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AESGP Euro OTC News
Issue 296 | October 2017
Medicines
Regulatory News
▪ BREXIT 3
▪ EMA Management Board October
meeting highlights 4
▪ Latest Update on EMA International
Organization for Standardization for
the identification of medicinal products
(ISO IDMP)/ Substance, product,
organisation and referential (SPOR)
database project 5
▪ HMA 89th Meeting Highlights 6
▪ CMDh reports – September and
October 2017 7
▪ Updated Annex to European Commission
Guideline on excipients in labelling &
package leaflet 9
▪ Outcome of EDQM conference on CEPs 11
▪ Final ICH guidelines 12
▪ Documents for comments 12
Pharmacovigilance
▪ PRAC Highlights - September 2017 13
▪ New EudraVigilance System 13
▪ Revision of Good Vigilance Practice models 14
Herbal News
▪ EMA Herbal Medicines Committee Report
- September 2017 14
▪ Publication of Final EU herbal monographs 16
▪ Documents for comments 16
Homeopathic News
▪ HMA working group on homeopathics
Report - June 2017 meeting 16
▪ Final HMPWG Points to Consider on
selection of microbial limits for non-sterile
homeopathics 17
AESGP Conference
Finding the right
balance for
consumer health
products
The Conference Report is
included at the end of
this issue AESGP had the honour of the presence of Adina-Ioana Vălean, Chair of the Committee
on the Environment, Public Health and Food Safety of the European Parliament, Vytenis
Andriukaitis, European Commissioner for Health and Food Safety, and Renate Sommer,
Member of the Committee on Environment, Public Health and Food Safety of the Euro-
pean Parliament, at its event in the European Parliament on 10 October 2017.
2 AESGP Euro OTC News | Issue 296
MDR Implementation
▪ AESGP participates in the COM/CAMD
Stakeholders meeting on the MDR
and IVDR 22
▪ Codes for designation of NBs 22
▪ Committee on Medical Devices -
5 October 2017 23
▪ AESGP collects editorial mistakes
for corrigendum to be launched soon 23
European Commission’s Scientific Committee on
Health, Environment and Emerging Risks (SCHEER)
▪ Mandate to issue Guidelines on
benefit-risk assessment of phthalates
in certain medical devices 23
Medical Devices
AESGP Conference with the Heads of EU Medicines Agencies, Lisbon | 26 - 27 February 2018
AESGP 54th
Annual Meeting, Amsterdam | 5 - 7 June 2018
Next AESGP conferences
Food
Food Additives
▪ EFSA workshop and ANS open plenary -
23/24 November 2017 in Parma -
Registration open 18
▪ EFSA opinion on re-evaluation of
12 modified starches 18
▪ Chlorophylls and chlorophyllins
re-evaluation - Update on step 2 19
Health Claims
▪ REFIT – AESGP participates in the Advisory
group ad hoc meeting on 27 October 19
Addition of Substances to Food
▪ Monacolins in red yeast rice - EFSA
call for data 19
Novel Food
▪ EFSA opinion on Safety of Ecklonia cava
phlorotannins 20
▪ EFSA opinion on Safety of dried aerial
parts of Hoodia parviflora 20
▪ EFSA requested to provide an opinion
on shrimp peptide concentrate and
Ferric Sodium EDTA 21
DRVs
▪ Public consultation on EFSA Scientific
Opinion on DRVs for sodium 21
▪ AESGP participates in the High-level
conference “Health in the Digital
Society. Digital Society for Health” in
Tallinn, 16-18 October 2017 24
▪ AESGP co-signs the Digital Health Society
Declaration 24
▪ AESGP participates in the General Data
Protection Regulation (GDPR) Workshop
on Health Data 24
▪ AESGP contributes to the Commission
Consultation on Transformation of Health
and Care in the Digital Single Market 24
Digital Health
3 AESGP Euro OTC News | Issue 296
Medicines
Regulatory News
■ BREXIT
EMA Management Board
The EMA press release on the highlights of the Manage-
ment Board meeting held on 5 October 2017 provides
an update on the Management Board discussions on
Brexit. It indicates that the European Commission’s as-
sessment of the 19 Member States’ bids to host the
Agency, which EMA contributed to, was published on 30
September 2017. EMA released its comments on the
offers of the Member States on 3 October. The General
Affairs Council of the European Union is scheduled to
decide on the Agency’s new location on 20 November
2017.
In view of the challenges EMA will face over the next
few years, the Board initiated an early discussion on the
implications for the draft budget for 2018 and the pre-
liminary draft budget for 2019.
While no firm predictions can be made until the new
location of the Agency is known, EMA is anticipating
staff losses which will not only challenge the Agency’s
operability but could also result in a major deficit in its
budget. If operations are delayed or have to stop be-
cause of massive staff losses, the Agency could experi-
ence a dramatic drop in fee income which would in turn
result in reduced payments to the national competent
authorities. The financial consequences would be fur-
ther exacerbated by the cost of replacing staff. Such
shortfall would need to be made up from the Union
budget.
The final budget will be proposed to the Board in De-
cember, after the new location of the Agency is an-
nounced in November.
The Board also heard an update on progress made by
the EMA working groups on Committee preparedness
for human and veterinary medicines. The groups dis-
cussed how the workload that is currently carried out by
the UK in relation to the assessment of medicines will
be distributed among the EU27 after the UK has left the
EU. Further meetings will be held in November with a
view to finalising recommendations for the Manage-
ment Board at their next meeting in December.
The Management Board was informed about the next
phase of EMA’s Brexit preparedness business continuity
plan to be launched as of 1 January 2018. The Manage-
ment Board agreed to continuously analyse the impact
of this plan.
EMA Brexit Preparedness Business Continuity Plan
The EMA has published its Brexit Preparedness Business
Continuity Plan which was endorsed by the Manage-
ment Board at its June 2017 meeting and aims to safe-
guard the continuity of EMA’s operations to protect
public health while the Agency prepares for its reloca-
tion to a new host city and the departure of the United
Kingdom from the European Union (EU).
The EMA Business Continuity Plan describes the meth-
odology by which EMA has categorised and prioritised
its activities and how it plans to reallocate resources to
its core activities if needed. It prioritises tasks and activi-
ties and classifies them into three categories according
to their impact on public health and the Agency’s ability
to function. The plan will be continuously reviewed and
adapted as necessary.
Heads of Medicines Agencies (HMA) Multi-Annual
Working Program (MAWP) in connection to BREXIT
The Heads reviewed progress on the 11 key priorities
for the HMA network to account for the shift in work-
load provoked by Brexit. Due to the high number of all
actions in the MAWP (63 actions in total) particular at-
tention was paid for revision of the need to refocus ac-
tions and priorities. The discussions were carried out in
4 AESGP Euro OTC News | Issue 296
smaller groups and reported back in the plenary. The
session was a great opportunity to confirm a common
understanding that most of the priorities are horizontal-
ly and vertically integrated and connected to others via
activities. As a result of the discussion none of the 11
priorities were deleted.
The Heads stressed that the HMA working groups and
initiatives are successfully engaged in the process and
to delivering the agreed actions in time. The Heads also
noted the need to add resources and encourage more
agencies to support delivery of the MAWP. Following
the previous discussions in Malta, the Heads decided
that there is a need for a coordinating group related to
Brexit issues, to support the information exchange be-
tween HMA and HMA working groups and to report at
each HMA plenary.
Other topics on the agenda were related to the updates
on the progress of various activities, including the HMA/
EMA Joint Task Force on Big Data, CMDh and CMDv
(veto). Based on the overview presented by the
Telematics Management Board the Heads were made
aware of all telematics and enhanced EudraVigilance
progress.
AESGP BREXIT Evidence Survey
AESGP circulated on 16 October 2017 a questionnaire
on Brexit which was also being sent by other pharma-
ceutical trade associations to their respective constitu-
encies in order to get a comprehensive view of the
pharmaceutical sector on Brexit.
Companies are invited to send their responses on this
survey by 8 November 2017 COB. In case the respond-
ing company is an SME, it is invited to indicate it in the
questionnaire or in the cover email. Global companies
having already received the questionnaire through an-
other channel are invited to make sure they complete it
only once.
AESGP participation in Authorities- Industry Stake-
holder meeting on Brexit
AESGP participated at the CMDh industry meeting on
Brexit on 23 September 2017. During the meeting a
joint list of questions prepared by all trade associations
was discussed. The CMDh agreed to continue the dis-
cussion in the next Interested Parties meeting in No-
vember and to have a regular exchange with trade asso-
ciations on the issue.
AESGP was also represented at the EMA Industry Stake-
holder meeting on Brexit and operation of the central-
ised procedure for human medicinal products on 4 Oc-
tober 2017. Notes from the meeting were circulated on
6 October 2017 and are available upon request.
AESGP is working together with the other European
pharmaceutical trade associations in developing an In-
dustry Regulatory Paper on Brexit presenting all issues
caused by the UK exit and advocating desired remedial
solutions to ensure a smooth transition and no interrup-
tion in supply of medicines.
■ EMA Management Board October meeting highlights
Beside the issue of Brexit, the EMA Management board
discussed the following:
Mid-year report
Despite the impact on EMA of the UK’s decision to
leave the EU, the Agency continues to deliver on its
main public health objectives as set out in its work pro-
gramme for 2017.
The mid-year report shows that PRIME, the Agency’s
scheme to support the development of promising med-
icines addressing unmet medical needs, continues to
generate high interest from medicine developers. In the
first half of 2017, EMA received 46 applications for
PRIME. By the end of June, 42 applications had been
assessed and ten had been accepted into the scheme.
Underlining the important role EMA plays in facilitating
the research and development of new medicines and
reducing time to patients, EMA also recorded a 20%
increase in the number of requests for scientific ad-
vice in the first half of 2017 (345 requests compared to
287 in the first half of 2016).
The Agency continued to provide high-quality, efficient
and consistent support to the evaluation process for
human and veterinary medicines. For human medicines,
the number of new applications for marketing authori-
sation received in the first half of 2017 was slightly low-
er than that received during the same period in 2016
5 AESGP Euro OTC News | Issue 296
(36 in the first half 2017 versus 42 in the first half of
2016). However, the overall forecast for 2017 is in line
with 2016 figures.
EMA continued to support early access to medicines for
patients through the accelerated assess-
ment framework. 57% of requests for accelerated as-
sessment were granted and 75% of the marketing au-
thorisation applications initiated under this mechanism
were completed under the accelerated timetable during
the first half of 2017.
