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Regulation of allergen products – A global perspective 1
Abstract 2
Regulatory approaches for allergen immunotherapy (AIT) products and the availability of high 3
quality AIT products are inherently linked to each other. While allergen products are available in 4
many countries across the globe, their regulation is very heterogeneous. Here, we describe the 5
regulatory systems applicable for AIT products in the European Union and in the US. For Europe, a 6
depiction of the different types of relevant procedures, as well as the committees involved is 7
provided and the fundamental role of national agencies of the EU member states in this complex 8
and unique network is highlighted. Furthermore, the regulatory agencies from Australia, Canada, 9
Japan, Russia, and Switzerland provided information on the system implemented in their countries 10
for the regulation of allergen products. While AIT products are commonly classified as biological 11
medicinal products, they are made available by varying types of procedures, most commonly by 12
either obtaining a marketing authorisation or by being distributed as named patient products. 13
Exemptions from marketing authorisations in exceptional cases, as well as import of allergen 14
products from other countries, are additional tools applied by countries to ensure availability of 15
needed AIT products. Several challenges, including regulatory and economical aspects, for AIT 16
products are apparent and will require further consideration. 17
18
19
Introduction 20
The availability of medicinal products to provide a reliable diagnosis of clinical allergy and an 21
effective treatment is of critical importance for patients with suspected or proven allergy. Products 22
for allergen immunotherapy (AIT) have been approved by national competent authorities in different 23
regions of the world. However, the regulatory landscape governing the approval of these products is 24
enormously heterogeneous – both within the European Union (EU) and even more so when looking 25
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globally – thereby rendering it extremely complicated and challenging to develop a harmonized, 26
international approach to regulating these products. 27
Pharmaceutical companies are increasingly focused on global strategies to develop and market their 28
products. It is therefore very important to understand the current regulatory situation for allergen 29
products from an international perspective, as this will have a direct impact on the availability of 30
these medicinal products to patients throughout the world. Certain regulatory patterns can be 31
observed on a global scale. For example, whereas AIT was previously mainly used and placed on the 32
market on the basis of expert opinions with limited regulatory oversight, the requirements for high 33
quality clinical data for granting market access have greatly increased during the last 20 years. In the 34
EU, legislation applicable for new and existing products (1, 2) demands that allergen products are 35
registered as medicinal products with corresponding requirements for clinical data. The development 36
of the guidelines on Good Clinical Practice (GCP) in the conduct of clinical trials has been the main 37
driving force for the specific requirements in the legislation. In the EU, the Clinical Trials Directive (3) 38
implemented GCP as a mandatory requirement for the conduct of clinical trials. Since 2004, EU 39
member states have needed to apply the provisions established by this Directive. For AIT products, 40
this has resulted in the performance of numerous state‐of‐the‐art, randomized, double‐blind, 41
placebo‐controlled trials in recent years as documented by the US and European databases on 42
clinical trials (4, 5). However, due to the seasonal nature of many allergic diseases and the protracted 43
immunological processes induced by AIT, clinical trials can be very time consuming and costly, 44
particularly if a disease modifying effect is the intended indication as defined by the respective 45
European Medicines Agency (EMA) Guideline (6). In this position paper, we provide an overview on 46
how products for the in vivo diagnosis of allergies, as well as for AIT, are regulated in different 47
regions of the world. Approval of allergen products involves large and complex regulatory networks 48
directing the independent assessment of allergen therapeutics and providing guidance on how to 49
determine whether or not a specific product shows a favorable risk‐benefit profile. Activities and 50
decisions of the responsible regulatory agencies directly influence the availability of products. This 51
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position paper has been prepared by the European Academy of Allergy and Clinical Immunology’s 52
(EAACI) Taskforce on Regulatory Aspects of Allergen Immunotherapy (AIT) and is part of the EAACI 53
AIT Guidelines. The primary audiences are expected to be clinical allergologists and regulators, but 54
the position paper is also likely to be of relevance to all other healthcare professionals dealing with 55
AIT. This EAACI Position Paper is not intended to be seen as a regulatory guidance document. 56
57
International and national regulation of allergen products 58
The regulatory system in the European Union 59
In the EU, allergen products are defined as medicinal products according to Directive 2001/83/EC (7). 60
As stated in this Directive, therapeutic allergen preparations are considered medicinal products as 61
they are substances or combination of substances presented as having properties for treating or 62
preventing disease in human beings. Furthermore, any substance or combination of substances that 63
may be used in or administered to human beings to obtain a medical diagnosis are also considered 64
medicinal products. This includes in vivo diagnostic test allergens, including skin prick tests, 65
provocation tests, intradermal tests and epicutaneous tests. Where such products are prepared 66
industrially or manufactured by a method involving an industrial process, these medicinal products 67
fall within the scope of the above mentioned Directive. Generally, these products are required to 68
obtain a marketing authorization in order to be placed on the market. Some exemptions apply, which 69
will be discussed later. 70
The EU has a unique combination of national regulatory agencies that work together in a network to 71
regulate market access of medicinal products. Each member state of the EU holds its own national 72
competent authority. The EMA (8), is a decentralized agency that is responsible for the coordination 73
of several types of procedures related to the marketing authorization of medicinal products, 74
including the centralized procedure. Furthermore, EMA accommodates a number of independent 75
scientific committees that are deeply involved in the assessment of specific aspects or types of 76
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medicinal products as well as the development of scientific guidelines that are then used for a 77
standardized assessment of the medicinal products. 78
Assessment of marketing authorization applications 79
It should be noted that the scientific assessment of all marketing authorizations, post‐marketing 80
authorization procedures (i.e. variations to a marketing authorization) as well as the development of 81
the guidance and opinions in scientific advice procedures is actually performed by the national 82
competent authorities. To this end, for centralized procedures, there is a call for countries that are 83
willing to act as Rapporteur (or Co‐Rapporteur) in a procedure. The scientific assessment itself occurs 84
in the national competent authorities of those countries that are acting as Rapporteur or Co‐85
Rapporteur; assessment reports are subsequently presented and discussed within the EMA’s 86
respective committees. 87
In the EU, different types of procedures may apply in order to obtain a marketing authorization (see 88
Figure 1). For certain products, depending on manufacturing and/or medical indication, the 89
centralized procedure is mandatory for marketing authorization (Table 1). This type of procedure is 90
therefore applied when marketing authorization is sought for recombinant allergen products. 91
However, in the EU, there are currently only marketing authorizations for products derived from 92
natural sources and neither products for the diagnosis of allergens nor products for AIT have yet 93
been authorized by the centralized procedure. Most allergen products, for which marketing 94
authorizations exist within the EU, have been authorized via a National Authorisation Procedure. In 95
such a case, a pharmaceutical company applies for marketing authorization in one member state 96
only. Consequently, after finalization of the procedure, the product is only authorized in the 97
respective country. In contrast to the agreed timelines for multinational procedures, the national 98
procedures are executed under national timelines and these vary among countries. If the company 99
then decides to apply for marketing authorizations in additional member states, the Mutual 100
Recognition Procedure (MRP) has to be applied. In this procedure, the country in which the 101
