1
New structure of MEDDEV 2_7_1 texts 1
All texts copied/pasted from the 2.7.1 draft dated 2013-06-03 (and distributed to the CIE meeting in 2
June 2013) have blue text colour; changes in those texts are “tracked” as well as new additions. 3
Texts excluded from the 2.7.1 draft dated 2013-06-03 have been moved to a separate document 4
named “Texts excluded from 2013_06_03 draft”. 5
=============================================================================== 6
Text on front page (same as on several other MEDDEVs): 7
The present guidelines are part of a set of guidelines relating to questions of application of EUEC-8
Directives on MEDICAL DEVICEs. They are legally not binding. The guidelines have been carefully 9
drafted through a process of intensive consultation of the various interested parties (competent 10
authorities, Commission services, industries, notified bodies, other interested parties) during which 11
intermediate drafts were circulated and comments were taken up in the document. Therefore, this 12
document reflects positions taken by representatives of interested parties in the MEDICAL DEVICEs 13
sector. 14
Contents 15
(To be filled in when new chapter structure has been reviewed) 16
1. Introduction 17
Pursuant to section 6a of Annex I to Directive 93/42/EEC and to section 5a of Annex 1 to Directive 18
90/385/EEC), the demonstration of conformity with Essential Requirements must include a clinical 19
evaluation conducted in accordance with Annex X to Directive 93/42/EEC or with Annex 7 to 20
Directive 90/385/EEC. If clinical data are not required for demonstration of conformity, a written 21
justification is included in the clinical evaluation report in accordance with section 1.5 of Annex 7 to 22
Directive 90/385/EEC and section 1.1d of Annex X to Directive 93/42/EEC. This is applicable for all 23
classes of medical devices. The clinical evaluation report (CER) is part of the technical documentation 24
for the medical device. 25
2. Scope 26
The primary purpose of Medical Device guidelines (MEDDEV) is to promote a common approach and 27
interpretation of the medical device directives. On certain issues not addressed in the Directives, 28
national legislation may be different from these guidelines. 29
The primary purpose scope of this document MEDDEV is to provide manufacturers and notified 30
bodies with guidance on how to conduct and document the clinical evaluation of a medical device as 31
part of the conformity assessment procedure prior to placing a medical device on the market as well 32
as to support its ongoing marketing. It is also intended to provide guidance to regulators and other 33
stakeholders when assessing clinical evaluation reports provided by manufacturers. 34
2
The guidance contained within this document is intended to apply to medical devices generally and 35
the device component of combination products. It is not intended to cover in vitro diagnostics. 36
These guidelines incorporate changes introduced by Directive 2007/47/EC amending Council 37
Directive 90/385/EEC and Council Directive 93/42/EEC. This document and is a revision of an earlier 38
document published in December 2009 as MEDDEV 2.7.1. The latest version of the guidelines should 39
always be used. This revision of these guidelines has: 40
streamlined the interpretation of the definitions of clinical data, clinical evidence and clinical 41
evaluation to promote a homogenous interpretation and further understanding of the 42
requirements of Directive 93/42/EEC concerning medical devices and Directive 90/385/EEC 43
relating to active implantable medical devices. 44
rephrased some paragraphsupdated texts to reflect the above listed changes and changed 45
the chapter structure. 46
described key aspects of clinical evaluation 47
3. References 48
49
European Legislation 50
Council Directive 90/385/EEC of 20 June 1990 concerning active implantable medical devices, as 51
amended by Directive 2007/47/EC of the European Parliament and of the Council of 5 September 52
2007 53
Council Directive 93/42/EEC of 14 June 1993 concerning medical devices, as amended by Directive 54
2007/47/EC of the European Parliament and of the Council of 5 September 2007 55
56
International standards 57
EN ISO 14155:2011 Clinical investigation of medical devices for human subjects – Good clinical 58
practice 59
EN ISO14971:2012 Medical devices – application of risk management to medical devices. 60
61
European guidance documents 62
MEDDEV 2.7/2 Guide for Competent Authorities in making an assessment of clinical 63
investigation notification 64
MEDDEV 2.7/3 Guidelines on medical devices: Clinical investigations, Serious Adverse Event 65
reporting under Directives 90/385/EEC and 93/42/EEC 66
MEDDEV 2.7/4 Guidelines on Clinical investigations: a guide for manufacturers and notified 67
bodies 68
Kommentiert [vs1]: Better wording is needed? Reworded?
Rephrased?
3
MEDDEV 2.10/2 Designation and monitoring of Notified Bodies within the framework of EC 69
Directives on medical devices 70
MEDDEV 2.12/2 Guidelines on post-market clinical follow up studies 71
NBOG BPG 2009-1 Guidance on design dossier examination and report content 72
http://www.nbog.eu/resources/NBOG_BPG_2009_1.pdf 73
NBOG BPG 2009-4 Guidance on NB‘s Tasks of Technical Documentation Assessment on a 74
Representative Basis 75
http://www.nbog.eu/resources/NBOG_BPG_2009_4_EN.pdf 76
NBOG CL2010-1 Checklist for audit of notified bodies review of clinical data/clinical 77
evaluation 78
REMARK. Check if NBOG checklist CL2010 and the Checklist in Appendix F of this MEDDEV should be 79
merged and/or better aligned 80
81
GHTF final documents archived on IMDRF website 82
SG1/N011:2008 Summary Technical Documentation for Demonstrating Conformity to the 83
Essential Principles of Safety and Performance of Medical Devices (STED) 84
SG1-N44:2008 Role of Standards in the Assessment of Medical Devices 85
SG1/N029:2005 Information Document Concerning the Definition of the Term “Medical 86
Device” 87
SG1/N040:2006 Principles of Conformity Assessment for Medical Devices 88
SG1-N41R9:2005 Essential Principles of Safety and Performance of Medical Devices 89
SG5/N1R8:2007 Clinical Evidence – Key Definitions and Concepts 90
SG5/N2R8:2007 Clinical Evaluation 91
92
Useful links to websites: 93
MEDDEV guidelines
http://ec.europa.eu/health/medical-
devices/documents/guidelines/index_en.htm
IMDRF
www.imdrf.org
EMBASE
a scientific database
http://www.embase.com/home
PubMed
a scientific database
http://www.ncbi.nlm.nih.gov/pubmed
Kommentiert [sci2]:
(Discussed by CA participants during 13.2.2013 meeting, and during
22.4.2013 CAMD Clinical TF teleconference)
http://www.nbog.eu/resources/NBOG_BPG_2009_1.pdf
http://www.nbog.eu/resources/NBOG_BPG_2009_4_EN.pdf
http://www.embase.com/home
http://www.ncbi.nlm.nih.gov/pubmed
4
94
4. Definitions 95
96
Adverse Event Any untoward medical occurrence, unintended disease or injury, or
untoward clinical signs (including abnormal laboratory findings) in
subjects, users or other persons, whether or not related to the
investigational medical device.
Notes: This definition includes events related to the procedures
involved. For users or other persons, this definition is restricted to
events related to investigational medical devices. (EN ISO
14155:2011)Any untoward medical occurrence in a subject. Note: For
the purposes of this document, this is intended to include any adverse
event whether device related or not.
Bias Bias is a systematic deviation of an outcome measure from its true
value, leading to either an overestimation or underestimation of a
treatment’s effect. It can originate from, for example, the way
patients are allocated to treatment, the use of outcome measures
and/or subgroup analysis different from the Clinical Investigation Plan,
the way treatment outcomes are measured and interpreted, and the
recording and reporting of data.
Clinical (adjective) involving or concerned with the direct observation and
treatment of living patients
Clinical Data Safety and/or performance information that are generated from the
clinical use of a medical device in humans. (This term is further
explained in GHTF document SG5/N1R8:2007 Clinical Evidence – Key
Definitions and Concepts)
Clinical Evaluation A methodologically sound procedure to collect and analyse clinical
data pertaining to a medical device and to assess whether there is
sufficient clinical evidence to confirm compliance with relevant
essential requirements for safety and performance. (definition derived
from 1.1 and 1.1.1 of Annex X of MDD and Annex 7 of AIMD)
Clinical Evaluator
A qualified person (e.g. a physician) with documented
clinical experience,
experience of research or health technology assessments, and
knowledge of the design of the medical device under
assessment.
Clinical Evidence Clinical data of an amount and quality to guarantee the scientific
validity of the conclusions. as to prove the validity and accuracy1 of a
claim or a statement. (definition derived from 2.3.1 Annex X of MDD
and Annex 7 of AIMD)
Kommentiert [vs3]: Definition from Merriam-Webster medical
dictionary:
http://www.merriam-webster.com/medical/clinical
5
Clinical Evaluation
Report
The documentation of the clinical evaluation and its outcome.
(definition derived from 1.1b Annex X of MDD and 1.3 Annex 7 of
AIMD)
Clinical Investigation Any systematic investigation or study in or on one or more human
subjects, undertaken to assess the safety and/or performance of a
medical device. (MEDDEV 2.7/4 December 2010)
Clinical Investigation
Plan
Document that states the rationale, objectives, design and proposed
analysis, methodology, monitoring, conduct and record-keeping of the
clinical investigation. (EN ISO 14155:2011)
Clinical Performance Behaviour of a medical device or response of the subject(s) to that
medical device in relation to its intended use, when correctly applied
to appropriate subject(s). (EN ISO 14155:2011)
Clinical Safety Freedom from unacceptable risk, when using the device according to
the manufacturer’s Instructions for Use. [[Check definition]]
Conformity
Assessment
The systematic examination of evidence generated and procedures
undertaken by the manufacturer, under requirements established by
the Regulatory Authority, to determine that a medical device is safe
and performs as intended by the manufacturer and, therefore,
conforms to the Essential Requirements.
Device Deficiency Inadequacy of a medical device with respect to its identity, quality,
durability, reliability, safety or performance. NOTE Device deficiencies
include malfunctions, use errors, and inadequate labelling. (EN ISO
14155:2011)
Feasibility study A clinical investigation that is commonly used to capture preliminary
initial clinical data on the safety and/or performance of a medical
device (at an early or late stage of product design) to justify and
adequately plan for a pivotal study. adequately plan further steps of
device development, including needs for design modifications or
parameters for a pivotal study.
Harmonised
Standards
Standards published by the European Commission deemed to offer
the presumption of conformity to the Essential Requirements of the
Directives.
Preclinical data Data obtained relating to a device and not involving or concerned with
the direct observation and treatment of living patients. Examples of
preclinical data are bench testing data, verification/validation test
data and animal test data.
Pivotal study A clinical investigation adequately designed and powered to collect
definitive clinical evidence of benefits to the patients, clinical risks,
clinical performance, and/or clinical aspects of the usability of a
device for a specified intended use.
Risk Combination of the probability of occurrence of harm and the severity
Kommentiert [J4]: To align with the definition of safety in ISO
14971.
Kommentiert [sci5]:
Sugestion EUCOMED, 3.6.2013: This is contradictory with the risk
assessment standard that recommends evaluating the overall
balanace risk/ benefits.
Suggest ‘positive benfit risk ratio’
Kommentiert [sci6]: - Definition of feasibility and pivotal
studies added
(Change reviewed and confirmed by CA participants during
13.2.2013 meeting, transferred to definitions section and adapted
following suggestion of Italian CA, text presented for 22.4.2013
CAMD Clinical TF teleconference, modiefied according to input of
CAMD Clinical taskforce member)
Kommentiert [vs7]: Agree with AESGP that this MEDDEV should
not invite to product development in patients. See MDD Annex X 2.1
regarding the objectives of clinical investigations that is to verify the
essential requirements and also Annex VIII with the requirement of
a statement that the device in question conforms to the
essential requirements, i.e. the device should be ready for the CE-
marking except for the lack of clinical data. See suggested tracked
changes in the definition.
Kommentiert [RB8]: AESGP, 3.6.13: An clinical Investigation is
hereabove defined as any systematic investigation or study in or on
one or more human subjects, undertaken to assess the safety
and/or performance of a medical device. However, it is not justified
to perform a study on human subjects with devices in development.
Therefore the term “clinical” should be deleted.
6
of that harm
(EN ISO 14971:2012 Medical devices - Application of risk management
to medical devices)
Serious Adverse Event Serious Adverse Event (SAE)
Adverse event that:
a) led to a death,
b) led to a serious deterioration in health that either:
1) resulted in a life-threatening illness or injury, or
2) resulted in a permanent impairment of a body
structure or a body function, or
3) required in-patient hospitalization or prolongation of
existing hospitalization, or
4) resulted in medical or surgical intervention to
prevent life threatening illness or injury or permanent
impairment to a body structure or a body function.
c) led to fetal distress, fetal death or a congenital abnormality or birth
defect.
NOTE 1: This includes device deficiencies that might have led to a
serious adverse event if
a) suitable action had not been taken or
b) intervention had not been made or
c) if circumstances had been less fortunate.
These are handled under the SAE reporting system.
NOTE 2: A planned hospitalization for pre-existing condition, or a
procedure required by the Clinical Investigation Plan, without a
serious deterioration in health, is not considered to be a serious
adverse event.
(MEDDEV 2.7/3)
Technical
Documentation
The documented evidence, normally an output of the quality
management system that demonstrates compliance of a device to the
Essential Requirements.
97
[[Add definitions for “sponsor, investigational medical device, USADE to name a few. Also, these 98
should be consistent with ISO 14155.]] 99
[[Efficacy, question asked by NSAI, 31.5.2013: : Should the definitions include one for efficacy to 100
highlight the difference compared with performance, as these definitions are often interchanged but 101
have different meanings.]] 102
5. Abbreviations 103
AIMD COUNCIL DIRECTIVE of 20 June 1990 on the approximation of the laws of the
Member States relating to active implantable medical devices (90/385/EEC)
as amended by Directive 2007/47/EC of the European Parliament and of the Council
of 5 September 2007
Kommentiert [sci9]:
Suggested by EUCOMED, 3.6.2013
7
CAPA corrective action and preventive action
CER clinical evaluation report
ER essential requirements of AIMD and MDD
GHTF The Global Harmonization Task Force
The organisation and their website is no longer operational
IFU instructions for use
IMDRF International Medical Device Regulators Forum
A voluntary group of medical device regulators from around the world who build on
and continue the work of GHTF to accelerate international medical device
regulatory harmonization and convergence.
MEDDEV acronym used for Medical Device guidelines published by the European Commission
MDD COUNCIL DIRECTIVE 93/42/EEC of 14 June 1993 concerning medical devices
as amended by Directive 2007/47/EC of the European Parliament and of the Council
of 5 September 2007
PMCF post market clinical follow-up
104
6. The roles of the clinical evaluation 105
106
Clinical evaluation is a methodologically sound procedure to collect and analyse clinical data 107
pertaining to a medical device, and to assess whether there is clinical evidence to confirm 108
compliance with relevant the analysis of clinical data pertaining to a medical device in order to assess 109
whether there is clinical evidence to verify compliance with Essential Requirements of the medical 110
devices directives, in particular with the following requirements that relate to clinical properties of 111
devices (benefits to the patient, risks, clinical performances described by the manufacturer and side-112
effects): 113
Annex 1 (sections 1, 2, 5) of Directive 90/385/EEC relating to active implantable medical devices, 114
Annex I (sections 1, 3, 6) of Directive 93/42/EEC concerning medical devices. 115
The clinical evaluation is an ongoing process intended to assert that the clinical properties of the 116
device and their acceptability are based on clinical evidence throughout the life cycle of the medical 117
device. 118
The clinical evaluation has several important roles: 119
Premarket research and development 120
8
The clinical evaluation will document the medical purpose of the medical device in its clinical context. 121
The clinical evaluation report can also identify if there are clinical data from equivalent devices that 122
can be used for conformity assessment. Another role is to determine if clinical investigations are 123
needed and if so, specify what clinical data needs to be generated before a clinical investigation is 124
planned. The clinical evaluation report can also give important information to the risk management 125
on risks and other safety issues relating to equivalent or similar devices. 126
CE marking process 127
The role of the clinical evaluation during the CE marking process is to document that there are clinical 128
evidence to confirm conformity with essential requirements (ER). 129
Post market surveillance 130
The clinical evaluation will regularly verify, with input from the post market surveillance, that there is 131
still clinical evidence to confirm the ER. This includes e.g. to verify that all undesirable side-effects, 132
previously known or new emerging, still constitute an acceptable risk when weighed against the 133
performances intended. If risks of undesirable side-effects are no longer acceptable when weighed 134
against the performances intended, or risks not acceptable when weighed against the benefits to the 135
patient, or risks not compatible with a high level of protection of health and safety, the device is not 136
in conformity with ER and no further devices can be CE-marked. 137
138
9
Flow chart for the work flow and the role of the clinical evaluation: 139
Numbered activities correspond to the chapters in this MEDDEV. Activities that are not numbered 140
are not within the scope of this MEDDEV. 141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
8. Describe the medical device
9. Specify performance and claims
10. Make a literature review
12. Assess if clinical data confirm
the essential requirements (ER)
13. Produce the
Clinical evaluation report
14. Update the Clinical evaluation report
with clinical data from PMS and PMCF:
- Periodically
- In between when warranted
Is the device
pre market?
Are clinical risks
acceptable so
far?
Continue
process to CE
marking
Redesign and/or
change intended
performance and
claims
Clinical
investiga-
tion
Are there still clinical
evidence to confirm
the ER and are risks
acceptable?
No further devices
can be CE marked
Yes
Risk
Management
Risk
Management
No
Yes
Yes
Yes
No
No
No
11. Summarise all clinical data for
the device under assessment
Risk management
and CAPA process
Clinical
evidence to
confirm ER?
10
187
7. Equivalence 188
Pursuant to Annex X of Directive 93/42/EEC and Annex 7 of Directive 90/385/EEC the evaluation of 189
clinical data, i.e. the clinical evaluation, where appropriate taking account of any relevant 190
harmonised standards, must follow a defined and methodologically sound procedure based on: 191
1. Either a critical evaluation of the relevant scientific literature currently available relating to 192
the safety, performance, design characteristics and intended purpose of the device, where: 193
there is demonstration of equivalence of the device to the device to which the data 194
relates, and 195
the data adequately demonstrate compliance with the relevant essential requirements. 196
2. Or a critical evaluation of the results of all clinical investigations made. 197
3. Or a critical evaluation of the combined clinical data provided from 1 and 2. 198
Clinical, technical and biological characteristics should usually be taken into consideration for the 199
demonstration of equivalence: 200
o Clinical: Used for the same clinical condition or purpose (including similar severity and stage 201
of disease), at the same site in the body, in a similar population (including age, anatomy, 202
physiology); have similar relevant critical performance according to the expected clinical 203
effect for a specific intended use. 204
o Technical: Be of similar design; used under similar conditions of use; have similar 205
specifications and properties (e.g. physicochemical properties such as intensity of energy, 206
tensile strength, viscosity, surface characteristics, wavelength); use similar deployment 207
methods (if relevant); have similar principles of operation and critical performance 208
requirements. 209
o Biological: Use same or similar materials or substances in contact with the same human 210
tissues or body fluids. 211
All three characteristics need to be fulfilled and These characteristics should be similar to such an 212
extent that there would be no clinically significant difference in the performance and safety of the 213
device. 214
Attention is needed to avoid bias if data on devices/interventions from many years ago is intended to 215
be used for equivalence assessment. There may be many confounding factors between patient 216
groups of that time and today’s patient groups, e.g. regarding advancement of sickness, risk factors 217
known today but not controlled for in older data, concomitant medications, concomitant diseases, 218
already received therapies/interventions etc. This may lead to the conclusion that old data on a 219
device/intervention is not equivalent to the use of the device today and therefore may not prove 220
safety and performance of a device today. 221
222
11
8. Device description 223
The description of the medical device under assessment should be detailed enough to allow for 224
assessment of equivalence to other devices described in the scientific literature. The description, 225
included in the CER, should contain the following topics: 226
o Intended use including the exact medical indications 227
Organs/parts of the body 228
Diseases/patient populations 229
Adults/infants 230
In hospital use/home care/other 231
Intended user 232
Contraindications 233
o General description of the medical device including the techniques used and the technical 234
specifications. 235
o Materials used in the device with focus on materials coming in contact (directly or indirectly) 236
with the patient/user, description of body parts concerned. 237
9. Device performance 238
The devices must achieve the performances intended by the manufacturer. As a basis for further 239
steps in the clinical evaluation, including the literature search, the intended performances of the 240
device must be documented. This includes the intended technical performance of the device, its 241
clinical benefits and any claims regarding clinical properties of the device that the manufacturer 242
intends to make use of. 243
10. Literature review 244
245
10.1 The relation between the Literature report and the risk management of the device 246
Documentation from the risk management of the device, e.g. a hazard identification list and 247
identified clinical risks from the risk analysis, is used as input for the literature search and for the 248
review to ensure that already identified safety issues will be covered in the literature review report. 249
The completed literature review report, on similar and equivalent devices (or the device under 250
assessment if applicable), is used as input to the risk management process for identification of 251
possible performances, benefits, hazards and other safety issues, as well as acceptable risks in terms 252
of type, severity, and incidence/frequency. 253
10.2 Literature search 254
10.2.1 Data generated through literature search 255
Literature searching will be used to identify published clinical data that is not in the possession of the 256
manufacturer and that may assist the manufacturer in the clinical evaluation.to establish acceptable 257
performance and safety of a medical device. The data generated through literature searching may 258
12
relate directly to the device in question (e.g. reports of clinical investigations of the device in 259
question that have been performed by third parties, adverse event reports) and/or, to equivalent 260
devices. All relevant clinical data must be considered irrespective of the findings (both supporting 261
and not supporting safety and performance). 262
The literature search will also provide data on current interventions/therapies for the intended 263
patient population (state of the art) to give input to the assessments of acceptable benefit/risk ratios 264
and what is currently considered as high level of protection of health and safety.or to devices or 265
therapies that define the state of the art in the corresponding medical field. 266
For some devices, clinical data generated through literature searching will represent the greater part 267
(if not all) of the clinical evidence. Thus, when conducting a literature review evidence should be 268
provided that a comprehensive search has been conducted and equivalence to the device in question 269
has been established. 270
Input for the literature search and review report is the device description and the intended device 271
performance and any claims the manufacturer wants to make use of, see chapters 8 and 9 of this 272
MEDDEV. Also information from the risk management process is needed as input, see chapter 10.1. 273
10.2.2 The key elements of literature search 274
The search strategy should be based on carefully constructed review questions (including patient 275
population, intervention, comparator/comparison and outcomes, comparator, e.g. so called PICO 276
process). A protocol should be developed to identify, select and collate relevant publications to 277
address these questions. This should be developed and executed by persons with expertise in 278
information retrieval, having due regard to the scope of the clinical evaluation set out by the 279
manufacturer. 280
The involvement of information retrieval experts will help to maximise data retrieval. 281
The literature search protocol should include: 282
- the sources of data that will be used and a justification for their choice; 283
- the extent of any searches of scientific literature databases (the database search strategy); 284
- the extent of any internet searches including the search strategy; 285
- the selection/criteria to be applied to published literature and justification for their choice; and 286
- strategies for addressing the potential for duplication of data across multiple publications; 287
288
For literature sources, as a minimum, the scientific databases EMBASE as well as PubMed should be 289
searched to ensure a thorough search of European journals not indexed in PubMed and to be able to 290
search by device name and manufacturer. 291
Search on the internet may for some devices also provide valuable data, e.g. national registry 292
reports. 293
Once the literature search has been executed, a report should be compiled to present the results of 294
the search. A copy of the protocol should be included and any deviations noted. A possible format for 295
the literature search report is located at Appendix A. 296
13
It is important that the literature search is documented to such a degree that the methods can be 297
appraised critically, the results can be verified, and the search reproduced if necessary. A possible 298
methodology is presented in Appendix B. 299
With respect to the clinical evaluation, it is important that the clinical evaluator be able to assess the 300
degree to which the selected papers reflect the intended application/use of the device, etc. The 301
selection of literature should be objective and justified, i.e. include all relevant both favourable and 302
unfavourable data. 303
304
10.3 Appraisal of clinical data 305
The purpose of undertaking appraisal of the data is to understand the merits and limitations of the 306
clinical data. Each piece of data is appraised to determine its suitability to address questions about 307
the device, and its contribution to demonstrating the safety and performance of the device (including 308
any specific claims about clinical properties of the device the manufacturer intends to make use of). 309
10.3.1 What should be covered by the appraisal? 310
The data needs to be suitable for appraisal. It should be assessed for its quality and for its relevance 311
to the device in question (i.e. the data demonstrating the safety and performance of the device must 312
be either generated for the device in question or for an equivalent device) and its intended use. In 313
addition, any reports or collations of data should contain sufficient information for the evaluator to 314
be able to undertake a rational and objective assessment of the information and make a conclusion 315
about its significance with respect to the performance and/or safety of the device in question, in line 316
with essential requirements. 317
Further appraisal needs to be undertaken to determine the contribution of each data subset to 318
establishing the safety and performance of the device. The evaluator should examine the methods 319
used to generate/collect the data and assess the extent to which the observed effect (performance 320
or safety outcome(s)) can be considered to be due to intervention with the device or due to 321
confounding influences (e.g. natural course of the underlying medical condition, concomitant 322
treatment(s)) or bias. 323
There is no single, well established method for appraising clinical data. Therefore, the evaluator 324
should identify, in advance, and justify the appropriate criteria for the appraisal to be applied for a 325
specific circumstanceliterature review. 326
These criteria should be applied consistently. Some examples to assist with the formulation of 327
criteria are given in Appendix C. 328
For many lower risk devices and devices based on long standing technology, the available data may 329
be qualitative rather than quantitative in nature, so the evaluation criteria should be adjusted 330
accordingly. The criteria adopted for the appraisal should be justified by the evaluator. 331
Although there will be some overlap of safety and performance data, the data should be categorised 332
to allow for separate analysis. Additional categories may also be needed, depending on the nature 333
Kommentiert [J10]: As opposed to defining the state of the art
14
and intended use of the device to address additional claims. The data should also be weighted 334
according to its relative contribution. An example of a method of data appraisal is shown in Appendix 335
D. 336
[[CAMD Clinical TF: Aspect covered in the grading? Multiple publications of same data/study 337
population]] 338
339
10.3.2 Scientific validity of clinical investigations and publications 340
Data that are not methodologically sound should not be used as a basis for evaluating clinical properties 341
of medical devices. If an evaluation is based on data such as the following, or if important information is 342
missing, this shall be described and justified in the clinical evaluation report: 343
o Omission of a control arm in situations with probable bias due to regression to the mean or 344
similar influences2: This includes use of non-controlled clinical trials for obtaining evidence of 345
efficacy in pathologies with a self-limiting natural course, fluctuating symptoms, subjective 346
symptoms, with patients likely to have used effective concomitant therapies, in seasonal 347
pathologies. 348
o Use of improper pass/fail criteria: When outcomes are multifactorial and do not solely 349
depend on the device, favourable results obtained by comparing historical data from 350
unfavourable settings with those in optimised investigational settings can be misleading. 351
Even harmful interventions may seem beneficial when inadequate pass/fail criteria are used. 352
o Lack of proper randomisation of patients in controlled studies: If patients are attributed to 353
the different study arms in a non random manner (e.g. by the investigator or his study 354
personnel, by patient preferences), selection bias is likely to influence results. 355
o Improper statistical methods: This includes reports and publications that do not disclose the 356
results the original clinical study protocol was intended to obtain, present results the original 357
clinical investigation plan was not designed to address and do not describe how the situation 358
was dealt with statistically, assume significance by omitting corrections for multiple 359
comparisons, or do not describe statistical methods. 360
o Improper collection of mortality and serious adverse events data: Demonstration of 361
benefits and safety can be based on mortality or other events that will limit the ability of 362
subjects to live in their homes and be contacted. In clinical investigations having such 363
endpoints, after a missed contact with a study subject, attempts should be made to contact 364
the subject. When these attempts fail, other persons or institutions should be contacted in 365
order to investigate the subject’s outcome. Adequate procedures for follow-up should be 366
described, numbers of subjects lost to follow-up should be fully disclosed in reports and 367
publications. When subjects cannot be contacted and their outcomes cannot be identified, 368
the subjects should be considered to meet the adverse endpoint or missing data dealt with 369
e.g. sensitivity analysis. 370
2 Example: Non-controlled observational study of an active medical device in acute back pain which
demonstrates patients feel significantly better days to weeks after the device was used. The condition
being self limiting, the results are in line with the natural course of an episode of acute back pain and
allow no conclusions regarding the efficacy of the device. In this population, bias is also probable in
this indication due to concomitant use of effective and readily available drugs.