For veterinary medicines, seven requests for marketing
authorisation were received in the first half of 2017. This
follows a spike in the number of applications
for marketing authorisation received in the same time
period in 2016 (12), demonstrating the fluctuations in
submission patterns between years. The number of re-
quests for scientific advice for veterinary medicines re-
ceived in the first half of 2017 was higher than that re-
ceived during the same period in recent years (14 versus
a range of 8-11 in recent years).
EMA’s mid-year report will be published on the EMA
website shortly.
Update on the EU Clinical Trial Regulation and de-
velopment of the clinical trial EU Portal and Data-
base
The Board heard an update on the EU Portal and Data-
base project. The development is progressing, though
still requires close monitoring. More precision of the
delivery timeframe will be possible after a planned cycle
of extensive testing by Member States and sponsor rep-
resentatives and when further progress with the audita-
ble version of the system has been made. The develop-
ment remains aligned to the schedule that enables the
EU Clinical Trial Regulation to come into application in
the second half of 2019.
■ Latest Update on EMA International Organization for Standardization for the identification of medici-
nal products (ISO IDMP)/ Substance, product, organisation and referential (SPOR) database project
The EMA Change Team for the SPOR Programme held
a webinar on the 4th of October with the Industry
members of the EU ISO IDMP/ SPOR Taskforce (the so
called "Change Liaisons"). The purpose of the webinar
was to update on progress with implementation of the
OMS and RMS (Organisational and Referential Man-
agement Services) elements of the EMA's SPOR master
data management system. In particular the webinar
gave details of what is expected from marketing au-
thorisation holders (MAHs) in regard to coming on
board with OMS and RMS, starting from mid-
December.
The key points of information were:
1. The OMS/ RMS Systems are undergoing the last
user acceptance testing and EMA Data Stewards
are in the meantime working to expand the content
of the OMS dictionary (list of organisations with
associated locations). The System is due to go Live
on the 16th December.
2. The integration of the eAF (EU electronic applica-
tion form) with OMS is planned for December
2017. RMS data dictionary is already integrated
with the eAF.
3. The use of OMS in the eAF will be initially optional,
but applicants are strongly recommended to per-
form a search in the form to familiarise themselves
with the use of OMS and to ensure they are familiar
with the process before any mandatory use.
▪ If the address is not found it is possible to
clear the address and provide the details us-
ing free text fields as previously.
▪ If the address/location is not found or not
correct, the user is advised to follow the new
OMS process to add new organisations or
modify organisation/location data.
▪ Priority is given to address data from
MAHs. O-data for most manufacturers is in
the process of being added, so the EMA asks
that change requests for manufacturers are
held off until such time as the OMS database
is complete.
4. The EMA will invite Industry to begin registering
their Super Users and Users in December and com-
mence use of both RMS and OMS.
6 AESGP Euro OTC News | Issue 296
In much the same way as done currently for the CESP,
access for individual company users will be managed
by official company Super Users. Accordingly each
company must decide on who will require access to
SPOR, and the roles that its users should hold. It is
advised for companies to set up an arrangement with
one parent/ HQ and many subsidiary organisations, if
applicable. Each will have its own organisation
ID. Whether a single entity or parent-subsidiary ar-
rangement, at least one Super User needs to be set up
(the EMA recommends at least two).
■ HMA 89th Meeting Highlights
The Heads of Medicines Agencies (HMA) have re-
leased the highlights from their 89th meeting held in
Tallinn on 5-7 September 2017:
Availability of appropriately authorised medicines
HMA focuses on the most commonly occurring as-
pects and identifies ways to improve the availability of
medicines in the context of the current legal frame-
work. During the meeting, updates from various work-
ing groups were presented. Factors that lead to availa-
bility problems and medicines shortages in EU Mem-
ber States were discussed as well the possibilities for
improvement.
The HMA/EMA Task Force on Availability of Appropri-
ately Authorised Medicines representative gave an
update on the type of availability problems and em-
phasized points for improvements. Improvement is
needed, taking into consideration all aspects starting
from the planning of manufacturing and ending with
effective communication between stakeholders.
Importance of the information exchange between
manufacturers, suppliers and regulators was also high-
lighted and activities to facilitate communication be-
tween agencies are planned. To mitigate availability
problems, repeat use of the mutual recognition proce-
dure should be facilitated and promoted.
The representative of the European Surveillance Strat-
egy Working Group highlighted that due to shortages
(e.g. quality defects), safety risks may occur. Often the
supply disruption affects multiple Member States and
therefore collaboration for consistent incident man-
agement and risk communication is needed.
Innovation and access to new medicines
The Heads reviewed progress in implementation of
the Clinical Trials Regulation, to ensure a harmonized
approach by Member States in order to facilitate re-
search in Europe and enable patients to access new
medicines. Therefore, particular attention was paid to
the readiness of the Member States for the introduc-
tion of the regulations. Critical points of implementa-
tion, such as preparedness for high-quality assess-
ment and work-sharing were discussed, and best
practices were shared. Readiness at a national level is
encouraging and progress has been made since the
last meeting. The importance of piloting in coopera-
tion with ethics committees was highlighted. Another
important subject for discussion was the EU clinical
trials portal and database, which is currently being
tested by Member States.
Optimisation of the Regulatory Operations
Estonia presented their Electronic Health Record sys-
tem. This is a nationwide system integrating data from
Estonia’s different healthcare providers to create a
common record. Each person in Estonia that has visit-
ed a doctor has an online e-Health record that can be
tracked. Patients have access to their own records, as
well as those of their children. The patient can review
doctor visits and current prescriptions. The presenter
also noted that 99% of all prescriptions to Estonian
patients are issued using a digital prescription. Overall
conclusion was that free movement of data increases
access and safety in healthcare, improves sustainability
of health systems, creates new economic opportuni-
ties and makes the regulatory environment more effi-
cient.
7 AESGP Euro OTC News | Issue 296
■ CMDh reports – September and October 2017
The CMDh has published the reports from its meeting
held on 11-13 September and 9-11 October 2017.
Election of CMDh Chair
Laura Oliveira Santamaria of the Agencia Española de
Medicamentos y Productos Sanitarios (AEMPS), Spain,
was elected as CMDh new chair by an absolute majori-
ty of the CMDh members at the October meeting,
with a three-year mandate starting from the Novem-
ber 2017 CMDh meeting.
CMDh position following periodic safety update
single assessment (PSUSA) procedure for national-
ly authorised products only
At its October meeting, the CMDh, having considered
the periodic safety update reports (PSURs) on the ba-
sis of the Pharmacovigilance Risk Assessment Com-
mittee (PRAC) recommendation and the PRAC assess-
ment reports, agreed by consensus on the variations
of the marketing authorisations of medicinal products
containing the following active substance:
flubendazole; saccharomyces boulardii. At its Septem-
ber meeting, the CMDh agreed by consensus on the
variations of the marketing authorisations of, amongst
others, medicinal products containing dexlansoprazole
and lansoprazole.
Renewals
The CMDh has continued the discussions on improve-
ments of the renewal process. In the October 2017
meeting the following agreements were reached:
The CMDh agreed to update the Best Practice
Guide on processing of renewals in the MRP/DCP
(clean / track version) to include the agreements
reached over the previous months, notably that of
the September meeting. The CMDh agreed then
that renewals for all medicinal products approved
according to Article 10(1) can be handled accord-
ing to the shortened renewal procedure, i.e. with a
30-day timetable, submitted with a cover letter and
an application form (without annexes) and a decla-
ration that full documentation will be available for
submission upon request. The decision is also ap-
plicable for renewal applications already submitted
for such products, even if they are submitted with
full documentation according to Annex 3 of the
Best Practice Guide on the processing of renewals
in MRP/DCP. It is up to the RMS to decide if al-
ready submitted applications will be run according
to the shortened timetable. Member States can
always choose to request the full documentation
and the RMS can in such cases choose to run the
procedure in accordance with the normal 60/90-
day timetable.
The CMDh further agreed to update the MRP as-
sessment report overview template and the tem-
plate for Concerned Member States (CMS) com-
ments in MRP to further improve the communica-
tion about the handling of renewals in CMSs when
the RMS has already granted unlimited validity.
Quality Review of Documents (QRD)
The CMDh has agreed a new QRD form for submission
and assessment of user testing bridging proposals
which has been developed to provide guidance and
facilitate the submission of user testing bridging pro-
posals by applicants as well as to facilitate the assess-
ment by the RMS. When applying bridging, all sec-
tions of this form should be completed by applicants
and submitted for assessment. The existing CMDh
guidance “Consultation with Target Patient Groups:
meeting the requirements of Article 59(3) without the
need for a full test - Recommendations for bridging”
will be revised in the near future to reflect the use of
the form.
Other
Updated Q&A on Variations (clean / track version)
– Minor changes have been made to Question 4.14
and a new Question 4.22 on the submission of sev-
eral changes to the pack size has been added.
Updated Position paper concerning applicants re-
quest of submission of multiple applications during
ongoing DCPs or inclusion of new CMS or addi-
tional strength(s) in an already ongoing DCP* – re-
moval of outdated background information.
Updated SOP on decision-making process for new
active substance status or extension of marketing
protection or data exclusivity (clean / track version)
8 AESGP Euro OTC News | Issue 296
– Removal of CMDh vote on one-year data exclu-
sivity related to Article 74a.
Updated Q&A on Product information/Information
on medicinal products (clean / track version) - mi-
nor administrative changes.
Updated Recommendations on submission dates
for applicants of the DCP and MRP – addition of
the timetables for MRP/DCP applications to be
submitted in 2018.
* The document has not yet been published
24
43
19
22
25
36
10
26
28
9
12
45
28
12
25
20
21
15
3
3
5
5
1
2
2
5
3
0
4
2
2
2
3
1
0 5 10 15 20 25 30 35 40 45 50
September 2017
July - August 2017
June 2017
May 2017
April 2017
March 2017
February 2017
December 2016
November 2016
October 2016
September 2016
July - August 2016
June 2016
May 2016
April 2016
March 2016
February 2016
January 2016
Rx Non-prescription
MRP
9 AESGP Euro OTC News | Issue 296
DCP
76
202
67
101
95
109
86
104
94
83
75
216
105
88
76
105
77
92
4
17
5
6
3
7
6
4
4
10
7
19
15
17
6
10
11
6
0 50 100 150 200 250
September 2017
July - August 2017
June 2017
May 2017
April 2017
March 2017
February 2017
December 2016
November 2016
October 2016
September 2016
July - August 2016
June 2016
May 2016
April 2016
March 2016
February 2016
January 2016
Rx Non-prescription
■ Updated Annex to European Commission Guideline on excipients in labelling & package leaflet
The European Medicines Agency (EMA) and
the European Commission have updated the Annex to
the European Commission guideline on excipients in
the labelling and package leaflet of medicinal prod-
ucts for human use.