marketing authorization has already been granted acts as so‐called Reference Member State (RMS) 102
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and will provide the assessment report that led to the original authorization of the product to those 103
countries in which an authorization is sought (Concerned Member States, CMS). In many cases, the 104
original assessment report will need to be updated by the RMS as considerable time may have 105
passed between the original authorization and the actual start of the MRP to reflect the up‐to‐date 106
status of the marketing authorization dossier. An important drawback of this approach is that two 107
procedures (national authorization followed by MRP) are conducted sequentially in the MRP, thereby 108
prolonging the timeframe from initial submission of a marketing authorization application and 109
eventual market access in intended countries. A speedier alternative is the Decentralized Procedure 110
(DCP), which is the preferred route for new allergen products to achieve marketing authorization in 111
multiple EU member states (see also (9–11)). 112
The Decentralized Procedure allows the decision and potential approval to be reached within a 113
shorter timeframe as there is no requirement for a national authorization to precede the DCP. To 114
initiate a DCP, an applicant will request the national competent authority (NCA) in a country of their 115
choice to act as coordinating authority (RMS), which will then be leading the assessment and 116
coordinating the procedure. If the requested authority agrees to be RMS, the company submits an 117
application for marketing authorization to the RMS and all involved member states, which are 118
selected by the applicant. Therefore, the result of both, a MRP and DCP, typically is that after positive 119
finalization of a procedure, the product will not be authorized in the entire EU, but only in the RMS 120
and respectively involved countries/CMS. The RMS prepares an assessment report including a list of 121
questions on issues that need to be resolved before authorization can be granted. The CMS comment 122
on the assessment report, which may result in additional issues to be raised. Next, the assessment 123
report as well as the list of outstanding issues is provided to the applicant to allow for resolution of 124
these issues. The RMS then reassesses the updated documentation and, in agreement with the CMS, 125
a decision is made on whether or not the medicinal product can be approved. In case there is 126
disagreement between the RMS and the CMS on issues that may potentially harm the patients 127
(“potential serious risk to public health” (12)), the procedure may be referred to the Co‐ordination 128
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group for Mutual recognition and Decentralized procedures – human (CMDh) (see below) and 129
possibly to the Committee for Medicinal Products for Human Use (CHMP) for arbitration (see also 130
(10, 11)). 131
For all marketing authorization procedures, a public assessment report is prepared (either by the 132
CHMP (for CP), the RMS (for MRP and DCP) or the respective national competent authority (for 133
national procedures)) upon granting of a marketing authorization, thereby publicly documenting the 134
assessment for a concerned medicinal product. However, those parts of the dossier that are 135
confidential will not be included in the public assessment report. This is typically the case for specifics 136
of the manufacturing process. Clinical data is typically not considered to be confidential. 137
For allergen products, several committees and working parties play crucial roles in the different 138
phases of development, marketing authorization, and post‐marketing authorization procedures 139
(Supplementary tables 1 and 2). 140
The networks of institutions and committees involved in procedures resulting in the marketing of a 141
medicinal product in the EU and resultant procedures (variations to an existing marketing 142
authorization, pharmacovigilance monitoring, etc.) are complex. We will therefore give an overview 143
of the most critical committees playing a role in regulatory procedures for allergen products in 144
Europe. 145
The Committee for Medicinal Products for Human Use (CHMP) and related committees 146
The CHMP is the committee at the EMA responsible for preparing opinions on issues with respect to 147
medicines for human use. In centralized procedures, the CHMP assesses the marketing authorization 148
application and gives a recommendation on whether or not a specific product may be approved. The 149
final decision on this will then be made by the European Commission on the basis of the opinion 150
provided (13, 14). The opinion by the CHMP is prepared within the European regulatory framework 151
and based on scientific criteria allowing a conclusion on the benefit‐risk balance using the 152
information provided by the applicant concerning quality, safety and efficacy of the medicinal 153
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product. A recommendation for marketing authorization is only made where this balance is 154
favorable. In addition to the initial marketing authorization procedure, the CHMP is also responsible 155
for a number of post‐authorization activities, such as changes to an existing marketing authorization 156
(variation) (14). 157
For Mutual Recognition and Decentralized Procedures, the CHMP plays an important role in 158
situations where the member states involved in a specific procedure (including the Reference 159
Member State as well as the Concerned Member States) do not come to an agreement concerning 160
the marketing authorization of a specific product. This may, for example, be the case where a CMS 161
raises issues of potential serious risk to public health while the RMS does not share this concern. In 162
such circumstances, the CHMP will arbitrate and take a decision on whether or not a concern should 163
be upheld (which results in a recommendation to deny a marketing authorization) or whether the 164
presented issues are not profoundly affecting the benefit‐risk balance in a negative way (which 165
would typically result in the approval of a specific product by the RMS and CMS). 166
Another very important aspect of the CHMP`s responsibilities is the development of scientific 167
guidance for the pharmaceutical industry. These guidelines, although not directly mandatory from a 168
legal perspective, reflect the scientific or regulatory state of the art and are typically applied by the 169
regulatory agencies of the EU Member States. Accordingly, applicants should follow these guidelines 170
or provide comprehensible justifications in case deviations from these documents are intended. As a 171
part of its mandate, the CHMP has established a number of working parties, which provide expertise 172
in particular scientific fields. These working parties are composed of European experts selected from 173
the national competent authorities. On varying issues, the CHMP will ask these working parties to 174
contribute to the development of specific guidelines or to the assessment of marketing 175
authorisations and EMA scientific advice procedures – for example the Safety Working Party (SWP) 176
for specific non‐clinical issues or the Biologics Working Party (BWP) for quality issues concerning 177
biologicals, including allergens from natural and recombinant sources (15). 178
179
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The Co‐ordination group for Mutual recognition and Decentralized procedures – human (CMDh) 180
The CMDh is not a committee of the EMA but is associated to the Heads of Medicines Agencies 181
(HMA), which is a network of the Heads of the National Competent Authorities in the European 182
Economic Area (EU and non‐EU countries Iceland, Liechtenstein, Norway). The CMDh was set up by 183
Directive 2004/27/EC (16) and plays a fundamental role with respect to procedural issues in Mutual 184
Recognition and Decentralized procedures. Based on its mandate as given in this directive, the 185
committee has developed guidance on all aspects of MRP and DCP and discusses issues that arise in 186
ongoing procedures. As stated previously, these types of procedures have steadily risen in relevance 187
for allergen products in recent years. As described above for CHMP’s role in CP, an unresolved 188
potential serious risk to public health issue in a marketing authorization procedure with 189
disagreement between RMS and CMS will first result in discussion of the relevant issues at CMDh. 190
Only if the disagreements remain unresolved in the CMDh, the issue is passed to the CHMP for 191
arbitration. Accordingly, in addition to procedural questions, the CMDh is also involved in scientific 192
issues. 193
Role of the Pharmacovigilance Risk Assessment Committee (PRAC) 194
The PRAC is responsible for assessing and monitoring safety issues for human medicines. These 195
responsibilities include the detection, assessment, minimization and communication of safety issues 196
such as adverse reactions observed for specific medicinal products (17). For this, the PRAC prepares 197
opinions and provides these to the CHMP and CMDh as well as to the European Commission in 198
related procedures. 199
