine treatments, these standards are not yet lived to the full extend in all therapeutic areas.

Compared to areas like cardiology, specific immunotherapy (SIT) was conducted based on comparatively weaker scientific evidence. A significant part of allergen products used for SIT is applied to patients as individual formulation so-called named patient products (NPP), as opposed to general marketing authorization while others have gained local marketing authorizations in single or few countries, governed by varying requirements. This is in contrast to well-intended European initiatives that strive to include more and more therapeutic areas and pharmaceutical products under the rulings of a centralized pan-European marketing authorization process by the European Medical Agency (EMA). Independent from the therapeutic area, this centralized procedure is mandatory for any pharmaceutical entity derived from biotechnological process, like recombinant DNA technology. This is where the general intention of the EMA meets with most recent scientific progress in the area of SIT. While in past years such immunotherapy has been carried out with material from natural sources with all the caveats of inherent biological variability, most recent achievements in the field of engineering of recombinant proteins have enabled the availability of highly standardized and most reproducible agents for such use. These two trends are highly appealing for pharmaceutical industry. In particular, the prospect of gaining more predictable, simultaneous and widespread marketing authorizations across Europe would constitute a major improvement with regard to business perspectives. There has been raising awareness of EMA of these scientific and economic drivers, and EMA was thus anticipating upcoming clinical development with such agents that need to undergo centralized authorization procedure. In light of this, EMA has undertaken efforts to regulate and guide clinical development to ensure approvable submission packages. Part of this is a new guideline on the conducts of clinical trials in the area of SIT effective from 1 July 2009. This article will review the regulatory environment related to clinical trials with SIT and the existing void prior to this new guideline and how it is addressed herein. While in the past the guidance for conduct of trials in this area simultaneously covered allergic rhinitis and allergic asthma; in the new EMA guideline, these two are dealt with separately now. Because of the fact that a complementary EMA guideline exists for allergic rhinitis independent from SIT, the new guideline presented here makes a comprehensive approach to address all pending issues with regard to SIT. Different to that, for asthma an alternative guideline exists and the new guideline for substantial elements simply refers to it. However, this old source does not fully address what is missing. For that reason, this article will focus on the part of the new guideline dealing with allergic rhinitis, which represents the bulk part of it, and which has the aspiration to provide exhaustive guidance in this area. This article will also evaluate how the guideline meets the expectations of researchers involved in this field to provide straightforward guidance in areas where controversies existed so far.

Specific immunotherapy

Allergen-specific immunotherapy is the only treatment that may affect the natural course of allergic diseases; and in particular, it also may prevent the subsequent development of asthma in patients with allergic rhinitis (1).

Specific immunotherapy is the administration of increasing doses of allergens to allergic patients with the aim to induce a state of allergen-specific nonresponsiveness. SIT has the potential to modify the course of allergic disease. This leads to a reduction in symptoms and a shorter period of serious complaints. In addition, there is a reduced need for symptomatic pharmacotherapy (2). Specific immunotherapy is recognized to be a biological response modifier, able to influence allergen-driven immunological responses. Specific immunotherapy improves to a certain degree the Th1/Th2 imbalance in allergic subjects with significant participation of B cells, T cells, blocking antibodies, IL-10 and other cytokines (3).

Allergen products used for SIT are from different sources like allergen extracts, allergoids, conjugates or allergens manufactured using recombinant DNA technology (4).

At the beginning of the 19th century, nearly nothing was known about immunological mechanisms underlying Type I allergy, when SIT was applied for the first time to treat grass pollen allergic patients. Nevertheless, patients having received injections containing grass pollen extract showed improvement, and this protection was found to last for at least 1 year after treatment was discontinued (5).

A major step forwards with regard to safety of SIT was achieved by the use of adjuvant-bound allergen extracts, which caused less systemic side-effects than the injections of aqueous allergen extracts (6).