15
Papers considered unsuitable for demonstration of performance because of poor study design or 371
inadequate analysis may still contain data suitable for assessing the safety of the device or the state 372
of the art. 373
It is recognised that, where manufacturers source clinical investigation data reported in the scientific 374
literature (i.e. investigations of either the device in question or equivalent devices that are 375
undertaken by a third party), the documentation readily available to the manufacturer for inclusion 376
in the clinical evaluation is likely to be no more than the published paper itself. Some of the above 377
listed detail of information may be missing in a publication, and shall be verified to the extent it is 378
available to a third party. 379
380
381
10.4 Make the literature review report 382
383
The following documentation should be included in the literature review report: 384
- the literature search protocol; 385
- the literature search report; and 386
- published articles and other references identified as being relevant to the device in question and 387
suitable for evaluation. 388
389
Copies of the actual papers and references are necessary to allow the evaluator to review the 390
methodology employed (potential sources of bias in the data), the reporting of results and the 391
validity of conclusions drawn from the investigation or report. Abstracts may lack sufficient detail to 392
allow these issues to be assessed thoroughly and independently. 393
394
The literature review should cover (non exclusive list): 395
a) All medical conditions covered by the intended use of the device 396
- Frequency of the condition and populations affected 397
- Condition severity or range of severities 398
- Consequences 399
- State of the art diagnoses or state of the therapy and management (depending on the purpose of 400
the device under assessment) 401
- Benefits of current approaches 402
- Current risks, drawbacks and limitations 403
404
b) Similar devices including the device under assessment if applicable 405
- Identify, from the objectively selected publications, similar devices on the market with regarding 406
the techniques used, materials in the device and the intended use (purpose and limitations) and 407
limit the review to articles concerning similar devices. 408
16
- If the literature review is an update pertaining to a medical device already on the market, 409
identify if there are publications concerning this device and that may not be in the 410
manufacturer’s possession. 411
- Compare all properties listed in chapter XXX of this MEDDEV (properties that are relevant for 412
establishing whether there is equivalence) in the device under assessment and the similar 413
devices 414
- Assess the scientific quality (appraisal of data, level of evidence) of the articles 415
- Identify if equivalence to CE marked devices can be established. 416
- Describe the performances and benefits for the equivalent devices in terms of outcome etc. and 417
statistical assessments/descriptions to show the scientific validity of the conclusions. 418
- Describe all the hazards and side-effects, both of the equivalent devices and of the 419
method/procedure used with the devices, in terms of the nature, severity, incidence/frequency, 420
development over time and outcome. 421
- Describe the performances, benefits and all hazards and side-effects published on the device 422
under assessment. 423
- Describe performances, benefits, hazards, side-effects and other safety issues of similar devices if 424
it is reasonable that it may be relevant for the hypothesis regarding the manufacturer’s medical 425
device. 426
427
11. Summarise all clinical data for the device under assessment 428
429
All clinical data that the manufacturer is in possession of is suggested to be summarised together, 430
even if parts of it, e.g. results of an investigation, has been published. Avoid duplication/overlap of 431
data between the literature review report and the summary of the manufacturer’s clinical data for 432
the device under assessment. 433
11.1. Identify all clinical data already obtained with the device under assessment 434
Potential sources of clinical data (non exclusive list): 435
- the manufacturers own clinical investigations (pre- and post-market clinical investigations, PMCF) 436
- clinical investigations carried out by customers or others 437
- clinical data from e.g. national quality registries on devices 438
- vigilance data 439
- complaints 440
- use under humanitarian exemptions 441
- other data 442
443
11.1.1 Clinical investigations 444
High risk devices, those based on technologies where there is little or no experience, and those that 445
extend the intended purpose of an existing technology (i.e. a new clinical use) are most likely to 446
require clinical investigation data. Therefore, clinical investigations are required unless it can be duly 447
justified to rely on existing clinical data alone, as stated in the annex X of Directives 93/42/EEC and 448
annex 7 of 90/385/EEC as amended. The manufacturer will need to give consideration to the 449
advantages and limitations of each data type and justify their use properly. 450
17
The guidance included within this section applies to cClinical investigations carried out by or on 451
behalf of a manufacturer specifically for the purposes of conformity assessment in accordance with 452
the applicable European medical device directive . Such clinical investigations are generally expected 453
to be designed, conducted and reported in accordance with EN ISO 14155 Clinical investigation of 454
medical devices for human subjects – Good clinical practice, or to a comparable standard, and in 455
compliance with local regulations. 456
Another important consideration for the evaluation will be to assess whether the conduct of the 457
investigation was in accordance with the current applicable ethical standards that have their origin in 458
the Declaration of Helsinki and in accordance with applicable regulations. Clinical investigations not 459
in compliance with applicable ethical standards or regulations should be rejected. The reasons for 460
rejection of the investigation should be noted in the report. Compliance with EN ISO 14155 ensures 461
that the above expectations have been met. 462
463
464
What are the types of clinical investigations?Feasibility studies versus pivotal studies 465
The type of clinical investigations used for clinical evaluations should be primarily pivotal studies that 466
adequately address regulatory questions related to the conformity assessment. Feasibility studies, 467
collecting initial data on safety and/or performance, are not intended to deliver clinical evidence to 468
prove conformity with the relevant essential requirementsanswers to regulatory questions. 469
Therefore, while observations made in feasibility studies can complement such data, feasibility 470
studies alone are not normally considered to be a valid basis for demonstration of compliance to the 471
medical devices directives. If feasibility studies are used for this purpose, reasons shall be explained 472
in the clinical evaluation report. 473
What clinical investigation documentation/data should be used in the clinical evaluation? 474
Where a clinical investigation has been carried out by or on behalf of a manufacturer, it is expected 475
that documentation relating to the design, ethical and regulatory approvals, conduct, results and 476
conclusions of the investigation needed for the clinical evaluation will be available for consideration 477
by the clinical reviewer and the Notified Body, as appropriate. These may include: 478
- the original clinical investigation plan; 479
- clinical investigation plan amendments and the rationale for these changes; 480
- the relevant Ethics Committee(s) documentation, opinion(s) and comments for each; 481
- investigation site, including a copy of the approved informed consent form(s) and patient 482
information documents; 483
- case report forms, monitoring and audit records; 484
- Regulatory Authority approvals and associated correspondence as required by applicable 485
regulations; and 486
- the original signed and dated final report. 487
488
The clinical investigation plan sets out how the study was intended to be conducted. It contains 489
important information about the study design such as the selection and assignment of participants to 490
treatment, masking (blinding of participants and investigators) and measurement of responses to 491
Kommentiert [vs11]: Interesting comment from Eucomed. How
do we write to promote two goals:
1. Invite to already when planning a pivotal clinical investigation,
plan for a PMCF study, i.e. get patient informed consent etc. from
the beginning. In that case an “interim report” would be fine.
2. Discourage the sudden use of an interim report for an untimely
CE-marking that is a recurrent problem.
Kommentiert [RB12]: EUCOMED, 3.6.2013:
Would there be any instances where an interim clinical report could
be used to support device conformance to the Medical Device
Directive? If yes, “interim clinical study report” as a line item should
be added.
This would allow for medical devices to be assessed for approval at
an interim point (e.g. agreed 3 year data could be presented for
device approval with long term follow-up of 5+ years as part of
PMS/PMCF).
18
treatment, which may be important sources of bias that can be assessed and discounted when trying 492
to determine the actual performance of the device. In addition the clinical investigation plan sets out 493
the primary and secondary endpoints, the intended participant follow-up, approaches to statistical 494
analyses (including planned subgroup analyses and whether per protocol (PP) or intent to treat (ITT)-495
analysis is planned with a justification) and methods for recording outcomes, which may impact on 496
the quality, completeness and significance of results obtained for performance and safety outcomes. 497
Also, by having the clinical investigation plan, its amendments and the final report available, the 498
evaluator will be able to assess the extent to which the investigation was conducted as planned and, 499
where deviations of from the original plan have occurred, the impact those deviations had on the 500
veracity of the data generated and the inferences that can be drawn about the performance and 501
safety of the device from the investigation. 502
The final clinical investigation report should be signed by its author(s) and appropriate reviewers to 503
provide assurance that the final report is an accurate reflection of the conduct and results of the 504
clinical investigation. 505
506
11.2 Assess the scientific quality (level of evidence) of the data 507
If the clinical evaluation is not based solely on clinical data from the scientific literature, it must 508
include a critical evaluation of the results of all clinical investigations made (Annex X, 1.1.2 of 509
Directive 93/42/EEC and Annex 7, 1.1.2 of Directive 90/385/EEC). Thus, the evaluation of the clinical 510
data from the device under assessment should be objective and e.g. not select data on the basis of 511
being favourable or not for the device. However, data that are not methodologically sound cannot be 512
used in the clinical evaluation for proving safety and performance. See chapter 10.3 and Appendix C 513
of this MEDDEV. 514
515
11.3 Summarise the benefits, risks, usability data and clinical properties intended to be used in 516
claims 517
The summary of clinical data for the device under assessment should include the following (non-518
exclusive list): 519
- Description of the performances and benefits for the device in terms of outcome etc. and 520
statistical assessments/descriptions to show the scientific validity of the conclusions. 521
- Descriptions of all the risks and side-effects, both of the device and of the method/procedure 522
used with the device, in terms of the nature, severity, incidence/frequency, development over 523
time and outcome. 524
- Regarding devices already CE-marked, description of any new emerging safety issues or side-525
effect detected from analysis of complaint or other reports. If data are e.g. incomplete or 526
conflicting this should give input to the design of PMCF studies and be further elaborated on in 527
the CER. 528
- Describe any usability problems detected during analysis of clinical investigations, complaint 529
reports or other reports? 530
- Summarise data to address/answer any questions posed from the risk management. 531
532
19
12. Assessment of conformity with essential requirements 533
534
The goal of the analysis stageassessment is to determine if the appraised clinical data sets available 535
for a medical device collectively demonstrate compliance with essential requirements. The level of 536
clinical evidence needed to demonstrate compliance with essential requirements should be justified. 537
Usually a higher level of clinical evidence is justified for medical devices of higher risk and/or class. 538
The methods available for analysis of clinical data generally are either quantitative or qualitative. 539
Given the context within which most medical devices are developed (i.e. limited need for clinical 540
investigations because of incremental changes in device design and therefore high use of literature 541
and experience data), often qualitative (i.e. descriptive) methods will need to be used primarily to 542
address such incremental changes, if justified. 543
Any evaluation criteria developed and assigned during the appraisal stage of the clinical data can be 544
used to identify those sets of data which may be considered to be “pivotal” to the demonstration of 545
the performance and safety of the device, respectively. It may be useful to explore the results of the 546
pivotal datasets, looking for consistency of results across particular device performance 547
characteristics and identified risks. If the different datasets report similar outcomes, certainty about 548
the performance increases. If different results are observed across the datasets, it will be helpful to 549
determine the reason for such differences. Regardless, all data sets should be included. 550
As a final step the evaluator should consider the basis on which it can be demonstrated that the 551
combined data show: 552
- the device does not pose any undue safety concerns to either the recipient or end-user; 553
- any risks which may be associated with their intended use constitute acceptable risks when 554
weighed against the benefits to the patient and are compatible with a high level of protection of 555
health and safety; 556
- the device performs as intended by the manufacturer; and 557
- any undesirable side-effect constitutes an acceptable risk when weighed against the 558
performances intended. 559
560
Such considerations should take into account the number of patients exposed to the device, the type 561
and adequacy of patient monitoring, the number and severity of adverse events, the adequacy of the 562
estimation of associated risk for each identified hazard, the severity and natural history of the 563
condition being diagnosed or treated. The availability of alternative diagnostic modalities or 564
treatments and the risks and benefits associated with the current standard of care should also be 565
taken into consideration. 566
Below follows additional guidance to the assessment of the specific essential requirements. 567
Note, there may be additional essential requirement(s) that need support of clinical evidence for the 568
conformity assessment. 569
570
12.1 Conformity assessment with requirement on safety (MDD/AIMD ER1) 571
572
20
The product literature and instructions for use should be reviewed to ensure they are consistent with 573
the data and that all the hazards and other clinically relevant information have been identified 574
appropriately. 575
Input from the risk management and the use of standards 576
577
Risk management documents should determine if all identified hazards are fully covered by 578
harmonised standards or other relevant standards or if there are gaps needed to be covered by 579
clinical data. 580
Risk management documents should determine if all identified risks relating to patient treatment, 581
method pertaining to the device or risks relating to usability have been minimised or if there are 582
question marks regarding clinical risks that need to be solved. 583
584
Examples: 585
Electrical hazards should be covered by full compliance to EN 60601-1 and applicable collateral standards 586
regarding Medical electrical equipment etc. That the device will not compromise the safety and health of 587
patients or users and that risks are acceptable regarding electrical hazards do not need clinical data to be 588
proven. 589
Harmonised standards on usability (EN 62366 and if applicable EN 60601-1-6) are expected to be fully 590
applied to ensure that usability aspects are taken into consideration during the device development. 591
However they do not give guidance on a detailed level of design. Also, usability aspects are known to 592
cause or contribute to a large portion of incidents. Therefore, usually clinical data is needed to prove that 593
the risk of use error, due to the ergonomic features of the device and the environment in which the 594
device is intended to be used, has been reduced as far as possible. 595
596
Harmonised standards are generally expected to be applied in full. Technical developments may however 597
provide a higher level of safety than current harmonized standards. In such cases a higher level of safety 598
should be prioritised in order to meet the essential requirements on reducing the risks as far as possible 599
and that risk must be compatible with a high level of protection of health and safety. 600
601
12.2 Conformity assessment with requirement on acceptable benefit risk ratio 602
(MDD/AIMD ER 1) 603
604
It is expected 605
that the clinical evaluation demonstrates that any risks which may be associated with the 606
intended use are minimised and acceptable when weighed against the benefits to the patient 607
and are compatible with a high level of protection of health and safety; 608
21
that the instructions for use correctly describe the intended use of the device as supported 609
by clinical evidence; and 610
that the instructions for use contain correct information about usability aspectsto reduce the 611
risk of use error, information on residual risks and their management as supported by clinical 612
evidence (e.g. handling instructions, description of risks, warnings, precautions, 613
contraindications). 614
615
Assessment of the description of the intended use of the device 616
The product literature and instructions for use should be reviewed. The evaluators should assess if 617
the description foreseen by the manufacturer correctly identifies in which medical conditions and 618
target groups conformity with the relevant essential requirements has been demonstrated through 619
clinical evidence. When reading the instruction for use, there should be no uncertainties for users as 620
to the question if use in a given medical condition or target population is covered by the CE marking 621
or entirely falls under his own responsibility (off label use). 622
Assessment of the device’s clinical benefits of devicesto the patient 623
Examples of clinical benefits to the patient include but are not limited to the device’s impact on the 624
clinical management of patients, patient health and patient satisfaction, such as allowing a correct 625
diagnosis to be made, significantly improving quality of life (including by simplifying care), reducing 626
the probability of adverse outcomes, improving patient function, providing relief from symptoms. 627
Ideally, these parameters should be directly clinically relevant. In certain cases benefits can be 628
assumed when validated surrogate endpoints are met (such as obtaining certain results with 629
laboratory tests or measurements of anatomical or physiological properties). Defining specified 630
endpoints is indispensible for setting up clinical investigations and to properly perform the literature 631
review. Based on the current state of medical knowledge, the evaluators shall justify and document 632
the clinical relevance of endpoints used for a clinical evaluation of a device, including the validity of 633
all surrogate endpoints used. For diagnostic medical devices, a benefit may be assessed according to 634
the public health impact of a particular device, due to its ability to identify a specific disease and 635
therefore prevent its spread, to identify phases, stages, location, severity or variants of disease, 636
predict future disease onset, provide earlier diagnosis of diseases or specifics of diseases, or identify 637
patients more likely to respond to a given therapy. 638
The magnitude of the benefit(s) – benefit(s) are often assessed along a scale or according to specific 639
endpoints or criteria (types of benefits), or by evaluating whether a pre-identified health threshold 640
was achieved. The change in subjects’ condition or clinical management as measured on that scale, 641
or as determined by an improvement or worsening of the endpoint, is what allows to 642
determinedetermining the magnitude of the benefit(s) in subjects, the clinical relevance of which 643
must be discussed and justified. Variation in the magnitude of the benefit across a population may 644
also be considered. 645
The probability of the patient experiencing one or more benefit(s) – is another important aspect of 646
assessing benefits and the clinical performance of a device. Based on the clinical data provided, a 647
reasonable prediction (based on a sound statistical approach) of the proportion of "responders" out 648
of the target group or subgroups can be expected. The data may show that a benefit may be 649
experienced only by a small portion of patients in the target population, or, on the other hand, that a 650
22
benefit may occur frequently in patients throughout the target population. It is also possible that the 651
data will show that different patient subgroups are likely to experience different benefits or different 652
levels of the same benefit. If the subgroups can be identified, the device may be indicated for those 653
subgroups. In some cases, however, the subgroups may not be identifiable. Magnitude and 654
probability of clinical benefits will have to be put together when weighing benefits against risks. That 655
is, a large benefit experienced by a small proportion of subjects may raise different considerations 656
than does a small benefit experienced by a large proportion of subjects. For example, a large benefit, 657
even if experienced by a small population, may be significant enough to outweigh risks, whereas a 658
small benefit may not, unless experienced by a large population of subjects. 659
The duration of effect(s) (i.e., how long the benefit can be expected to last for the patient) – should 660
be predictable (maybe as a statistical distribution) on the basis of sound clinical data and appropriate 661
statistical approaches. Post Market Clinical Follow-up will be decisive to refine and corroborate 662
reasonable predictions over time. The mode of action may play an important role: Some treatments 663
are curative, whereas, some may need to be repeated frequently over the patient’s lifetime. To the 664
extent that it is known, the duration of a treatment’s effect may directly influence how its benefit is 665
defined. Treatments that must be repeated over time may introduce greater risk, or the benefit 666
experienced may diminish each time the treatment is repeated. 667
668
Assessment of the clinical risks of devices 669
To demonstrate the extent of the probable risk(s)/harm(s) the following factors - individually and in 670
the aggregate - will have to be addressed: 671
o Severity, types, number and rates of harmful events associated with the use of the device: 672
Device-related serious adverse events: Those events that may have been or were 673
attributed to the use of the device and produce an injury or illness that is life-674
threatening, results in permanent impairment or damage to the body, or requires 675
medical or surgical intervention to prevent permanent harm to the body. 676
Device-related non-serious adverse events: Those events that may have been or were 677
attributed to the use of the device and that do not meet the criteria for classification as a 678
device-related serious adverse event. 679
Procedure-related complications: Harms to the patient that would not be included under 680
serious or non-serious adverse events, and that do not directly result from use of the 681
device. For example, anesthetic-related complications associated with the implantation 682
of a device. 683
684
o Probability of a harmful event: 685
The proportion of the intended population that would be expected to experience a harmful 686
event; whether an event occurs once or repeatedly may be factored into the measurement 687
of probability. 688
o Duration of harmful events (i.e., how long the adverse consequences last): 689
23
Some devices can cause temporary, minor harm; some devices can cause repeated but 690
reversible harm; and other devices can cause permanent, debilitating injury. The severity of 691
the harm should be considered along with its duration. 692
o Risk from false-positive or false-negative results for diagnostic medical devices : 693
If a diagnostic device gives a false-positive result, the patient might, for example, receive 694
an unnecessary treatment and incur all the risks that accompany that treatment, or 695
might be incorrectly diagnosed with a serious disease. If a diagnostic device gives a false-696
negative result, the patient might not receive an effective treatment (thereby missing 697
out on the benefits that treatment would confer), or might not be diagnosed with the 698
correct disease or condition. The risks associated with false-positives and false-negatives 699
can be multifold, but have to be considered in light of probable risks. 700
It is also important to look at the totality of the harmful events associated with the 701
device. 702
The number of different types of harmful events that can potentially result from using 703
the device and the severity of their aggregate effect has to be considered. When multiple 704
harmful events occur at once, they have a greater aggregate effect. 705
706
Assessment of acceptability of the benefit-to-risk ratio 707
The evaluators will assess if the clinical data on benefits and risks are acceptable for all medical 708
conditions and target populations covered by the intended use when compared with the current 709
state of the art in the corresponding medical field. The current state of the art therefore needs to be 710
identified, possibly also relevant comparators. Evidence based data suitable for that purpose can be 711
found in scientific medical literature, medical guidelines, and in the assessments, systematic reviews, 712
meta-analyses of HTA- and EBM-Institutes and networks. If or when treatment comparability versus 713
accepted therapy is not available at the time of placing on the market, this should be clearly 714
described in the device information for use. 715
Even if a device cannot compete with an agreed first-line treatment or the best in class, it may add to 716
the portfolio of acceptable treatments, as even a first-line treatment will likely have 717
contraindications or non-responders. Devices, that might not be best-in-class, might provide clinical 718
evidence for an acceptable benefit/risk-ratio for specific, defined subgroups or even superior clinical 719
performance under specific conditions (e.g. emergency outdoor conditions). The position within the 720
treatment portfolio has to be specified properly in the IFU, clinical evaluation report, summary of 721
safety and clinical performance and other relevant documentation. 722
723
12.3 Conformity assessment with requirement on performance (MDD ER 3, AIMD 724
ER 2) 725
726
It is expected 727
24
that the device achieves its intended performance during normal conditions of use, and are 728
supported by suitable evidence (clinical performance includes all claims about clinical 729
properties of the device that the manufacturer intends to make use of) 730
731
Assessment of clinical evidence 732
The evaluators should assess whether clinical investigations have been defined in such a way as to 733
confirm or refute the manufacturer's claims for the device. These investigations must include an 734
adequate number of observations to guarantee the scientific validity of the conclusions. 735
736
12.4 Conformity assessment with requirement on acceptability of side-effects 737
(MDD ER 6, AIMD ER 5) 738
739
It is expected 740
that any undesirable side-effect constitutes an acceptable risk when weighed against the 741
performances intended. 742
743
Assessment of the side-effects of a device 744