The Paediatric Committee (PDCO) 200
As part of a valid marketing authorization application, European legislation (in this case Paediatric 201
Regulation (EC) 1901/2006 (18)) mandates that an applicant for the marketing authorization of a 202
medicinal product and therefore also for allergen products for therapy and in‐vivo diagnosis, must 203
provide a paediatric investigation plan (PIP) that has been assessed and approved by the PDCO of the 204
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EMA. This plan is provided by the applicant during development of the medicinal product to 205
delineate how data on the clinical efficacy and safety of a specific product will be generated in 206
children to support the authorization and use of this medicine in this population group. For certain 207
classes of medicines, the requirement to submit a PIP is waived due to the fact that these classes of 208
medicines are likely to be ineffective or unsafe in paediatric populations, are intended for conditions 209
that occur only in adults, or will not result in a significant therapeutic benefit compared to existing 210
treatments in paediatric populations. As allergen products typically do not fall in any of these 211
categories, an approved PIP is mandatory for these products and, if missing, will prohibit 212
authorization even at the national level. 213
National specifics on regulatory issues for allergens in Europe 214
Allergen products are regulated according to European law since 1989 (1, 2). The implementation of 215
the European Directive 2001/83/EC (7) crucially advanced the legal framework for allergen products 216
so that it is basically harmonized in the EU. Yet, there is still a high level of heterogeneity in how EU 217
member states regulate market access for this type of products. For most parts, this is due to specific 218
regulations such as Article 5 of above mentioned Directive that allows member states to place 219
specific allergen products, especially named patient products (NPP), on the market without the 220
requirement of a marketing authorization. Furthermore, while implementing the particulars of the 221
European Directive 2001/83/EC into national legislation, many member states adapted or elaborated 222
this legislation by specific national law such as ordinances or decrees. Some examples are provided in 223
the supplementary section of this document to demonstrate the spectrum of approaches on how 224
allergens are currently regulated in the EU. For reasons of brevity, there are specifics in additional EU 225
member states that are not covered by this review. 226
227
Allergen products in the US 228
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Allergen products in the US are regulated as biological medicinal products under the Public Health 229
Service Act and as drug products under the Food, Drug and Cosmetics Act. Multiple other Acts apply 230
but these two Acts, which have the force of law, are the primary legislation under which the products 231
are regulated. Generally, there are no differences in the regulation of allergens for diagnosis versus 232
therapy. Allergen products require a marketing authorisation termed a Biologics License Application 233
(BLA). A separate BLA is issued to each new allergenic product upon approval. 234
US‐licensed allergen extracts are either “standardized” or “non‐standardized”, depending on the 235
labeled units. Standardized extracts are labeled in units tied to biological activity (AU, BAU, specific 236
allergen units, or mass units) and each released lot of a standardized allergen extract meets potency‐237
related specifications. Non‐standardized allergen extracts carry labeled unit (PNU or w/v) that has 238
not been demonstrated to be associated with potency. US‐licensed allergen products that are not 239
aqueous extracts do not carry the designation of standardized or non‐standardized. 240
Separate BLAs are assigned for each of the existing standardized allergenic extracts, but 241
non‐standardized allergen extracts from each manufacturer are licensed under one BLA. That BLA 242
includes every non‐standardized extract manufactured by a specific license holder, regardless of 243
extract type. Therefore, a specific license holder’s BLA for non‐standardized allergenic extracts could 244
encompass many different products. The model for non‐standardized allergen extracts is historical; 245
any new allergen product for which licensure is sought is regulated as a biological under the 246
Investigational New Drug (IND) and BLA regulation. Briefly, the new product is first assessed for 247
safety and efficacy in clinical trials conducted under an IND Application filed by a sponsor at FDA. 248
After successful completion of clinical trials, the product is submitted for licensure under a BLA. A 249
BLA includes an electronic file (dossier) that contains all required information on the quality of the 250
medicinal product, as well as the clinical, pharmacological and toxicity data. FDA expects that a BLA 251
will demonstrate that an applicant uses the current state‐of‐the‐art to manufacture a quality product 252
that is safe, pure and potent. After licensure, changes to the manufacturing process are submitted to 253
FDA according to a three‐tiered supplement system, depending on the nature of the proposed 254
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changes. NPPs are not marketed in the US, and the marketing of allergen products manufactured in 255
pharmacies is not permitted. 256
Guidance documents provide FDA’s current thinking on implementation of regulations or law. FDA 257
Guidance documents span a wide range of topics under the categories of clinical, CMC and GMP, 258
application submissions, adverse events and product deviations reporting, labeling and promotion, 259
biosimilar products, and manufacturing facilities inspections. As in other regions of the world, there 260
are changes in regulatory procedures and FDA guidance documents as they are regularly updated to 261
represent current state‐of‐the‐art. These changes then apply to a wide range of FDA‐regulated 262
products, including allergen products, regardless of their use in therapy or diagnosis. ICH guidance 263
documents may also apply to allergen products, depending on the scope of the guidance. 264
Pharmacovigilance monitoring is required in the U.S. for allergen products under specific regulations 265
for reporting of adverse events. Periodic Safety Update Reports are also required for licensed 266
products. During the conduct of clinical trials, adverse events are also reported in the IND annual 267
report. 268
Allergen products in selected parts of the world 269
General regulation of allergen products 270
Allergic diseases affect people all over the world. Hence, allergen products are available in many 271
countries and yet there is little information available on how such products are regulated on a global 272
scale. We therefore developed a questionnaire in which national competent authorities from a 273
selection of countries were asked to provide information on the regulation of allergen products in 274
their countries. Responses were received from the NCAs in Australia, Canada, Japan, Russia and 275
Switzerland as well as feedback on selected questions from China and Indonesia. The responses to 276
the questionnaire received give an impression of such regulation from various areas of the world. 277
Table 2 displays some key findings extracted from the responses to the questionnaire. Some general 278
observations can be made from the responses received. For example, it becomes clear that as in the 279
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EU and US, allergens are considered biological medicinal products in most countries (Australia, 280
Canada, Russia, Japan, China, Indonesia) and typically allergen products are not in general exempted 281
from the requirement for a marketing authorization. Such authorizations are issued for the finished 282
product. Furthermore, the basic regulatory frameworks typically do not differentiate between 283
therapy and test allergens. Nevertheless, although allergen products are considered as biological 284
medicinal products, some countries have implemented specific regulations for this type of products. 285
For example, Switzerland has implemented an allergen ordinance in December 2009 allowing for a 286
simplified authorization procedure for test and therapy allergens from natural sources (19). In this 287
ordinance, specifics on the requirement on data to be provided for marketing authorization are laid 288
down individually for test and therapy allergens. Among other addressed issues, there are details 289
provided on the requirements for data from clinical studies for both groups of allergen products. 290
Additionally, Swissmedic published a guidance document on the simplified authorization of allergen 291
products (20). 292
In Canada, there are currently two regulatory authorization pathways for allergen extracts in place. 293
Firstly, there are so‐called Grandfathered Products. These products were approved under a 294
framework that was applicable before 2012. In this framework, there are two main types of 295
allergenic extracts to be considered: non‐standardized and standardized extracts. Non‐standardized 296