The updated annex, which is published in all European
Union languages along with scientific reports, contains
all excipients that must be declared in a medi-
cine’s labelling and package leaflet and their agreed
safety warnings.
The comments received for each excipient during public
consultations have been taken into consideration when
revising the annex. AESGP submitted comments on the
following excipients which had been released for public
consultation. A majority of which have been reflected,
notably those made on ethanol.
The revised annex applies to both centrally
and nationally authorised products. For new marketing
authorisation applications the revised annex is effective
from its day of publication and applicants must imple-
ment the information in the labelling. For already au-
thorised medicines, marketing authorisation holders
should use the first opportunity to implement the word-
ing in compliance with the revised annex. For medicines
with no foreseeable regulatory submissions, marketing
authorisation holders should submit a type IB varia-
tion within three years after the publication of the re-
vised annex.
Analysis of changes
Benzalkonium chloride – compared to the previous
information in the package leaflet:
10 AESGP Euro OTC News | Issue 296
The threshold for the inhalation route of administra-
tion (formerly “respiratory”) has been brought down
from 10 mcg /delivered dose to zero.
Information for the ocular administration route is
more detailed.
Nasal route of administration added. However,
AESGP’s suggestion to introduce two sub-categories
based on dose was not retained.
Benzyl alcohol – compared to the previous information
in the package leaflet:
Oral use has been added in the same lines as paren-
teral administration, all with a threshold of
‘zero’ (compared to maximum 90mg/kg/day in the
previous PL information).
The AESGP suggestion to delete a number of the
proposed warnings for the topical use of Benzyl al-
cohol has been retained – there now remains only
the information that “Benzyl alcohol may cause mild
local irritation.”
Boric acid – there was no previous information in the
package leaflet. Compared to the draft proposal, the
‘zero’ threshold category has been removed; the other
categories and corresponding language for the PIL have
been left unchanged.
Cyclodextrins – there was no previous information in
the package leaflet:
For the oral administration of cyclodextrins, the
AESGP suggestion to replace the proposed thresh-
old of ‘zero’ was retained, however the amounts
provided by AESGP were not – the threshold for oral
use now is 200 mg/kg/day.
The AESGP request to delete the proposed state-
ment on the possibility of interactions was accepted.
Ethanol – no modification has been made compared to
the previous information in the package leaflet (i.e. sug-
gested modifications in the draft have not been reflect-
ed) – this reflects the comments submitted by AESGP.
Fragrances containing allergens – compared to the
draft only minor modifications have been made – our
comments have not been reflected.
Fructose – compared to the previous information in the
package leaflet:
The oral/parenteral administration route with a
threshold of 5g has been deleted.
The threshold for the oral/parenteral administration
route entry concerning intolerance to some sugars
has been increased from Zero to 5 mg/kg/day.
Propylene glycol – compared to the previous infor-
mation in the package leaflet:
The threshold for the oral/parenteral administration
route, which was 400 mg/kg for adults and 200 mg/
kg for children has been split into 5 entries: 1 mg/
kg/day for babies under 4 weeks; 50 mg/kg/day for
children under 5 years; 50 mg/kg/day for pregnant
or breast-feeding women; 50 mg/kg/day for per-
sons suffering from liver or kidney disease; and 500
mg/kg/day for children over 5 years and adults,
with the remaining warning that propylene glycol
can have the same effects as drinking alcohol.
The ‘topical’ administration route has been replaced
by ‘Cutaneous’ and the threshold, which was origi-
nally of Zero, has been split into 2 entries: 50 mg/
kg/day for children over 4 weeks and adults; and
500 mg/kg/day with the warning not to use it on
open wounds or large areas of broken or damaged
skin without checking with a doctor or pharmacist
first.
Sodium – compared to the previous information in the
package leaflet:
‘Oral’ administration route has been added for the
threshold of less than 1 mmol (23mg) per dose.
For the oral/parenteral administration route with a
threshold of 1 mmol (23mg) per dose, the following
SmPC wording is added: “This medicinal product
contains x mg sodium per <dosage unit>, equivalent
to y% of the WHO recommended maximum daily
intake of 2 g sodium for an adult.”
An oral/parenteral administration route has been
added with a threshold of 17 mmol (391 mg) in the
maximum daily dose, with the warning to talk to a
doctor or pharmacist in case of prior advice to fol-
low a low salt diet.
11 AESGP Euro OTC News | Issue 296
Sodium laurilsulfate – there was no previous infor-
mation in the package leaflet; compared to the draft for
consultation, only minor modifications have been made.
Sorbitol – compared to the previous information in the
package leaflet:
The threshold of 10g for the oral administration
route has been modified to 140 mg/kg/day.
As for fructose, the threshold for the oral/parenteral
administration route entry concerning intolerance to
some sugars has been increased from Zero to 5 mg/
kg/day.
Wheat starch – compared to the previous information
in the package leaflet:
‘containing gluten’ has been added in brackets after
Wheat starch in the name of the excipient.
The following information has to be added to the
package leaflet: “One <dosage unit> contains no
more than x micrograms of gluten.”
A multidisciplinary group of experts from National Competent Authorities and the EMA was created in 2011 to update the labelling of selected
excipients listed in the Annex of the European Commission guideline on excipients in the label and package leaflet of medicinal products for
human use, as well as to add new excipients to the list, based on a review of their safety. The main safety aspects to be addressed were summa-
rised in a concept paper published in 25 March 2012.
i
■ Outcome of EDQM conference on CEPs
The European Directorate for the Quality of Medicines &
HealthCare (EDQM) issued a press release on the out-
come of its Conference on “Procedure of Certification of
Suitability to the Monographs of the European Pharmaco-
poeia (CEP)” which took place in Prague on 19-20 Sep-
tember 2017.
It is reported that the event – aimed to exchange with the
worldwide pharmaceutical sector and to keep authorities
and manufacturers alike informed of recent developments
and of the future of its Certification of suitability to the
monographs of the European Pharmacopoeia in the glob-
al regulatory environment – was attended by 175 repre-
sentatives of medicines authorities and manufacturers
from all continents.
Reflecting the developments of the European Pharmaco-
poeia (Ph. Eur.) and the Certification procedure in recent
years, the first session at the conference covered the ex-
perience of European regulators and trade associations
from Europe, with additions from China and India. Dedi-
cated workshops focused on practical information on spe-
cific aspects of the Certification procedure such as the
content of a CEP application, the change to electronic
submissions, and information on GMP (Good Manufactur-
ing Practices) inspections. The last part was dedicated to
international initiatives for information and work sharing
on medicinal products, as well as to the use of CEPs by
those authorities which accept CEPs in spite of not being
based in Europe. Ph. Eur. monographs and CEPs in fact
support the development of generic drugs, which are cru-
cial to ensure the sustainability of healthcare systems, and
also facilitate the work of regulatory authorities in as-
sessing the quality of medicinal products.
The Certification procedure has become increasingly used
by authorities worldwide: the current globalised context
brings limited resources and similar challenges, prompt-
ing authorities to share not only information, but also
working practices, such as those supported by the CEPs.
The EDQM encourages these exchanges of good practic-
es, but also actively seeks feedback from manufacturers
and national authorities in order to help them to use the
Certification procedure correctly and in a way which will
support everyone, without delay, towards the common
goal of protecting the health of medicines users in Europe
and beyond.
AESGP, represented by Helen Robbins (RB), spoke at the
conference. Helen indicated that several participants in
the conference expressed an interest in looking more into
the work of the AESGP and said they appreciated our
comments. In particular, EDQM representatives seemed
interested in learning more about the Regulatory Optimi-
sation Group (ROG) which was mentioned in the AESGP
presentation; they however said that the feedback on ho-
meopathic products is still as it previously was and that
more work needs to be done on establishing the mono-
graphs for these ingredients first but that this could be
looked at in the future.
12 AESGP Euro OTC News | Issue 296
■ Final ICH guidelines
The following ICH guidelines, which have been finalised
(Step 5) and will come into effect on 28 February 2018,
have been published:
ICH E11(R1) guideline on clinical investigation of me-
dicinal products in the pediatric population - Revi-
sion 1 (addendum)
ICH guideline Q11 on development and manufacture
of drug substances (chemical entities and biotechno-
logical / biological entities) – questions and answers
AESGP did not submit any comments on the draft ver-
sions of the documents as no input was received.
ICH E11 > Since the adoption of the ICH E11 Guideline on Clinical Investigation of Medicinal Products in the Pediatric Population in 2000,
pediatric drug development has been enhanced by advancements in several areas of general adult drug development. Targeted scientific and
technical issues relevant to pediatric populations, regulatory requirements for pediatric study plans, and infrastructures for undertaking complex
trials in pediatric patient populations has been considerably advanced in the last decade, without a parallel development of harmonised guid-
ance in these areas. This Addendum is proposed to address new scientific and technical knowledge advances in pediatric drug development.
ICH Q11 > Since reaching Step 4 in 2012, worldwide experience with implementation of the ICH Q11 Guideline and its recommendations on the
development and manufacture of drug substances has given rise to requests for clarification relating to the selection and justification of starting
materials.
The Q11 Implementation Working Group (IWG), established by ICH in 2014, developed a Questions and Answers (Q&A) document which
reached Step 2b of the ICH Process in November 2016. These Q&As are intended to provide additional clarification and to promote convergence
on the considerations for the selection and justification of starting materials and on the information that should be provided in marketing au-
thorisation applications and/or Master Files. The focus of the Q&A document is on chemical entity drug substances.
i
■ Documents for comments
DOCUMENT AESGP DEADLINE FOR COMMENTS
EMA draft Reflection paper on the use of extrapolation
in the development of medicines for paediatrics 22 December 2017
EMA reflection paper on how medicine developers can
better address the needs of older people 10 January 2018
EMA draft ICH E9 (R1) Addendum on estimands and
sensitivity analysis in clinical trials 9 February 2018
13 AESGP Euro OTC News | Issue 296
Pharmacovigilance
■ PRAC Highlights - September 2017
The Pharmacovigilance Risk Assessment Committee
(PRAC) has published the highlights from its meeting
held on 25-29 September 2017.