In order to assess the acceptability of side-effects the nature and frequency of potential side-effects 745
need to be known, i.e. the clinical data should contain an adequate number of observations to 746
guarantee the scientific validity of the conclusions relating to side-effects. 747
Statistical example: 748
To have a reasonable probability (80%) of observing at least one event of a side-effect when 15 749
subjects are studied requires a side-effect with an actual probability of 0.10 (10%). I.e. if only 15 750
patients have been studied, there could theoretically from a statistical point of view, be a serious 751
side-effect with an actual probability of 10% that has not had a reasonable chance to be detected. 752
See table below with corresponding numbers for side-effects with an actual probability of 5% and 753
1%. 754
Case 1 Case 2 Case 3
Chance of observing 1 event, P 0,800 0,800 0,800
Actual probability of event, 0,102 0,050 0,010
n (number of subjects studied) 15 32 161
755
Lack of clinical data or too limited number of observations does not reveal if there are important 756
side-effects and can therefore not prove the acceptability of side-effects. 757
25
When assessing the acceptability of side-effects consideration has to be given to the state of the art 758
treatment/interventions and the patient’s other options to ensure that the treatment/intervention 759
with the device under assessment is compatible with a high level of protection of health and safety. 760
761
Devices allowing a therapeutic breakthrough 762
High potential benefits to patients may be present when there are no acceptable alternatives on the 763
market for a serious medical condition, and current interventions are inadequate or highly 764
burdensome or carry significant risks. The potential benefits may legitimate high level of 765
uncertainties, an early access to the market, and a clinical evaluation based on little clinical data, 766
and/or little long term data. The evaluator shall fully address the uncertainties and all consequences, 767
including 768
o The limitation of the intended use to the niche indication the product was developed for and 769
were risks and uncertainties where considered acceptable; 770
o inclusion in the instruction for use of correct descriptions of the limited intended use, the 771
current low level of experience, the large level of uncertainties, uncertainties about residual 772
risks ; 773
o the need for a stringent Post-Market Clinical Follow-up Plan (PMCF) plan that will allow to 774
rapidly gather more complete data in the post-market phase, and for frequent updates of the 775
clinical evaluation report, risk management file and instructions for use. 776
Devices entering the market subsequent to a therapeutic breakthrough 777
In case of a therapeutic breakthrough, clinical evidence is likely to rapidly grow in the post market 778
phase. When medical knowledge evolves, large uncertainties will no longer be acceptable. Late New 779
similar devices entering the market will have to meet the new state of the art in the corresponding 780
medical field. Manufacturers shall not assume devices can continue to enter the market with the 781
minimal dataset that was formerly acceptable for earlier productstherapeutic breakthrough 782
device(s). 783
784
13. Produce the Clinical evaluation report 785
786
At the completion of the clinical evaluation process a report should be compiled that outlines the 787
scope and context of the evaluation; the inputs (device description, intended 788
use/performance/claims, data from risk management, clinical data from literature review and/or 789
clinical investigations); the appraisal and analysis stagesof data; and conclusions about the safety, 790
and performance, including side-effects and benefit/risk assessment, for the device in question. 791
The clinical evaluation report should contain sufficient information to be read as a standalone 792
document by an independent party (e.g. Regulatory Authority or Notified Body). It is important that 793
the report outline: 794
26
o the technology on which the medical device is based, the intended use of the device and claims 795
about clinical properties of the device the manufacturer intends to make use of; 796
o the nature and extent of the clinical data that has been evaluated together with relevant 797
documentation of the literature search and the clinical investigations; and 798
o how whether the referenced information (together with recognised standards, Common 799
Technical Specifications and/or clinical data) constitutes clinical evidence to demonstrate the 800
conformity to relevant Essential Requirements (General Safety and Performance Requirements) 801
for the device in question. 802
o conclusions relating to questions on clinical risks raised from the risk management 803
documentation 804
o conclusions for pre market devices: 805
whether risks so far are acceptable 806
whether the requirements for clinical data are fulfilled or, if there are parts that need to 807
be covered by further premarket clinical investigations 808
o conclusions for CE-marked devices on the market: 809
whether post market clinical data have changed the assessment of conformity with 810
essential requirement 811
whether clinical evidence still indicate that the risks are acceptable 812
o the authors should also elaborate on the need for PMCF 813
814
The clinical evaluation report should be signed and dated by the evaluator(s) and include evidence of 815
the suitability of evaluator. It The CER should also be signed by the manufacturer in case the clinical 816
evaluation is not done by the manufacturer. 817
818
A suggested format for the clinical evaluation report is located at Appendix E. [[Check elements of 819
the clinical evaluation report: Still OK? The CER should also include PMS data if applicable. Adapt to 820
revised previous chapters]] It should be noted that the level of detail in the report content can vary 821
according to the scope of the clinical evaluation. For example, where a manufacturer relies on clinical 822
data for an equivalent device which has been the subject of an earlier clinical evaluation (for which 823
the manufacturer holds the evaluation report), it may be possible to cross-reference the data 824
summary and analysis sections to the earlier clinical evaluation report, which also becomes part of 825
the clinical evidence for the device in question. 826
The depth and extent of clinical evaluations should be flexible, not unduly burdensome, and 827
appropriate to the nature, classification, intended use, manufacturer’s claims and risks of the device 828
in question. 829
The clinical evaluation report, along with other design verification and validation documentation, 830
device description, labelling, risk analysis and manufacturing information, is needed to allow a 831
manufacturer to demonstrate conformity with the Essential Requirements and is part of the 832
technical documentation of a medical device. 833
14. Update of the Clinical evaluation report 834
835
27
After the device under assessment has been placed on the market, the clinical evaluation report 836
should be updated with data from post market surveillance: 837
Annually as a minimum for implantable devices and Class III devices. 838
Every second year for other devices. 839
An update with shorter interval should be conducted for all devices if the manufacturer gets 840
information that may indicate a change in clinical risks related to the device. 841
This ongoing clinical evaluation process should allow manufacturers to communicate with conformity 842
assessment bodies and Regulatory Authorities in accordance with local reporting requirements, any 843
information that has an important bearing on the benefit-risk assessment of the device or that would 844
indicate a need for labelling changes regarding contraindications, warnings, precautions, appropriate 845
training and/or qualification criteria for users or instructions for use, stop of further CE-marking etc. 846
The information is also fed into the ongoing risk management and CAPA processes. 847
848
Post market surveillance 849
Systematic collection of information from post-market surveillance and post-market clinical follow-850
up of the device should always be planned and properly considered. 851
With regard to post market activities, manufacturers are expected to implement and maintain 852
surveillance programmes that routinely monitor the clinical performance and safety of the device. 853
The scope and nature of such post market surveillance should be appropriate to the device and its 854
intended use. 855
Using Clinical data generated from surveillance such programmes may include (non exclusive list): 856
safety reports, including adverse event reports; 857
adverse events databases (held by either the manufacturer or Regulatory Authorities); 858
manufacturer-generated post market surveillance reports, details of clinically relevant field 859
corrective actions (e.g. recalls, notifications, hazard alerts); 860
any further clinical investigations and formal post market clinical follow-up studies; 861
cohort studies which may contain unpublished long term safety and performance data from 862
representative setting(s) for average patient care; 863
registry evaluation data, etc. and 864
results from published literature; information regarding the state of the art in the 865
corresponding medical field, including general changes to the performance of devices in the 866
market and the level of protection of health and safety of patients and users 867
a manufacturer should periodically/regularly review performance, safety and the benefit-risk 868
assessment for the device through a clinical evaluation, and update the clinical evaluation report 869
accordingly. 870
871
Data generated through clinical experience 872
28
These types of clinical data are generated through clinical use that is outside the conduct of clinical 873
investigations and may relate to either the device in question or equivalent devices. 874
The value of clinical experience data is that it provides real world experience obtained in larger, 875
heterogeneous and more complex populations, with a broader (and potentially less experienced) 876
range of end-users than is usually the case with clinical investigations. (In contrast, clinical 877
investigations involve the use of specific inclusion criteria to create a homogenous population to 878
reduce sources of variation and, therefore, increase confidence that the outcomes observed in the 879
investigation are due to intervention with the device in question. Also, investigators participating in 880
the investigation are chosen on the basis of their expertise and competence and often undergo 881
training over and above that available to other end-users of the device.) 882
The clinical experience data are most useful for identifying less common but serious device-related 883
adverse events; providing long term information about safety and performance, including durability 884
data and information about failure modes and elucidating the end-user “learning curve”. It is also a 885
particularly useful source of clinical data for low risk devices that are based on long standing, well-886
characterised technology and, therefore, unlikely to be the subject of either reporting in the scientific 887
literature or clinical investigation. However, there is also a possibility that data are distorted by 888
under-reporting and manufacturers should develop strategies as part of their post market 889
surveillance programme to counteract this. 890
How may clinical experience data/documentation be used in the clinical evaluation? 891
If a manufacturer chooses to use clinical experience data it is important that any reports or collations 892
of data contain sufficient information to be able to undertake a rational and objective assessment of 893
the information and make a conclusion about its representativity and significance with respect to the 894
performance and safety of the device in question. Reports of clinical experience that are not 895
adequately supported by data, such as anecdotal reports or opinion, should not be used. 896
Post market surveillance reports are compiled by the manufacturer and often include details of the 897
device’s regulatory status (countries in which the device is marketed and date of commencement of 898
supply), regulatory actions undertaken during the reporting period (e.g. recalls, notifications), a 899
tabulation of adverse events (particularly serious events and deaths, stratified into whether the 900
manufacturer considers them to be device-related or not) and estimates of the incidence of adverse 901
events. Post-marketing data about adverse events are generally more meaningful when related to 902
usage but caution is needed because the extent of reporting may vary considerably between 903
countries. The analyses of data within these reports may, for some devices, provide reasonable 904
assurance of both clinical safety and performance. 905
It may be helpful to provide a table summarising device-related adverse events, paying particular 906
attention to serious adverse events, with comments on whether observed device-related adverse 907
events are predictable on the basis of the mode of action of the device. Manufacturers should 908
comment specifically on any clinical data that identifies hazards not previously considered in the risk 909
management documentation, outlining any additional mitigation required (e.g. design modification, 910
amendment of product literature such as inclusion of contraindications etc). 911
912
29
15. Then comes chapter on Notified Body, appendices and 913
appendix on checklist for NB etc 914
915
916
917
31.07.2014
Datei
PD
Page 1of35
EUROPEAN COMMISSION
ENTERPRISE AND INDUSTRY DIRECTORATE-GENERAL
Consumer goods
Cosmetics and Medical Devices
MEDDEV 2.7.2 Revision 2
Draft version 01.07.2014
GUIDELINES ON MEDICAL DEVICES
GUIDE FOR COMPETENT AUTHORITIES
IN MAKING AN ASSESSMENT OF CLINICAL INVESTIGATION
NOTIFICATION / APPLICATION
Note
The present Guidelines are part of a set of Guidelines relating to questions of application of EC-
Directives on medical Devices. They are legally not binding. The Guidelines have been carefully
drafted through a process of intensive consultation of the various interest parties (competent authorities,
Commission services, industries, other interested parties) during which intermediate drafts where
circulated and comments were taken up in the document. Therefore, this document reflects positions
taken by representatives of interest parties in the medical devices sector.
Kommentar [Rapp1]: EUCO:
1. Language consistency is
recommended: Page 1 mentions
‘Notification/ Application’; page 2 has
only ‘notification’ in the title and Chapter
C mentions ‘Letter of no objection’.
- For notification, you do not require a
‘letter of no objection’.
Recommendation to specify the scope
of a letter of no objection.
- For application: ‘Letter of Competent
Authority decision’ may cover better
that there might be some objections
(with justification). ...
Formatiert: Links, Einzug: Links: 0
cm, Erste Zeile: 0 cm
Page 2of35
MEDICAL DEVICES DIRECTIVES - CLINICAL INVESTIGATION-
GUIDELINES FOR COMPETENT AUTHORITIES IN MAKING AN
ASSESSMENT OF CLINICAL INVESTIGATION
NOTIFICATION/APPLICATION
Index
0. PREFACE
1. INTRODUCTION
2. SCOPE
3. REFERENCES
0.4. DEFINITIONS
5. ETHICAL CONSIDERATIONS
1.6. VALIDATION
2.7. ASSESSMENT
8. DECISION
9. ?INFORMATION TO BE EVALUATED DURING THE CONDUCT OF A
CLINICAL INVESTIGATION AND AT THE END
8.1 Serious Adverse Events
8.2 Amendments
8.3 Final report?
APPENDICES
1: Guidance notes on medical devices incorporating a medicinal substance having
ancillary action
2a: List of the standards applied in full or in part
2b: Matrix of Essential Requirements applicable to IMD
3: Guidance on medical devices which require sterilization
4: Guidance on clinical investigations of active devices
5: Guidance on clinical investigations of software
6:Guidance on medical devices incorporating tissues of animal origin
7?: Clinical investigation assessment checklist for Competent Authorities
8?: Clinical investigation assessment checklist for Ethics Committees
PREFACE: These guidelines on the assessment of a clinical investigation
notification/application are part of a set of Medical Device Guidelines that, according to the
relevant annexes of the Medical Devices Directives, promote a common approach in clinical
investigation evaluationassessment procedures by Competent Authorities and Ethics
Committees, charged with safeguarding public health.
Kommentar [Rapp2]: See EUCO
Comment on page 1
Formatiert: Schriftart: 10 Pt., Nicht
Fett, Schriftartfarbe: Automatisch
Formatiert: Schriftart: 10 Pt., Nicht
Fett
Page 3of35
The guidelines are regularly updated according to regulatory developments. The latest
version of the guidelines should always be used. This revision of these guidelines has:
modified the structure in analogy with the structure of other Medical Device
Guidelines and to better address the relevant Directives and take note of the
harmonized standard EN ISO 14155:2011;
provided some basic criteria to promote a harmonized approach in clinical
investigation assessment among Member States and further understanding of the
requirements of Directive 93/42/EEC concerning medical devices and Directive
90/385/EEC relating to active implantable medical devices as amended by Directive
2007/47/EC ;
rephrased some paragraphs to reflect the above listed changes;
introduced new Appendices to standardize specific procedures.
These guidelines are not legally binding. It is recognised that under given circumstances, for
example, as a result of scientific developments, an alternative approach may be possible or
appropriate to comply with the legal requirements.
Nevertheless, due to the participation of the aforementioned interested parties and of experts
from National Competent Authorities, it is anticipated that the guidelines will be followed within
the Member States and, therefore, support uniform application of relevant EU Directive
provisions and common practices within Member States.
However, only the text of the Directives is authentic in law. On certain issues not addressed in
the Directives, national legislation may be different from these guidelines.
3.10. INTRODUCTION
This guideline is addressed to Competent Authorities responsible for assessment of
clinical investigation notification/application referred to in article 10 of Council
Directive 90/385/EEC[1] and in article 15 of Council Directive 93/42/EEC[2], as amended. .
However roles of Competent Authorities (CA) may vary between Member States, and
other bodies, such as Ethics Committees, are involved in the assessment/approval
process of clinical investigations mentioned above, according to national regulation.
Competent Authorities shall encourage the use of these guidelines by all the Ethics
Committees and other possible national bodies involved in the assessment of clinical
investigational notification/application, according to national law.”
Competent Authorities shall ensure that the information submitted in the
notification/application pursuant to annex 6 of Directive 90/385/EEC or annex VIII of
Directive 93/42/EEC, contains the items listed below (if appropriate) and is adequate
in detail.
It is also important to ensure that the clinical investigation plan shall include
documented procedures and a study design in accordance with the provisions of
Section 2 of Annex 7 of Directive 90/385/EEC or Section 2 of Annex X of Directive
93/42/EEC. Furthermore it is important that the clinical investigation plan correctly
reflects the clinical evaluation as planned by the manufacturer.
It is equally important to note that any substantial change to the clinical investigation
plan or other substantial amendments and updates to the original documents, shall
be equally submitted in a timely manner to the Competent Authorities according to
national legislation.
[1]
Council Directive 90/385/EEC on the approximation of the laws of the Member States relating to active implantable
medical devices, last amended by Directive 2007/47/EC of the European Parliament and of the Council.
[2]
Council Directive 93/42/EEC concerning medical devices, last amended by Directive 2007/47/EC of the
European Parliament and of the Council.
Formatiert: Hervorheben
Formatiert: Hervorheben
Page 4of35
The clinical investigations described above are generally expected to be designed,
conducted and reported in accordance with harmonized standard EN ISO 14155 –
Clinical investigation of medical devices for human subjects- good clinical practise-
or to comparable standards, and in compliance with the Declaration of Helsinki and
national regulations.
2. SCOPE
The primary purpose of this document is to provide guidance to Competent Authorities and
Ethics Committees when assessing a clinical investigation notification/application provided
by manufacturers.
This document provides the following guidance:
Description of the documents to be validated and/or assessed;
Criteria to be applied for general assessment
Criteria in Appendices for specific aspects of assessment
The guidance contained within this document is intended to apply to medical devices
generally and the device component of combination products. It is not intended to cover in
vitro diagnostics.
3. REFERENCES
European Legislation
Council Directive 90/385/EEC of 20 June 1990 concerning active implantable medical devices
Council Directive 93/42/EEC of 14 June 1993 concerning medical devices
Commission Regulation (EU) No 722/2012 - OJ 212/3 of 9.08.2012 concerning medical
devices manufactured utilising tissues of animal origin
Commission Decision of 19 April 2010 No. 2010/227/EU on the European Databank on
Medical Devices (Eudamed)
GHTF final documents
SG1-N41R9:2005 Essential Principles of Safety and Performance of Medical Devices
SG5/N2R8:2007 Clinical Evaluation
……………………………………………………..
……………………………………………….
Harmonized and International standards
EN ISO 14155:2011 Clinical investigation of medical devices for human subjects – Good
clinical practice
EN ISO14971:2012 Medical devices – application of risk management to medical
devices.
European guidance documents
MEDDEV 2.7/1 Clinical Evaluation: a guide for manufacturers and notified
bodies
MEDDEV 2.7/3 Clinical investigations: serious adverse event reporting
Formatiert: Block
Kommentar [sci3]:
- Standards information in this chapter
updated in January 2013
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2012:212:0003:0012:EN:PDF
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2010:102:0045:0048:EN:PDF
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2010:102:0045:0048:EN:PDF
Page 5of35
MEDDEV 2.7/4 Guidelines on Clinical investigations: a guide for manufacturers and
notified bodies
MEDDEV 2.12/2 Guidelines on post-market clinical follow up studies
MEDDEV 2.1/3 rev.3 (182 KB) Borderline products, drug-delivery products and medical
devices incorporating,as integral part, an ancillary medicinal
substance or an ancillary human blood derivative
MEDDEV 2.1/2 rev.2 (14 KB) Field of application of directive "active implantable medical
devices"
MEDDEV 2.1/2.1 (12 KB) Field of application of directive "active implantable medical
devices"
MEDDEV 2.1/6 (323 KB) Qualification and Classification of stand alone software
MEDDEV 2.4/1 rev.9 (654 KB) Classification of medical devices
Manual on borderline and classification in the Community Regulatory framework for medical
devices
(302 KB)(version 1.15 of 06-2013)
4. DEFINITIONS (to be revised together with the other revision groups!)
Adverse Event: Any untoward medical occurrence in a subject. Note: For the purposes of
this document, this is intended to include any adverse event whether
device related or not.
Clinical Data: Safety and/or performance information that are generated from the use of a
medical device in humans. (This term is further explained in GHTF
document SG5/N1R8:2007)
Clinical Evaluation: A methodologically sound procedure to collect and analyse clinical data
pertaining to a medical device and to assess whether there is sufficient
clinical evidence to confirm compliance with relevant essential
requirements for safety and performance.
Clinical Evidence: Clinical data of an amount and quality as to prove the validity and
accuracy
1
of a claim or a statement.
Clinical Evaluation Report: The documentation of the clinical evaluation
Clinical Investigation: Any systematic investigation or study in or on one or more human
subjects, undertaken to assess the safety and/or performance of a medical
device.
Clinical Investigation Plan: Document that states the rationale, objectives, design and
proposed analysis, methodology, monitoring, conduct and record-keeping
of the clinical investigation.
http://ec.europa.eu/health/medical-devices/files/meddev/2_1_3_rev_3-12_2009_en.pdf
http://ec.europa.eu/health/medical-devices/files/meddev/2_1-2___04-1994_en.pdf
http://ec.europa.eu/health/medical-devices/files/meddev/2_1_2-1__02-1998_en.pdf
http://ec.europa.eu/health/medical-devices/files/meddev/2_1_6_ol_en.pdf
http://ec.europa.eu/health/medical-devices/files/meddev/2_4_1_rev_9_classification_en.pdf
http://ec.europa.eu/health/medical-devices/files/wg_minutes_member_lists/borderline_manual_ol_en.pdf
http://ec.europa.eu/health/medical-devices/files/wg_minutes_member_lists/borderline_manual_ol_en.pdf
http://ec.europa.eu/health/medical-devices/files/wg_minutes_member_lists/borderline_manual_ol_en.pdf
http://ec.europa.eu/health/medical-devices/files/meddev/2_1_3_rev_3-12_2009_en.pdf
http://ec.europa.eu/health/medical-devices/files/meddev/2_1-2___04-1994_en.pdf
http://ec.europa.eu/health/medical-devices/files/meddev/2_1_2-1__02-1998_en.pdf
http://ec.europa.eu/health/medical-devices/files/meddev/2_1_6_ol_en.pdf
http://ec.europa.eu/health/medical-devices/files/meddev/2_4_1_rev_9_classification_en.pdf
http://ec.europa.eu/health/medical-devices/files/wg_minutes_member_lists/borderline_manual_ol_en.pdf
Page 6of35
Clinical Investigator: The individual responsible for the conduct of a clinical investigation
who takes the clinical responsibility for the well-being of the subjects
involved.
Clinical Performance: The ability of a medical device to achieve its intended purpose as
claimed by the manufacturer.
Clinical Safety: Freedom from unacceptable risk, when using the device according to the
manufacturer’s Instructions for Use.
Conformity Assessment: The systematic examination of evidence generated and
procedures undertaken by the manufacturer, under requirements
established by the Regulatory Authority, to determine that a medical device
is safe and performs as intended by the manufacturer and, therefore,
conforms to the Essential Requirements.
Device Deficiency: Inadequacy of a medical device with respect to its identity,
quality, durability, reliability, safety or performance. NOTE Device
deficiencies include malfunctions, use errors, and inadequate
labelling.
Ethics Committee – EC Independent body whose responsibility it is to review clinical
investigations in order to protect the rights, safety and well-being of
human subjects participating in a clinical investigation.
Feasibility study: A clinical investigation that is commonly used to capture preliminary
information on a medical device (at an early or late stage of product
design) to adequately plan further steps of device development,
including needs for design modifications or parameters for a pivotal
study.
Investigator’s brochure – IB
Compilation of the current clinical and non clinical information on the investigational
medical device(s) relevant to the clinical investigation.
Pivotal study: A clinical investigation adequately designed and powered to collect
definitive evidence of benefits to the patients, clinical risks, clinical
performance, and/or clinical aspects of the usability of a device for a
specified intended use.
Serious Adverse Event: An adverse event that
1 led to a death;
2 led to a serious deterioration in health of a patient, user, or others that:
(a) results in a life threatening illness or injury;
(b) results in a permanent impairment of a body structure or body
function;
(c) requires in-patient hospitalisation or prolongation of existing
hospitalisation
(d) results in medical or surgical intervention to prevent life-
threatening illness or injury or permanent impairment to body
structure or a body function;
(e) led to foetal distress, foetal death or a congenital abnormality/
birth defect.
Kommentar [J4]: This differs from
ISO 14155, which defines both
investigator and Principal Investigator.
It would be better to use ISO definitions
Kommentar [J5]: To align with the
definition of safety in ISO 14971.
Kommentar [J6]: Additional definition
needed to ensure consistency with ISO
14155 and MEDDEV 2.7/3
Page 7of35
Harmonised Standards: Standards, the titles of which arepublished by the European
Commission deemed to offer apresumption of conformity to the Essential or
other Requirements of the Directives.