allergenic extracts are further divided into extracts derived from pollen or non‐pollen materials. 297
Currently, for these non‐standardized products, one authorization is given for all pollen products and 298
one authorization is given for all non‐pollen products per company. In contrast, for standardized 299
allergenic extracts, one authorization is given to each product per company. In addition, Health 300
Canada follows the FDA standards for the Standardized Allergenic Extracts. 301
Secondly, in November 2012, Health Canada published a guidance document entitled Regulatory 302
framework for unauthorized new allergen products of biological origin used for the diagnosis or 303
treatment of allergic diseases which introduced a new policy for the regulation of allergen extracts 304
(21). All Allergen Extracts approved after the introduction of the new framework in 2012 are 305
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regulated and authorized under the same regulatory authorization pathway as other Biologic Drugs. 306
Each product requires its own authorization. As stated in the response provided by Health Canada, 307
the agency is currently examining options for aligning these two pathways. 308
Named patient products 309
As is the case within the EU, the regulation and acceptance of named patient products differs widely 310
globally. For example, according to the Russian legislation it is allowed to produce medicinal products 311
on the basis of a prescription only in cases where authorized substances are used in the production 312
process. However, according to the NCA in Russia, no authorized allergen drug substances are 313
currently available on the Russian market, only finished products. Therefore no NPPs can be 314
produced based on a prescription for an individual patient. In Switzerland, the Swiss Therapeutic 315
Products Law defines so‐called 'formula magistralis' medicinal products which are exempt of a 316
marketing authorization. These medicinal products have to be manufactured upon a specific 317
prescription by a physician which would potentially also be feasible for allergens. The information on 318
the actual availability of such products on the market lies at the regional Cantonal Health Authorities. 319
Contrasting with the previous examples, Australia, Canada and Japan generally do not allow NPPs to 320
be placed on the market. However, while NPPs are not available as such in Australia, practitioners 321
there may obtain so‐called Authorized Prescriber status for allergens under a special program, the 322
Authorized Prescriber program (22). This may be applied in cases where patients require access to 323
medicines or medical devices that have not been approved for supply by the Australian agency. For 324
those countries for which NPPs are allowed on the market, specific information on the number and 325
type of NPPs on the market is often non‐available to the NCAs responsible for the marketing 326
authorization and monitoring of the authorized allergen products. 327
Import of allergen products 328
Non‐availability of authorized allergen products may result in crucial gaps in the provision of needed 329
products to patients. To overcome this, some countries allow alternative routes for such products to 330
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be made available. In addition to the above mentioned Authorized Prescriber program, Australia also 331
applies a so‐called special access scheme (23). For this, the import and/or supply of a specified 332
unapproved therapeutic good (or class of unapproved therapeutic goods) to specific patients (or 333
classes of recipients) with a particular medical condition can be granted upon request of a 334
prescribing physician. The decision on such requests is taken on a case‐by‐case basis, and is based on 335
the clinical information supplied by the doctor. Any approval or rejection is limited to the named 336
patient only for a defined dose and duration of therapy and does not allow supply to another patient 337
and is not tantamount to progression to general marketing. Also, extemporaneous compounding by 338
pharmacies is permitted for individual patients on prescription‐based orders of treating physicians 339
but is not an avenue for general marketing to other patients. In Switzerland, patients and health 340
professionals are allowed to import medicinal products authorized in a third country by specific rules 341
(24). This is only possible, when there is no authorized product available in Switzerland. This is not 342
applicable for NPPs. In Japan, based on the responsibility of the physician, allergen products are 343
allowed to be imported from other countries. However, these products are then exempt from Relief 344
System for Suffers from Adverse Drug Reactions. In Russia, the import of therapeutic allergen 345
products is allowed for those products that are also authorized within the Russian Federation. In 346
Canada, all products to be sold must be authorized for sale by Health Canada. China allows the 347
import of certain allergen products from overseas, adding to the domestic products registered there. 348
Apart from the exceptions described above, manufacturing of allergen products in pharmacies 349
without marketing authorization is not allowed in any country replying to the questionnaire. 350
Post‐authorization requirements for allergen products 351
All countries stated that there are post‐authorization requirements such as pharmacovigilance 352
monitoring in place (for example Risk Management Plans and/or Periodic Safety Update Reports) for 353
authorized allergen products. In Canada, In addition, each lot of a biological medicinal product is 354
subject to the Lot Release Program before sale. The risk‐based Lot Release Program covers both pre‐ 355
and post‐market stages and derives its legislative authority from section C.04.015 of the Food and 356
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Drug Regulations. Products are assigned to one of four evaluation groups, with each group having 357
different levels of regulatory oversight (testing and/or protocol review) based on the degree of risk 358
associated with the product. The graded risk‐based approach to testing and oversight allows the 359
Biologics and Genetic Therapies Directorate of Health Canada to focus ongoing testing on products 360
for which enhanced surveillance is indicated such as vaccines and blood products. The criteria used 361
to determine the appropriate Evaluation Group include, but are not limited to, the nature of the 362
product, the target population, the lot testing history in the Directorate, and the manufacturer's 363
production and testing history. 364
Regulations for specific types of allergen products 365
As was previously described for the EU and the US, there is no particular regulation or guidance in 366
place in any country that responded to our questions for allergen challenge products, for example for 367
food challenge. Typically they are considered to be diagnostic allergen products and are treated as 368
such. 369
Moreover, thus far there are no authorizations for recombinant allergen product or for peptides 370
derived from allergen sequences. Special requirements are applicable in some countries for such 371
products, for example, in Switzerland, an administrative ordinance for human medicines with new 372
active pharmaceutical ingredients (25) must be followed. 373
374
Current regulatory challenges for allergen products and unmet needs 375
Recent years have shown tremendous rearrangements in the allergen market and consequently the 376
availability of allergen products. While many allergen products have disappeared in some countries 377
(i.e. in Germany and Netherlands), for other products, state‐of‐the‐art clinical and quality data has 378
been generated resulting in the development and even marketing authorization of a new generation 379
of products (26–28). Although such positive developments are observed, other aspects may be more 380
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ambivalent. Several recommendations have been made by academia to improve thoroughly 381
standardized definitions for future trial in AIT and should be consequently followed (29, 30). 382
It should be noted that this is a dynamic situation and the ongoing developments in this field will 383
continue to reshape the allergen market fundamentally. 384
Several issues have surfaced in recent years that are thought to be key triggers of the current 385
developments. Overall, the requirements on the data that must be provided to successfully apply for 386
a marketing authorization have risen significantly in the last 20 years. There has been a clear shift 387
towards products with proven quality, safety and efficacy, which has also been evident in some cases 388
for previously authorized products. Randomized, double‐blind placebo controlled studies according 389
to current GCP‐regulation are required as the current state‐of‐the‐art approach. Products for which 390
such proof is not provided will not be approved for marketing. Furthermore, it has become evident in 391
recent years that the distribution of products as NPP for in vivo diagnosis and AIT for highly prevalent 392
allergies is neither necessary nor desirable. The data to be generated for documentation of clinical 393