Specific immunotherapy has been practised in patients with success for a long time although the molecular and cellular mechanisms involved in the pathogenesis of Type I allergy were not fully understood (7, 8).

Currently, the most common form of SIT is injection immunotherapy with repeated subcutaneous injection of increasing amounts of adjuvant-bound allergen extracts (9). New routes of administration of SIT are these days being explored, such as nasal, sublingual-swallow, or oral immunotherapy probably requiring high doses of allergen (10–12). Actual preparations with allergens made by recombinant technology are under evaluation in Phase II and III (7, 8).

EMA guidelines for allergic rhinitis/rhino-conjunctivitis and asthma before July 2009

Clinical development for the treatment of allergic diseases before July 2009 was mainly addressed by two guidelines. The ‘Guideline on the Clinical Development of Medicinal Products for the Treatment of Allergic Rhino-Conjunctivitis’ (13) from 2004 deals with clinical trials of preventive and therapeutic drugs against allergic rhino-conjunctivitis but excludes products on SIT. The ‘Note for Guidance on the Clinical Investigation of Medicinal Products in the Treatment of Asthma’ (14) from 2002 does not cover allergen products because according to this guideline asthma is not necessarily linked with atopy and increasing IgE level. Both documents focus exclusively on the development of medicinal products to treat allergic symptoms and do not include SIT, which aims to alter the course of allergic diseases.

Situation in specific immunotherapy

According to Art. 1 ‘Immunological medicinal product’ paragraph 4b of Directive 2001/83/EC (15) an allergen product ‘shall mean any medicinal product which is intended to identify or induce a specific acquired alteration in the immunological response to an allergising agent.’ With regard to the requirements for source materials, manufacturing process and quality of these allergen products guidance documents do exist (7). In the past, the only requirements referring to safety and efficacy are listed in the Note for Guidance on Allergen Products (16) from 1996 indicating that the ‘concept of taxonomic family’ or ‘homologous groups’ as defined in the current version of this guideline (4) can be applied for safety testing and extrapolation of clinical data if cross-reactivity/structural homology and identical manufacturing processes exists.

This means that toxicological and clinical data obtained with one allergen may be extrapolated to other allergens within a defined group. This concept may be applied to clinical trials with the consequence that trials with some allergens that are of the same group need not to be performed. However, no further details on the conduct of clinical trials are contained herein. In summary, guidance documents with special emphasis on clinical trials with allergen products and detailed information on performing SIT-studies were lacking in Europe.

Specific immunotherapy for respiratory allergy is used since one century, and there is solid documentation of its efficacy (17, 18). As no common accepted methodological standard exist, the methods of evaluation and the trial designs used in clinical trials were different. Many trials evaluating SIT have not been designed to confirm the effect on patients disease burden but have been looking at numerous isolated technical parameters, instead. Several trials showed methodological flaws such as too small sample size, a high frequency of withdrawals and conclusions based on comparison of unmatched groups concerning disease severity. A further area of question in SIT trials is that Symptom Scores and Medication Scores are evaluated independently, whereas successful treatment should reduce both, measured by the combined Symptom Scores and Medication Scores (19).

In such unregulated situation, the Word Health Organization (WHO), the Nordic Guidelines, medical associations and the Food and Drug Administration (FDA) with their recommendations, guidance documents and regulations influenced the way of drug development of allergens since the late 80s until today.

When judging from today’s standards of clinical trials, there was an obvious deficit in the way of proving clinical efficacy of allergen products. However, the therapeutic use has developed widespread and is covered in numerous recommendations, guidelines and position papers (Table 1).

Table 1.   Scientific/academic publications with major impact on clinical trials in specific immunotherapy (SIT) in Europe
Scientific/academic publicationYear of publicationReference number
  1. EAACI, European Academy of Allergy and Clinical Immunology; EMA, European Medical Agency; FDA, Food and Drug Administration.

  2. *Date for coming into effect: 1 June 2009.