We shall note that the PRAC will start the re-
examination of modified-release paracetamol following
the request made by some marketing authorisation
holders involved in the review (the initial review con-
cluded on 1 September with the recommendation by
the PRAC to remove modified- or prolonged-release
paracetamol products from the market). The re-
examination is expected to conclude at the PRAC meet-
ing of 27-30 November 2017.
A short overview of the PRAC first public hearing – on
Valproate – is also given.
■ New EudraVigilance System – Information on final preparations for change-over
In preparation of the change-over
to the new EudraVigilance System –
which will go live on 22 November
2017 – the European Medicines
Agency (EMA) has informed that
some functionalities of the Eudra-
Vigilance system will be entirely or
partially unavailable for a period of
ten working days, from 8 to 21 No-
vember 2017 to allow for the trans-
fer of more than 11 mil-
lion Individual Case Safety Re-
ports from the post-authorisation
phase and clinical trials, as well as
associated information.
In relation to this, the following
documents have been published:
E u d r a V i g i l a n c e g o - l i v e
plan describing the alternative
reporting arrangements for sus-
pected adverse reactions for
authorised medicines by nation-
al authorities and marketing au-
thorisation holder (MAHs) in the
European Economic Area (EEA),
and of suspected unex-
pected serious adverse reac-
tions (SUSARs) for products sub-
ject to investigation by sponsors
of clinical trials.
Technical Note describing the IT
s y s t e m s , i n c l u d -
ing EudraVigilance, which will be
affected by the planned down-
time from 8 to 21 November
2017 and providing further in-
structions to Member States,
applicants, marketing authorisa-
tion holders and sponsors
of clinical trials.
As indicated by the EMA, the
planned EudraVigilance downtime
period will not affect the direct re-
porting of side effects by patients
and healthcare professionals to na-
tional authorities in the EU Member
States or to marketing authorisa-
tion holders. Similarly, the publicly
accessible European database of
suspected adverse drug reac-
tion reports will remain live. Alter-
native reporting arrangements are
being put in place to ensure that
important processes can continue
during the downtime. These include
in particular the established process
for MAHs and sponsors of clinical
trials to notify any emerging safety
issues immediately to EU Member
States and EMA.
The updated EU pharmacovigilance
legislation brought about significant
changes to electronic reporting re-
quirements for suspected adverse reac-
tions, to support better safety monitor-
ing for medicines and a more efficient
system for stakeholders. To support
these changes, the European Medicines
Agency (EMA) wi l l launch
the EudraVigilance system with en-
hanced functionalities on 22 November
2017.
i
14 AESGP Euro OTC News | Issue 296
■ Revision of GVP module IX - signal management, XV- safety communication, VIII - PASS and others
published
The introductory cover note of the
Guidelines on good pharmacovigi-
lance practices (GVP) has been up-
dated in light of today’s publication
of the following final GVP modules
and annexes:
Guideline on good pharma-
covigilance practices (GVP):
Module IX – Signal management
(Rev. 1) (clean version / track
changed version).
▪ Comments received from
public consultation on good
pharmacovigilance practices
(GVP): Module IX – Signal
management (Rev. 1).
▪ It will come into effect on 22
November 2017 together
with the new Eudravigilance
functionalities and applica-
tion of the ICH-E2B (R3)
guideline.
Guideline on good pharma-
covigilance practices (GVP):
Module IX Addendum I – Meth-
odological aspects of signal de-
tection from spontaneous re-
ports of suspected adverse reac-
tions (clean version / track-
changed version).
▪ Comments received from
public consultation on good
pharmacovigilance practices
(GVP): Module IX Addendum
I – Methodological aspects of
signal detection from sponta-
neous reports of suspected
adverse reactions.
▪ It will come into effect on 22
November 2017, together
with the new EudraVigilance
functionalities and applica-
tion of the ICH-E2B (R3)
guideline.
Guideline on good pharma-
covigilance practices: Module XV
– Safety communication (Rev. 1)
(clean version/ track-changed
version).
▪ Comments received from
public consultation on good
pharmacovigilance practices
(GVP): Module XV – Safety
communication (Rev. 1).
Guideline on good pharmacovi-
gilance practices (GVP): Annex II
– Templates: Communication
Plan for Direct Healthcare Pro-
fessional Communication (CP
DHPC).
▪ Comments received from
public consultation on good
pharmacovigilance practices
(GVP): Annex II – Templates:
Communication Plan for Di-
rect Healthcare Professional
Communication (CP DHPC).
Guideline on good pharma-
covigilance practices (GVP) -
Module VIII – Post-authorisation
safety studies (Rev. 3) (clean ver-
sion / track-changed version).
The revision 3 is published in
order to align this module with
the recently published revision 2
of module VI.
Guideline on good pharma-
covigilance practices: Annex I -
Definitions (Rev. 4). Revision 4 of
the Annex I on definitions is
published, mainly with terms
introduced by Regulation (EU)
No 536/2014 Art 2(2)(1) on clini-
cal trials and other terms rele-
vant to recently developed or
revised GVP documents.
At this occasion, an updated
Guideline on good pharma-
covigilance practices: Annex V –
Abbreviations (Rev. 1) is pub-
lished too.
Herbal News
■ EMA HMPC Report - September 2017
The report of the 78th
meeting of EMA Committee on
Herbal Medicinal Products (HMPC) held on 18-19 Sep-
tember 2017 has been released.
Revised European Union herbal monographs
Revised EU herbal monograph on Ribis nigri folium
was adopted.
Final Revised Guidelines
Assessment of clinical safety and efficacy in the
preparation of EU herbal monographs for well-
established and of EU herbal monographs/entries to
the EU list for traditional herbal medicinal products/
substances/preparations (EMA/HMPC/104613/2005
Rev. 1) was adopted.
15 AESGP Euro OTC News | Issue 296
Other
Call for proposals of substances for HMPC assess-
ment
In line with the Committee work plan to identify gaps in
herbal substances used by EU citizen but without har-
monized standards so far, the HMPC enquires all Inter-
ested Parties and National Competent Authorities to
submit proposals for substances to be assessed by the
HMPC. Proposals can include substances/preparations
used as single active substance in herbal medicinal
products but also specific combinations. The HMPC in-
vites also to consider substances of non-European tra-
ditions. Interested parties should limit proposals to
maximum 6 specific single substances or 6 specific
combinations and provide for each a short justification
on EU market relevance and availability of supporting
data to prove 15/30 years of safe medicinal use with a
specified therapeutic indication, strength and posology.
Proposals should reach AESGP by 2 November 2017
COB.
Background documents: the list of substances previously
proposed for European assessment and list of substances
added to the work programme of the committee and the
current status of work.
Interested parties to the HMPC
Upon request the HMPC accepted EUROCAM
(European Complementary and Alternative Medicine
Stakeholder Group) as new Interested Party to the
HMPC. The list of Interested Parties will be updated ac-
cordingly.
Quality Drafting Group (QDG)
Concept paper on the development of a Reflection
Paper on new analytical methods/technologies in the
quality control of herbal medicinal products (EMA/
HMPC/541422/2017) was adopted; it will be pub-
lished for consultation until 30 April 2018.
The HMPC further noted a report on topics under dis-
cussion including revision of the herbal specification
guideline, considerations on the concept of markers
after consultation of quality assessors across the net-
work, the follow-up on the reflection paper on Polycy-
clic Aromatic Hydrocarbons (PAH), the preparation of
an HMPC assessors training in December and the cur-
rent status and limitations of WHO guidelines in the
herbal area.
Organisational Matters Drafting Group (ORGAM
DG)
Procedure for the review and revision of European
Union herbal monographs and European Union list
entries (EMA/HMPC/124695/2011 Rev. 2) was adopt-
ed for public consultation until 31 January 2017.
The aim is to streamline the process, EU herbal mono-
graphs are kept up-to-date as a workable standard for
applicants and National Competent Authorities taking
into account available resources at the HMPC and
Working Party On European Union Monographs And
European Union List (MLWP). The scope of the proce-
dure has been widened from the periodic review/
revision to unscheduled reviews/ revisions in line with a
previous Reflection paper (EMA/HMPC/326440/2007).
As a main principle, the revision of monographs and
supporting documents will only be started if during the
review of newly available data relevant new information
has been identified that potentially change the content
of a monograph.
The committee further heard a report on other discus-
sions held at the drafting group either linked to the new
procedure (template adaptations and best practice
guidance) or regarding the addition of new substances
to the HMPC work programme (template, criteria for
prioritisation, call for proposals).
Working Party on European Union Monographs and
European Union List (MLWP) – Report from the July
2017 Meeting
Finalisation
The working party finalised the assessment of Piperis
methystici rhizoma and supporting documents includ-
ing the Overview of comments received during public
consultation for peer review and possible final adoption
by the HMPC in November 2017.
Drafts
The working party continued its assessment of Fragariae
folium, Malvae folium, Malvae sylvestris flos, Species
sedativae and Species digestivae / stomachicae.
16 AESGP Euro OTC News | Issue 296
Revisions-finalisation
After public consultation, the working party finalised the
revision of the documents on Meliloti herba, for peer
review and transfer to the HMPC in November 2017 for
possible final adoption. MLWP had first discussions of
comments received on the revised monograph on Uvae
ursi folium.
Revisions-Drafts
The working party agreed to the revision of the docu-
ments on Valerianae radix/Lupuli flos and Curcumae
longae rhizoma for peer review and transfer to the
HMPC in November 2017 for possible release for public
consultation. The MLWP continued the systematic re-
view of Cynarae folium, Hyperici herba, Rusci aculeati
rhizoma and Calendulae flos and had first discussions
on the review of Agni casti fructus, Gentianae radix and
Oenotherae oleum.
■ Publication of Final EU herbal monographs
The European Union herbal monograph on Artemisia absinthium L., herba, adopted by consensus.