efficacy and safety as well as proof of adequate manufacturing of these products should be provided 394
and independently assessed. 395
In addition, considering the (non‐)availability of allergen products, it should be distinguished 396
between a potential lack of newly developed products (e.g. for allergies with low prevalence) and the 397
withdrawal of products from the market due to the decision of companies to cease marketing. 398
Consequently, while certain causes resulting in these two scenarios are overlapping (e.g. economic 399
profit to be expected with respect to reimbursement), they are differing in other aspects. For 400
example, the requirement to provide GCP‐compliant clinical data on efficacy and safety as requested 401
by Directive 2001/83/EC will not necessarily affect products for which a marketing authorization has 402
already been issued. 403
Economic considerations influencing the availability of allergen products 404
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As several factors are influencing the current and future availability of allergen products, pricing and 405
reimbursing are among those most commonly discussed. Just as the regulatory framework, 406
reimbursing for allergen products is very heterogeneous and even more differing between the 407
countries considered. However, it should be noted that regulators involved in scientifically assessing 408
the medicinal products are neither in a position nor are they commissioned to include considerations 409
on reimbursement in their decision making on a marketing authorization application (31). 410
Complicating matters, in addition to the differences in reimbursement, the fees that are to be paid to 411
the respective National Competent Authorities involved in a marketing authorization procedure (as 412
well as post‐marketing procedures such as variations to an existing marketing authorization) in 413
national procedures, MRP and DCP are defined on a national level, resulting in enormous differences 414
in the magnitude of fees. Furthermore, these national fees may add up to considerable sums, 415
thereby enticing companies to market their product in a selected number of countries, limiting the 416
availability of products in countries not considered for marketing authorization. Adding up to the fees 417
applicable for marketing authorization itself, there are national fees to be paid in each country where 418
a variation to an existing marketing authorization is applicable as well as fees for pharmacovigilance 419
activities. Besides, in many cases fees do not consider the economic attractiveness of a specific 420
product and therefore do not distinguish between, for example, a commonly prescribed therapy 421
allergen and a test allergen for diagnosis of an allergy with low prevalence, thereby likely intensifying 422
the focus of pharmaceutical companies on allergen products for the most prevalent allergies. 423
However, some countries have implemented measures to account for the specific characteristics of 424
allergen products. For example, in Switzerland, the fees raised for allergen products are 425
differentiated for allergens for therapeutic and diagnostic purpose (the latter ones with a fee 426
reduction of 90%). Variation fees are also reduced by 50% for both therapeutic and diagnostic 427
allergens in comparison to other medicinal products. 428
Future perspectives 429
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18
Considering the current position, companies are tending to focus on a core group of allergens. While 430
it is reasonable that products for rare allergies that are of insufficient quality or have no or very little 431
data on clinical efficacy are disappearing from the market, this is problematic for patients who 432
require them and where there is no adequate alternative. This situation is especially evident for 433
allergen products for in vivo diagnosis. However, to do sufficient justice to this topic and its 434
significance, it requires separate discussion elsewhere. 435
Furthermore, the situation concerning the heterogeneity of the regulatory status of allergen 436
products worldwide and in the EU is deeply rooted in their regulatory history, as for decades these 437
products have been managed on a national level only. Resulting diverseness is evident, for example, 438
in the applicability and prevalence of use for NPPs in the EU. In contrast, while NPPs are not 439
marketed as such in the US, it has been reported that products are frequently mixed at the 440
physician’s office. Although respective guidance has been developed for this approach (32, 33), there 441
is a lack of evidence to support the efficacy of the individual mixtures used. Moreover, the EU is an 442
evolving structure with the decision of the UK to leave the EU and several countries having joined the 443
EU in the last decades. The latter ones have had the challenge of integrating their own national 444
regulations and medicinal products available on their markets into the regulatory system of the EU. 445
In light of these differences, companies are faced with the challenge to keep their products (and 446
manufacturing processes) standardized during development as well as post‐marketing in a global 447
distribution setting. 448
Some of the issues concerning allergen products and their availability have resulted in activities by 449
responsible European committees. For example, due to problems resulting from the regulatory 450
disharmony observed in the EU, for example with respect to pharmacovigilance obligations, the 451
CMDh has started an activity to develop proposals for harmonized regulatory approaches for allergen 452
products within the EU (34). 453
While for certain types of medicinal products in life‐threatening diseases, considerations for 454
application of a life cycle approach are made, this is typically not the case for allergen products. In 455
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19
such lifecycle approaches, a product will be granted market access based on a reduced set of data 456
available and will be assessed for its benefit‐risk balance on an on‐going basis post‐marketing (35). 457
Similar approaches are being applied in different parts of the world (36), although they are often 458
criticized, especially because products within such a lifecycle approach are made available with 459
insufficient data to fully determine a benefit‐risk ratio at the time of market access. 460
Several projects are in place targeted at supporting manufacturers in developing effective and safe 461
medicinal products, for example the Innovative Medicines Initiative (37). Also, PRIME (38)(derived 462
from priority medicines) has been founded to support in the development of medicines aiming at 463
currently unmet needs. With respect to allergies, there are several fields, where medical need can 464
currently not be adequately addressed with authorized medicinal products (e.g. in oral 465
immunotherapy of food allergies) and where such programs may be of benefit for future 466
developments. 467
468
Acknowledgments 469
We thank the colleagues at the Therapeutic Goods Administration Australia, Health Canada, 470
Swissmedic, Scientific Centre for Expert Evaluation of Medicinal Products Russia, and the 471
Pharmaceuticals and Medical Devices Agency Japan for their support. 472
473
474
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0660.jsp&mid=WC0b01ac058096f643. 578
Draft
National Marketing
Authorisation
Marketing authorisation in one country
DecentralizedProcedure (DCP)
Expand existing national marketing authorisation from one country to
additional EU countries
Mutual Recognition Procedure (MRP)
Marketing authorisation in
several EU countries at once
CentralizedProcedure (CP)
Marketing authorisation in allEU countries at once
Intention of the procedure:
Applicant submitsmarketing
authorisation application to a country of choice
List of questionsfrom National CompetentAuthority
Country in whichNational Marketing
Authorisation exists acts asReference
Member State (RMS)
ConcernedMember States (CMS) commenton assessment
report of the RMS resulting in a listof questions tothe applicant
Response of theapplicant to list of
questions
Agreement byRMS and CMS
Positive Opinion:Approval of theapplication formarketing
authorisation in all countries involved
Negative Opinion:Rejection of theapplication formarketing
authorisation in all countries involved
Disagreement byRMS and CMS
Arbitration byBreak‐out session
Arbitration byCMDh
Arbitration byCHMP
Response of theapplicant to list of
questions
Applicant choosescountry to act as
Reference Member State (RMS) andchooses
ConcernedMembers States
(CMS)
Rapporteur andCo‐rapporteur aremandated by the
CHMP
Rapporteur andCo‐rapporteur
prepareindependentassessments
EMA Peer Review and resulting listof questions from
CHMP
Response of theapplicant to list of
questions
CHMP preparesopinion, European Commission thendecides on theapplication formarketing
authorisation
Decision byNational
CompetentAuthority
Agreement Disagreement
Disagreement
Figure 1: Simplified flowchart of the marketing authorisation procedures in the European Union. For reasons of clarity, some details of the procedures have been omitted in the figure, e.g. timetables for each procedure are differing.