Nordic guidelines198920
EAACI position paper19932
WHO recommendation19981
FDA draft guidance for industry, allergic rhinitis200022
WAO recommendations200719
EMA guideline for SIT2008*31

Impact of regulatory authorities

Nordic guidelines

The first international initiative on regulating products for SIT was the Nordic Guidelines. They were the first to establish a regulatory demand for such products in 1989 (20). The Nordic Council on Medicines who published the Nordic Guidelines is a joint Nordic organization, comprising Denmark, Finland, Iceland, Norway and Sweden. These guidelines introduced the concept of biological units (BU) as a potency measure of extracts and other important quality standards. The requested standardization of products was the foundation, which improved the scientific base, reproducibility and safety of treatment for allergic diseases (21).

But the requirements for clinical trials to prove the therapeutic value of a product were very basic. Using open label trials with a restricted number of patients, and the recommended methods such as provocation tests as an endpoint, are no longer an acceptable standard for marketing authorization. In summary, the recommendations on how to conduct the appropriate clinical trials to obtain marketing authorization are only of supportive character.

FDA draft guidance for industry, allergic rhinitis: clinical development programmes for drug products

Changing from an European perspective to an American perspective, there is one remarkable draft guidance document from 2000 by the ‘FDA’ on clinical development programmes for drug products for allergic rhinitis (22).

This is primarily intended to assist sponsors of new drug applications (NDA) in designing development programmes for oral and intranasal drug products for the treatment of allergic rhinitis. Study design, effectiveness and safety for new drugs being developed for the treatment of seasonal and perennial allergic rhinitis are addressed. This guidance document is mentioned here as it had an impact on the grading of the severity of rhinitis symptoms for the evaluation of drug efficacy in SIT. The concept of symptom grading is accepted and also implemented in the new EMA guideline for SIT. The generally accepted rating scale definition commonly used in clinical trials is summarized in Table 2.

Table 2.   Generally accepted 4-point rating system for patient self-rated symptom scores according to the FDA draft guidance for industry
0–3 scale definitionAdditional explanation
  1. FDA, Food and Drug Administration.

0 = absent symptomsNo sign/symptom evident
1 = mild symptomsSign/symptom clearly present, but minimal awareness;easily tolerated
2 = moderate symptomsDefinite awareness of sign/symptom that is bothersome but tolerable
3 = severe symptomsSign/symptom that is hard to tolerate; causes interference with activities of daily living and/or sleeping

Impact of medical associations

Despite the fact that this article is addressing the shortcomings of existing guidelines with regard to the conduct of clinical trials, it needs to be acknowledged that these have the primary intention to provide guidance on patient’s care rather than on conduct of clinical trials.

WHO position paper

Guidelines and indications for SIT with inhalant allergens were proposed first in 1987 (23) by a working group of the European Academy of Allergy and Clinical Immunology (EAACI) and have been published within the following years by the World Health Organization (WHO) (24, 25) the EAACI (2, 23) and several national and international associations and expert groups [e.g. the International Consensus Report on Asthma (26), the Global Strategy for Asthma Management and Prevention (27), the International Consensus Report on Rhinitis (28), the British Society for Allergy and Clinical Immunology (29), the American Academy of Allergy, Asthma and Immunology (AAAAI), and the American College of Allergy, Asthma and Immunology (ACAAI) (1, 30)].

All publications from above societies or expert groups provide guidance for use of SIT. However, none of these represented a consensus of a widespread number of experts in the respective field. Some only address specific issues for one of the target organs, e.g. for asthma (26, 27) or rhinitis (28).