■ Documents for comments
DOCUMENT AESGP DEADLINE FOR COMMENTS
EMA HMPC Draft revised Guideline on non-clinical doc-
umentation in applications for marketing authorisa-
registration of well-established and traditional herbal
medicinal products
10 November 2017
EMA HMPC Draft European Union herbal monograph
on Senna alexandrina Mill. (Cassia senna L.; Cassia an-
gustifolia Vahl), folium and fructus – Revision 1
15 December 2017
Homeopathic News
■ HMA HMPWG Report - June 2017 meeting
The Heads of Medicines Agencies Homeopathic Medici-
nal Products Working Group (HMA HMPWG) has pub-
lished the Report from its 25th meeting held in Gozo
(Malta) on 26-27 June 2017.
HMA HMPWG
The Chair informed the group about the conference
of World Integrated Medicine Forum on the regula-
tion of homeopathic medicinal products: National
and Global Strategies, held in Delhi 23-24 February
2017.
HMPWG was informed regarding a request from the
Association of the European Self-Medication Industry
(AESGP) on the implementation of ICH Q3D to ho-
meopathic medicines.
Legislation
An update on the development of the Minamata Con-
vention on Mercury (“Convention”) was given by the
representative of EMA’s Legal Department. The Con-
vention was adopted by the United Nations in 2013
with the aim to protect human health and the envi-
ronment from the adverse effects of mercury.
Topics related to the published revised Notice to Ap-
plicants Vol. 2B Presentation and content of the dossier
- Part 1 Summary of the dossier Part 1A or Module 1:
17 AESGP Euro OTC News | Issue 296
Administrative information Application form - Homeo-
pathic Medicinal product for Human Use and on the
Draft revision 2 – VOLUME 2C – Guidelines – Medicinal
products for human use – Safety, environment and in-
formation – Excipients in the labeling and package
leaflet of medicinal products for human use were pro-
vided after collecting an update with EC. A new Appli-
cation form, adopted by Notice to Applicants for ho-
meopathic medicinal products, was released in De-
cember 2016. This document will replace the existing
one on the HMA website.
Quality
The Chairperson of the Sub working Group on
“Quality” gave an overview of the activities complet-
ed, in progress and discussed during the sub-WG
meeting. A draft guidance document related to the
quality of nosodes as stocks was presented. This will
be further discussed and elaborated by the HMPWG.
The Draft quality “Questions & Answers document” (1-
3), and the “Compilation of comments on Questions &
Answers document (1-3)” received by the Stakeholders
during the consultation phase were also presented.
New versions of the documents will be released after
further consultation amongst HMPWG members.
Comments collected by the HMPWG on the docu-
ment “Questions & Answers document” (4-8) were pre-
sented. It will be released for public consultation fol-
lowing adoption by written procedure, by HMPWG, in
the coming months.
A document, regarding the comments received after
public consultation on HMA website, on the Draft
Points to consider on the selection of the Ph. Eur. mi-
crobial limits for non-sterile homeopathic raw materi-
als, stocks, preparations and products, was presented.
A new draft ‘Points to Consider’ document, compre-
hensive of the outcome of the discussion that took
place during the Sub working Group on “Quality”
meeting, was also presented. Both documents were
adopted by HMPWG.
Safety
In conjunction with FSD-sub WG, the opportunity to
revise the Points to Consider on Non Clinical Safety of
Homeopathic Medicinal Products of botanical, mineral
and chemical origin, was discussed. In particular a
proposal to draft a new Guidance Documents on Mod-
ule 4, that will take into consideration the discussion
of the FSD sub-working group meeting, was consid-
ered. The new document will be comprehensive of all
aspects of safety and it will replace existing docu-
ments.
The outcome of the use of homeopathic medicinal
products in pregnancy and lactation, distributed to
the MSs was also presented.
An update to the Contamination of herbal substances
with pyrrolizidine alkaloids was presented.
Homeopathic Use
The Chairperson of the Homeopathic use sub working
Group presented the work done by the members.
A draft First list of stocks of justified homeopathic use
for nosodes, considering the stocks Medorrhinum,
Luesinum, Psorinum, Tuberculinum and Pyrogenium,
was presented.
A discussion took place on homeopathic manufactur-
ing methods to be used for nosodes not described in
an official Pharmacopoeia of a MS.
Considering the definition of homeopathic medicines
in Directive 2001/83/EC: it was decided that further
discussion and investigation on approaches used by
the MSs and their legal interpretation of the Directive,
is needed, following on from clarification from the
EMA on the issue.
■ Final HMPWG Points to Consider on selection of microbial limits for non-sterile homeopathics
The Heads of Medicines Agencies Homeopathic Medicinal Products Working Group (HMA HMPWG) has published
the final Points to Consider on the Selection of Microbial Limits for Non-Sterile Homeopathic Raw Materials, Stocks,
Preparations and Products which was adopted at their June 2017 meeting.
Food
18 AESGP Euro OTC News | Issue 296
Food Additives
■ EFSA workshop and ANS open plenary - 23/24 November 2017 in Parma - Registration open
The registration for the a one-day workshop on the sta-
tus of the EU re-evaluation programme of food addi-
tives which will take place in Parma on Friday
24.11.2017 is now open.
Note that registrations will close once the maximum
number of participants is reached or, at the latest, by
Monday 06.11.2017.
The registration to observe the open plenary of the ANS
Panel is also open. The meeting will take place in Parma,
Italy, on 21-23 November 2017 (draft agenda of the
meeting available here). Sessions open to Observers are
on 22 and 23 November 2017.
Among others, the following agenda items are of partic-
ular interest :
Draft Guidance on Nutrient Sources (EFSA-Q-2016-
00150)
Re-evaluation of silicon dioxide (E 551) (EFSA-Q-
2011-00576)
Scientific opinion on the safety of hydroxyanthra-
cene derivatives (EFSA-Q-2016-00562)
If you wish to attend as an observer please register here
by 7 November 2017.
■ EFSA opinion on re-evaluation of 12 modified starches
EFSA has published its scientific opinion on the re-
evaluation of oxidised starch (E 1404), monostarch
phosphate (E 1410), distarch phosphate (E 1412), phos-
phated distarch phosphate (E 1413), acetylated distarch
phosphate (E 1414), acetylated starch (E 1420), acetylat-
ed distarch adipate (E 1422), hydroxypropyl starch (E
1440), hydroxypropyl distarch phosphate (E 1442),
starch sodium octenyl succinate (E 1450), acetylated
oxidised starch (E 1451) and starch aluminium octenyl
succinate (E 1452) as food additives.
The Panel concluded that:
there is no need for a numerical ADI for modified
starches.
there is no safety concern for the general population
at the reported uses of modified starches as food
additives.
The usage data in food supplements submitted by
AESGP have been taken into account in the risk assess-
ment.
The above modified starches are authorised according to Annex II of the Food Additives Regulation 1333/2008 as part of Group I in Food Sup-
plements (Category 17) in all forms at quantum satis level.
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19 AESGP Euro OTC News | Issue 296
■ Chlorophylls and chlorophyllins re-evaluation - Update on step 2
The Commission has published the List of interested
business operators who responded to the call for scien-
tific and technical data regarding the re-evaluation of
chlorophylls (E 140(i)), chlorophyllins (E 140(ii)), copper
complexes of chlorophylls (E 141(i)) and copper com-
plexes of chlorophyllins (E 141(ii)). Now the operators
have confirmed their commitment to submit data and
the Commission published the document summarising
the outcome of step 2 of the call for data on chloro-
phylls and chlorophyllins, and overview of data that will
be submitted, deadlines and milestones.
Two operators including the Natural Food Colours As-
sociation (NATCOL) have committed to submit the re-
quested toxicological data and the data related to the
specifications.
Health Claims
■ REFIT – AESGP participates in the Advisory group ad hoc meeting on 27 October
AESGP will participate in the ad hoc
working group meeting on nutrition
and health claims which will be held
on Friday, 27 October 2017.
The objectives of the meeting are
for the contractor to present the
draft final report of the study on the
evaluation of Regulation (EC) No
1924/2006 on nutrition and health
claims made on foods and for
stakeholders to share any com-
ments they may have.
Addition of Substances to Food
■ Monacolins in red yeast rice - EFSA call for data
EFSA has launched the call for data on new scientific
information as regards the use of monacolins
(monacolin K) in red yeast rice.
The purpose of this call for data is to offer to interested
parties and/or stakeholders the opportunity to submit
documented information (mainly unpublished or newly
generated) relevant to the evaluation of monacolins in
red yeast rice from all sources in foods including prepa-
rations such as food supplements.
Deadline for registering interest: 3/11/2017
Deadline for submission of data: 6/12/2017
Members interested in submitting the requested infor-
mation on monacolins are requested to communicate
directly their availability to EFSA by Friday 3 November
2017 in accordance with the instructions detailed in the
call for data.
In the context of Article 8(2) of Regulation (EC) 1925/2006 on the
addition of vitamins and minerals and of other substances to
foods, the European Commission requested EFSA to assess the
available information on the safety of monacolins in red yeast rice
from all sources in foods including preparations such as food sup-
plements. In order to ensure an effective evaluation of monacolins
in red yeast rice, it is important that EFSA retrieves from interested
parties all relevant data for the evaluation of the selected sub-
stance. Therefore EFSA launches a public call for data in order to
acquire documented information (published, unpublished or newly
generated) on monacolins in red yeast rice, with specific focus on
monacolin K. EFSA will consider the relevance of the information
provided for the risk assessment of monacolins in red yeast rice.
The submission of the requested information is without prejudice
to the final opinion of the ANS Panel.
i
20 AESGP Euro OTC News | Issue 296
Deadline for submission of data and disclosure of
contact details
Interested parties and stakeholders should provide
by 6/12/2017 the information described below.
By 3/11/2017, please communicate in writing by e-mail
to: fip@efsa.europa.eu, your availability to submit the
requested information by the timeline specified above
or any proposal for a new deadline providing justified
reasons.
Depending on the replies received the final deadline will
be communicated to you through e-mail and by updat-
ing the current call.
In order to facilitate the collaboration of all interested
parties to provide the data needed, we are seeking your
consent to disclose your personal data (name, e-mail
address and telephone number) to the other parties
that have expressed an interest in providing the re-
quested information. If you do not wish to make your
contact details available, clearly indicate it in your first
communication.
Information sought
EFSA kindly invites business operators and other inter-
ested parties (governments, interested organisations,
universities, research institutions, companies) to submit
information on monacolin K for the following specific
topics: technical data, biological and toxicological data
(botanical preparation and its components).
Novel Food
■ EFSA opinion on Safety of Ecklonia cava phlorotannins
The EFSA Panel on Dietetic Products, Nutrition and Al-
lergies (NDA) published an opinion on the Safety of Eck-
lonia cava phlorotannins as a novel food pursuant to
Regulation (EC) No 258/97.