Draft
Table 1: Medicinal products to be authorized by the centralized procedure according to [Ref]
Human medicines containing a new active substance to treat
acquired immune deficiency syndrome (AIDS)
cancer
diabetes
neurogenerative diseases
auto‐immune diseases and other immune dysfunctions
viral diseases
Medicines derived from biotechnology processes
Advanced‐therapy medicines
Orphan medicines
Optional for other medicines
containing new active substances
that are a significant therapeutic, scientific or technical innovation
whose authorisation would be in the interest of public health at EU level
Draft
Table 2: Overview on responses of NCAs to selected questions of the questionnaire
Requirement for a MA for allergen products
Stage of the production process to be authorized
Named Patient Products marketed
Import of allergen products
Australia MA required Finished Product
No named patient products but practitioners may obtain Authorised Prescriber status for allergens under the Authorised Prescriber program
If a specific allergen product is not approved in Australia, a prescribing physician may request it for use in an individual named patient under the Special Access Scheme.
Switzerland MA required Finished Product
Formula magistralis Medicinal Products corresponding to NPP
Patients and health professionals are allowed to import medicinal products authorized in a third country by specific rules. This is only possible, when there is no authorized product available in Switzerland. This is not applicable for NPPs.
Canada MA required Finished Product
Not allowed All products sold in Canada must be authorized for sale in Canada by Health Canada.
Russia MA required Finished Product
It is allowed to produce medicinal products on the basis of a prescription only if authorized substances are used in the production process. Since currently no authorized allergenic substances are available in the Russian market, no NPPs can be produced based on a prescription for an individual patient.
Only those therapeutic allergens that have been authorized in Russia are allowed to be imported
Japan MA required Finished Product
Not allowed Based on the responsibility of the physician, products may be imported from other countries. Such products are exempt from Relief System for Suffers from Adverse Drug Reactions in Japan.
Draft
Supplementary table 1: Main tasks, composition and legal basis of major committees involved in
regulatory procedures in the EU – CHMP and CMDh
Committee Committee for Medicinal Products for Human Use (CHMP)
Co‐ordination group for Mutual recognition and Decentralized procedures (CMDh)
Main Tasks Preparing EMA's opinions on medicines for human use in the centralized procedure and post‐authorisation procedures (e.g. variations) to an existing marketing authorisation
Arbitration in Mutual Recognition and Decentralized Procedures in cases of disagreement between Member States
Execution of referrals initiated in relation to the protection of public health or where Community interests are concerned
Arbitration in Mutual Recognition and Decentralized Procedures in cases of disagreement between Member States
Examination of questions related to marketing authorisations in two or more Member States, including new applications, variations, renewals and pharmacovigilance activities
Provide recommendations on the classification of unforeseen variations
Support worksharing between Member States
Composition One member and an alternate nominated by each of the 28 Member States as well as Iceland and Norway
Up to five co‐opted members (experts chosen by Members States or EMA) to provide additional expertise in particular scientific fields
One representative per Member State and Norway, Iceland and Liechtenstein
Member States may appoint an alternate to the CMDh member
The European Commission participates on a regular basis as an observer.
Legal Basis Regulation (EC) No 726/2004 Directive 2001/83/EC, Directive 2004/27/EC and Directive 2010/84/EU
Draft
Supplementary table 2: Main tasks, composition and legal basis of major committees involved in
regulatory procedures in the EU – PRAC and PDCO
Committee Pharmacovigilance Risk Assessment Committee (PRAC)
Paediatric Committee (PDCO)
Main Tasks Providing recommendations to the CHMP and the CMDh on any question relating to pharmacovigilance activities in respect of medicinal products for human use and on risk management systems
Monitoring the effectiveness of those risk management systems
The detection, assessment, minimisation and communication relating to the risk of adverse reactions
Assess the content of paediatric investigation plans (PIPs) and adopt opinions on them including the assessment of applications for a full or partial waiver and assessment of applications for deferrals
Assessing data generated in accordance with agreed PIPs
Adopting opinions on the quality, safety or efficacy of a medicine for use in the paediatric population, at the request of the CHMP or a medicines regulatory authority in the EU
Providing advice on questions on paediatric medicines, at the request of the Agency's Executive Director or the European Commission
Composition A chair and a vice chair, elected by serving PRAC members;
One member and an alternate nominated by each of the 28 Member States as well as Iceland and Norway
Six independent scientific experts nominated by the European Commission
One member and an alternate representing healthcare professionals
One member and one alternate representing patients associations
Five members of the CHMP, with their alternates. These members are appointed by the CHMP itself
One member and one alternate appointed by each EU Member State that is not represented by the members appointed by the CHMP
Three members and alternates representing healthcare professionals
Three members and alternates representing patient associations
Legal Basis Directive 2001/83/EC and Regulation (EC) No 726/2004
Regulation (EC) No 1901/2006
Draft
1
Online supplement 1
Supplementary information on country‐specific regulatory approaches for allergen products in the 2
EU 3
Germany 4
Allergen products for in vivo diagnosis and therapy are subject to a marketing authorization in 5
Germany. However, there are exemptions from this demand for NPP. In 2005, due to changes in the 6
German Medicinal Products Act (Arzneimittelgesetz) which would have resulted in the obligation for 7
all NPP to obtain a marketing authorization, Germany introduced an exemption for NPP used for 8
therapeutic purposes. As a result of this, therapy allergens manufactured for an individual patient on 9
the basis of an individual prescription were, as was the case before, not required to obtain a 10
marketing authorization. Allergens for therapy are thereby allowed to be placed on the market as 11
NPP on the basis of an individual prescription. This is independent of the co‐existence of already 12
authorized products from the same allergenic source. While such NPP are not authorized and are 13
therefore not assessed for their benefit‐risk balance, manufacturers of NPP do need to follow specific 14
regulation in terms of manufacturing, e.g. there is a requirement for a manufacturing license and 15
production under Good Manufacturing Practice (GMP). Nevertheless, NPP are not further supervised 16
by the authorities and thus there is no list of marketed NPPs and no information on their market 17
share. However, since 2008 a national regulation (Therapy Allergen Ordinance (TAO)) is in force for 18
all therapy allergens distributed as NPP that are intended to treat the most prevalent allergies 19
(caused by grass pollen (Poaceae), tree pollen (birch, alder, hazel), house dust mites 20
(Dermatophagoides sp.), bee and wasp venom) (1, 2). For such products, a marketing authorization is 21
mandatory without any exemption. For NPPs already marketed before the regulation came into 22
effect there is a transition procedure. They are still allowed to be distributed whilst in a marketing 23
authorization application procedure, in which the quality, safety and efficacy is assessed for each 24
product. Taking into account the data available for the concerned products when the TAO came into 25
force, prolonged transition periods allowing for the conduct of clinical trials are in place, thus 26
allowing the compilation of a full dossier according to the current state‐of‐the‐art to evaluate efficacy 27
Draft
2
and safety. The implementation of the TAO has resulted in the removal from the market of more 28
than 6400 NPP, for most of which there were no clinical data available. Furthermore, there were a 29