5. ETHICAL CONSIDERATIONS
In their sections 2.2 of Annex 7/Annex X, directives 90/385/EEC and 93/42/EEC require:
“Clinical investigations must be carried out in accordance with the Helsinki Declaration
adopted by the 18th World Medical Assembly in Helsinki, Finland, in 1964, as last amended
by the World Medical Assembly. It is mandatory that all measures relating to the protection of
human subjects are carried out in the spirit of the Helsinki Declaration. This includes every
step in the clinical investigation from first consideration of the need and justification of the
study to publication of the results.”
As a general principle, “the rights, safety and wellbeing of clinical investigation subjects shall
be protected consistent with the ethical principles laid down in the Declaration of Helsinki” (EN
ISO 14155:2011).
It is ethically important in deciding to conduct a clinical investigation that it should generate
new data and answer specific safety and/or performance questions that remain unanswered
by the current body of knowledge.
The desire to protect human subjects from unnecessary or inappropriate experimentation
must be balanced with the need to protect public health through the use of clinical
investigations where they are indicated. In all cases, however, care must be taken to ensure
that the necessary data are obtained through a scientific and ethical investigational process
that does not expose subjects to undue risks or discomfort. The rights, safety and well-being
of subjects are paramount and appropriate trial design and conduct is essential to generate
meaningful data.
The following procedures/documents/information will have primary - but not exclusive -
importance for Validation, Assessment and Decision making with regard to ethical
considerations:
seeking research ethics committee favourable opinion,
the confirmation of insurance of subjects,
the process and documents used to obtain informed consent (usually CAs request
that documents to be (also) in national language(s)),
procedures with regard to vulnerable groups and individuals,
justification of the clinical investigation under ethical and scientific aspects,
appropriate risk management and benefit/risk determination,
Qualification of Clinical Investigators and suitability of clinical investigation sites.
National and/or regional regulations usually play a major role in ethical considerations.
6. VALIDATION
The Validation of a clinical investigation Notification/Application as an administrative review
has to assure whether
The investigational product falls under one of the medical device directives
(Qualification),
A notification (preferably in xml-format) is present with basic information on the
clinical investigation to be uploaded to the EUDAMED database and to provide the
correct CIV ID code;
A rationale is given for the classification of the IMD (under Directive 93/42/EEC only:
class III or implantable or long-term-invasive device under classes IIa or IIb) to decide
on the procedure to be applied for the clinical investigation;
The statement together with the relevant documentation requested in Annex 6 resp.
VIII are present according to national provisions;
relevant information in accordance with additional national requirements
Page 8of35
have been provided.
Validation should be based on the following considerations:
A. CHECKLIST of information to be supplied in notifications/applications
I. A Notification/application form with basic data on clinical investigations to be included
in the EUDAMED CI module by MS will have to be provided and should be contained in an
xml-format, to make upload by MS easy. A template is provided in Appendix xy. MS may
require additional data in their own national notification/application forms.
Decision 2010/227/EU requests the following information:
(a) Manufacturer, where applicable authorised representative:
(i) Name; (ii) Street; (iii) Locality; (iv) Postcode; (v) Country; (vi) Phone or E-mail; (vii) Role.
(b) Device:
(i) Internationally recognised nomenclature code (for data generated after 1 May 2011);
(ii) Device Name/Make or, where not available, generic name.
(c) Title of investigation;
(d) Protocol number;
(e) Primary objective;
II. Additional general information usually supplied in Notification/Application
Form
I.1 Sponsor’s and/or manufacturer’s name (if the manufacturer is not the sponsor) and
contact points for communication (similarly for authorised representative in the EU if
applicable).
II.2 Whether first submission or resubmission
2
.
II.3 If resubmission with regard to same device, previous date(s) and reference
number(s) of earlier submission(s).
II.4 Member States and other countries participating in this clinical investigation as part of
a multicentre/multinational study at the time of filing.
II.5 A Eudamed Clinical Investigation identification number (CIV ID)
II.6 A signed statement (by the managing director or regulatory affairs manager or
manager responsible for compliance with the essential requirements) to the effect
that the device in question complies with the essential requirements except with
regard to those aspects of the device which are to be investigated; and that, in
respect of those aspects, every precaution has been taken to protect the health and
safety of the subject.
II.7 Copy of the Ethics committee opinion as soon as available according to national
requirements.
II.8 Title of the clinical investigation
II.9 Other relevant documentation according to national requirements.
III. Rationale for Qualification (both Directives) and Classification (Directive
93/42/EEC only):
2
“resubmission“: application of a clinical investigation previously submitted reporting
the same title, the same identification number/code and same EUDAMED code (CIV
ID) of the previous one.
Kommentar [sci7]:
Input of Portugal: We propose to
change the text in line with the wording
used on point C.(is more clear and
harmonized)
Kommentar [Rapp8]: EUCO:1.1.Spo
nsor’s and/or manufacturer’s name and
contact points for communication
(similarly for the authorised
representative in the EU if relevant).
In case of multi-centre studies in
different countries, how will CAs interact
/ exchange info between CAs regarding
their assessment and conclusion?
Page 9of35
A rationale must be given, that the device under investigation falls under Directive 93/42/EEC
resp. Directive 90/385/EEC. Reference concerning qualification must address Art.1 of
Directive 90/385/EEC resp. Directive 93/42/EEC. Helpful Guidance is contained in MEDDEV
and Manual.
For Classification rationale, Art. 9 and Annex IX provide the legal basis; helpful guidance may
be found in MEDDEV and Manual.
IV. Statement and Documentation acc. to Annex 6 resp. Annex VIII:
Directives 90/385/EEC and 93/42/EEC request specific information to be provided or made
available to CAs by manufacturers or ARs, serving as sponsors. MS may vary in their
requests to provide the content of the statement or the documentation mentioned below
without further notice at the time of notification/application or may have a policy to request the
content of the statement immediately and the more detailed information of the documentation
if needed in the specific cases. Subsequent information requests may trigger clock-stop
procedures:
Annex 6 of Directive 90/385/EEC and Annex VIII of Directive 93/42/EEC request the following
content of a statement for devices intended for the clinical investigations covered by Annex
7 resp. Annex X to be provided:
— data allowing identification of the device in question,
— the clinical investigation plan,
— the investigator's brochure,
— the confirmation of insurance of subjects,
— the documents used to obtain informed consent (usually CAs request that in national
language(s)),
— a statement indicating whether or not the device incorporates, as an
integral part, a substance or human blood derivative referred to in
Section 10 of Annex 1 of Directive 90/385/EEC resp. section 7.4 of Annex I of Directive
93/42/EEC,
— a statement indicating whether or not the device is manufactured
utilising tissues of animal origin as referred to in Commission Regulation 722/2012/EC
3
,
— the opinion of the ethics committee concerned and details of the aspects
covered by its opinion,
— the name of the medical practitioner or other authorized person and of
the institution responsible for the investigations,
— the place, starting date and scheduled duration for the investigations,
— a statement that the device in question conforms to the essential
requirements apart from the aspects covered by the investigations and
that, with regard to these aspects, every precaution has been taken to
protect the health and safety of the patient.
For devices intended for clinical investigations, Annexes 6 resp. VIII request that the
documentation must contain:
— a general description of the product and its intended use,
— design drawings, methods of manufacture envisaged, in particular as
regards sterilisation, and diagrams of components, sub-assemblies,
circuits, etc.,
— the descriptions and explanations necessary to understand the abovementioned
drawings and diagrams and the operation of the product,
— the results of the risk analysis and a list of the standards referred to in
Article 5, applied in full or in part, and descriptions of the solutions
adopted to meet the essential requirements of this Directive if the
standards referred to in Article 5 have not been applied,
— if the device incorporates, as an integral part, a substance or human
blood derivative referred to in Section 10 of Annex 1 of Directive 90/385/EEC resp. Section
7.4 of Annex I of Directive 93/42/EEC, the data on the
tests conducted in this connection which are required to assess the
safety, quality and usefulness of that substance or human blood derivative,
taking account of the intended purpose of the device,
3
Adjustment needed following COM Regulation 722/2012/EC.
Page 10of35
— if the device is manufactured utilising tissues of animal origin as
referred to in COM Regulation 722/2012/EC
4
, the risk management measures in
this connection which have been applied to reduce the risk of infection,
— the results of the design calculations, and of the inspections and
technical tests carried out, etc.
The manufacturer must take all the measures necessary to ensure that the
manufacturing process produces products which are manufactured in
accordance with the documentation referred to in the first paragraph of
this Section.
The manufacturer must authorise the assessment, or audit where necessary,
of the effectiveness of these measures.
The information contained in the declarations concerned by these Annexes mentioned above
5
shall be kept for a period of time of at least five years. In the case of
implantable devices the period shall be at least 15 years.
V. Specific national information requests, mainly on ethical or local issues (eg on
qualification of clinical investigators or suitability of clinical investigation sites; liability issues;
protection of vulnerable subjects etc)
6
B Outcome of Validation:
Validation usually leads to a statement of the CA to the Sponsor/MF/AR that:
1. A valid notification/application has been submitted and the clock now is running for
the assessment phase within a certain time frame, acc. to national provisions; or
2. A valid notification/application has been submitted and the Sponsor/MF/AR now may
commence the clinical investigation, on condition that the relevant Ethics Committee
has issued a favourable opinion; or
3. An incomplete/invalid notification/application has been submitted, which must be
completed/adjusted (possibly within a time frame); or
4. An incomplete/invalid notification/application has been submitted, which has not been
completed/adjusted within a legal time frame or after (a) reasonable attempt(s) of the
CA to have the notification/application repaired, and the clinical investigation is
rejected; or
5. No favourable opinion of a relevant Ethics Committee, acc. to national regulations,
has been obtained, and the clinical investigation is rejected; or
6. The notification/application submitted does not fall under the medical device regime.
7. ASSESSMENT:
1. Assessment is a detailed ethical, technical and scientific review of documents/information
submitted in an application (possibly after a further information request) and of other relevant
information, usually performed by experts, to ascertain, whether
The Essential Requirements, applicable to the IMD in question, apart from those,
which are to be examined in this clinical investigation, are fulfilled (see Appendices 2a
and 2b, with templates as a help to outline this information),
All applicable safety measures and risk mitigation have been taken with regard to the
aspects under investigation (under consideration of the risk management provisions
in Annexes 1/I, pts I.2 of the Directives and the harmonized standard EN ISO 14971),
The benefit/risk estimation has been correctly performed and is acceptable according
to the state of the art in medicine,
4
Adjustment needed following COM Regulation 722/2012/EC.
5
Necessary adjustment
6
Usually indicated at homepages of CAs; list of relevant CA contact points at URL …
Page 11of35
Scientific aspects and methodology have been duly considered and warrant, that the
clinical data generated will be robust and reliable and are appropriate with regard to
the clinical evaluation plan,
Ethical requirements of the Declaration of Helsinki and, if applicable national
requirements are met.
This assessment is usually primarily based on the information delivered in the Clinical
Investigation Plan (CIP) and the Investigators Brochure (IB),which are extensively covered by
the harmonized Standard EN ISO 14155, in its Annexes A and B. Considerations for the
review of the CIP and IB as given by the Annexes to the harmonized standard are given
below.
NOTE: The following is a list of items that should be covered although the information may
be provided in different documents or in different formats as required by individual Competent
Authorities. Competent Authorities may also require additional documentation for their
assessment needs.
Note: Where the harmonized Standard EN ISO 14155 is not followed or only partly followed, a
justification for that and for the alternative solutions taken should be given.
Ethical considerations are usually covered by the documentation delivered under 5.
Depending on national provisions. the roles of EC and the CA in this detailed ethical,
technical and scientific review will have to be considered.
2. CLINICAL INVESTIGATION PLAN (CIP):
(The numbering follows Annex A of EN ISO 14155:2011 for easy reference and coherence
and adds comments or additional specific considerations as proposed by members of TF)
A.1.3: THE FOLLOWING INFORMATION SHOULD BE CONSIDERED UNDER ANNEX A.1.3: OF EN ISO
14155:2011
A.1.3 Consideration: Name(s), address(es) and contact points for communication of the
Sponsor and Manufacturer (if the manufacturer is not the sponsor). Similarly for authorised
representative, if applicable.
A.2: THE FOLLOWING INFORMATION SHOULD BE CONSIDERED UNDER ANNEX A.2: OF EN ISO
14155:2011
Consideration: When the handling of the specific device is complex or unfamiliar to the
investigator: Have risks associated with learning been properly mitigated?
a. Training ahead of first use should be foreseen for each investigator and properly
described in the CIP (or IB).
b. In addition, when inadequate handling can cause serious adverse events (SAE)::
Supervision of every investigator by an experienced person during the first use
should be foreseen and properly described in the CIP (or IB)
A.3: THE FOLLOWING INFORMATION SHOULD BE CONSIDERED UNDER ANNEX A.3: OF EN ISO
14155:2011
Consideration: There should be a clear reference to the Clinical Evaluation Plan and the
position and justification of this clinical investigation within, based on a proper scientific
literature review, the related gap analysis, the benefit/risk estimation before the background of
the state of the art in medicine in the relevant field (see MEDDEV 2.7.1). It should be made
clear whether the current notification/application is for an exploratory (eg. FIM, feasibility, pilot
or proof of concept clinical investigation) or a confirmatory (pivotal) clinical investigation or a
combined one. These may have different risk management and statistical approaches and
procedures, eg. see considerations under A.4 FIM studies or possible transition regimes. Also
the possible conclusions from the clinical investigation with regard to demonstration of safety
Page 12of35
and performance and to creation of clinical evidence will differ. This should also be reflected
in the letters of (no) objections to avoid misunderstandings, eg. towards NBs.
[To be superseded by new text above: Objectives of clinical investigation, including indication
and justification of the planned role of this clinical investigation in the clinical evaluation of the
device (e.g. feasibility study or pivotal study)Description and justification whether the CI is
based on explorative or confirmative considerations and statistics.
To be superseded by new text above: Description of general methods of diagnosis or
treatment of the medical condition for which the clinical investigation is being proposed.]
A.4: THE FOLLOWING INFORMATION SHOULD BE CONSIDERED UNDER ANNEX A.4: OF EN ISO
14155:2011
Considerations:
In first-in-man (FIM) trials of devices that are potentially dangerous to study subjects: How will
unexpected risks be addressed and mitigated? There may be a need for improvement before
the next subject is exposed to the device.
a. The interval between the treatment/exposure of each of the first study subjects
should be sufficient. The sponsor should review a subject’s relevant clinical data,
relevant information related to the device (functioning, method, usability) and
evaluate the need for improvement before the next subject is exposed to the device.
b. If the CIP foresees large numbers of study subjects (combination of first in man
feasibility trial and pivotal trial):
- First in man feasibility trials and pivotal trials are in general organised as separate
clinical investigations. The competent authority / ethics committee should receive
the results of the FIM phase before a pivotal phase can start.
- It is unclear, if combining FIM and pivotal phases in one investigation should not
be permissible for devices with significant high or unknown risks.
SECOND INPUT:
FIM and pivotal phases must not be combined unless the sponsor presents adequate
fundamentals for the need to do so and explain how to mitigate the foreseen risks (special
attention should be given to high risk class devices).
- The sponsor should always properly separate a FIM-cohort, and produce an interim
report of FIM patients that includes an adequate duration of follow-up. Based on
FIM experience, the sponsor shall analyse if clinical development can be continued
as originally planned or if there is a need to adapt the device or the CIP.
- The sponsor should send the FIM report to the CA and/or the ethics committee for
evaluation before recruitment is extended to the pivotal cohort continued.
Consideration: Description and justification of hazards caused by procedures that are
specifically required by the clinical investigation, in particular with regard to invasive and
innovative ones (if applicable).
A.6.1: THE FOLLOWING INFORMATION SHOULD BE CONSIDERED UNDER ANNEX A.6.1: OF EN ISO
14155:2011
Consideration: Is duration of follow up sufficient?
a. Long enough to gather data necessary for ensuring the basic safety of
participating subjects and take remedial action if necessary,
b. Long enough to fully achieve study objectives,
c. Observations should cover at least entire duration of clinical healing phase/
recovery phase connected to use of investigational devices. Longer observations
are necessary if required by a or b (e.g. for implants if long term side-effects can
be expected).
A.6.4: THE FOLLOWING INFORMATION SHOULD BE CONSIDERED UNDER ANNEX A.6.4: OF EN ISO
14155:2011
Considerations for implants:
Kommentar [Rapp9]: Italy proposes
to replace this point with: “description of
the purpose of the clinical investigation,
including indication and justification of
the planned role of this clinical
investigation in the clinical evaluation of
the device (e.g. pilot study or pivotal
study)"
Kommentar [Rapp10]: EUCO:
Recommend deleting this portion of the
sentence since the justification of the
investigation is listed already in 4.9.
Statistical considerations do not belong
to the endpoint : as per ISO14155,
separated section
Kommentar [RB11]: Pilot study
would be a more appropriate term
Kommentar [sci12]:
Divergent language preferences: One
input suggests to correct “feasibility” to
“pivotal”, Another (for MEDDEV 2.7.1)
suggests the opposite.
CIE participants are asked to make a
decision. The selected term will be used
consistently in both MEDDEV
documents.
Kommentar [DG13]: Danielle Giroud
TC 194 WG4: what does this mean?! 1.
Statistics do not belong under
objectives but are a separate section of
the protocol and 2. What is wrong with
using the wording ‘statistical
significance rather than again vague
new technology which leads to tons of
different interpretations. Please stay in
line with ISO 14155 do not reinvent for
the sake of improving protocol design
by industry.
Kommentar [Rapp14]: EUCO:
Further details needed on :
- Definition of “potentially dangerous”? (
no definition neither in this Meddev nor
in MDD or ISO 14971).
- Definition of significant risk? FIM and
pivotal studies(additional clarifications,
instructions that will fit with appendix ...
Kommentar [sci15]:
Input of Portugal, sentence
completed.
Kommentar [RB16]: for devices with
unknown or high risks in the beginning,
two phases should be obligate
Kommentar [sci17]: Input of
Portugal
Kommentar [DG18]: Danielle Giroud
TC 194 WG4: If when combining FIM
and pivotal trial in one is done with an
interim analysis after the FIM phase to
allow all stakeholders to consider
justification to continue with the pivotal ...
Kommentar [DG19]: Danielle Giroud
TC 194 WG4: these paragraphs are
regulatory requirements intermingled
with study design issues. For the sake
of clarity, it should be restructured in
this document
Page 13of35
retrieval analyses: Retrievals (failed implants removed in a revision intervention) should be
collected and assessed in a structured process by the manufacturer. Comprehensive
documentation should be available for inspection.
Retrieval collection and analysis plan incl. further investigation scheduled for retrievals in case
of failure, Incl. inhouse possibilities and external expertise (CoI!!).
Workflow of retrieval assessment, incl. forms for documentation, institutions involved.
Arrangements for long-term follow-up of subjects beyond primary endpoint e.g. for
implantable devices.
Consideration: Description and justification of hazards caused by procedures that are
specifically required by the clinical investigation, in particular with regard to invasive and
innovative ones (if applicable).
A.7: THE FOLLOWING INFORMATION SHOULD BE CONSIDERED UNDER ANNEX A.7: OF EN ISO
14155:2011
Consideration: Patients lost to follow-up
a. There should be clear procedures on how patients lost to follow-up are handled.
b. If study endpoints include death or outcomes that can cause disability / loss of
autonomy:
- If a study subject cannot be contacted, the procedure should foresee that the
centre should contact other persons or institutions (in certain countries the
family doctor). Such contacts should take place rapidly, especially in FIM
studies of devices with relevant risks, in order to enable he sponsor to
promptly identify undue risks and take measures that are necessary for
preserving the health and safety of study subjects (i.e. temporary stop of
recruitment in order to review the design of the device).
- The consent form should name the persons or institutions to be contacted
and clearly state that the subject allows exchange of medical information with
these persons or institutions. (see also 4.7.4.j) of EN ISO 14155:2011)
A.11: THE FOLLOWING INFORMATION SHOULD BE CONSIDERED UNDER ANNEX A.11: OF EN ISO
14155:2011
Consideration: What provisions, if any have been made by the manufacturer for the
recovering of the device (if applicable, i.e. implantable devices, multiple use devices) and
subsequent prevention of unauthorised use.
A.13: THE FOLLOWING INFORMATION SHOULD BE CONSIDERED UNDER ANNEX A.14: OF EN ISO
14155:2011
Besides the process described in A.13 the Copy of informed consent or the draft informed
consent intended for the Ethics Committee shall be examined.
NOTE: these can be separate documents.
Mind reference to Insurance coverage in case of injury.
A.14: THE FOLLOWING INFORMATION SHOULD BE CONSIDERED UNDER ANNEX A.14: OF EN ISO
14155:2011
Consideration: also relationship of events to investigational procedures should be captured!
A.17: THE FOLLOWING INFORMATION SHOULD BE CONSIDERED UNDER ANNEX A.17: OF EN ISO
14155:2011
Consideration: the Chapter "Research Registration” and “Publication and Dissemination of
Results" (points 35 and 36) of the Declaration of Helsinki shall be considered here, as this is
mandated by the Directives’ reference to the DoH.
Kommentar [Rapp20]: EUCO:Rewor
ding :
- Broader statement and indicate that
Lost to Follow Up procedure should be
indicated
- Recommend that this be addressed in
section 6.6 with the Withdrawal
procedure sections. Also
recommendthat the.
- The information regarding informed
consent requirements should be
included in 4.7. However, it seems as
though there are other informed
consent requirements and this one is
the only one mentioned. So, either all of
the informed consent requirements
should be listed or a standard should
be referenced
Background questions
5.4.b: This version is requesting more
efforts than what is commonly
requested, even in drug for collection of
information in patient lost of follow up.
On which legislative basis is this
based?
To define in which circumstances
exchange of medical information to a
third person is necessary and the
rational?
Until which extend should we
investigate when patient cannot be
contacted (ex patient death)?
Further details needed on :
Definition of FIM same comments as
5.2.
Page 14of35
3. INVESTIGATOR BROCHURE (IB):
(The numbering follows Annex B of EN ISO 14155:2011 for easy reference and coherence
and adds comments or additional specific issues as proposed by members of TF)
B.2: THE FOLLOWING INFORMATION SHOULD BE ADDED TO ANNEX B.2: OF EN ISO 14155:2011
Devices Identification
2.1 Details allowing device(s) to be identified
2.2 Trade name of device(s)
2.3 Generic name of device(s).
2.4 Model name of device(s)
2.5 Model number(s) including revision number(s), if any (or reference from apparent
model number if appropriate).
2.6 Copy of device(s) labels and IFU(s) including risks, contraindications and warnings (if
available).
2.7 A description of the device including a list of accessories, principles of operation and
block or flow diagrams of major components, together with a brief description of other
devices designed to be used in combination for purpose of the investigation, if
applicable.
2.8 Identification of any features of design that are different from a previously similar
marketed product (if relevant).
2.9 Details of any new or previously untested features of the device including, where
applicable, function and principles of operation.
2.10 Description of software, logic and constraints, version (if relevant).
2.11 Design drawings, if necessary for the understanding of the functioning of the device.
2.12 Identification of any special manufacturing conditions required and if so, how such
requirements have been met.
Comment to B.2.b) Device(s) Classification: the rationale for device classification should
rather be provided as a separate document, see chapter VALIDATION.
B.3: THE FOLLOWING INFORMATION SHOULD BE ADDED TO/CONSIDERED UNDER ANNEX B.3: OF EN
ISO 14155:2011
3.1 Description of materials coming into contact with the body, body fluids, rationale for
choice of materials and which Standards apply (if relevant).
3.2 Identification of any any medicinal substance or human blood derivatives
incorporated into the device with description of intended purpose and previous
experience with the use of substance(s) (see Appendix 1).
3.3 Method of sterilisation and validation (method, justification, if ETO-residuals) (if
applicable) and methods of cleaning, disinfection and sterilisation for devices
indicated as reusable (see Appendix 3).
3.4 Identification of any tissues of animal origin incorporated within the device together
with information on the sourcing and collection of animal tissue(s) prior to
manufacturing operation and other relevant information on the origin of tissue(s) (eg:
Kommentar [Rapp21]: EUCO
Kommentar [Rapp22]: EUCO
Kommentar [sci23]: Input of
Portugal
Page 15of35
copy of ‘TSE certificate of suitability’, if available); and details with regard to validation
of manufacturing procedures employed for the reduction or inactivation of
unconventional agents
7
as well as details concerning the manufacturer’s risk analysis
and risk management process and the justification for the use of animal tissues or
derivatives, taking into consideration lower risk tissues or synthetic alternatives. This
is also applicable in circumstances of genetically produced material (see Appendix 5).
In case of devices falling under COMMISSION REGULATION (EU) No 722/2012 the
relevant requirements have to be observed.
B.4: THE FOLLOWING INFORMATION SHOULD BE ADDED TO/CONSIDERED UNDER ANNEX B.4: OF EN
ISO 14155:2011
4.1 Summary of experience with any similar devices made by same manufacturer
including length of time on market and a review of safety and performance related
problems and complaints together with any corrective or preventive actions taken to
address these issues.