To fill this deficit, in 1998, the WHO together with various allergy, asthma and immunology societies throughout the world published one of the most important publications in the field of SIT: The WHO Position Paper ‘Allergen immunotherapy: therapeutic vaccines for allergic diseases’ (1). This position paper laid the foundation for subsequent research and development run by the pharmaceutical industry. In a situation where no clear regulatory requirements were available such an international position paper was considered a major improvement as it was a step towards a common agreement throughout the medical parties. This publication gave guidance not only for treatments, diagnosis, risk factors and indications for SIT, but also for allergen standardization, storage and mixing of allergen vaccines, declaration of allergen content and quality of allergy vaccines. This guideline improved the understanding of the scientific background of SIT as well as included recommendations to improve safety, dealt with paediatric issues, discussed new techniques and offered recommendations for areas of necessary and additional research.

While this can be considered a major step forward in various areas, key questions related to the conduct of clinical trials for academic research and marketing authorization are not comprehensively covered, such as trial design, endpoint selection and dose finding.

The World Allergy Organization (WAO)

In 2007, the World Allergy Organization (WAO) published recommendations for standardization of clinical trials with SIT for respiratory allergy (19). The recommendations should ensure that patients are treated based on scientific evidence and should minimize the risk of misusing limited financial resources for inappropriate trials. The document contained the recommendations for study design, patient selection, appropriate endpoints and statistical considerations. A randomized placebo-controlled and double-blind design is defined as gold standard for efficacy evaluation. A baseline period is not generally recommended. A proper randomization method has to be used to avoid imbalances. Stratification should be carried out, i.e. using age gender and severity.

Eligibility criteria should be clearly defined in the trial protocol reflecting concomitant sensitizations, which may have an effect on the efficacy evaluation.

The expert group recommend the use of a combined Symptom Medication Score (SMS) by providing a diary to the patient and give recommendations to standardize the rescue medication.

The examples for a scoring of rescue medication were very useful but not validated. For grading of severity, the document is referring to the EAACI grading system (2). Recommendations to assess and plan long-term and preventive effects were given. Overall, the recommendations by the WAO are very useful and should be considered in the planning of confirmatory clinical trials. The recommendations are not intended for the use of other aspects of the development (e.g. early development or dose finding).

The new EMA guideline on the clinical development of products for specific immunotherapy for the treatment of allergic diseases

In Europe until 2009, no common agreement and guidance exists on the performance of clinical trials for SIT. Moreover, there was no consensus on the evaluation and interpretation of results of clinical trials for SIT. Up to now, there is a wide variety of study designs in terms of e.g. choice of endpoints, study duration and dose regimes. The existing guidelines fail to solve such specific problems and do not support a robust design of clinical trials, which will be accepted by all European Union (EU) member states. In summary, detailed guidance on the planning and design of clinical trials in SIT was necessary to harmonize the marketing authorization process for medicinal products for SIT within the EU. This is of importance as the most recently developed recombinant allergen products by virtue of their origin have to undergo the centralized procedure for marketing authorization, and several Phase II and III clinical trials with both natural and recombinant allergens are ongoing (8). Through the ‘Efficacy Working Party’ (EWP) the EMA initiated in 2006 a Concept Paper on the preparation of a guideline on the clinical development of products for allergen-specific immunotherapy (8). The responsible EWP is a board of currently 33 European experts from the national Regulatory Authorities in the field of clinical trials, composed of one expert per member state and an additional expert, nominated from an expert list by the Committee for Medicinal Products for Human Use (CHMP). This team shall ensure an objective evaluation of different treatment strategies, although not necessarily all members have expertise in allergen products or of SIT (7). The EWP agreed on a draft guideline in April 2007. In May 2007, the CHMP adopted the draft of the guideline, and it was published on the website of the EMA for consultation. Over a period of 6 months, the public was invited to send comments on the draft to the EMA. The final guideline has come into effect on 1st of June 2009 (31).

This new guideline (31) is establishing standards that applies to pharmaceutical industry and Regulatory Authorities pertaining to the clinical development and assessment of (natural and recombinant) allergen products for SIT and is hard to ignore for academic research too. The guideline gives detailed information on aspects of study design such as inclusion/exclusion criteria, endpoints, study duration, comparison of data resulting from different routes of application, pharmacodynamic, pharmacokinetic and dose response studies, as well as safety and clinical trials in children. All affected organ systems (e.g. nose, upper and lower airways, eyes and multi organ affection) are covered, except atopic eczema and dermatitis.