considerable number of products where the reasoning behind the composition was very 30
questionable and was not in line with the recommendations of the medical societies (3), as, for 31
example, seasonal and perennial allergens were combined in a single product. 32
As allergens for diagnosis are usually produced industrially and supplied in multi‐use vials for several 33
patients, allergens for diagnosis require a marketing authorization and cannot be placed on the 34
market as NPP. Requirements for content and the evaluation of the marketing authorization 35
application are very similar to therapeutic allergen products. For new products, full dossiers 36
according to the current state‐of‐the‐art have to be submitted. For established substances, a 37
procedure according to Article 10a of the Directive EC/2001/83 (well‐established use) may be 38
applicable (case‐by‐case decision). 39
Furthermore, whereas allergens for diagnosis may be manufactured in pharmacies without a 40
marketing authorisation under certain conditions, this is not allowed for allergen products for 41
therapy. 42
According to the German Medicinal Products Act, allergen products (including test and therapy 43
allergens) under the premises of the TAO or having a marketing authorisation are subject to official 44
batch release by the Paul‐Ehrlich‐Institute. Therefore, a respective batch may only be placed on the 45
market if it is shown that the batch has been manufactured and tested according to the prevailing 46
standard of scientific knowledge. 47
48
Italy 49
In Italy allergen products have been and are largely marketed under the NPP provision, upon request 50
by physicians. These are medicinal products supplied in response to a bona fide unsolicited order, 51
formulated in accordance with the specifications of an authorized health care professional and for 52
Draft
3
use by his individual patients. In parallel, as an outcome of classical assessment process with regards 53
to MRP or DCP (see above), at least three products have been authorized and are marketed. 54
Manufacturers of allergen preparations in Italy are currently inspected for GMP compliance by the 55
Italian Medicines Agency (AIFA). 56
Similarly to other European Member States, in Italy the adoption of Directive 89/342/EEC (4) in 1991 57
into national law (Decree 13 December 1991 (5)) implied that any allergen product had to comply 58
with the requirements of the European pharmaceutical legislation. At that time, manufactures were 59
requested to file a list of existing products according to a number of “families” or “groups” such as 60
food, pollens of various origin, mites, molds, insects, epithelia and venoms which were identified on 61
the basis of a “grouping” (not taxonomic) approach with the addition of a few more categories such 62
as bacteria extracts and chemical preparations (for patch tests). For each applicant the list had to be 63
integrated with representative dossiers for several allergens for each of the families/groups 64
mentioned above. For these existing products a transitional period was allowed, provided an 65
application had been received by the end of April, 1992. More recently the manufacturers were 66
requested to file a full updated quality section of the dossier concerning the drug substance of 67
several allergens. According to a specific timeline defined by the Italian Medicines Agency, 68
manufactures had to submit afterwards a comprehensive set of dossier dealing with quality aspects 69
but limited to the Drug Substance part. In summary, more than 250 dossiers were scrutinized and 70
the assessment process confirmed a general overall improvement of the information provided at the 71
end of the questions and answers steps that were part of the assessment process. Further steps of 72
the process moving onwards from the evaluation of the drug substance aspects of the dossiers are 73
currently in progress. For this, decisions on the timeline and the procedure for handling the 74
assessment of the drug product aspects of the dossiers will be taken by the Italian Medicines Agency 75
after the conclusion of the assessment step involving the respective drug substances. 76
There is no batch release requirement for allergen products on the Italian market. 77
78
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4
The Netherlands 79
Brief history 80
Before 1993, allergen diagnostics and therapeutics in the Netherlands were not regulated as 81
medicinal products. The adoption of Directive 89/342/EEC (4) in 1992 implied that any allergen 82
product was now subject to the requirements of European pharmaceutical legislation. From 31 83
December 1992 this was also applied to allergen products already existing on the market in The 84
Netherlands. As a result, all industrially produced immunotherapeutic and diagnostic allergen 85
products needed to be registered as medicinal products based on a full dossier, including quality, 86
non‐clinical and clinical information. For the existing products a transitional period was allowed, 87
provided an application had been received by December 1993. In this period the marketing 88
authorisation holder could provide the complete dossier, develop all required analytical methods and 89
especially obtain the required clinical efficacy evidence. The product could be marketed until 90
authorities had irrevocably decided about the MAA (Marketing Authorization Application). 91
For the majority of the existing products a MAA was received. MAA was generally only sought for the 92
main indications (grass and tree pollens, house dust mite, bee/wasp venom and cat epithelia). By 93
2003, 10 allergen products had been approved, several rejected and for three products the 94
applications were still pending. Of the latter, one product was eventually approved while the other 95
two were rejected. 96
Current regulatory situation 97
Currently, the following allergen therapeutics (SCIT) are available as registered medicinal products in 98
the Netherlands: Grass pollen extracts, Tree pollen extracts (Alnus, Betula , Corylus), House dust mite 99
extract, Cat epithelia, Hymenoptera Venom (Vespula and Apis). All of these were registered following 100
a national MAA procedure of products that were already on the market before 1993. In addition two 101
SLIT grass allergen products have been registered, as new applications received after 2003 (via 102
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5
Mutual Recognition Procedure). For many other indications (e.g. weed pollen, fungi or horse/dog 103
epithelia allergies) allergen therapeutics are available as Named‐Patient Products. 104
There is no batch release requirement for allergen products on the Dutch market. 105
106
Named‐Patient Products (NPP) 107
Directive 89/341/EEC (6) also lays down exemptions from the general requirements of the EEC 108
pharmaceutical legislation. It is under these exemptions (Article 1, par. 4) that the so‐called NPP are 109
regulated. These are medicinal products supplied: “ …..in response to a bona fide unsolicited order, 110
formulated in accordance with the specifications of an authorized health care professional and for 111
use by his individual patients on his direct personal responsibility ('named patient exemption')”. 112
The current legislation in the Netherlands allows dispensing of non‐licensed medicinal products (so‐113
called Named Patient products) only under strict regulation (article 3.17 of the Dutch Regulation 114
medicinal product act.; (7)) meeting several conditions: 115
1) The doctor has to consider it necessary to treat the patient with that preparation, 116
2) There is no registered adequate alternative available 117
3) The doctor should apply in writing to the manufacturer/pharmacist separately for each 118
patient 119
4) The manufacturer must provide each application to the Dutch Health Care Inspectorate 120
5) The Inspectorate determines the amount and period it can be given for 121
6) The manufacturer/pharmacist has to record the number of patients, amount of medicine 122
supplied and adverse events. 123
The regulation of NPP is under the responsibility of the Dutch Health Care Inspectorate. The 124
Inspectorate has clear instructions concerning all conditions for use of non‐registered (allergen) 125
products on her website (8). These include that for each patient a doctor’s declaration is required 126
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6
and that these are only valid for one year to allow regular evaluation. Furthermore, the 127