4.2 Summary of existing clinical data, in particular
o of the relevant scientific literature available relating to the safety,
performance, design characteristics and intended purpose of the
device and/or of equivalent or similar devices;
o of previous clinical investigations, relating to the device in question
and/or to equivalent or similar devices, if available.
4.3 Reference should be made as to how experience with previous device models has
affected the current iterations of design, if applicable. The Modifications should be
described, rational and expected improvement shall be mentioned in order to check if
the expected effect was achieved in the monitoring process.
B.5: THE FOLLOWING INFORMATION SHOULD BE ADDED TO/CONSIDERED UNDER ANNEX B.5: OF EN
ISO 14155:2011
5.1 Benefit/Risk analysis to include identification of hazards and estimated risks
associated with the manufacture (including factors relating to device choice, choice of
materials, software) and the use of the device, together with the description of what
actions have been taken to minimise or eliminate the identified risks. (Note: may
also be included in the clinical investigation plan).
3.10 Description of how biocompatibility and biological safety have been addressed
including identification of the risks and hazards associated with the use of the device
and how these have been addressed.
3.17 List of relevant Standards applied in full or in part, or description of solutions adopted
to meet the essential requirements of the Directive if relevant standards have not
been fully applied (Appendix 2 shows an example of a list with all relevant elements.
Competent authorities may encourage manufacturers to use the template).
8. DECISION
7
Mind COMMISSION REGULATION (EU) No 722/2012
of 8 August 2012 concerning particular requirements as regards the requirements laid down in
Council Directives 90/385/EEC and 93/42/EEC with respect to active implantable medical devices and
medical devices manufactured utilising tissues of animal origin, as of 29 August 2013
Kommentar [sci24]: Input of
Portugal
Kommentar [Rapp25]: EUCO
Kommentar [Rapp26]: EUCO
Recommendations: documentation of
any deviations and define information
needed rather than enforcing a
mandatory template that may not apply
outside EU.
Page 16of35
Based on the outcome of Validation and/or Assessment by the entitled parties (primarily CA,
EC
8
) acc. to national provisions, the following decisions may be taken:
1. Approval of the Clinical Investigation
2. Approval with conditions
(1+2: See template letter of no objection in A)
3. Tacit Approval (acc. to national provisions)
4. Rejection of/Objection to the Clinical Investigation
(4: See template letter of objection in B)
A) LETTER OF NO OBJECTION
Letters of no objection / decisions of Competent Authorities should contain the following
information:
The name of the sponsor Tacit Approval of the Clinical Investigation (acc. to national
provisions)
1.
2. The name of the authorised representative, if applicable
3. The name of the manufacturer of the investigational device (if the manufacturer is not the
sponsor)
4. The title of the clinical investigation, the CIOP code and version
5. The name of the investigational device(s)
6. The EUDAMED CIV-ID
7. The date
8. The decision
9. Any conditions imposed (i.e. recruitment limited to a subgroup (e.g. FIM cohort), need to
submit an interim report in order to extend recruitment beyond the subgroup, approval
from the Ethics Committee.
10. Summary of duties (such as serious adverse event reporting, amendments, reports
required as a condition of approval.
11. For pilot studies
9
: That the clinical investigation is a pilot study and therefore by design is
not suitable for the purpose of meeting the essential requirements and CE marking.
12. Any comments that may not be grounds for objections but are comments which the CA
consider that the sponsor should take into account.
B. LETTER OF OBJECTION
Letters of objection / decisions of Competent Authorities should contain the following
information:
8
others, eg.Hospital Owners, Health Insurance Providers, according to national provisions,
may also play a role.
9
Not directly designed to deliver confirmatory answers to regulatory questions for CE
marking. Primary purpose of the study is to guide further product development or the
planning of subsequent pivotal studies. Similar terminology for this kind of exploratory
studies may be “feasibility-“, “proof of concept-“, “FIM-“ or “Early-studies”.
Kommentar [Rapp27]: EUCO:
Further details needed on :
- Definition of COP code
- Definition of FIM (same as 5.3)
Kommentar [Rapp28]: EUCO:
Rewording :
8. The decision. With clear rationale in
case of negative decision.
Kommentar [Rapp29]: EUCO: Shall
be conditional to the approval
Formatiert: Schriftart: 10 Pt., Nicht
Fett
Kommentar [DG30]: Danielle Giroud
TC 194 WG4: suggest to consider
adding here:reporting of serious
violations of the CIP.
Kommentar [sci31]: Input R.
Higgins
Kommentar [DG32]: Danielle Giroud
TC 194 WG4: suggestion: if you want
to ensure this is to be taken into
account by sponsor then it should be a
condition not a comment.
Page 17of35
1. The name of the sponsor
2. The name of the authorised representative, if applicable
3. The name of the manufacturer of the investigational device (if the manufacturer is not the
sponsor)
4. The title of the clinical investigation, the CIP code and version
5. The name of the investigational device(s)
6. The EUDAMED CIV-ID
7. The date
8. The decision
13.9. Detailed reason for the objection – to include all grounds for objection being raised
10. Description of legal remedies open to the applicant under national legislation,
11. Specific information required in a resubmission in order to address the grounds for
objection
Formatiert: Nummerierte Liste +
Ebene: 1 +
Nummerierungsformatvorlage: 1, 2, 3,
… + Beginnen bei: 1 + Ausrichtung:
Links + Ausgerichtet an: 0 cm +
Einzug bei: 0,63 cm
Formatiert: Nummerierte Liste +
Ebene: 1 +
Nummerierungsformatvorlage: 1, 2, 3,
… + Beginnen bei: 1 + Ausrichtung:
Links + Ausgerichtet an: 0 cm +
Einzug bei: 0,63 cm
Formatiert: Schriftart: Fett
Page 18of35
APPENDIX 1
GUIDANCE NOTES ON MEDICAL DEVICES INCORPORATING A MEDICINAL
SUBSTANCE OR HUMAN BLOOD DERIVATIVE HAVING ANCILLARY ACTION
Additional information required with regard to the medicinal substance and/or the
human blood derivative:.
Information if it is an authorized medicinal substance, or not. If yes, it’s authorized on
the EU market? Since how long? The approved indication(s) must be mentioned and
the EU SPC must be included.
Intended purpose within the context of the device and the risk analysis.
Source, product license (where applicable), quantity/dosage of the medicinal
component, and the method by which the substance is incorporated into the device.
Method of manufacture (solvents/reagents used in processing, residuals).
Stability data in relation to the expected shelf-life/lifetime of the device.
Qualitative and quantitative tests carried out on the medicinal substances.
Clinical documentation (clinical data demonstrating the usefulness of the medicinal
substance)
Additional information required with regard to the medicinal substance only:
Control of the starting materials
- (medicinal substance specifications eg, summary of the European Drug
Master File, reference to European Pharmacopoeia or national monograph of
a European Member State).
- Manufacturers may wish to cross-reference a granted Clinical Trial
Exemption (CTE).Authorisation (CTA)
- Please refer to “The rules governing medicinal products in the European
Community” volume III, Addendum II.
Qualitative and quantitative tests carried out on the medicinal substances.
Stability data in relation to the expected shelf-life/lifetime of the device.
Toxicological profile (summary of results of toxicity testing/biological compatibility).
- This should include the effect on reproductivity, embryo/foetal and perinatal
toxicity and the mutagenic/carcinogenic potential of the medicinal substance.
Pharmacodynamics of the medicinal substance in the context ofrelation to the device.
Pharmokinetic characteristics (local/systemic exposure patterns, duration and
maximum exposure and the maximum plasma concentration peak taking into account
individual variability, area under the curve (AUC), in the context of the
device).Notably, for thenewactive substances the release of the substance from the
device, its subsequent distribution and eliminationshould be addressed.
Local tolerance (particularly where the route of exposure is different to the
conventional application) eg, the results of EN/ISO 10993 testing, or a review of
scientific literature.
Kommentar [Rapp33]: EUCO:
Replace Annex
Formatiert: Schriftart: Fett
Kommentar [sci34]: Input of
Portugal
Kommentar [Rapp35]: EUCO: To
refer to the applicable drug regulation
and national regulation
Formatiert: Listenabsatz, Keine
Aufzählungen oder Nummerierungen
Formatiert: Listenabsatz, Keine
Aufzählungen oder Nummerierungen
Formatiert: Keine Aufzählungen oder
Nummerierungen
Formatiert: Keine Aufzählungen oder
Nummerierungen
Page 19of35
NOTE: Referral to MEDDEV 2.1.3, Section B3, which describes the documentation to be
provided by the Notified Body to the Medicinal Product Competent Authority for medicinal
products as part of the consultation procedure may be helpful.
Additional information required with regard to the human blood derivative only:
Control of the starting materials
- Control of plasma source e.g. summary of the European Plasma Master File
- Production of the blood derivative
Page 20of35
APPENDIX 2a
List of the standards applied in full or in part
Investigational device (name, size, model):
Manufacturer:
Date:
Standard
(identifier and title)
Version/
Year
Compliance
(with the exception of clinical requirements that will be assessed during clinical investigation)
Full Partial Description of all deviations and of the alternative solutions adopted to meet the essential
requirements of directive 90/385/EEC or 93/42/EEC
Kommentar [Rapp36]: EUCO:
Added (please refer to the table of the
draft for further details)
Commonly, the standard identifier goes
together with the publication year, the
title can then be stated separately. The
template suggests having the standard
identifier with the title and then have the
publication year in a separate column.
This is not the common practice of
standards citation.
Page 21of35
Appendix 2b: Matrix of Essential Requirements, being applicable or not to an Investigational Medical Device, with rationales
(to be provided by volunteers! May be combined with App. 2a)
Page 22of35
APPENDIX 3
Guidance on medical devices which require sterilization
Additional information required for sterile devices, which are either provided sterile or sterilized at the point of use:
Documentation to demonstrate that the method of sterilization renders the device sterile.
If provided sterile, this should include where appropriate:
• the method of sterilization
• details of the sterilization facility, name, location, process
• proof of validation to demonstrate that the sterilization process can be delivered effectively and reproducibly to the specified devices in the
sterilization load, e.g. results, certificates and justification for the choice of sterilization process
• details of the records for product release (indicator testing, dosimetric release, parametric release), this should include the results and
outcomes
• data relating to bioburden, e.g. nature, frequency and outcome
• details of any environmental precautions undertaken on the device during manufacture or sterilization. Information to include; nature,
frequency of monitoring and outcome
• details of any standards applied to the any of the sterilization processes.
If devices are to be sterilized at the point of use, this should include where appropriate:
• a copy of the instructions for decontamination (i.e. cleaning, disinfection and or sterilization) including details of any special precautions for
handling
• appropriate validation data to demonstrate that the processes can be delivered effectively and reproducibly to the specified devices must
be provided.
Important points to note
• Documentation should be provided for each investigation device (non-CE marked) which requires sterilization. This includes any
instruments or accessories.
• Where devices are sterilized at the point of use, and moist heat (steam) is chosen as the method of sterilization, particular attention should
be taken with regards to the ‘standard sterilization parameters’ applicable within the country where the devices are to be processed and
sterilized. The appropriate sterilization qualification and validation reports should take account of these ‘standard’ requirements.
Kommentar [Rapp37]: UK proposal
Page 23of35
Appendix 4
Guidance on clinical investigations of active devices (excluding Software, see Appendix 5)
Additional information to support claims of compliance with the essential requirements of the Council Directive, e.g. 93/42/EEC or 90/385/EEC.
General
1. Essential requirements checklist detailing how these requirements have been addressed, including references to harmonised standards
as appropriate.
Note: The application of harmonised standards is voluntary and applicants may choose alternative methods of demonstrating compliance with
the essential requirements. For example, compliance with international, national or in-house standards. This should be supported by a risk
benefit analysis, preferably to EN ISO 14971.
2. Documentary evidence supporting compliance with any of the standards referenced. This may include certification by an independent
body, or test house. Alternatively, self-certification is acceptable, providing this is supported with evidence of design input and
subsequent in-house verification.
3. For those applicants choosing self-certification against EN 60601-1 (which includes protection against electric shock hazards,
mechanical hazards, fault conditions, constructional requirements, etc) a checklist for that standard, or equivalent, should be provided.
This should be completed and signed by a competent engineer. Where clauses are considered not applicable, a justification should be
given. Where measurements of leakage currents are made, the values should be recorded.
4. When the medical device is to be used with other devices as part of a system, e.g. connection to laptop computers, etc an additional EN
60601-1-1 checklist or equivalent covering the whole system under investigation should also be provided.
Specialist technologies including: infra-red, laser, microwave, MRI, RF ultrasound, ultraviolet, X-ray etc.
5. Details of how this technology has been incorporated in the design and what steps have been taken to assure the safe application in the
device. Information pertaining to output power, justification of safety limits used and reference to appropriate standards should be
included, e.g. the relevant part 2 of the EN 60601 series.
Active Implants
6. A summary of the Failure Mode, Effects [and Criticality] Analysis (FMEA/FMECA).
7. The results of animal studies.
Kommentar [Rapp38]: UK proposal
Page 24of35
8. Performance statistics and adverse incident data of earlier model, when device is the next generation of an earlier design.
Formatiert: Einzug: Links: 0,63 cm,
Hängend: 0,63 cm
Page 25of35
Appendix 5: Software and programmable devices
Where the device includes a software component the following should be addressed in the notification:
Describe any standards used in the development of the software (e.g. IEC 62304, IEC 80002, IEC 80001-1).
Describe the role of the software including whether:
• The normal operation, initial setting up, maintenance, calibration, adjustment, or monitoring of the medical device, depend on software;
• The correct operation of the medical device depends on the execution of the software within a limited time i.e real time software is used;
• Any part of the medical device’s software can be run independently on hardware not directly connected to the medical device.
Describe the relationship of software to safety including:
• Whether essential performance depends on software (essential performance is the performance whose absence would pose a threat of
harm to the patient);
• Which risk control measures depend on software;
• What opportunities there are for informed intervention by clinical staff or the patient to prevent harm in the event of a software failure.
Describe the risk management of software including:
• A risk management process that includes software items;
• Identification of causative sequences of events that includes software defects;
• Whether hardware risk control measures are used to prevent the consequences of software defects;
• Whether the software development process is used as a risk control measure;
• Whether software verification or software validation is used as a risk control measure (verification = ‘did we do the thing right’, validation =
‘did we do the right thing?’).
Describe the software development processes including:
• Whether the system and software architecture is documented in such a manner that it is possible to reason about the contribution of each
component and software item to safety;
• Whether software units (the lowest level of software decomposition) were tested before being integrated into larger software items.
Describe the purpose of the clinical investigation with regard to:
Page 26of35
• Whether the clinical investigation is intended to evaluate the fitness for clinical purpose of any part of the software and, if so, how this will be
done;
• Detail of any specific protocols designed to evaluate the operation of the software in the clinical context.
Describe the human interface including:
• The user interfaces (mechanisms intended to allow humans to interact with the software) that the software has (including user interfaces for
the patient, clinical technician, physician, service engineer, etc.).
• The target population for each type of user interface (for example, age, expertise, language, etc) and whether this is documented.
• The tests that have been done prior to the clinical investigation to evaluate the effectiveness of the user interfaces for each target
population, or how this will be evaluated in the study.
• The measures used to ensure that only appropriate people are allowed to operate each different type of user interface.
Describe how the software is protected including:
• Protection from accidental or unauthorised change.
• Identification of roles which have the authority to make software changes during the clinical trial.
• The measures that are in place to ensure that software changes do not adversely affect the clinical investigation.
Page 27of35
APPENDIX 6 (proposed draft)
Clinical investigation assessment checklist for Competent Authorities
Investigational device :
Manufacturer:
Title of clinical investigation :
Date:
Version:
General Information
Requirement Fulfilled Comment
Identification of Manufacturer
YES
NO
Incomplete/insufficient
Identification of Authorized
Representative YES
NO
Incomplete/insufficient
Identification of Sponsor
YES
NO
Incomplete/insufficient
Identification of clinical
investigation (title ,ID code,
version, date etc)
YES
NO
Incomplete/insufficient
…………………………….. ……………………… ………………………..
…………………………….. …………………… ……………………………..
………………………………. ……………………………… …………………………………………….
Page 28of35
CIP
Requirement Fulfilled Comment
Identification of CIP (title,
revision, date, Sponsor,
Manufacturer……....)
YES
NO
Incomplete/insufficient
Synopsis of the clinical
investigation plan YES
NO
Incomplete/insufficient
literature data and rationale
for the design and intended
use of the investigational
device
sufficient/ adequate
non adequate
insufficient -
incomplete
Identification and description
of the device sufficient /adequate
non adequate
insufficient
/incomplete
primary and secondary
objectives sufficient /adequate
non adequate
insufficient -
Page 29of35
incomplete
endpoints, variables to be
used, methods and timing of
the assessments
sufficient /adequate
non adequate
insufficient -
incomplete
type and design of clinical
investigation adequate/sufficient
non adequate
insufficient
/incomplete
type of comparison (e.g.,
superiority, non-inferiority,
equivalence
adequate /sufficient
non
adequate/insufficient
NA
choice of controls (e.g.,
cohort, sham, historical) adequate
non
adequate/insufficient
NA
Numbers of subjects
Adequate/sufficient
non
adequate/insufficient
criteria for subject selection
adequate /sufficient
non
adequate/insufficient
proposed follow up
adequate/sufficient
Page 30of35
non
adequate/insufficient
Description of the medical
procedures related to the
clinical investigation.
adequate /sufficient
non
adequate/insufficient
training experience with the
device or type of device in
question, if applicable.
sufficient /adequate
non
adequate/insufficient
…………………………………
………………..
CIP: Control of risks due to innovation
………..
…………………
Mitigation of the risks due to
the learning curve sufficient /adequate
non
adequate/insufficient
Training of first use foreseen
for each investigator sufficient /adequate
non
adequate/insufficient
Supervision of every
investigator during the first
use
sufficient /adequate
non
adequate/insufficient
Page 31of35
Combined FIM and pivotal
phases in the clinical
investigation
YES
NO
NA
………………………..
……………………………
………………………………..
………………………………….
IB
Requirement Fulfilled Comment
Identification of IB (version,
date, title, sponsor,
manufacturer etc)
sufficient /adequate
non
adequate/insufficient
rationale for the design and
intended use of the
investigational device
sufficient /adequate
non
adequate/insufficient
Details allowing device(s) to
be identified sufficient /adequate
non
adequate/insufficient
Risk classification of medical
device.
sufficient /adequate
non
adequate/insufficient
Description of the intended
clinical performance and the
mechanism of action of the
sufficient /adequate
Page 32of35
investigational medical device
non
adequate/insufficient
Description of device
sufficient /adequate
non
adequate/insufficient
Existing clinical data
sufficient /adequate
non
adequate/insufficient
NA
In vitro pre-clinicaltesting
sufficient /adequate
non
adequate/insufficient
NA
In vivo preclinical testing
sufficient /adequate
non
adequate/insufficient
NA
Ex vivo preclinical testing
sufficient /adequate
non
adequate/insufficient
NA
…………………
……………………………..
Benefit/Risk analysis
sufficient /adequate
Page 33of35
non
adequate/insufficient
Identification of hazards and
estimated risks associated
with the manufacture and the
use of the device
sufficient /adequate
non
adequate/insufficient
Estimation of the
associated risks for each
identified hazard by:
a) characterising the
severity of the hazard;
b) estimating and
characterising the
probability of occurrence of
the harm (or health
impairment or loss of
benefit of the treatment)
(document with rationale)
sufficient /adequate
non
adequate/insufficient
actions taken to minimize or
eliminate the identified risks sufficient /adequate
non
adequate/insufficient
…………………….
…………………………………
………………………………….
Other documents
Requirement Fulfilled Comment
Copy of the Ethics
committees opinion YES
NO
The CIP evaluated by the
CA is the same as that
submitted to the ECs
YES
Page 34of35
NO
Comments/conditions arising
from the review of the ECs YES
NO
…………….
………………..
…………………………….
Page 35of35
31.07.2014
Datei
PD
Verordnungsentwurf der Bundesregierung
Achtundzwanzigste Verordnung zur Änderung betäubungsmittelrecht-
licher Vorschriften
A. Problem und Ziel
Mit Artikel 1 dieser Verordnung werden zum Schutz der Gesundheit des Einzelnen und
der Bevölkerung neue psychoaktive Substanzen (NPS) in den Anlagen I und II des Be-
täubungsmittelgesetzes (BtMG) aufgenommen, um den Missbrauch dieser gesundheits-
gefährdenden synthetischen Stoffe einzudämmen und die Strafverfolgung zu erleichtern.
Für das Betäubungsmittel Lisdexamfetaminmesilat wird eine Höchstverschreibungsmenge
festgelegt.
Daneben werden mit Artikel 2 die Regelungen zum Substitutionsregister angepasst, um
geänderten Erfordernissen der praktischen Anwendung sowie dem Datenschutz Rech-
nung zu tragen. Dadurch sollen die Ziele des Substitutionsregisters mit geringerem Auf-
wand in besserer Qualität erreicht sowie die Sicherheit und Kontrolle des Betäubungsmit-
telverkehrs verbessert werden. Zu den Aufgaben des Substitutionsregisters gehören ins-
besondere, die frühestmögliche Verhinderung von Mehrfachverschreibungen von Substi-
tutionsmitteln durch verschiedene Ärzte für denselben Patienten, die Feststellung der Er-
füllung der Mindestanforderungen an eine suchttherapeutische Qualifikation der substitu-
ierenden Ärzte, die Übermittlung statistischer Auswertungen an die zuständigen Überwa-
chungsbehörden und obersten Landesgesundheitsbehörden.
Im Übrigen werden redaktionelle Klarstellungen und Anpassungen an geltende Rechts-
vorschriften vorgenommen.
B. Lösung
Erlass der vorliegenden Verordnung.
C. Alternativen
Keine.
D. Haushaltsausgaben ohne Erfüllungsaufwand
Keine.
E. Erfüllungsaufwand
E.1 Erfüllungsaufwand für Bürgerinnen und Bürger
Für Bürgerinnen und Bürger entsteht kein zusätzlicher Erfüllungsaufwand.
- 2 - Bearbeitungsstand: 03.07.2014 14:15 Uhr
E.2 Erfüllungsaufwand für die Wirtschaft
Für die Wirtschaft entsteht durch die Aufnahme weiterer NPS in die Anlagen I und II des
BtMG kein zusätzlicher Erfüllungsaufwand.
E.3 Erfüllungsaufwand der Verwaltung
Für die Bundesverwaltung entsteht durch die Aufnahme weiterer NPS kein nennenswerter
zusätzlicher Erfüllungsaufwand.
Gegebenenfalls entstehender Mehrbedarf an Sach- oder Personalmitteln im Bereich des
Bundes sind finanziell und stellenmäßig im jeweiligen Einzelplan auszugleichen.
Durch die Neuregelungen zum Substitutionsregister, die damit verbundene Verringerung
des Datenbestandes und durch den Wegfall einiger regelmäßiger Meldungen können sich
geringfügige derzeit nicht quantifizierbare Einsparungen ergeben.
Für die Länder entsteht durch die Ausdehnung der Überwachung des Betäubungsmittel-
verkehrs aufgrund der Aufnahme weiterer NPS in die Anlagen I und II ein erhöhter, derzeit
aber nicht quantifizierbarer Vollzugsaufwand.
F. Weitere Kosten
Keine.
- 3 - Bearbeitungsstand: 03.07.2014 14:15 Uhr
Achtundzwanzigste Verordnung zur Änderung betäubungsmittelrecht-
licher Vorschriften*
Vom [Datum der Ausfertigung]
Die Bundesregierung verordnet
– auf Grund des § 1 Absatz 2 des Betäubungsmittelgesetzes in der Fassung der Be-
kanntmachung vom 1. März 1994 (BGBl. I S. 358) nach Anhörung von Sachverstän-
digen und
– auf Grund des § 13 Absatz 3 des Betäubungsmittelgesetzes, der zuletzt durch Artikel
4 Nummer 3 Buchstabe c des Gesetzes vom 19. Oktober 2012 (BGBl. I S. 2192) ge-
ändert worden ist:
Artikel 1
Änderung der Anlagen des Betäubungsmittelgesetzes
Die Anlagen des Betäubungsmittelgesetzes in der Fassung der Bekanntmachung
vom 1. März 1994 (BGBl. I S. 358), das zuletzt durch Artikel 1 des Gesetzes vom 9. Juli
2013 (BGBl. I S. 2274) geändert worden ist, werden wie folgt geändert:
1. In Anlage I werden die folgenden Positionen jeweils alphabetisch in die bestehende
Reihenfolge eingefügt:
INN andere nicht geschützte
oder Trivialnamen
chemische Namen
(IUPAC)
„― 5-(2-Aminopropyl)indol
(5-IT)
1-(1H-Indol-5-yl)propan-2-amin
― 25B-NBOMe
(2C-B-NBOMe)
2-(4-Brom-2,5-dimethoxyphenyl)-
N-[(2-methoxyphenyl)methyl]
ethanamin
― 2C-C 2-(4-Chlor-2,5-
dimethoxyphenyl)ethanamin
― 2C-D (2C-M) 2-(2,5-Dimethoxy-4-
methylphenyl)ethanamin
― 2C-E 2-(4-Ethyl-2,5-
*) Notifiziert gemäß der Richtlinie 98/34/EG des Europäischen Parlaments und des Rates
vom 22. Juni 1998 über ein Informationsverfahren auf dem Gebiet der Normen und
technischen Vorschriften und der Vorschriften für die Dienste der Informationsgesellschaft
(ABl. L 204 vom 21.7.1998, S. 37), zuletzt geändert durch Artikel 26 Absatz 2 der Verord-
nung (EU) Nr. 1025/2012 des Europäischen Parlaments und des Rates vom 25. Oktober
2012 (ABl. L 316 vom 14.11.2012, S. 12).