Safety aspects

The guideline is referring to the general existing EMA guidelines on safety which have to be followed (32, 33). Other important safety aspects like observation period of the patient, handling of overdosing, the emergency treatment of anaphylaxis, possible dose adjustments, drug interactions and the handling and control of patients with asthma should be considered by using other sources.

Reporting of adverse events

The guideline is giving clear advice for the documentation and evaluation of adverse events. A classification into mild, moderate or severe and the assessment for relationship to study medication should be documented. The onset of reactions has to be documented very carefully allowing for a separation of immediate effects (during the first 30 min) from delayed effects (onset after 30 min from administration).

The adverse events should be described using MedDRA (Medical Dictionary for Regulatory Activities). Severity of allergic reactions has to be graded according to the EAACI (2).

In future following such approach will facilitate comparison of adverse events profiles between drugs generated from different trials.

Therapeutic allergens not requiring clinical trials for marketing authorization and the attempt to restrict such market access

Allergen products for SIT require either marketing authorization or in some European countries can be prescribed as NPP without a marketing authorization. According to Directive 2001/83/EC (15) medicinal products, including allergen products for diagnosis and therapy, that are either prepared industrially or manufactured by a method involving an industrial process need a marketing authorization (15). This has implications for the use of NPP, when applied to patients without a marketing authorization, despite the fact that most of these do meet the above criteria of industrialized origin (7).

The attempts to implement what is intended by Directive 2001/83/EC is difficult and sometimes may takes several steps, e.g. in Germany, where NPP represent a significant share of the market for immunotherapy. In 2005, when the German Drug Law was amended (14. Arzneimittelgesetz (AMG)) in principle a marketing authorization for therapeutic allergens from industrial origin was called for (34). However, it took another 3 years before tangible action was taken with the enactment of the ‘Regulation for Therapy Allergens’ (Therapieallergeneverordnung (TAV)) in 2008 (35). Therein, the standard regulations for marketing authorization of medicinal product were extended to the seven most prevalent classes of allergens used in SIT, however, wide transition periods granted.


Improving the conduct of clinical development should lead to more quality evidence that can only result in broader acceptance of the therapy in question. Because of the lack of standardized clinical trials, there has been some reluctance to include SIT into the portfolio of treatments for allergic diseases. In addition, the therapeutic concept almost disappeared from clinical practice in the United Kingdom when in 1986 the British Committee for Safety of Medicines (CSM) reported a series of deaths caused by subcutaneous SIT. This report contained 26 deaths because of anaphylactic reaction. The Committee raised general concern about the risk/benefit profile and cautioned against the use of SIT in the setting of general practice with limited emergency facilities standby (36).

After critical review of the situation prior to the launch of the new guideline, which reveals the deficits described earlier, the initiative of the EMA to standardize the clinical development in the area of SIT can be considered beneficial. For some important areas, substantial guidance is provided to all kind of research (academic or pharmaceutical industry). However, still significant topics are not fully addressed and await future regulation. One key area, which will be discussed in more detailed here, is the appropriate selection and handling of the primary endpoint (PE).

In particular, credit goes to the guideline for the inauguration of the SMS as the PE, ending the use of multiple nonstandardized technical variables (e.g. provocation tests). By fostering the impact of standardized rescue medication and the inclusion of it into the SMS, a transition to patient-derived outcomes is achieved. Thus, patient disease burden rather than laboratory values will determine efficacy of treatment. This parallels now very much the requirements for registration of drugs in other therapeutic areas, e.g. cardiology (where a common PE is e.g. the composite of death, myocardial infarction and stroke).