manufacturers, wholesalers and pharmacists that have a permission for NPP need to provide an 128
annual overview of the number of patients treated with these. If this number is too large a 129
registration with the MEB or EMA is expected, as the article 3.17 (NPP) regulation is not intended to 130
evade the obligatory Marketing Authorization. In 2009 the inspectorate decided that non‐registered 131
allergen therapeutics could only be used in exceptional cases (9). From 2014 the regulation with 132
respect to the dispensing of non‐registered allergen products is further enforced (10). 133
It is noted that the Dutch market for allergen extracts decreased about 30% between 2009 and 2013 134
(from 50 Million Euro to around 32 million Euro with a similar development in prescriptions) (11). At 135
the same time, the market share of NPP dropped from around 80% to around 52% in 2013. Based on 136
condition 2 of article 3.17 the use of NPP would be limited to allergens for which no registered 137
adequate alternative is available (around 1‐2% of total use of allergen therapeutics). Considering this, 138
it is expected that the use of NPP will further decrease and be limited to small categories of patients. 139
Just as for registered allergen products, there is no batch release requirement for NPP allergen 140
products on the Dutch market. 141
142
Spain 143
In Spain, allergen products for both in vivo diagnostics and immunotherapy have been traditionally 144
placed on the market as NPP. Thus, apart from the few products registered by the Decentralized or 145
the Mutual Recognition Procedures, the majority are in use today without any previous marketing 146
authorization and as such, without any regulatory assessment of their quality, safety and efficacy, 147
irrespective of whether they are manufactured by an industrial process or not. Manufacturers are 148
required to hold a manufacturing license and to comply with the GMP guidelines. However, given 149
that a very important aspect of GMP inspections is to make sure that the products are manufactured 150
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7
according to the approved specifications, assurance of full GMP compliance is difficult in the absence 151
of previous quality assessment. 152
Consequently, a proposal to regulate allergen products already on the market has been drafted in 153
Spain, which is still pending publication. The proposal has established specific regulatory routes for 154
the different types of products, summarized as follows: 155
1) Allergens for in vivo diagnostic: in general, most of these products are industrially‐manufactured 156
and as such, submission of a full dossier will be expected. After assessment, successful products will 157
receive a full marketing authorization. 158
2) For specific immunotherapy products, several scenarios are envisaged: 159
bona fide named‐patient products will not need to present a Marketing Authorization 160
Application (MAA), but a communication to the national Competent Authority (AEMPS) 161
before manufacturing may be required. For these products, information on manufacturing 162
history, number of units, etc. should be kept ready for inspection for a specified time; 163
specific mixtures for individual patients, prepared from industrially manufactured bulks. In 164
this case, mixtures will only be possible from previously authorized bulks. Authorization of 165
bulks will only be possible after assessment of the relevant quality information. It is intended 166
that the authorization includes those mixtures in which the bulk can be used, hence 167
restricting the mixtures to those previously authorized. Final mixtures prepared on a named‐168
patient basis will be subject to similar requirements than those on the previous point; 169
industrially‐manufactured finished products will require submission of a full dossier for 170
assessment. The amount of clinical data required for authorization will be determined on a 171
case by case basis. 172
Finally, a very important aspect of this proposal is that both bulks and allergens for in vivo diagnostics 173
will benefit from a highly reduced tax. This was prompted by the restricted market for many of the in 174
Draft
8
vivo diagnostic products, which would not make feasible their registration at full tax. Implementation 175
of official batch release is not planned initially, but it cannot be ruled out for the future. 176
Once the regulation comes into force, no product others than the real NPPs will be expected to be on 177
the market without previous authorization. 178
179
Additional approaches in the EU 180
There are numerous additional approaches by the EU member states. For example, in France, a 181
national decree (12) was implemented in 2004 that resulted in the selection of clinically relevant 182
allergen sources based on published evidence in relation to data available on AIT efficacy for these 183
allergen sources. Only products that contained allergen from these sources were allowed to be 184
placed on the market based on the exemptions allowed by Art. 5 of Directive 2001/83/EC. The 185
appropriate pharmaceutical quality must still be secured for these products. 186
187
188
References189
1. Englert L, May S, Kaul S, Vieths S. The therapy allergens ordinance ("Therapieallergene‐190
Verordnung"). Background and effects. Bundesgesundheitsblatt, Gesundheitsforschung, 191
Gesundheitsschutz 2012;55:351‐357. 192
2. Bonertz A, Kaul S, Ruoff C, Vieths S. Die Umsetzung der Therapieallergene‐ Verordnung bei der 193
spezifischen Immuntherapie. Eine Bestandsaufnahme. AL 2014;37:395‐402. 194
3. Pfaar O, Bachert C, Bufe A, Buhl R, Ebner C, Eng P et al. Guideline on allergen‐specific 195
immunotherapy in IgE‐mediated allergic diseases: S2k Guideline of the German Society for 196
Allergology and Clinical Immunology (DGAKI), the Society for Pediatric Allergy and 197
Environmental Medicine (GPA), the Medical Association of German Allergologists (AeDA), the 198
Austrian Society for Allergy and Immunology (OGAI), the Swiss Society for Allergy and 199
Immunology (SGAI), the German Society of Dermatology (DDG), the German Society of Oto‐ 200
Rhino‐Laryngology, Head and Neck Surgery (DGHNO‐KHC), the German Society of Pediatrics and 201
Adolescent Medicine (DGKJ), the Society for Pediatric Pneumology (GPP), the German 202
Respiratory Society (DGP), the German Association of ENT Surgeons (BV‐HNO), the Professional 203
Federation of Paediatricians and Youth Doctors (BVKJ), the Federal Association of 204
Pulmonologists (BDP) and the German Dermatologists Association (BVDD). Allergo journal 205
international 2014;23:282‐319. 206
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4. The Council of the European Communities. Council Directive 89/342/EEC of 3 May 1989 207
extending the scope of Directives 65/65/EEC and 75/319/EEC and laying down additional 208
provisions for immunological medicinal products consisting of vaccines, toxins or serums and 209
allergens, 1989: Official Journal of the European Communities. 210
5. D.M. 13 dicembre 1991 ‐ Disposizioni sui radiofarmaci e sugli allergeni. In: Gazz. Uff. , n. 297 211
1991. 212
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Directives 65 /65 / EEC, 75 / 318 / EEC and 75 / 319/ EEC on the approximation of provisions laid 214
down by law, regulation or administrative action relating to proprietary medicinal products: 215
Official Journal of the European Communities. 216
7. Minister van Volksgezondheid, Welzijn en Sport. Regeling Geneesmiddelenwet. 217
http://wetten.overheid.nl/BWBR0022160/geldigheidsdatum_03‐09‐2014#Hoofdstuk3 (Dec 14, 218
2016). 219
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http://www.igz.nl/onderwerpen/geneesmiddelen/productie_en_distributie_geneesmiddelen/a221
anvragen_toestemming/vragen_over_afleveren_ongeregistreerde_geneesmiddelen.aspx (Dec 222
14, 2016). 223
9. Nederlandse Vereniging voor Kindergeneeskunde. IGZ beperkt gebruik allergeenpreparaten. 224
http://www.nvk.nl/Nieuws/tabid/606/articleType/ArticleView/articleId/51/IGZ‐beperkt‐225
gebruik‐allergeenpreparaten.aspx (Dec 14, 2016). 226
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https://www.cooperatievgz.nl/zorgaanbieders/zorgsoorten/farmaceutische‐zorg/machtigingen 228
(Dec 14, 2016). 229
11. Zorginstituut Nederland. Genees‐ en hulpmiddelen Informatie Project (GIP‐)databank. 230
https://www.gipdatabank.nl (Dec 14, 2016). 231
12. Décret n8 2004‐188 du 23 février 2004 relatif auch allergènes préparés spécialement pour un 232
seul individu et modifiant le code de la santé publique. 233 Draft