- 4 - Bearbeitungsstand: 03.07.2014 14:15 Uhr
dimethoxyphenyl)ethanamin
― 25C-NBOMe
(2C-C-NBOMe)
2-(4-Chlor-2,5-dimethoxyphenyl)-
N-[(2-methoxyphenyl)methyl]
ethanamin
― 2C-P
2-(2,5-Dimethoxy-4-
propylphenyl)ethanamin
― N-Ethylbuphedron
(NEB)
2-(Ethylamino)-1-phenylbutan-1-
on
― 4-Ethylmethcathinon
(4-EMC)
1-(4-Ethylphenyl)-2-
(methylamino)propan-1-on
― Ethylon
(bk-MDEA, MDEC)
1-(1,3-Benzodioxol-5-yl)-2-
(ethylamino)propan-1-on
― 2-Fluormethamfetamin
(2-FMA)
1-(2-Fluorphenyl)-N-
methylpropan-2-amin
― 3-Fluormethamfetamin
(3-FMA)
1-(3-Fluorphenyl)-N-
methylpropan-2-amin
― 25I-NBOMe
(2C-I-NBOMe)
2-(4-lod-2,5-dimethoxyphenyl)-N-
[(2-methoxyphenyl)methyl]
ethanamin
― 4-Methylbuphedron
(4-MeMABP)
2-(Methylamino)-1-(4-
methylphenyl)butan-1-on
― 3-Methylmethcathinon
(3-MMC)
2-(Methylamino)-1-(3-
methylphenyl)propan-1-on
― Pentylon
(bk-MBDP)
1-(1,3-Benzodioxol-5-yl)-2-
(methylamino)pentan-1-on
― Thienoamfetamin
(Thiopropamin)
1-(Thiophen-2-yl)propan-2-amin“.
2. In Anlage II werden die folgenden Positionen jeweils alphabetisch in die bestehende
Reihenfolge eingefügt:
INN andere nicht geschützte
oder Trivialnamen
chemische Namen
(IUPAC)
„— AB-FUBINACA N-(1-Amino-3-methyl-1-
oxobutan-2-yl)-1-[(4-
fluorphenyl)methyl]-1H-
indazol-3-carboxamid
— AB-PINACA N-(1-Amino-3-methyl-1-
oxobutan-2-yl)-1-pentyl-1H-
indazol-3-carboxamid
— AH-7921
(Doxylam)
3,4-Dichlor-N-{[1-
(dimethylamino)cyclo-
- 5 - Bearbeitungsstand: 03.07.2014 14:15 Uhr
hexyl]methyl}benzamid
— APICA (SDB-001, 2NE1) N-(Adamantan-1-yl)-1-pentyl-
1H-indol-3-carboxamid
— BB-22 (QUCHIC) Chinolin-8-yl[1-
(cyclohexylmethyl)-1H-indol-3-
carboxylat]
— Desoxypipradrol (2-DPMP) 2-(Diphenylmethyl)piperidin
— Dimethocain
(DMC, Larocain)
(3-Diethylamino-2,2-
dimethylpropyl)-4-
aminobenzoat
— 2,5-Dimethoxy-4-iodamfetamin
(DOI)
1-(4-Iod-2,5-dimethoxyphenyl)
propan-2-amin
— EAM-2201
(5-Fluor-JWH-210)
(4-Ethylnaphthalin-1-yl)[1-(5-
fluorpentyl)-1H-indol-3-
yl]methanon
— FDU-PB-22 Naphthalin-1-yl{1[(4-
fluorphenyl)methyl]-1H-indol-3-
carboxylat}
— 5F-PB-22
(5F-QUPIC)
Chinolin-8-yl[1-(5-
fluorpentyl)indol-3-carboxylat]
— FUB-PB-22 Chinolin-8-yl{1-[(4-
fluorphenyl)methyl]-1H-indol-3-
carboxylat}
— PB-22
(QUPIC)
Chinolin-8-yl(1-pentylindol-3-
carboxylat)
— STS-135
(5F-2NE1)
N-(Adamantan-1-yl)-1-(5-
fluorpentyl)-1H-indol-3-
carboxamid
— THJ-2201
(AM-2201 Indazol-Analogon)
[1-(5-Fluorpentyl)-1H-indazol-
3-yl]-(naphthalin-1-
yl)methanon“.
Artikel 2
Änderung der Betäubungsmittel-Verschreibungsverordnung
Die Betäubungsmittel-Verschreibungsverordnung vom 20. Januar 1998 (BGBl. I S.
74, 80), die zuletzt durch Artikel 2 des Gesetzes vom 20. Juli 2012 (BGBl. I S. 1639) ge-
ändert worden ist, wird wie folgt geändert:
1. In § 2 Absatz 1 Buchstabe a wird nach Nummer 11 folgende Nummer 11a eingefügt:
„Lisdexamfetaminmesilat 2100 mg“
- 6 - Bearbeitungsstand: 03.07.2014 14:15 Uhr
2. § 5a wird wie folgt geändert:
a) Absatz 1 Satz 2 wird wie folgt geändert:
aa) In Nummer 1 wird das Wort „verhindern“ durch das Wort „unterbinden“ er-
setzt.
bb) Nummer 2 wird wie folgt gefasst:
„2. zu überprüfen, ob die ein Substitutionsmittel verschreibenden Ärzte die
Mindestanforderungen nach § 5 Absatz 2 Satz 1 Nummer 6 oder die An-
forderungen nach § 5 Absatz 3 Satz 1 Nummer 2 und 3 erfüllen sowie“.
b) Absatz 2 Satz 1 wird wie folgt geändert:
aa) Nummer 5 wird wie folgt gefasst:
„5. Name, Vorname, Geburtsdatum, dienstliche Anschrift und Telefonnum-
mer des verschreibenden Arztes sowie“.
bb) Nummer 6 wird wie folgt gefasst:
„6. im Falle des Verschreibens nach § 5 Absatz 3 Satz 1 Name, Vorname
und dienstliche Anschrift des Konsiliarius.“
c) Absatz 4 wird wie folgt geändert:
aa) Satz 3 wird wie folgt gefasst:
„Liegen Übereinstimmungen vor, teilt dies das Bundesinstitut jedem beteilig-
ten Arzt unter Angabe des Patientencodes, des Datums der ersten Ver-
schreibung und der Namen und Vornamen, dienstlichen Anschriften und Te-
lefonnummern der anderen beteiligten Ärzte unverzüglich mit.“
bb) In Satz 8 werden das Wort „einen“ durch das Wort „denselben“ ersetzt und
nach dem Wort „Patienten“ die Wörter „und denselben Zeitraum unverzüg-
lich“ eingefügt.
d) Absatz 5 wird wie folgt gefasst:
5. „Die Ärztekammern haben dem Bundesinstitut auf dessen Anforderung, un-
ter Angabe von Vorname, Name, dienstlicher Anschrift und Geburtsdatum
eines nach Absatz 2 Satz 1 Nummer 5 oder Nummer 6 gemeldeten Arztes,
unverzüglich zu melden, ob der Arzt die Mindestanforderungen nach § 5 Ab-
satz 2 Satz 1 Nummer 6 erfüllt. Die Ärztekammern haben dem Bundesinstitut
unverzüglich die Angabe „Hinweis: Suchttherapeutische Qualifikation liegt
nicht mehr vor.“ zu denjenigen Ärzten, welche zuvor von den Ärztekammern
dem Bundesinstitut gemeldet wurden, zu übermitteln, die die Mindestanfor-
derungen nach § 5 Absatz 2 Satz 1 Nummer 6 bisher erfüllt haben, aktuell
aber nicht mehr erfüllen. Das Bundesinstitut kann zum Zweck der Datenbe-
reinigung von den Ärztekammern auch Meldungen zu allen Ärzten, die die
Mindestanforderungen nach § 5 Absatz 2 Satz 1 Nummer 6 erfüllen, mit fol-
genden Angaben verlangen:
1. Name und Vorname,
2. dienstliche Anschrift,
- 7 - Bearbeitungsstand: 03.07.2014 14:15 Uhr
3. Geburtsdatum.
Das Bundesinstitut unterrichtet aus dem Datenbestand des Substitutionsregisters un-
verzüglich die zuständigen Überwachungsbehörden der Länder über Name, Vorname
und Anschrift
1. der Ärzte, die ein Substitutionsmittel nach § 5 Absatz 2 verschrieben haben und
2. der nach Absatz 2 Nummer 6 gemeldeten Konsiliarien,
wenn diese die Mindestanforderungen nach § 5 Absatz 2 Satz 1 Nummer 6 in Ver-
bindung mit den übermittelten Daten nach § 5a Absatz 5 nicht erfüllen.“
e) Absatz 6 wird wie folgt gefasst:
6. „Das Bundesinstitut teilt aus dem Datenbestand des Substitutionsregisters
den zuständigen Überwachungsbehörden zum 30. Juni und 31. Dezember
eines jeden Jahres folgende Angaben mit:
1. Namen, Vornamen und Anschriften der Ärzte, die nach § 5 Absatz 2 Sub-
stitutionsmittel verschrieben haben,
2. Namen, Vornamen und Anschriften der Ärzte, die nach § 5 Absatz 3 Satz
1 Substitutionsmittel verschrieben haben,
3. Namen, Vornamen und Anschrifteen der Ärzte, die nach Absatz 2 Satz 1
Nummer 6 als Konsiliarius gemeldet worden sind, sowie
4. Anzahl der Patienten, für die ein unter Nummer 1 oder Nummer 2 genann-
ter Arzt ein Substitutionsmittel verschrieben hat.
Die zuständigen Überwachungsbehörden können auch jederzeit im Einzelfall
vom Bundesinstitut entsprechende Auskunft verlangen.“
f) Absatz 7 wird wie folgt gefasst:
7. „Das Bundesinstitut teilt aus dem Datenbestand des Substitutionsregisters
den obersten Landesgesundheitsbehörden für das jeweilige Land zum 31.
Dezember eines jeden Jahres folgende Angaben mit:
1. die Anzahl der Patienten, denen ein Substitutionsmittel verschrieben wur-
de,
2. die Anzahl der Ärzte, die nach § 5 Absatz 2 Substitutionsmittel verschrie-
ben haben,
3. die Anzahl der Ärzte, die nach § 5 Absatz 3 Satz 1 Substitutionsmittel ver-
schrieben haben,
4. die Anzahl der Ärzte, die nach Absatz 2 Satz 1 Nummer 6 als Konsiliarius
gemeldet worden sind, sowie
5. Art und Anteil der verschriebenen Substitutionsmittel.
Auf Verlangen erhalten die obersten Landesgesundheitsbehörden die unter
den Nummern 1 bis 5 aufgeführten Angaben auch aufgeschlüsselt nach
Überwachungsbereichen.“
- 8 - Bearbeitungsstand: 03.07.2014 14:15 Uhr
3. § 5 b wird wie folgt geändert:
a) In der Überschrift werden die Wörter „Alten- und Pflegeheimen“ durch die Wörter
„Alten- oder Pflegeheimen“ ersetzt.
b) In Absatz 1 Satz 1 werden die Wörter „Alten- und Pflegeheim“ durch die Wörter
„Alten- oder Pflegeheim“ und in Satz 2 die Wörter „Alten- und Pflegeheimes“
durch die Wörter „Alten- oder Pflegeheimes“ ersetzt.
c) In Absatz 2 werden die Wörter „Alten- und Pflegeheimes“ durch die Wörter „Al-
ten- oder Pflegeheimes“ ersetzt.
d) In Absatz 3 Satz 1 werden die Wörter „Alten- und Pflegeheim“ durch die Wörter
„Alten- oder Pflegeheim“ ersetzt.
e) In Absatz 4 Nummer 1 werden die Wörter „Alten- und Pflegeheimes“ durch die
Wörter „Alten- oder Pflegeheimes“ und die Wörter „ambulanten spezialisierten“
durch die Wörter „spezialisierten ambulanten“ sowie in Nummer 2 die Wörter „Al-
ten- und Pflegeheim“ durch die Wörter „Alten- oder Pflegeheim“ ersetzt.
4. § 5 c Absatz 1 Nummer 3 wird wie folgt gefasst:
3. „ mit einer Apotheke die Belieferung für den Notfallvorrat sowie eine mindestens
halbjährliche Überprüfung der Notfallvorräte insbesondere auf deren einwand-
freie Beschaffenheit sowie ordnungsgemäße und sichere Aufbewahrung schrift-
lich zu vereinbaren. Der unterzeichnende Apotheker zeigt dies der zuständigen
Landesbehörde vor der ersten Belieferung schriftlich an. § 6 Absatz 3 Satz 2 bis
4 gilt entsprechend.“
5. In § 6 Absatz 3 wird Satz 2 gestrichen.
6. In § 9 Absatz 1 Nummer 5 werden die Wörter „Vermerk Gemäß schriftlicher Anwei-
sung“ durch die Wörter „Hinweis auf diese schriftliche Gebrauchsanweisung“ ersetzt.
Artikel 3
Inkrafttreten und Übergangsvorschriften
Diese Verordnung tritt am Tag nach der Verkündung in Kraft.
Artikel 2 Nummer 2d) Satz 3 tritt am [einsetzen: Datum des ersten Tages, der nach
drei Jahren auf die Verkündung folgt] außer Kraft.
Der Bundesrat hat zugestimmt.
Berlin, den … 2014
D i e B u n d e s k a n z l e r i n
D e r B u n d e s m i n i s t e r f ü r G e s u n d h e i t
- 9 - Bearbeitungsstand: 03.07.2014 14:15 Uhr
Begründung
A. Allgemeiner Teil
I. Ziel und Gegenstand des Verordnungsentwurfs
Artikel 1
Mit dieser Verordnung werden die Anlagen des Betäubungsmittelgesetzes (BtMG) geän-
dert.
Auf der Grundlage der Ermächtigung in § 1 Absatz 2 BtMG werden bestimmte gesund-
heitsgefährdende neue psychoaktive Substanzen (NPS) den Anlagen I und II des BtMG
unterstellt. Der Sachverständigenausschuss für Betäubungsmittel nach § 1 Absatz 2
BtMG wurde angehört und hat sich für alle in dieser Verordnung enthaltenen Änderungen
der Anlagen des BtMG ausgesprochen.
Artikel 2
Für das Betäubungsmittel Lisdexamfetaminmesilat wird eine Höchstverschreibungsmenge
festgelegt.
Daneben werden die Regelungen zum Substitutionsregister (Register mit Daten über das
Verschreiben von Substitutionsmitteln) in § 5a BtMVV geändert. Sie dienen der Funktions-
fähigkeit des Substitutionsregisters und somit der Sicherheit und Kontrolle des Betäu-
bungsmittelverkehrs beim Verschreiben von Substitutionsmitteln im Rahmen einer substi-
tutionsgestützten Behandlung Opiatabhängiger. Hierzu wird die Vorschrift klarer gefasst.
Insbesondere werden die Aufgaben des Bundesinstituts für Arzneimittel und Medizinpro-
dukte (BfArM), bei dessen Bundesopiumstelle das Substitutionsregister im Auftrag der
Bundesländer geführt wird, konkretisiert. Zudem werden durch ein geändertes Meldever-
fahren in § 5a Absatz 5 BtMVV die Aktualität und die Qualität der Daten verbessert.
Im Übrigen erfolgen sprachliche Anpassungen und Klarstellungen.
II. Haushaltsausgaben ohne Erfüllungsaufwand
Bund, Länder und Kommunen werden nicht mit weiteren Bürokratiekosten belastet.
III. Erfüllungsaufwand
Für Bürgerinnen und Bürger entsteht kein zusätzlicher Erfüllungsaufwand.
Für die Wirtschaft entsteht durch die Unterstellung weiterer NPS in die Anlagen I und II
des BtMG kein zusätzlicher Erfüllungsaufwand.
Für die Bundesverwaltung entsteht kein nennenswerter zusätzlicher Erfüllungsaufwand.
Durch die Neuregelungen zum Substitutionsregister können sich geringfügige derzeit
nicht quantifizierbare Einsparungen ergeben.
Gegebenenfalls entstehende Mehrbedarfe an Sach- oder Personalmitteln im Bereich des
Bundes sind finanziell und stellenmäßig im jeweiligen Einzelplan auszugleichen.
Für die Überwachungsbehörden der Länder entsteht durch die Ausdehnung der Überwa-
chung des Betäubungsmittelverkehrs aufgrund der Aufnahme weiterer NPS in die Anla-
gen I bis III ein erhöhter, derzeit aber nicht quantifizierbarer Vollzugsaufwand.
- 10 - Bearbeitungsstand: 03.07.2014 14:15 Uhr
IV. Nachhaltigkeit
Mit dieser Verordnung werden Gefahren und unvertretbare Risiken für die menschliche
Gesundheit durch die Unterstellung weitererNPS langfristig abgewendet.
Mit der Festlegung einer Höchstverschreibungsmenge für Lisdexamfetaminmesilat wird
die Therapiesicherheit für die Behandlung vom Aufmerksamkeit Defizit Hyperkinese Syn-
drom erhöht.
Die Änderungen zu § 5a BtMVV stellen die Funktionalität des Substitutionsregisters si-
cher, reduzieren nachhaltig die vorgehaltene Datenmenge und tragen in gleicher Weise
zur Sicherheit und Kontrolle des Betäubungsmittelverkehrs bei.
V. Gleichstellungspolitische Bedeutung
Die Verordnung hat keine gleichstellungspolitischen Auswirkungen.
VI. Befristung
Eine Befristung der durch die Verordnung getroffenen Regelungen ist lediglich für die Än-
derung des § 5a Absatz 5 Satz 3 BtMVV vorgesehen. Diese Vorschrift ist für einen Gel-
tungszeitraum von drei Jahren vorgesehen, in dem das Bundesinstitut die vorgegebene
Aufgabe der Datenbereinigung erledigen kann, und tritt danach außer Kraft.
VII. Vereinbarkeit mit EU-Recht
Der Verordnungsentwurf ist mit dem Recht der Europäischen Union vereinbar. Insbeson-
dere wurde zu den Änderungen in Artikel 1 die Notifizierung gemäß der Richtlinie
98/34/EG des Europäischen Parlaments und des Rates vom 22. Juni 1998 über ein In-
formationsverfahren auf dem Gebiet der Normen und technischen Vorschriften und der
Vorschriften für die Dienste der Informationsgesellschaft (ABl. L 204 vom 21.7.1998, S.
37), zuletzt geändert durch Artikel 26 Absatz 2 der Verordnung (EU) Nr. 1025/2012 des
Europäischen Parlaments und des Rates vom 25. Oktober 2012 (ABl. L 316 vom
14.11.2012, S. 12) eingehalten.
B. Besonderer Teil
Zu Artikel 1 (Änderung der Anlagen des Betäubungsmittelgesetzes)
In den letzten Jahren hat das europäische Frühwarnsystem für NPS in zunehmendem
Maße Informationen über NPS übermittelt, die in Europa bislang noch nicht aufgetreten
sind. Das von der Europäischen Beobachtungsstelle für Drogen und Drogensucht (EBDD)
und Europol betriebene Informationssystem baut auf den nationalen Daten auf. In
Deutschland werden Informationen über NPS insbesondere durch die Strafverfolgungs-
behörden gewonnen. Innerhalb der Europäischen Union wurden zwischen 2005 und 2011
mehr als 164 NPS ermittelt. Im Jahr 2012 wurde eine Rekordzahl von 73 erstmalig ent-
deckten NPS gemeldet. Synthetische Cannabinoide und synthetische Phenylethylami-
ne/Cathinone machen seit 2005 zwei Drittel aller neuen Substanzen aus, die über das
Frühwarnsystem gemeldet werden.
NPS werden oft durch Abwandlung (Derivatisierung) bekannter chemischer Grundstruktu-
ren synthetisiert. Dabei wird häufig die chemische Struktur bereits unterstellter Betäu-
bungsmittel so verändert, dass die neue Substanz nicht mehr dem BtMG unterliegt. Die
für Missbrauchszwecke geeignete Wirkung von NPS auf die Psyche bleibt jedoch erhalten
oder wird sogar verstärkt. Zudem gibt es vermehrt Meldungen über NPS aus bislang eher
unbekannteren chemischen Gruppen.
- 11 - Bearbeitungsstand: 03.07.2014 14:15 Uhr
Begünstigt wird die Vermarktung von NPS durch einen raschen Informationsaustausch
und ein entsprechendes Angebot über das Internet. Hierdurch werden NPS in einer bisher
nicht erreichten Geschwindigkeit und Menge breiter verfügbar.
Zu Nummer 1
Die Anlage I des BtMG (nicht verkehrsfähige Betäubungsmittel) wird um die folgenden
Derivate des Phenylethylamins und verwandter Verbindungen ergänzt:
- 5-(2-Aminopropyl)indol (5-IT),
- 2C-C,
- 2C-D,
- 2C-E,
- 2C-P,
- N-Ethylbuphedron (NEB),
- 4-Ethylmethcathinon (4-EMC),
- Ethylon (bk-MDEA),
- 2-Fluormethamfetamin (2-FMA),
- 3-Fluormethamfetamin (3-FMA),
- 25B-NBOMe (2C-B-NBOMe),
- 25C-NBOMe (2C-C-NBOMe)
- 25I-NBOMe (2C-I-NBOMe),
- 4-Methylbuphedron (4-MeMABP),
- 3-Methylmethcathinon (3-MMC),
- Pentylon (bk-MBDP),
- Thienoamfetamin (Thiopropamin).
Die wichtigste Untergruppe der sich vom Phenylethylamin ableitenden Verbindungen sind
die Amfetamine, von denen einige mit arzneilicher Verwendung der Anlage III des BtMG
bereits unterstellt sind. Daneben wurde bereits eine Reihe missbräuchlich verwendeter
Amfetamine in die Anlagen I und II des BtMG aufgenommen. Bei den Cathinon-Derivaten
handelt es sich um die ß-Keto-Analoga eines entsprechenden Phenylethylamins. Synthe-
tische Cathinone lassen sich auf den natürlich vorkommenden Wirkstoff Cathinon (Anlage
I des BtMG) zurückführen, der als einer von mehreren psychoaktiven Wirkstoffen im
Kathstrauch (Catha edulis) enthalten ist.
Der mit den Phenylethylaminen verwandte Stoff 5-IT hat starke, amfetaminähnliche Wir-
kungen und Nebenwirkungen. Aufgrund von schweren Intoxikationen einschließlich To-
desfällen in mehreren europäischen Staaten, die mit dem Konsum von 5-IT in Verbindung
stehen, wurde von EBDD und Europol ein gemeinsamer Bericht gemäß Artikel 5 des
Ratsbeschlusses 2005/387/JI erstellt, der zu einer Risikobewertung durch die EBDD ge-
mäß Artikel 6 dieses Ratsbeschlusses führte. Aufgrund dieses Risikobewertungsberichts
erfolgte am 7. Oktober 2013 ein Durchführungsbeschluss des Rates über Kontrollmaß-
nahmen für 5-IT gemäß Artikel 9 des o.g. Ratsbeschlusses, die von den Mitgliedstaaten
spätestens nach einem Jahr zu ergreifen sind.
Die Phenylethylamine 2C-C, 2C-D, 2C-E und 2C-P stammen aus der sogenannten „C-
Serie“, deren Konsum insbesondere nach der Publikation des Buches „Pihkal“ von Ale-
xander und Ann Shulgin 1991 populär wurde. Sie haben eine entaktogene und LSD-
ähnliche halluzinogene Wirkung, in den USA wurden Todesfälle nach Einnahme von 2C-E
berichtet. Ein Teil der Stoffe (2C-B, 2C-I, 2C-T-2, 2C-T-7) ist bereits Anlage I des BtMG
unterstellt, aktuell gibt es immer noch eine größere Anzahl an Sicherstellungen durch Po-
lizei- und Zollbehörden insbesondere von 2C-C, 2C-D, 2C-E und 2C-P.
25B-NBOMe, 25C-NBOMe und 25I-NBOMe sind erstmals in den Jahren 2011 bzw. 2012
an die EBDD gemeldete Derivate der oben beschriebenen „C-Serie“ mit einer um ein
mehrfaches erhöhten Wirkpotenz. Aufgrund seiner starken halluzinogenen Wirkung wird
25I-NBOMe auch als LSD-Ersatz angeboten. Die Substanz wird mit mehreren Todesfällen
in den USA, dem Vereinigten Königreich und Belgien sowie schweren Vergiftungen in den
- 12 - Bearbeitungsstand: 03.07.2014 14:15 Uhr
USA, dem Vereinigten Königreich, Schweden, Belgien und Polen in Verbindung gebracht.