The Panel concludes that the novel food (NF), Ecklonia
cava phlorotannins, is safe for the use in food supple-
ments at a maximum daily intake level of 163 mg/day
for adolescents from 12 to 14 years of age, 230 mg/day
for adolescents above 14 years of age and 263 mg/day
for adults.
The NF that is the subject of the application is a phloro-
tannin-rich alcohol extract of Ecklonia cava, which is an
edible marine brown alga species. The information pro-
vided on the composition, the specifications, the pro-
duction process and the batch-to-batch variability of
the novel food is sufficient and does not raise safety
concerns.
The intention is to market the novel food as a food sup-
plement for healthy individuals over the age of 12 years.
A subchronic repeated dose oral toxicity study in ro-
dents tested the novel food at daily doses of 0, 375, 750
and 1,500 mg/kg body weight (bw). The Panel considers
the middose as the no-observed-adverse-effect-level
(NOAEL) of the study. Taking into account this NOAEL
of 750 mg/kg bw per day and by applying an uncertain-
ty factor of 200, the Panel considers an intake level of
3.75 mg/kg bw per day as safe.
The Panel however notes that iodine intake from the NF
may be of concern for people at risk of thyroid disease
and that intake of other food supplements containing
iodine in addition to the NF might lead to iodine intakes
above the UL.
■ EFSA opinion on Safety of dried aerial parts of Hoodia parviflora
The EFSA Panel on Dietetic Products, Nutrition and Al-
lergies (NDA) published an opinion on the Safety of
dried aerial parts of Hoodia parviflora as a novel food
pursuant to Regulation (EC) No 258/97.
The Panel concludes that the addition of the NF to
foods as a food ingredient at the uses and use levels as
proposed by the applicant would exceed intake levels
considered safe in humans. The Panel considers that the
NF is safe to be used as a food supplement at a maxi-
mum dose of 9.4 mg/day. The target population is
adults.
The NF that is the subject of the application is the whole
dried aerial parts of Hoodia parviflora, which is a succu-
lent cactus-like milkweed plant native to southern Afri-
21 AESGP Euro OTC News | Issue 296
■ EFSA requested to provide an opinion on shrimp peptide concentrate and Ferric Sodium EDTA
EFSA has received from the Com-
mission a request to provide a sci-
entific opinion on:
Shrimp peptide concentrate as a
novel food ingredient by 31
March 2018 (EFSA-Q-2017-
00679). The application is still to
be validated.
Ferric Sodium EDTA as a novel
food ingredient by 30 April 2018
(EFSA-Q-2017-00696). The ap-
plication is still to be validated.
DRVs
■ Public consultation on EFSA Scientific Opinion on DRVs for sodium
ca. The raw material, which is harvested from plants of
more than 3 years, is sanitised, freeze-dried and ground
into a fine powder.
The information provided on the composition, the spec-
ifications, the production process, the batch-to-batch
variability and the stability of the NF is sufficient and
does not raise safety concerns. The applicant intends to
use the NF in a number of energy-reduced/sugar-free/
no-added-sugar foods in quantities of up to 15 mg per
serving. The applicant also proposes to provide the NF
as a food supplement. The target population proposed
by the applicant is adults. The highest intake estimates
were found in the group of elderly (≥ 65 years) individu-
als, with a high intake of 1.0 mg/kg body weight (bw)
per day. One 90-day toxicity study in rodents was pro-
vided from which a benchmark dose lower confidence
limit (BMDL05) of 53.5 mg/kg bw per day was derived for
effects of the NF on bodyweight.
The EFSA Panel on Dietetic Prod-
ucts, Nutrition and Allergies (NDA)
launched a Public consultation on
the intermediate draft scientific
opinion on dietary reference values
for sodium and related protocol.
Sections 1 to 5.4. of the draft scien-
tific opinion, as well as the draft
protocol developed for Sections 5.5
and 6 (Annex A), are published for
public consultation. This is to re-
ceive input from stakeholders on
the parts of the opinion which have
been used to inform the draft pro-
tocol, and on the methodology
foreseen to inform the parts cov-
ered by the protocol. The draft
opinion and draft protocol will be
revised in the light of the com-
ments received. The protocol will
then be implemented and the opin-
ion completed. Another public con-
sultation will be organised once the
opinion is finalised (Spring 2019).
The draft protocol (Annex A) ap-
plies to the missing sections of the
scientific opinion (Sections 1 to 5.4),
namely:
the assessment of possible rela-
tionships between sodium in-
take and health outcomes, in-
cluding dose-response relation-
ship(s), where applicable
(Section 5.5), and;
the integration of different lines
of evidence for setting DRVs
(Section 6). The two documents
are published together in order
to receive input from stakehold-
ers on the parts of the opinion
which have been used to inform
the draft protocol, and on the
methodology foreseen to in-
form the remaining parts cov-
ered by the protocol.
The non-finalised draft opinion
gives an Overview of Dietary Refer-
ence Values for sodium for adults in
Table 2 (page 27) and an Overview
of Dietary Reference Values for so-
dium for children in Table 4 (page
29) but does not propose any draft
conclusion at this stage.
Written comments might be sub-
mitted to EFSA via the following
links by 12 November 2017.
Comments on the draft opinion
Comments on the draft protocol
Sodium (Na+) is an alkali metal with an atomic mass of 22.99 Da (Lide, 2009; Coplen et al., 2013). Only one sodium isotope (23Na) is stable in
nature. At normal temperature and pressure, sodium is a solid metal. Sodium is highly reactive in both water and air and is not found naturally
in its elemental form. In the earth’s crust there is an abundance of sodium salts such as those with carbonate, nitrate, sulphate, borate, and par-
ticularly with halogens, especially chloride (Greenwood and Earnshaw, 1997; Lide, 2009).
Sodium chloride (NaCl) is table salt. One gram of sodium chloride provides 0.4 g sodium and 0.6 g chloride which is 17 mmol sodium and chlo-
ride.
i
Medical Devices
22 AESGP Euro OTC News | Issue 296
MDR Implementation
■ AESGP participates in the COM/CAMD Stakeholders meeting on the MDR and IVDR
AESGP participated in the second meeting with stake-
holders organized by the European Commission and the
Competent Authorities for Medical Devices (CAMD)
Group on Wednesday, 18 October 2017 in Brussels.
The CAMD MDR/ IVDR implementation taskforce pre-
sented the latest consolidated version of its roadmap
which results from a priority listing exercise intended to
help identify the key issues to be addressed and collect-
ed comments from stakeholders. Following CAMD en-
dorsement, the taskforce, in collaboration with the
Commission, initiated a formal engagement exercise
with European Stakeholders with the ultimate aim of
using the priorities as the basis for the development of
a single European ‘roadmap’ for implementation. The
feedback from Stakeholders provided at the first stake-
holder meeting on 9 March and in the following months
has been assessed by the Taskforce, and where consid-
ered appropriate, amendments to the priorities have
been made accordingly. The intention is to publish the
final roadmap taking into account the stakeholder input
at the 18 October meeting on the CAMD website.
AESGP gave at this occasion two presentations:
one on its key challenges associated with the imple-
mentation of the new medical device Regulations;
one on its training experience and identification of
additional future training needs
■ Codes for designation of NBs
The European Commission has run the 4-week
‘feedback procedure’ consultation on the draft Commis-
sion Implementing Regulation (EU) …/... on the list of
codes and corresponding types of devices for the purpose
of specifying the scope of the designation as notified bod-
ies in the field of medical devices under Regulation (EU)
2017/745 of the European Parliament and of the Council
and in vitro diagnostic medical devices under Regulation
(EU) 2017/746 of the European Parliament and of the
Council (and its annexes) until 25 October 2017.
The list of codes and corresponding types of devices for
the purpose of specifying the scope of the designation
as notified bodies in the field of medical devices under
the MDR is set out in Annex I to the draft Regulation.
Conformity assessment of medical devices under the Medical Device
Regulation (MDR) and the In Vitro Diagnostic Regulation (IVDR) may
require involvement of conformity assessment bodies. Only conformi-
ty assessment bodies that have been designated under the MDR or
IVDR may carry out such assessment and only for the activities relat-
ed to the types of devices concerned. In order to enable specifying the
scope of the designation of conformity assessment bodies notified
under these regulations it is necessary to draw up list of codes and
corresponding types of devices.
The lists of codes and corresponding types of devices should take into
account various device types which can be characterised by design
and purpose, manufacturing processes and technologies used, such as
sterilisation and the use of nanomaterials. The lists of codes should
provide for a multi-dimensional typology of devices which ensures
that conformity assessment bodies designated as notified bodies are
fully competent for the devices they are required to assess.
In accordance with Article 42(3) of MDR and Article 38(3) of IVDR,
when notifying the Commission and the other Member States of the
conformity assessment bodies they have designated Member States
are to clearly specify, using the codes, the scope of the designation
indicating the conformity assessment activities and the types of devic-
es which the notified body is authorised to assess. In order to facilitate
such notification and the assessment of the application for designa-
tion, conformity assessment bodies should use the lists of codes and
corresponding types of devices set out in this Regulation when apply-
ing for designation.
i
23 AESGP Euro OTC News | Issue 296
■ Committee on Medical Devices - 5 October 2017
The Commission published the summary record of the
first meeting of the Committee on Medical Devices
which took place on 5 October 2017.
This was the first meeting of the Committee on Medical
Devices following the entry into force of Regulation (EU)
2017/745 on medical devices (MDR) and Regulation
(EU) 2017/746 on in vitro medical devices (IVDR). The
purpose of the meeting was to agree on operation of
the Committee (the Rules of Procedure) and to discuss
the ongoing implementation works with regard to both
Regulations.
The following agenda items were discussed:
Presentation and discussion on a draft implementing
act on the codes used for designation as a notified
body in the MDR and IVDR fields;
Discussion on a draft implementing act on the appli-
cation for designation as a notified Body in the MDR
and IVDR fields;
AOB:
▪ Update on a future implementing act on MDR
Annex XVI products
▪ Update on a future implementing act on repro-
cessing
▪ Update and orientation on preparations for new
EUDAMED
The Committee on Medical Devices is a regulatory committee
which is involved in the adoption of implementing acts per
Article 114 MDR. The Committee on Medical Devices is similar to
the one existing currently under the Medical Devices Directives,
i.e. Article 6(2) of Directive 90/385/EEC, Article 7(1) of Directive
93/42/EEC, and Article 7(1) of Directive 98/79/EC.
i
■ AESGP collects editorial mistakes for corrigendum to be launched soon
A process to adopt a corrigen-
dum to the two Regulations will be
launched by the end of 2017. The
objective of the corrigendum is to
correct those mistakes contained in
the two Regulations, having pure
editorial nature.