However, the guideline stops at an intermediate step by ending without clear definition of the composition of such SMS. For the symptom part of the score, they refer to an algorithm that has previously been proposed by the FDA (22). For the more difficult part of the medication score, the EMA leaves it to the interested parties (medical societies, individual investigators, but also pharmaceutical industry) to define this component of the score and later to validate the entire score.

The use of multiple SMS with different compositions/definitions (37, 38) prohibits the comparison of trials performed with different allergens or after a couple of years. One solution to that problem could be a more widespread agreement on what could be called a ‘least common denominator score’, which could be determined in each future trial as a secondary endpoint independent from whatever possible more complex SMS may be used as a PE.

One problem with SMS, however, is a time shift of the drugs that go into the medication score. General intentions to step away from short acting remedies (e.g. antihistamines) may prevent comparison between trials run a few years apart, or even hamper evaluations from within one trial, in particular trials with long-term follow-up.

One issue attached to PEs like SMS which will yield a numerical output is that these are easy to come up with statistically significant differences. More difficult, however, and still not resolved is what detected differences in score represent a clinical relevant improvement. Arbitrarily set margins of improvement (e.g. 30% decrease in SMS) lack external validation and uniform acceptance. One might think of validating the SMS vs symptom and medication-free days, quality of life or productivity measures at work.

When accepting the SMS as PE, the researcher pays a price at several levels: First, on average, the sample sizes used in trials powered for SMS as PE are much larger than for previous trials with technical endpoints like provocation tests. Part of the concept of SMS is a recommended baseline assessment that will mandate one additional year that adds to the overall trial duration. Furthermore, the measurement of a valid SMS endpoint depends on the occurrence of a sufficient level of allergen (e.g. pollen) exposure from environmental sources in the target time window. In extreme, this may result in the inability to assess the PE in a given year, which may lead to further study prolongation. In worst case, this may mean failure of a Phase III trial for an effective agent and conducted in an appropriate way simply because of biological variation in pollen exposure. Additionally, this will require the availability of pollen traps close to any participating site. This has revealed as a major obstacle in various countries where such logistics are densely available and thus limiting the number of study sites. All the above has major impact on research budget and net present value calculations, provided patent expiry plays a major role.

This problem of relying on natural occurrence could be overcome by application of allergens in standardized way concerning level and duration of exposure by means of allergen challenge chambers. However, the use of such facilities is accepted by the EMA guideline up to Phase II (dose finding) studies only, thus no solution for Phase III.

Because of the complex requirements as outlined earlier, this new guideline likely will result in industry focusing on the development of allergens for SIT that will target mass markets while the development for allergens relevant for limited populations (=customer based) may be restricted.

On the one hand, the compliance with this new guideline requires increased efforts by pharmaceutical industry when there is intention to seek market authorization through the centralized procedure. This is opposed to a leaner approach when trying to meet the requirements of local competent authorities in a country by country approach. In return, the centralized approach will grant simultaneous and widespread market access with all the economical implications.

Locking into future basic science and early phase clinical development has shifted towards recombinant allergens for use in SIT. These are up for evaluation in large-scale Phase III trials, and because of their biological origin they need to undergo the centralized procedure. For pharmaceutical industry embarking on such developments, the new guideline is most welcome as it will help to guide towards using study designs/endpoints that will meet the standards required for approval by the EMA.

Besides the perspective of marketing authorization, the guideline will more generally impact clinical research. It should help to fill knowledge gaps and rule out inherited concerns to SIT, all of this eventually leading to more safety and certainty for both patient and physicians.

Author contributions

The manuscript is part of Viola Gödicke’s thesis for the Master of Science in Pharmaceutical Medicine at the University Duisburg-Essen.

Conflict of interest

Viola Gödicke is employee of Allergopharma Joachim Ganzer KG, Reinbek, Germany. Ferdinand Hundt is employee of Sanofi-Aventis Deutschland GmbH, Berlin, Germany.