Aufgrund des gemeinsamen Berichts von EBDD und Europol vom 17. Dezember 2013
gemäß Artikel 5 des Ratsbeschlusses 2005/387/JI wurde eine Risikobewertung gemäß
Artikel 6 dieses Ratsbeschlusses erstellt, die zur Einführung von Kontrollmaßnahmen ge-
mäß den Artikeln 8 und 9 des Ratsbeschlusses führen kann. Auch in Deutschland gibt es
Beschlagnahmungen von 25B-NBOMe, 25C-NBOMe und 25I-NBOMe durch Polizei- und
Zollbehörden.
Die synthetischen Cathinone Ethylon und Pentylon sind chemisch eng verwandt sowohl
mit anderen bereits dem BtMG unterstellten Cathinonen (Butylon, Methylon), als auch mit
Amfetaminderivaten wie MDMA (Ecstacy). Die weiteren synthetischen Cathinone N-
Ethylbuphedron, 4-Methylbuphedron, 3-Methylmethcathinon und 4-Ethylmethcathinon
sind enge chemische Verwandte und teilweise Positionsisomere der bereits dem BtMG
unterstellten Cathinone Buphedron, Mephedron, Pentedron und 4-MEC. Die Stoffe haben
ein vergleichbares, für Amfetamin- und Cathinonderivate typisches Wirkungs- und Ne-
benwirkungsprofil und wurden in den Jahren 2012 und 2013 häufiger in Deutschland si-
chergestellt.
Bei 2-FMA (2-Fluormethamfetamin) und 3-FMA (3-Fluormethamfetamin) handelt es sich
um Positionsisomere von 4-FMA, welches bereits dem BtMG unterstellt ist. Alle drei Stoffe
haben ein Methamfetamin ähnliches Wirkungs- und Nebenwirkungsprofil. Das Hinzufügen
eines Fluoratoms zur chemischen Struktur ist dazu bestimmt, die Fettlöslichkeit und die
Fähigkeit zur Überwindung der Blut-Hirn-Schranke zu erhöhen. Für 2-FMA waren in den
Jahren 2012 und 2013 häufiger Sicherstellungen durch Polizei- und Zollbehörden zu ver-
zeichnen, aber auch 3-FMA wurde bereits in Deutschland sichergestellt.
Bei Thienoamfetamin handelt sich um ein Thiophenanalog von Amfetamin, das anstelle
von Amfetamin zur Grundstruktur für eine neue Gruppe von Designerdrogen werden
könnte. Das chemisch verwandte Methiopropamin, das ein Thiophenanalog von Metham-
fetamin darstellt, wurde bereits mit der 27. Verordnung zur Änderung betäubungsmittel-
rechtlicher Vorschriften dem BtMG unterstellt. Thienoamfetamin wurde erstmalig im Jahr
2012 an die EBDD gemeldet und führte auch in Deutschland bereits zu Sicherstellungen
durch Polizei- und Zollbehörden. Auch wenn noch keine umfangreichen Informationen zu
Thienoamfetamin vorliegen, ist davon auszugehen, dass die Wirkungen und Nebenwir-
kungen vergleichbar sind mit Methiopropamin und den dem BtMG bereits unterstellten
Amfetaminderivaten.
Alle vorgenannten Substanzen sind bereits in verschiedenen europäischen Ländern dem
dortigen Betäubungsmittelrecht unterstellt. Eine arzneiliche Anwendung dieser Stoffe,
insbesondere als Fertigarzneimittel, ist für Deutschland bislang nicht bekannt geworden.
Vor dem Hintergrund dieser Erkenntnisse ist es geboten, diese Substanzen der Anlage I
des BtMG als weitere Stoffe zu unterstellen.
Zu Nummer 2
In die Anlage II des BtMG (verkehrsfähige, aber nicht verschreibungsfähige Betäubungs-
mittel) werden die folgenden synthetischen Substanzen als weitere Stoffe aufgenommen:
- AH-7921 (Doxylam),
- Desoxypipradrol (2-DPMP),
- Dimethocain (DMC, Larocain),
- 2,5-Dimethoxy-4-iodamfetamin (DOI).
Das synthetische Opioid AH-7921 ist im Jahr 2012 erstmals über das europäische Früh-
warnsystem gemeldet worden. Sowohl die psychoaktiven und physiologischen Wirkungen
als auch die Nebenwirkungen sollen mit Morphin vergleichbar sein. Auch wenn AH-7921
in Deutschland noch nicht sehr häufig sichergestellt wurde, gab es aus Schweden, dem
Vereinigten Königreich und Norwegen bereits Meldungen über insgesamt 15 Todesfälle.
Aufgrund des gemeinsamen Berichts von EBDD und Europol vom 17. Dezember 2013
gemäß Artikel 5 des Ratsbeschlusses 2005/387/JI wurde eine Risikobewertung gemäß
- 13 - Bearbeitungsstand: 03.07.2014 14:15 Uhr
Artikel 6 dieses Ratsbeschlusses erstellt, die zur Einführung von Kontrollmaßnahmen ge-
mäß den Artikeln 8 und 9 des Ratsbeschlusses führen kann.
Desoxypipradrol ist ein Stimulanz aus der Gruppe der Piperidin-Derivate und das Desoxy-
Derivat des Betäubungsmittels Pipradrol (Anlage III des BtMG). Desoxypipradrol stammt
wie Pipradrol aus der Pharmaforschung. Eine arzneiliche Anwendung, insbesondere als
Fertigarzneimittel, ist für Deutschland derzeit nicht bekannt. Im Vereinigten Königreich
wurden für das Jahr 2010 drei Todesfälle in Verbindung mit dem Missbrauch von Desoxy-
pipradrol berichtet. Die Substanz wurde in der Folge den dortigen betäubungsmittelrecht-
lichen Regelungen unterstellt. Auch in Deutschland gibt es aktuelle Sicherstellungen von
Desoxypipradrol.
Dimethocain ist ein synthetisches Kokain-Derivat und wurde ursprünglich in der Pharma-
forschung als Lokalanästhetikum entwickelt, wird aber u.a. aufgrund seiner psychoakti-
ven, kokainähnlichen Wirkungen und Nebenwirkungen nicht als Arzneimittel vermarktet.
Dimethocain wird mit Anfängen im Jahr 2010 zunehmend als Designerdroge durch Poli-
zei- und Zollbehörden in Deutschland sichergestellt. Aus systematischen Gründen emp-
fiehlt es sich, Dimethocain wie bereits das verwandte 4-Fluortropacocain (pFBT), in die
Anlage II des BtMG aufzunehmen.
2,5-Dimethoxy-4-iodamfetamin (DOI) ist ein Amfetaminderivat, das aufgrund seiner stark
halluzinogenen Wirkung auch als LSD-Ersatz angeboten wird. Neben amfetamin-
ähnlichen Nebenwirkungen besteht wegen der hohen Wirksamkeit und langen Wirkdauer
die erhebliche Gefahr einer Überdosierung. Die chemisch eng verwandten Stoffe 2,5-
Dimethoxy-4-bromamfetamin (DOB) und 2,5-Dimethoxy-4-chloramfetamin (DOC) sind
bereits der Anlage I des BtMG unterstellt. Aufgrund einer Verwendung von DOI in der
medizinischen Forschung, z.B. hinsichtlich einer entzündungshemmenden Wirkung durch
Hemmung des Tumornekrosefaktors TNF-alpha, erfolgt eine Einstufung in Anlage II des
BtMG.
Weiterhin werden in die Anlage II des BtMG die folgenden synthetischen Cannabinoide
aufgenommen:
- AB-FUBINACA,
- AB-PINACA,
- APICA (SDB-001, 2NE1),
- BB-22 (QUCHIC),
- EAM-2201 (5-Fluor-JWH-210),
- FDU-PB-22,
- FUB-PB-22,
- PB-22 (QUPIC),
- 5F-PB-22,
- STS-135 (5F-2NE1),
- THJ-2201.
Synthetische Cannabinoide sind Substanzen, die ein cannabisähnliches Wirkungsspekt-
rum aufweisen und meist Bezüge zu den chemischen Strukturen der in der Cannabis-
pflanze vorkommenden Wirkstoffe, den sogenannten klassischen Cannabinoiden, haben.
Einige synthetische Cannabinoide sind in Deutschland bereits den betäubungsmittelrecht-
lichen Vorschriften unterstellt (z.B. die sog. „Spice“-Wirkstoffe in sog. "Kräutermischun-
gen"). In jüngerer Zeit ist zu beobachten, dass vielfältige neue Kräutermischungen haupt-
sächlich über Internetplattformen auf den Markt kommen. Diese werden mit modifiziertem
Design, in anderen Verpackungen und mit neuen Wirkstoffen kombiniert, aber auch als
einzelne Wirkstoffe zum Selbstmischen angeboten und sind u.a. laut Foreneinträgen in
der Anbieter- und Konsumentenszene verbreitet.
Die oben aufgeführten Cannabinoide stammen teilweise aus der Pharmaforschung, teil-
weise handelt es sich offenbar um Designerdrogen, die speziell für den Drogenmarkt ent-
wickelt wurden. Aufgriffe in Deutschland sowie anderen europäischen Ländern und das
- 14 - Bearbeitungsstand: 03.07.2014 14:15 Uhr
Angebot in verschiedenen, auch deutschsprachigen Internetportalen weisen auf eine wei-
te Verbreitung hin. Diese Stoffe haben meistens ein dem THC (delta-9-
Tetrahydrocannabinol) sehr ähnliches Wirkungsspektrum und werden daher als Ersatz für
natürliches Cannabis missbräuchlich verwendet. Sie haben jedoch oft gegenüber THC
vielfach stärkere Wirkungen und Nebenwirkungen, insbesondere erhöhten Blutdruck,
Übelkeit, beschleunigten Puls, euphorisierende Wirkungen und psychische Störungen zur
Folge. Wegen der hohen Wirksamkeit besteht zusätzlich die erhebliche Gefahr einer
Überdosierung.
Zu AB-FUBINACA, AB-PINACA, BB-22, EAM-2201, FDU-PB-22, FUB-PB-22, PB-22, 5F-
PB22 und STS-135 gibt es seit den Jahren 2012 bzw. 2013 eine größere Anzahl an Si-
cherstellungen in Deutschland, während APICA und THJ-2201 in Proben hervorgetreten
sind, die auf neu in Deutschland auf dem Markt befindliche Kräutermischungen hinweisen.
Alle aufgeführten Stoffe haben eine strukturelle Verwandtschaft mit dem BtMG bereits
unterstellten synthetischen Cannabinoiden. Bei sieben dieser Substanzen wurde ein
Wasserstoffatom durch ein Fluoratom ersetzt, um eine weitere Wirkungsverstärkung zu
erzielen.
Alle Stoffe sind bereits in verschiedenen europäischen Ländern dem dortigen Betäu-
bungsmittelrecht unterstellt. Eine arzneiliche Anwendung dieser Stoffe, insbesondere als
Fertigarzneimittel, ist für Deutschland bislang nicht bekannt geworden, eine Verwendung
in der wissenschaftlichen Forschung ist jedoch nicht auszuschließen. Vor dem Hinter-
grund dieser Erkenntnisse ist es geboten, die Stoffe der Anlage II des BtMG zu unterstel-
len.
Zu Artikel 2 (Änderung der Betäubungsmittel-Verschreibungsverordnung)
Zu Nummer 1 (§ 2 Absatz 1 BtMVV)
Für Lisdexamfetaminmesilat wird aufgrund wissenschaftlicher Erkenntnisse und der vor-
liegenden Therapieerfahrungen nach der Markteinführung eines Fertigarzneimittels eine
Höchstverschreibungsmenge festgelegt. Wegen des hohen Gewichtsanteils des Mesilats
am Molekulargewicht von Lisdexamfetaminmesilat wird gemäß § 1 Absatz 1 Satz 3
BtMVV eine eindeutige Zuordnung der Höchstverschreibungsmenge zum jeweiligen Salz
vorgenommen.
Zu Nummer 2 (§ 5a BtMVV)
Zu Buchstabe a (§ 5a Absatz 1 Satz 2 BtMVV)
Zu Buchstabe aa (§ 5a Absatz 1 Satz 2 Nummer 1 BtMVV)
Es handelt um eine sprachliche Anpassung an § 5a Absatz 4 Satz 8.
Zu Buchstabe bb (§ 5a Absatz 1 Satz 2 Nummer 2 BtMVV)
Die Aufgaben des Bundesinstitutes für Arzneimittel und Medizinprodukte ('BfArM', im Fol-
genden "Bundesinstitut") bei der Führung des Substitutionsregisters werden präzisiert.
Das Bundesinstitut prüft nicht wie, sondern nur ob die Mindestanforderungen an die Quali-
fikation der verschreibenden Ärzte erfüllt sind. Da sich die Regelung auf die substituie-
renden Ärztinnen und Ärzte selbst bezieht, wird anstatt des Wortes „und“ der Begriff
„oder“ verwendet: Die betroffenen Ärztinnen und Ärzte müssen jeweils nur eine der bei-
den Anforderungen (suchttherapeutische Qualifikation oder Einhaltung der Konsiliarrege-
lung) erfüllen.
Zu Buchstabe b (§ 5a Absatz 2 Satz 1 BtMVV)
Zu Buchstabe aa (§ 5a Absatz 2 Satz 1 Nummer 5 BtMVV)
- 15 - Bearbeitungsstand: 03.07.2014 14:15 Uhr
Die dem Bundesinstitut zu übermittelnden Angaben werden präzisiert. Zur eindeutigen
Zuordnung und Identifikation der Meldungen der Ärztinnen und Ärzte im Datenbestand
des Substitutionsregisters sind neben der Angabe des Namens auch die Angabe des
Vornamens, des Geburtsdatums und der dienstlichen Anschrift der Ärztinnen und Ärzte
erforderlich. Unter der dienstlichen Anschrift ist die Anschrift zu verstehen, an der die
Substitutionsbehandlung durch die Ärztin oder den Arzt überwiegend ausgeübt wird. Die
dienstliche Telefonnummer dient der schnellen Kontaktaufnahme durch das Bundesinsti-
tut bei klärungsbedürftigen Sachverhalten. Die Änderung des Wortes „Adresse“ in „An-
schrift“ dient der redaktionellen Bereinigung, damit das Wort „Anschrift“ in der BtMVV
durchgängig verwendet wird (vgl. §§ 5, 9, 11, 12, 14).
Zu Buchstabe bb (§ 5a Absatz 2 Satz 1 Nummer 6 BtMVV)
Es handelt sich um eine Präzisierung der Angaben der konsiliarisch tätigen Ärztinnen und
Ärzte.
Zu Buchstabe c (§ 5a Absatz 4 BtMVV)
Zu Buchstabe aa (§ 5a Absatz 4 Satz 3 BtMVV)
Es handelt sich um eine Präzisierung der Angaben, die das Bundesinstitut den jeweiligen
substituierenden Ärztinnen und Ärzten zur weiteren Abklärung übermittelt. Diese Angaben
sollen eine schnelle Kontaktaufnahme der Ärztinnen und Ärzte untereinander ermögli-
chen.
Zu Buchstabe bb (§ 5a Absatz 4 Satz 8 BtMVV)
Es handelt sich um eine Präzisierung sowie eine sprachliche Anpassung an § 5a Absatz 1
Satz 2 Nummer 1.
Zu Buchstabe d (§ 5a Absatz 5 BtMVV)
Für die Ärztekammern wird folgendes, geändertes Meldeverfahren eingeführt. Das Bun-
desinstitut fordert bei einer Erstmeldung oder einer Meldung einer Anschriftenänderung
substituierender oder konsiliarisch tätiger Ärztinnen und Ärzte in einen anderen Ärzte-
kammerbereich die Meldung bei der nunmehr zuständigen Ärztekammer an. Diese teilt
dem Bundesinstitut unverzüglich mit, ob die betreffenden Ärztinnen und Ärzte die Min-
destanforderungen nach § 5 Absatz 2 Satz 1 Nummer 6 erfüllen. Dieses neue Verfahren
weist eine Reihe von Vorteilen auf: Nach bisherigen Erfahrungen erfolgen rund 200 Erst-
meldungen pro Jahr. Die Häufigkeit eines Wechsels in einen anderen Ärztekammerbe-
reich lässt sich nicht konkret feststellen. Es dürften aber geschätzt maximal 100 Fälle pro
Jahr auftreten. In der Summe müssten somit für maximal 300 Ärztinnen und Ärzte pro
Jahr die Angaben zur suchttherapeutischen Qualifikation bei der jeweils zuständigen Ärz-
tekammer angefordert und im Substitutionsregister erfasst werden. Die sonstigen Daten
(Vorname, Name, Anschrift und Geburtsdatum) werden direkt anhand der Meldungen der
Ärztinnen und Ärzte im Substitutionsregister erfasst. Die Pflege der Daten kann mit Been-
digung der ärztlichen Tätigkeit im Rahmen der Substitutionstherapie entfallen Vorteilhaft
ist zudem, dass mit dieser Änderung die im Bundesinstitut gespeicherten Daten soweit
reduziert werden, dass mittelfristig nur noch diejenigen Ärztinnen und Ärzte, die aktiv sub-
stituieren oder die konsiliarisch tätig sind, erfasst werden. Dadurch werden lediglich die
Daten, die für die Sicherheit des Betäubungsmittelverkehrs zwingend erforderlich sind,
erhoben, verarbeitet und genutzt. Aufgrund der Anzahl von Ärztinnen und Ärzten mit
suchttherapeutischen Qualifikationen, die jedoch nicht substituierend tätig sind, pflegt das
Bundesinstitut bislang eine erhebliche Anzahl lebenslanger persönlicher Daten, ohne
dass diese für die Sicherheit und Kontrolle des Betäubungsmittelverkehrs im Substituti-
onsbereich relevant wären. Durch die Neuregelung wird dem Grundsatz der Datenspar-
samkeit im Ergebnis besser Rechnung getragen. Weiterer Vorteil der Verfahrensänderung
ist, dass das Bundesinstitut den zuständigen Überwachungsbehörden die Angaben nach
- 16 - Bearbeitungsstand: 03.07.2014 14:15 Uhr
Absatz 5 Satz 4 nicht mehr lediglich im halbjährlichen Rhythmus, sondern unverzüglich
mitteilen kann, und somit auch hierdurch die Sicherheit und Kontrolle des Betäubungsmit-
telverkehrs verbessert wird. Satz 2 betrifft insbesondere diejenigen Fälle, in denen die
ärztliche Approbation oder die suchttherapeutische Qualifikation ruht oder entzogen wur-
de.
Satz 3 gibt dem Bundesinstitut die Möglichkeit, den Datenbestand des Substitutionsregis-
ters zu bereinigen. Durch Artikel 3 Satz 2 wird diese Möglichkeit auf einen Zeitraum von
drei Jahren nach Verkündung dieser Verordnung befristet. Hierdurch soll eine planvolle
und zeitlich überschaubare Durchführung der Datenbereinigung durch das Bundesinstitut
gewährleistet und gleichzeitig der zeitliche Rahmen für die dabei zu beteiligenden Ärzte-
kammern begrenzt werden, die mit dem Ziel der Reduzierung von Bürokratieaufwand
nach durchgeführter Datenbereinigung im Umfang der Bereinigung von Meldeaufwand
entlastet werden sollen. In Satz 4 wird die Datenquelle klargestellt. Es handelt sich zudem
um eine Folgeänderung zu den Klarstellungen in § 5a Absatz 2 Nummer 5 und 6 und den
Meldungen der Ärztekammern nach diesem Absatz. Bei dem Begriff „Anschrift“ handelt es
sich zugleich um eine Bereinigung entsprechend § 5 a Absatz 2 Satz 1 Nummer 5. Es
werden zudem rechtsförmliche Anpassungen vorgenommen.
Zu Buchstabe e (§ 5a Absatz 6 BtMVV)
Bei Satz 1 handelt es sich um eine Klarstellung der Datenquelle sowie um eine Präzisie-
rung der Meldefrequenz der Angaben, die das Bundesinstitut an die zuständigen Überwa-
chungsbehörden der Länder übermittelt.
Bei Satz 1 Nummer 1 und Nummer 2 handelt es sich um eine Klarstellung der zu übermit-
telnden Angaben.
Satz 1 Nummer 3 (alt) wird in Folge des geänderten Meldeverfahrens nach § 5a Absatz 5
gestrichen. Satz 1 Nummer 3 (neu) enthält nun eine Klarstellung der zu übermittelnden
Angaben nach § 5a Absatz 2 Satz 1 Nummer 6.
Bei Satz 1 Nummer 4 handelt es sich um eine rechtsförmliche Anpassung.
Zu Buchstabe f (§ 5a Absatz 7 BtMVV)
Es handelt sich um eine Klarstellung der Datenquelle sowie um eine Präzisierung der
Meldefrequenz derjenigen Angaben, die das Bundesinstitut den obersten Landesgesund-
heitsbehörden mitteilt.
Satz 1 Nummer 4 (alt) wird in Folge des geänderten Meldeverfahrens nach § 5a Absatz 5
gestrichen. Die Nummerierung der nachfolgend bezeichneten Angaben wird entspre-
chend angepasst.
Zu Nummer 3 (§ 5b BtMVV)
Es handelt sich um sprachliche Klarstellungen, um eindeutig auch solche Heime in den
Anwendungsbereich der Vorschrift aufzunehmen, die entweder Alten- oder Pflegeheim
sind. Damit wird gegenüber der bisherigen Formulierung für die Rechtsanwender verdeut-
licht, dass nicht kumulativ beide Tatbestandsmerkmale erfüllt sein müssen..
Zu Nummer 4 (§ 5c BtMVV)
Es handelt sich um Folgeänderungen zu Nummer 5.
Zu Nummer 5 (§ 6 BtMVV)
- 17 - Bearbeitungsstand: 03.07.2014 14:15 Uhr
Die Anzeigepflicht der Versorgungsvereinbarung wird gestrichen, da die Versorgung von
Einrichtungen des Rettungsdienstes durch eine Apotheke nach § 14 Apothekengesetz
(bereits) eines von der zuständigen Landesbehörde genehmigten Versorgungsvertrages
bedarf. Hierdurch wird mit Entlastungswirkung bei der Apothekerschaft ein Beitrag zur
Entbürokratisierung geleistet.
Zu Nummer 6 (§ 9 BtMVV)
Die Angaben auf dem Betäubungsmittel bezüglich der Gebrauchsanweisung werden fle-
xibler gestaltet, um Fehler beim Ausfertigen des Betäubungsmittelrezeptes zu vermeiden.
Zu Artikel 3 (Inkrafttreten)
Dieser Artikel regelt das Inkrafttreten der Verordnung. Abweichend von den übrigen Vor-
schriften der Verordnung, die am Tag nach der Verkündung in Kraft treten, wird die für
das Bundesinstitut vorgesehene Möglichkeit zur Bereinigung des Datenbestandes des
Substitutionsregisters gemäß § 5a Absatz 5 Satz 3 auf einen angemessenen Zeitraum
von drei Jahren befristet.
31.07.2014
Datei
PD
Bundesinstitut
für Arzneimittel und Medizinprodukte
Neufassung der Bekanntmachung
zur Betäubungsmittel-Verschreibungsverordnung
(BtMVV)
Vom 31. Januar 2013
Die oben genannte Bekanntmachung vom 30. Juni 2001 (BAnz. S. 16 661) wird wie folgt neu gefasst:
Auf Grund des § 15 der BtMVV vom 20. Januar 1998 (BGBl. I S. 74, 80), die zuletzt durch Artikel 2 der Verordnung vom
20. Juli 2012 (BGBl. I S. 1639) geändert worden ist, wird nachfolgend unter Nummer 1 das amtliche Formblatt nach § 8
(Betäubungsmittelrezept) der vorgenannten Verordnung in geänderter Form bekannt gemacht. Die als Anlagen zu den
Nummern 2 bis 4 bekannt gemachten amtlichen Formblätter haben sich inhaltlich nicht geändert. Der Wortlaut der
Nummern 2 bis 6 wurde aktualisiert.
1. Betäubungsmittelrezept
Das Betäubungsmittelrezept besteht aus einem dreifachen Belegsatz und entspricht dem Muster der Anlage 1. Aus
technischen Gründen ist das erste (oberste) Blatt der für die Apotheke zur Verrechnung bestimmte Teil II, das zweite
(mittlere) Blatt der bei der/dem Verschreibenden verbleibende Teil III und das dritte (unterste) Blatt der in der Apotheke
verbleibende Teil I.