In this respect, the Commission val-
ue very much stakeholders’ contri-
bution and would be extremely
grateful whether we could report
any identified editorial mistake
(both in the English and translated
versions of the two texts) by 17 No-
vember at the latest.
AESGP members having identified
editorial mistakes (both in
the English and translated versions
of the MDR) are kindly asked to
report them to AESGP by Friday 10
November 2017.
European Commission’s Scientific Committee on Health,
Environment and Emerging Risks (SCHEER)
■ Mandate to issue Guidelines on benefit-risk assessment of phthalates in certain medical devices
The European Commission’s Scientific Committee on Health, Environment and Emerging Risks (SCHEER), at its plena-
ry meeting on 28 September 2017, approved the mandate from the Directorate-General for Internal Market, Industry,
Entrepreneurship and SMEs to issue guidelines on the benefit-risk assessment of the presence of phthalates in cer-
tain medical devices by 31 March 2019. These cover phthalates which are carcinogenic, mutagenic, toxic to reproduc-
tion (CMR) or have endocrine-disrupting properties.
Digital Health
24 AESGP Euro OTC News | Issue 296
■ AESGP participates in the High-level conference “Health in the Digital Society. Digital Society for
Health” in Tallinn, 16-18 October 2017
AESGP took part in the high-level conference organized
by the Estonian Presidency of the European Union,
ECHAlliance and HIMSS “Health in the Digital Society.
Digital Society for Health” from 16th to 18th October
2017 in Tallinn, Estonia. The conference brought togeth-
er various stakeholders in eHealth from EU policy mak-
ers, patients/citizens organisation representatives, in-
dustry representatives to professional from IT and start-
ups. The conference focused on how digital technolo-
gies and wider use of health data are changing our lives
and the ways of healthcare. During the sessions partici-
pants address the current status and trends in digital
health around the world, the changing stakeholder rela-
tionships, the role of the free flow of date, investment
and innovation, and especially the opportunities that
eHealth developments offer to the challenges of health
and healthcare in Europe.
■ AESGP co-signs the Digital Health Society Declaration
The highlight of the “Health in the Digital Society. Digi-
tal Society for Health” conference was the presentation
of the Digital Health Society Declaration of which
AESGP is a co-signatory. AESGP is among the 1st con-
tributing organisations to the Digital Health Society
Group and has contributed to the consultation and to
the Declaration itself. The Declaration is a result of the
Digital Health Society initiative, which aims to support
the European Commission in its work in establishing of
the Digital Single Market. The Declarations is still open
for co-endorsement and co-signature, with signatories
forming a permanent multi-stakeholders group.
■ AESGP participates in the General Data Protection Regulation (GDPR) Workshop on Health Data
On Monday 23rd
October AEGSP participated in a stake-
holder workshop on General Data Protection Regulation
(DGPR) implementation and Health Data. The workshop
was organized by the European Commission (DG CON-
NECT, DG JUST, DG SANTE and DG RTD). The purpose
of the workshop was to share practical experiences of
eHealth stakeholders when it comes to the handling
health data and the implication of the GDPR.
■ AESGP contributes to the Commission Consultation on Transformation of Health and Care in the
Digital Single Market
AESGP participated in the European Commission Public
consultation on Transformation of Health and Care in
the Digital Single Market, which purpose is to define the
need and scope of policy measure that will encourage
digital innovation in improving people’s health as well
as address systemic challenges to healthcare systems.
Some of the issues relevant for the AESGP, that were
address in the consultation, were cross-border access to
personal health data, sharing of data and especially the
obstacles which hinder both. AESGP expressed its views
and concerns as well as offer some suggestion for fur-
ther policy action in the digitalization of healthcare.
1
Conference report
Opening Evening in the European Parliament
The meeting started with a well-attended evening event
in the European Parliament hosted by Adina-Ioana
Vălean, Chair of the Committee on the Environment,
Public Health and Food Safety (European Parliament),
who cordially welcomed participants and underlined the
importance of the self-care industry for offering product
choices and for providing the necessary information.
AESGP also had the honour of the presence of Commis-
sioner Vytenis Andriukaitis who, in his speech, shared
his thoughts on the role of self-care in managing the
increasing pressure on health systems. “A greater focus
on prevention and prophylaxis– in addition to early di-
agnostics and treatment are essential” stressed Mr An-
driukaitis, “self-care and empowerment can make pa-
tients more autonomous and by extension less depend-
ent on our health systems”.
At the AESGP event in the European Parliament on 10 October 2017 (from left to right): Hubertus Cranz (AESGP Director General),
Adina-Ioana Vălean (European Parliament), Vytenis Andriukaitis (European Commission), Renate Sommer (European Parliament),
and Dirk Ossenberg-Engels (AESGP Vice-President, Bayer Consumer Care)
2
Two projects relating to self-care have been funded by
the European Commission: PiSCE, a project of self-care
systems in the EU, and PRO STEP, which promotes self-
care in chronic diseases. “The PiSCE project developed
guidelines and communication tools on how to pro-
mote self-care for chronic diseases. This can contribute
to improved patient centred care.” The Commissioner
furthermore stated : “The project also provides recom-
mendations for the implementation of non-prescription
drugs and stresses the importance of early involvement
of stakeholders, training of health professionals and
improving the knowledge and skills of citizens and pa-
tients. “ He underlined the investment in self-care as an
integral part of health literacy in education system.
The Commissioner explained the patients’ need for
tools to strengthen their knowledge and better monitor
their condition. This includes a “wide range of medical
devices and mHealth tools, some of them used in a self-
care context”, whose safety and effectiveness will be
ensured by the two new Regulations.
Mr Andriukaitis also focused on anti-microbial re-
sistance (AMR), one of the major priorities for the Com-
mission which adopted the EU One Health Action Plan
against AMR. He outlined that in July the Commission
published guidelines on the prudent use of antimicrobi-
als in human medicine, which stress the importance of
avoiding treatment when there is only evidence of a
viral infection such as the flu or of an infection after rel-
evant clinical examination. Non-prescription medicines
can play an important role in alleviating the symptoms
of patients who do not require antibiotics to treat minor
ailments and disorders.
At the end of his speech, he stressed the collective re-
sponsibility in the development of healthy societies and
sustainable health systems, encouraged an open and
insightful debate including all stakeholders and wished
the participants a fruitful conference.
AESGP Director General, Hubertus Cranz, thanked both
Mrs Vălean and Commissioner Andriukaitis for their im-
portant statements and underlined the commitment of
the European self-care industry to address healthcare
challenges such as antimicrobial resistance.
Session 1 Food Products and Health –
Which Direction to Go?
The Health Claims Regulation - ‘A Mistake
from the Very Beginning?’
Dr Renate Sommer introduced the session with an an-
ecdote about how difficult it was for her daughter to
find regular milk in the United States. Almost all types
of milk were labelled as fortified or lactose free. She is
‘glad’ that we do not yet live in such conditions because
EU requirements for making such claims are very high.
However, she remarked that the US legal setting might
be preferable for some manufacturers. “The market for
foodstuffs is saturated and it makes sense to add to
food to make it functional to place new products on the
market”. She pointed to the success of functional foods
and the willingness of consumers to pay a higher price
for them in the supermarket. She noted that lots of pro-
ducers of functional foods and food supplements are
Small and Medium-sized Enterprises (SMEs), who con-
stitute the draft force of economic growth in the EU.
The EU and its institutions did therefore not want to
prevent such innovation, although the Commission did
attempt to regulate the use of food supplements and
medical components in foodstuffs. She remarked that
from her perspective the scientific evaluation with re-
gard to the amounts of vitamins and minerals that may
be added to foodstuffs in the EU was quite successful.
She believes that Regulation (EC) No 1925/2006 on the
addition of vitamins and minerals and of certain other
substances to foods ensures that food supplements are
added in a manner that ensures a positive effect on
health while preventing an oversupply of certain sub-
stances. However, regarding advertising of these inno-
vative foods, she believes the EU has failed.
Large parts of the Nutrition and Health Claims regula-
tion, Regulation (EC) No 1924/2006, that was intended
to regulate advertising claims, are not in force yet. The
evaluation of the vast majority of claims submitted for
approval took years and 80% of evaluated claims were
3
Conference report
denied. She added that this was also a heavy burden for
EFSA. That was when the EU postponed the evaluation
of botanicals claims. Up until now, there has been no
new progress on 1600 claims on botanicals leading to
market distortion and legal uncertainty for all stake-
holders. Manufacturers whose claims have already been
denied are particularly disadvantaged as other botanical
claims are still unregulated and allowed. Equally the
Commission has not yet come up with a proposal for
the nutrient profiles, which should have been the basis
for the entire regulation. “The Health Claims Regulation
judges on single foods, but it is nonsense to think that
people eat just one food all the time”. She therefore
believes that the Health Claims Regulation was a
‘mistake’ from the very beginning, as to date, 9 years
after it came into force, the most important elements
are still missing.
Meanwhile, the Regulation on the provision of
food information to consumers (FIC) (Regulation (EU)
No 1169/2011) is implemented, which in her view
makes the health claims regulation superfluous. She
believes that if we want to educate people on how food
can contribute to health, we should inform consumers
on a balanced diet and the composition and prepara-
tion of food. This does not mean that the inclusion of
vitamins and minerals should be prohibited, however, if
consumers are better informed, they can use the FIC
Regulation to decide for themselves. Food labelling al-
lows consumers to see immediately if the product is
supplemented with vitamins and minerals as it has to be
included in the ingredients list, and can be added to the
nutrition declaration, which can act as a marketing in-
strument. Article 7 of the FIC Regulation further protects
consumers from misleading information.
The European Parliament asked to review the Health
Claims Regulation in the REFIT procedure. Recent objec-
tions in the Parliament show that MEPs ‘are sceptical’
towards new claims, and rejected several claims such as
the effect of caffeine or carbohydrates. Mrs Sommer
concluded that from her perspective ideally all health
claims should be banned.