Die drei Blätter der ab März 2013 ausgegebenen Belegsätze sind am l inken Rand durch einen 15 mm breiten Klebe-
streifen verbunden. Der Druck ist rotviolett auf weißem Papier, bei Teil II des Betäubungsmittelrezeptes zum Teil mit
gelb-grauem und gelb-orange-grauem Guillochenmuster. Unter UV-A-Licht zeigt das Guillochenmuster einen fluores-
zierenden Farbverlauf von orangegelb – über gelbgrünlich – wieder nach orangegelb.
Das Betäubungsmittelrezept trägt im linken unteren Quadranten die Kennung „555 ⑁“ in OCR-A-Schrift, die auf Teil II
schwarz, auf den Teilen I und III rotviolett eingedruckt ist. Im rechten unteren Quadranten ist auf Teil II eine schwarze,
fortlaufende, neunstellige Rezeptnummer eingedruckt, die sich unter UV-A-Licht grünlich fluoreszierend darstellt. Auf
den Teilen I und III ist die Nummer als schwarzer Durchdruck zu erkennen. Die zu beschriftenden weißen Felder tragen
auf Teil II eine feine, graue Linienstruktur. In die rotviolette Umrandung der Felder „Zuzahlung“ und „Gesamt-Brutto“ ist
in Mikroschrift auf allen drei Teilen fortlaufend „BTM-REZEPTVORDRUCK“ eingedruckt.
Die drei Blätter der seit Februar 1998 bis Februar 2013 ausgegebenen und bis einschließlich Dezember 2014 weiterhin
gültigen Belegsätze sind am rechten Rand durch einen 15 mm breiten Klebestreifen verbunden. Der Druck ist rotvio-
lett auf weißem Papier, bei Teil II zum Teil mit gelbem Guillochenmuster. Das erste (oberste) Blatt (Teil II) entspricht dem
Muster der Anlage 2. In der rotvioletten Linie oberhalb von „Name, Vorname“ ist in Mikroschrift fortlaufend „BETÄU-
BUNGSMITTELREZEPT“ eingedruckt. Alle Teile sind oberhalb des für die Abrechnung durch die Krankenkassen vor-
gesehenen Feldes mit einer schwarzen Kodierzeile in OCR-A-Schrift versehen, bestehend aus der Kennung 555 ⑁, der
BtM-Nummer der/des Verschreibenden, dem technischen Ausgabedatum und der Rezeptnummer.
2. Betäubungsmittelanforderungsschein
Der Betäubungsmittelanforderungsschein besteht aus einem dreifachen Belegsatz und entspricht dem Muster der
Anlage 3.
Jeweils 30 Belegsätze sind zu einem kartonierten Heft zusammengefasst. Die Hefte sind nummeriert; die 30 Belegsätze
eines Heftes sind zudem von 01 bis 30 durchnummeriert. Das erste Blatt eines jeden Belegsatzes ist gelb mit schwar-
zem Druck, die anderen beiden Blätter sind weiß mit schwarzem Druck. Die ersten beiden Blätter (Teil I und Teil II) sind
entlang der Trennlinie perforiert. Die Rückseite des Heftes ist aufklappbar, so dass sie als Durchschreibeschutz hinter
den jeweils auszufüllenden Belegsatz gelegt werden kann.
3. Karteikarten
Karteikarten zur Nachweisführung bestehen aus grauem Karton mit schwarzem Druck im Format 210 x 297 mm und
entsprechen dem Muster der Anlage 4.
4. Betäubungsmittelbuch
Das Betäubungsmittelbuch wird im gleichen Format angeboten wie die vorgenannten Karteikarten. Jedes Buch enthält
ein Inhaltsverzeichnis sowie einhundert fortlaufend nummerierte Seiten aus weißem Papier mit schwarzem Druck ent-
sprechend der in Anlage 4 dargestellten Karteikarten.
www.bundesanzeiger.de
Bekanntmachung
Veröffentlicht am Freitag, 15. Februar 2013
BAnz AT 15.02.2013 B6
Seite 1 von 6
5. Anfertigung der amtlichen Formblätter
Die unter den Nummern 1 und 2 bekannt gemachten Formblätter werden im Auftrag des Bundesinstituts für Arznei-
mittel und Medizinprodukte (BfArM) angefertigt.
Die unter den Nummern 3 und 4 bekannt gemachten Formblätter werden im Auftrag der Bundesanzeiger Verlag GmbH
angefertigt.
6. Ausgabe und Vertrieb der amtlichen Formblätter
Die unter den Nummern 1 und 2 bekannt gemachten Formblätter werden von der Bundesopiumstelle im BfArM – auf
Anforderung nach § 8 Absatz 2 bzw. § 10 Absatz 2 BtMVV – kostenlos ausgegeben.
Die unter den Nummern 3 und 4 bekannt gemachten Formblätter werden durch die Bundesanzeiger Verlag GmbH oder
in deren Auftrag vertrieben.
EDV-Programme zur elektronischen Nachweisführung können von jedermann erstellt und vertrieben werden. Die Ver-
antwortung dafür, dass das jeweilige Programm den Anforderungen des § 13 Absatz 1 BtMVV entspricht, liegt beim
Anwender. EDV-Ausdrucke entsprechen unter anderem nur dann den Anforderungen des § 13 in Verbindung mit § 15
BtMVV, wenn die Aufzeichnungen darin ausschließlich elektronisch erfolgten.
Die Bekanntmachung zur BtMVV vom 30. Juni 2001 (BAnz. S. 16 661) wird mit Inkrafttreten dieser Neufassung gegen-
standslos.
Die Neufassung dieser Bekanntmachung tritt am Tag nach der Bekanntmachung im Bundesanzeiger in Kraft.
Bonn, den 31. Januar 2013
84 - 4150 - 01
Bundesinstitut
für Arzneimittel und Medizinprodukte
Im Auftrag
Dr. P. Cremer-Schaef fer
www.bundesanzeiger.de
Bekanntmachung
Veröffentlicht am Freitag, 15. Februar 2013
BAnz AT 15.02.2013 B6
Seite 2 von 6
Anlage 1
Betäubungsmittelrezept, Teil II
Betäubungsmittelrezept, Teil III
Betäubungsmittelrezept, Teil I
www.bundesanzeiger.de
Bekanntmachung
Veröffentlicht am Freitag, 15. Februar 2013
BAnz AT 15.02.2013 B6
Seite 3 von 6
Anlage 2
Betäubungsmittelrezept, Teil II (gültig bis 31. Dezember 2014)
www.bundesanzeiger.de
Bekanntmachung
Veröffentlicht am Freitag, 15. Februar 2013
BAnz AT 15.02.2013 B6
Seite 4 von 6
A
n
la
g
e
3
www.bundesanzeiger.de
Bekanntmachung
Veröffentlicht am Freitag, 15. Februar 2013
BAnz AT 15.02.2013 B6
Seite 5 von 6
A
n
la
g
e
4
www.bundesanzeiger.de
Bekanntmachung
Veröffentlicht am Freitag, 15. Februar 2013
BAnz AT 15.02.2013 B6
Seite 6 von 6
2013-02-15T13:50:16+0100
Amtlicher Teil - Bundesanzeiger Verlag:PN
31.07.2014
Datei
PD
3338 Bundesgesetzblatt Jahrgang 2001 Teil I Nr. 64, ausgegeben zu Bonn am 7. Dezember 2001
Sechzehnte Verordnung
zur Änderung betäubungsmittelrechtlicher Vorschriften
(Sechzehnte Betäubungsmittelrechts-Änderungsverordnung – 16. BtMÄndV)
Vom 28. November 2001
Auf Grund des § 1 Abs. 4 des Betäubungsmittelgesetzes in der Fassung der
Bekanntmachung vom 1. März 1994 (BGBl. I S. 358) verordnet das Bundes-
ministerium für Gesundheit:
Artikel 1
Änderung des Betäubungsmittelgesetzes
Das Betäubungsmittelgesetz in der Fassung der Bekanntmachung vom
1. März 1994 (BGBl. I S. 358), zuletzt geändert durch die Verordnung vom 19. Juni
2001 (BGBl. I S. 1180), wird wie folgt geändert:
1. In Anlage II wird folgendes Betäubungsmittel in alphabetischer Reihenfolge
eingefügt:
„–– Isocodein 4,5α-Epoxy-3-methoxy-17-
methylmorphin-7-en-6β-ol“.
2. In Anlage III werden folgende Betäubungsmittel in alphabetischer Reihenfolge
eingefügt:
N,N-Dimethyl-2-[6-methyl-2-
„Zolpidem –– (p-tolyl)imidazo[1,2-a]pyri-
din-3-yl]acetamid
– ausgenommen in Zubereitungen zur oralen Anwendung, die ohne einen
weiteren Stoff der Anlagen I bis III je abgeteilte Form bis zu 8,5 mg Zolpi-
dem, berechnet als Base, enthalten –“
„–– γ-Hydroxybuttersäure (GHB) 4-Hydroxybutansäure
– ausgenommen in Zubereitungen zur Injektion, die ohne einen weiteren
Stoff der Anlagen I bis III bis zu 20 vom Hundert und je abgeteilte Form bis
zu 2 g γ-Hydroxybuttersäure, berechnet als Säure, enthalten –“.
Artikel 2
Inkrafttreten
Diese Verordnung tritt am 1. März 2002 in Kraft.
Bonn, den 28. November 2001
D i e B u n d e s m i n i s t e r i n f ü r G e s u n d h e i t
U l l a S c h m i d t
31.07.2014
Datei
PD
Gesetz
zur diamorphingestützten Substitutionsbehandlung
Vom 15. Juli 2009
Der Bundestag hat das folgende Gesetz beschlos-
sen:
Artikel 1
Änderung
des Betäubungsmittelgesetzes
Das Betäubungsmittelgesetz in der Fassung der Be-
kanntmachung vom 1. März 1994 (BGBl. I S. 358), das
zuletzt durch Artikel 2 der Verordnung vom 19. Januar
2009 (BGBl. I 49) geändert worden ist, wird wie folgt
geändert:
1. § 13 wird wie folgt geändert:
a) In Absatz 2 wird nach Satz 1 folgender Satz ein-
gefügt:
„Diamorphin darf nur vom pharmazeutischen Un-
ternehmer und nur an anerkannte Einrichtungen
nach Absatz 3 Satz 2 Nummer 2a gegen Vorlage
der Verschreibung abgegeben werden.“
b) Absatz 3 wird wie folgt geändert:
aa) In Satz 2 werden nach Nummer 2 folgende
Nummern 2a und 2b eingefügt:
„2a. das Verschreiben von Diamorphin nur in
Einrichtungen, denen eine Erlaubnis von
der zuständigen Landesbehörde erteilt
wurde, zugelassen,
2b. die Mindestanforderungen an die Aus-
stattung der Einrichtungen, in denen
die Behandlung mit dem Substitutions-
mittel Diamorphin stattfindet, festge-
legt,“.
bb) Nach Satz 2 werden folgende Sätze einge-
fügt:
„Für das Verfahren zur Erteilung einer Erlaub-
nis nach Satz 2 Nummer 2a gelten § 7 Satz 2
Nummer 1 bis 4, § 8 Absatz 1 Satz 1, Absatz 2
und 3 Satz 1 bis 3, § 9 Absatz 2 und § 10
entsprechend. Dabei tritt an die Stelle des
Bundesinstitutes für Arzneimittel und Medi-
zinprodukte jeweils die zuständige Landesbe-
hörde, an die Stelle der zuständigen obersten
Landesbehörde jeweils das Bundesinstitut für
Arzneimittel und Medizinprodukte.“
2. In § 19 Absatz 1 Satz 3 werden nach dem Wort „Tier-
ärzten“ die Wörter „ , pharmazeutischen Unterneh-
mern im Falle der Abgabe von Diamorphin“ einge-
fügt.
3. § 29 Absatz 1 Satz 1 wird wie folgt geändert:
a) Nummer 7 wird wie folgt gefasst:
„7. entgegen § 13 Absatz 2
a) Betäubungsmittel in einer Apotheke oder
tierärztlichen Hausapotheke,
b) Diamorphin als pharmazeutischer Unter-
nehmer
abgibt,“.
b) In Nummer 14 werden nach der Angabe 㤠13
Abs. 3 Satz 2 Nr. 1“ ein Komma und die Angabe
„2a“ eingefügt.
4. In § 32 Absatz 1 Nummer 2 wird nach der Angabe
„§ 10a Abs. 3“ die Angabe „oder § 13 Absatz 3
Satz 3“ eingefügt.
5. In Spalte 2 der Anlage I zu § 1 Absatz 1 wird der
Stoffbezeichnung „Heroin (Diacetylmorphin, Diamor-
phin)“ die Angabe „– ausgenommen Diamorphin zu
den in den Anlagen II und III bezeichneten Zwe-
cken –“ angefügt.
6. In Anlage II (verkehrsfähige, aber nicht verschrei-
bungsfähige Betäubungsmittel) zu § 1 Absatz 1 wird
nach der Position „Dextropropoxyhen" die folgende
Position eingefügt:
INN
andere nicht geschützte
oder Trivialnamen
chemische Namen
(IUPAC)
„— Diamorphin [(5R,6S)-4,5-Epoxy-17-
methylmorphin-7-en-3,6-
diyl]diacetat
– sofern es zur Herstellung von Zubereitungen zu
medizinischen Zwecken bestimmt ist –“.
7. In Anlage III (verkehrsfähige und verschreibungs-
fähige Betäubungsmittel) zu § 1 Absatz 1 wird nach
der Position „Dexmethylphenidat" die folgende
Position eingefügt:
INN
andere nicht geschützte
oder Trivialnamen
chemische Namen
(IUPAC)
„— Diamorphin [(5R,6S)-4,5-Epoxy-17-
methylmorphin-7-en-3,6-
diyl]diacetat
– nur in Zubereitungen, die zur Substitutionsbehand-
lung zugelassen sind –“.
Artikel 2
Änderung
des Arzneimittelgesetzes
Das Arzneimittelgesetz in der Fassung der Bekannt-
machung vom 12. Dezember 2005 (BGBl. I S. 3394),
das zuletzt durch Artikel 9 Absatz 1 des Gesetzes
vom 23. November 2007 (BGBl. I S. 2631) geändert
worden ist, wird wie folgt geändert:
1. In der Inhaltsübersicht wird nach § 47a folgende An-
gabe eingefügt:
„§ 47b Sondervertriebsweg Diamorphin“.
2. Nach § 47a wird folgender § 47b eingefügt:
1801Bundesgesetzblatt Jahrgang 2009 Teil I Nr. 41, ausgegeben zu Bonn am 20. Juli 2009
Das Bundesgesetzblatt im Internet: www.bundesgesetzblatt.de | Ein Service des Bundesanzeiger Verlag www.bundesanzeiger-verlag.de
㤠47b
Sondervertriebsweg Diamorphin
(1) Pharmazeutische Unternehmer dürfen ein dia-
morphinhaltiges Fertigarzneimittel, das zur substitu-
tionsgestützten Behandlung zugelassen ist, nur an
anerkannte Einrichtungen im Sinne des § 13 Absatz 3
Satz 2 Nummer 2a des Betäubungsmittelgesetzes
und nur auf Verschreibung eines dort behandelnden
Arztes abgeben. Andere Personen dürfen die in
Satz 1 genannten Arzneimittel nicht in Verkehr brin-
gen.
(2) Die §§ 43 und 47 finden auf die in Absatz 1
Satz 1 genannten Arzneimittel keine Anwendung.“
Artikel 3
Änderung der
Betäubungsmittel-Verschreibungsverordnung
Die Betäubungsmittel-Verschreibungsverordnung
vom 20. Januar 1998 (BGBl. I S. 74, 80), die zuletzt
durch die Verordnung vom 19. März 2009 (BGBl. I
S. 560) geändert worden ist, wird wie folgt geändert:
1. In § 1 Absatz 3 werden nach dem Wort „Rettungs-
dienste“ die Wörter „ , den Einrichtungen nach § 5
Absatz 9b“ eingefügt.
2. § 2 wird wie folgt geändert:
a) In Absatz 1 Buchstabe a wird nach Nummer 3
folgende Nummer 3a eingefügt:
„3a. Diamorphin 30 000 mg,“.
b) Dem Absatz 3 werden folgende Sätze angefügt:
„Diamorphin darf der Arzt bis zur Menge seines
durchschnittlichen Monatsbedarfs verschreiben.
Die Vorratshaltung soll für Diamorphin den
durchschnittlichen Zweimonatsbedarf des Arz-
tes nicht überschreiten.“
3. In § 3 Absatz 1 Buchstabe b wird nach dem Wort
„Cocain,“ das Wort „Diamorphin,“ eingefügt.
4. In § 4 Absatz 1 Buchstabe b wird nach dem Wort
„Cocain,“ das Wort „Diamorphin,“ eingefügt.
5. § 5 wird wie folgt geändert:
a) Dem Absatz 3 wird folgender Satz angefügt:
„Die Sätze 1 bis 9 gelten nicht für die Behand-
lung nach den Absätzen 9a bis 9d.“
b) Absatz 4 wird wie folgt geändert:
aa) Die Sätze 2 bis 4 werden wie folgt gefasst:
„Als Substitutionsmittel darf der Arzt nur
1. Zubereitungen von Levomethadon, Me-
thadon und Buprenorphin,
2. in begründeten Ausnahmefällen Codein
oder Dihydrocodein,
3. Diamorphin als zur Substitution zugelas-
senes Arzneimittel oder
4. ein anderes zur Substitution zugelasse-
nes Arzneimittel
verschreiben. Die in Satz 2 Nummer 1, 2
und 4 genannten Substitutionsmittel dürfen
nicht zur parenteralen Anwendung bestimmt
sein. Für die Auswahl des Substitutionsmit-
tels ist neben den Vorschriften dieser Verord-
nung der allgemein anerkannte Stand der
medizinischen Wissenschaft maßgebend.“
bb) Es wird folgender Satz angefügt:
„Für die Verschreibung von Diamorphin nach
Satz 2 Nummer 3 gelten die Absätze 6 bis 8
nicht.“
c) Dem Absatz 5 wird folgender Satz angefügt:
„Der Arzt, der Diamorphin verschreibt, darf die
Verschreibung nur einem pharmazeutischen Un-
ternehmer vorlegen.“
d) Nach Absatz 9 werden folgende Absätze 9a
bis 9d eingefügt:
„(9a) Zur Behandlung einer schweren Opiat-
abhängigkeit kann das Substitutionsmittel Dia-
morphin zur parenteralen Anwendung verschrie-
ben werden. Der Arzt darf Diamorphin nur ver-
schreiben, wenn
1. er selbst eine suchttherapeutische Qualifi-
kation im Sinne des Absatz 2 Satz 1 Num-
mer 6 erworben hat, die sich auf die Behand-
lung mit Diamorphin erstreckt, oder er im
Rahmen des Modellprojektes „Heroinge-
stützte Behandlung Opiatabhängiger" min-
destens sechs Monate ärztlich tätig war,
2. bei dem Patienten eine seit mindestens fünf
Jahren bestehende Opiatabhängigkeit, ver-
bunden mit schwerwiegenden somatischen
und psychischen Störungen bei derzeit über-
wiegend intravenösem Konsum vorliegt,
3. ein Nachweis über zwei erfolglos beendete
Behandlungen der Opiatabhängigkeit, davon
eine mindestens sechsmonatige Behandlung
gemäß den Absätzen 2, 6 und 7 einschließlich
psychosozialer Betreuungsmaßnahmen, vor-
liegt und
4. der Patient das 23. Lebensjahr vollendet hat.
(9b) Die Behandlung mit Diamorphin darf nur
in Einrichtungen durchgeführt werden, denen
eine Erlaubnis durch die zuständige Landesbe-
hörde erteilt wurde. Die Erlaubnis wird erteilt,
wenn
1. nachgewiesen wird, dass die Einrichtung in
das örtliche Suchthilfesystem eingebunden
ist,
2. gewährleistet ist, dass die Einrichtung über
eine zweckdienliche personelle und sachliche
Ausstattung verfügt,
3. eine sachkundige Person, die für die Einhal-
tung der in Nummer 2 genannten Anforderun-
gen, der Auflagen der Erlaubnisbehörde so-
wie der Anordnungen der Überwachungsbe-
hörde verantwortlich ist (Verantwortlicher),
benannt worden ist.
(9c) Diamorphin darf nur innerhalb der Ein-
richtung nach Absatz 9b verschrieben, verab-
reicht und zum unmittelbaren Verbrauch überlas-
sen werden. Diamorphin darf nur unter Aufsicht
des Arztes oder des sachkundigen Personals in-
nerhalb dieser Einrichtung verbraucht werden. In
den ersten sechs Monaten der Behandlung müs-
1802 Bundesgesetzblatt Jahrgang 2009 Teil I Nr. 41, ausgegeben zu Bonn am 20. Juli 2009
Das Bundesgesetzblatt im Internet: www.bundesgesetzblatt.de | Ein Service des Bundesanzeiger Verlag www.bundesanzeiger-verlag.de
sen Maßnahmen der psychosozialen Betreuung
stattfinden.
(9d) Die Behandlung mit Diamorphin ist nach
jeweils spätestens zwei Jahren Behandlungs-
dauer daraufhin zu überprüfen, ob die Voraus-
setzungen für die Behandlung noch gegeben
sind und ob die Behandlung fortzusetzen ist.
Die Überprüfung erfolgt durch Einholung einer
Zweitmeinung durch einen Arzt, der die Qualifi-
kation gemäß Absatz 2 Satz 1 Nummer 6 besitzt
und der nicht der Einrichtung angehört. Ergibt
diese Überprüfung, dass die Voraussetzungen
für die Behandlung nicht mehr gegeben sind,
ist die diamorphingestützte Behandlung zu be-
enden.“
6. In § 8 Absatz 1 Satz 3 werden nach dem Wort
„Apotheke“ die Wörter „ , im Falle des Verschrei-
bens von Diamorphin nach § 5 Absatz 9a zur Vor-
lage bei einem pharmazeutischen Unternehmer,“
eingefügt.
7. § 12 wird wie folgt geändert:
a) Dem Absatz 2 wird folgender Satz angefügt:
„Für die Verschreibung von Diamorphin gelten
die Sätze 2 bis 4 nicht.“
b) Dem Absatz 4 wird folgender Satz angefügt:
„Die Sätze 1 und 2 gelten im Falle der Abgabe
von Diamorphin für den Verantwortlichen für Be-
täubungsmittel des pharmazeutischen Unter-
nehmers entsprechend.“
8. In § 13 Absatz 2 Satz 1 werden nach Nummer 6 ein
Komma und folgende Nummer 7 eingefügt:
„7. vom Verantwortlichen im Sinne des § 5 Ab-
satz 9b Nummer 3“.
9. In § 14 Absatz 1 Satz 1 werden in Nummer 5 der
Punkt am Ende des Satzes durch ein Komma er-
setzt und folgende Nummer 6 angefügt:
„6. beim pharmazeutischen Unternehmen im Falle
der Abgabe auf Verschreibung von Diamorphin
Name und Anschrift des verschreibenden Arz-
tes und die Nummer des Betäubungsmittelre-
zeptes.“
10. § 16 wird wie folgt geändert:
a) In Nummer 4 wird der Punkt am Ende durch ein
Komma ersetzt.
b) Folgende Nummer 5 wird angefügt:
„5. entgegen § 5 Absatz 9c Satz 1 Diamorphin
verschreibt, verabreicht oder überlässt.“
11. § 17 Nummer 10 wird wie folgt gefasst:
„10. entgegen § 5 Absatz 2 Satz 1 Nummer 6 oder
Absatz 3 Satz 1 Nummer 2 und 3, Satz 2 und 7
oder Satz 5 und 6 oder Absatz 9a Satz 2
Nummer 1 ein Substitutionsmittel verschreibt,
ohne die Mindestanforderungen an die Quali-
fikation zu erfüllen oder ohne einen Konsilia-
rius in die Behandlung einzubeziehen oder
ohne sich als Vertreter, der die Mindestanfor-
derungen an die Qualifikation nicht erfüllt, ab-
zustimmen oder ohne die diamorphinspezi-
fischen Anforderungen an die Qualifikation
nach Absatz 9a Satz 2 Nummer 1 zu erfüllen.“
Artikel 4
Inkrafttreten
Dieses Gesetz tritt am Tag nach der Verkündung in
Kraft.
Die verfassungsmäßigen Rechte des Bundesrates
sind gewahrt.
Das vorstehende Gesetz wird hiermit ausgefertigt. Es
ist im Bundesgesetzblatt zu verkünden.
Berlin, den 15. Juli 2009
D e r B u n d e s p r ä s i d e n t
H o r s t K ö h l e r
D i e B u n d e s k a n z l e r i n
Dr. A n g e l a M e r k e l
D i e B u n d e sm i n i s t e r i n f ü r G e s u n d h e i t
U l l a S c hm i d t
1803Bundesgesetzblatt Jahrgang 2009 Teil I Nr. 41, ausgegeben zu Bonn am 20. Juli 2009
Das Bundesgesetzblatt im Internet: www.bundesgesetzblatt.de | Ein Service des Bundesanzeiger Verlag www.bundesanzeiger-verlag.de
31.07.2014
Datei
PD