‘Pharmafoods’ and Botanical Claims ‒ State
of Play
Nathalie Chaze, Deputy Head of Cabinet of Commis-
sioner Vytenis Andriukaitis, European Commission, ex-
plained that the overall food policy in the EU is under
review, as a number of re-evaluations and REFIT
(Regulatory Fitness and Performance Programme) exer-
cises have been launched to assess whether it is ‘fit for
purpose’ and aspects of the legislation have not been
implemented. This is being carried out not just for the
Health Claims legislation but also the General Food Law
which is celebrating its 15-year anniversary this year
(end of November). “We have a good system in place to
ensure food safety, which was why the General Food
Law was established in the first place, and it’s not easy
and we face regular crises and it is never a finished job,
it is ongoing,” she explained. The REFIT exercise also
looks at the re-evaluation of the pesticide legislation.
She acknowledged the challenges faced, particularly in
recent years, in relation to science, as scientific opinions
with an unfavourable outcome were challenged. “It is
difficult to take a decision as policy makers, as civil soci-
ety and stakeholders challenge scientific opinions. In the
field of food, it is one of the first challenges we are fac-
ing and we see it in different fields”. Another challenge,
she explained, is the evolution in consumer choice.
In the past, food safety and quality were the main con-
cern. Now, more and more, food is seen as a means for
physical health and no longer just for nutrition. She al-
luded to the Joint Research Centre’s (JRC) study pub-
lished by the Commission which looks at EU Health and
Nutrition in 2050. The study describes different scenari-
os of where ‘food’ will go, and one of them is
‘Pharmafoods.’ “We are seeing this trend more and
more in society, in particular with the growing trends in
obesity, food needs to be healthy and maximise our
healthy life years”. There is a huge demand from society
for truth about healthy food. This is why, she explained,
the Health Claims Regulation plays an important role.
It was established to ensure that customers would have
information about food which was not misleading and
that health claims were approved after scientific assess-
Nathalie Chaze
4
ment by EFSA. The level of scientific evidence required
to make such claims, however, is quite high. Applying
the same scientific evidence requirement for food and
botanicals was therefore extremely challenging for the
Commission as it has a significant impact on the prod-
uct and on the market. In addition, would the EU society
be ready to accept that the Commission rejects all
health claims on botanicals?
The lines are blurred between what constitutes a medi-
cine and what constitutes a food. She believes the Com-
mission has been lenient when it comes to health
claims. “Although they have rejected a lot, they have
permitted quite a few”. Regarding botanical claims, the
Commission is looking for a solution and is aware of the
issue.
She believes that the intention of the Health Claims
Regulation is to provide consumers with accurate infor-
mation. By banning all claims, she believes, an infor-
mation ‘vacuum’ might be created which needs to be
addressed. The Health Claims Regulation does not ad-
dress requirements for production, quality and safety
for botanicals to the same extent as their evaluation as a
medicine, and she believes that we should maybe have
looked beyond health claims for botanicals and that “we
stopped short in 2006” when attempts were made to
regulate botanicals.
The Commission is looking in particular at the playing
field between botanicals and herbal medicines, which
sometimes contain the same ingredient, or may be clas-
sified in one Member State as a botanical and in anoth-
er as an herbal medicine. These different regulatory
frameworks can create distortions in terms of the EU
single market.
An important question we are faced with is whether we
can have different regulatory frameworks if it cannot be
clearly defined at EU level, as the purpose of the legisla-
tion is not to give a competitive advantage to a catego-
ry of food supplement over another. We need to have a
consistent and balanced approach.
Regarding the timelines for the REFIT evaluation, the
Commission is waiting for the contractor to prepare its
report by the end of 2017. The draft final report of the
study will be presented to stakeholders at an ad hoc
working group meeting on nutrition and health claims
on Friday, 27 October 2017. Results of the evaluation
are expected for the second quarter of 2018.
As society becomes more health conscious, and the
trend towards self-care increases, she remarked that the
question of ‘which direction we are going with regard to
food’ is very timely.
The Assessment of ‘Other Substances’
Added to Food by EFSA
Camilla Smeraldi, Senior Scientific Officer, in the Food
Ingredients and Packaging Unit of European Food Safe-
ty Authority (EFSA), presented EFSA’s role in the safety
assessment of certain other substances added to foods.
Annexes I and II of the so-called ‘Fortification Regula-
tion’ (Regulation (EC) No 1925/2006 on the addition of
vitamins and minerals and of certain other substances
to foods) list vitamins and minerals and their formula-
tions which may be added to foods. Annex III, which
applies to foods in general and food supplements, lists
certain other substances whose use in foods is prohibit-
ed, restricted or under Community scrutiny. Article 8 of
this Regulation forms the legal basis for a safety assess-
ment of certain other substances by EFSA.
Conference report
5
After a safety assessment by EFSA, the Commission, on
the basis of the EFSA opinion, will take a decision to
restrict the substance by placing it in Part A (prohibited)
or Part B (restricted) of Annex III if a harmful effect on
health is identified, or in Part C (under Community scru-
tiny), if scientific uncertainty persists on the identifica-
tion of potential harmful effects on health.
She explained that to start an assessment EFSA needs a
mandate. In the case of Article 8, procedures carried out
by EFSA always come from the Commission, either of its
own initiative or on request from the Member States. In
the latter case, the request must contain available and
relevant generally accepted scientific evidence that the
substance is added to food, the amount exceeds what
could be expected in the diet and evidence on its po-
tential risk to the general population.
To start a scientific assessment EFSA always needs a
mandate which contains the question the scientific
opinion needs to answer. Ten scientific panels support
the remit of EFSA. These are composed of independent
experts who evaluate the data (available data is re-
trieved from the literature and calls for data are
launched), provide the scientific assessment and pre-
pare the draft opinion in multidisciplinary working
groups.
She then described the current structure of EFSA. The
NDA (Panel on Dietetic Products, Nutrition and Aller-
gies) panel is tasked with the evaluation of health
claims. The Assessment of Nutrient Sources (ANS) panel
is currently tasked with the safety assessment of food
additives, nutrient sources and the bioavailability of the
nutrient from the sources, and safety assessments under
Article 8 procedure. The ANS panel supports the deci-
sion-making procedure in the authorisation procedure
for new food additives/changes to permitted uses and
the re-evaluation of permitted additives since 2009. The
ANS panel in EFSA also has self-tasked mandates and is
due to publish an opinion on the approach followed for
the refined exposure assessment as part of the safety
assessment of food additives under re-evaluation. The
panel is also in the process of drafting Guidance on the
Evaluation of Nutrient Sources. With the evaluation of
nutrient sources there is an overlap with the NDA panel
as often it is involved in novel food assessment.
However, as of July 2018, all EFSA’s scientific panels will
be renewed. The ANS panel will be re-established as the
panel on Food Additives and Flavourings (FAF), tasked
with the safety assessment of food additives and fla-
vourings. The new panel will hand over responsibility for
the evaluation of nutrient sources and the evaluation of
Article 8 procedures to the NDA panel, which makes
Camilla Smeraldi
Article 8 procedure
6
sense as often Article 8 procedures are a direct follow-
up of a health claim evaluation.
EFSA has a limited experience with safety assessments
conducted under this regulatory framework. In total, five
mandates have been received to date, all related to sub-
stances from botanical sources, mainly used as food
supplements ingredients.
In August 2012, EFSA received two mandates from the
Commission regarding Yohimbe and Ephedra species
triggered by the Member States, in particular, BfARM,
the Federal Institute for Drugs and Medical Devices in
Germany. As a result of the EFSA scientific assessment,
Yohimbe was placed under Community scrutiny (part C
of Annex III) in 2015 and Ephedra was placed in the list
of substances which are prohibited (part A of Annex III).
In the case of Yohimbe, a valid dossier was not received
so the Commission must take a decision to restrict, pro-
hibit or allow Yohimbe by April 2019.
For substances placed under scrutiny in Annex III Part C
(i.e. harmful effects are identified but scientific uncer-
tainty persists) a follow-up mechanism is foreseen by
the legislation. There is a period of 18 months for food
business operators to submit a follow-up opinion dossi-
er to EFSA. The evaluation by EFSA has to be completed
9 months from the date of receipt of a valid dossier. So
far, there has been no experience with the follow-up, if
the dossier can come from groups of interested parties
for example, or if it can be product specific. Within 4
years from the date a substance has been listed in An-
nex III, Part C (under Community scrutiny), the Commis-
sion must take a decision to either generally allow the
use of the substance or list it in Annex III, Part A
(prohibited) or B (restricted) as appropriate. This deci-
sion should take into account any further opinion of
EFSA based on dossiers submitted by any food business
operators/interested parties.
EFSA currently has three ongoing mandates. One of
these, relating to Hydroxyanthracene derivatives, was
started by the Commission of its own initiative and is a
follow-up of an earlier health claim opinion issued by
the NDA panel on the substantiation of a health claim
related to an improvement of bowel function. Five pos-
sible botanical sources have been identified: Aloe, Rhu-
barb, Cascara, Senna and Frangula. The assessment is
ongoing with preliminary conclusions presented to the
ANS Panel in September 2017. An extension of the
deadline was requested from the Commission to allow
for a call for data. The opinion is to be adopted by the
end of November 2017.
The Commission initiated another Article 8 procedure
shortly afterwards, on request from Member States
(Denmark, Sweden and Norway) following safety con-
cerns related to hepatotoxicity with Green tea catechins,
in particular (-)-Epigallocatechin-3-gallate (EGCG). The
assessment is ongoing and a draft opinion was dis-
7
Conference report
cussed by the ANS Panel ad-hoc working group in Sep-
tember 2017. An extension of the deadline until Q1
2018 was requested, as the US pharmacopeia is con-
ducting a similar assessment.
The last mandate received relates to Monacolins in red
yeast rice. The procedure was initiated by the Commis-
sion of its own initiative and is a follow-up of a health
claim issued related to monacolin K from red yeast rice
and the maintenance of normal blood LDL-cholesterol
concentrations. The assessment is ongoing, and a public
call for data was just launched. Completion of the as-
sessment is anticipated for February 2018.
Food Supplements and Internet Sales —
A View from Austria
Dr Amire Mahmood from the Federal Ministry of
Health, Austria, began by recalling a previous AESGP
conference on the then newly released Food Supple-
ments Directive 2002/46/EC, where she believed maxi-
mum levels of vitamins and minerals would be estab-
lished by 2006. Now in 2017, it is still not harmonised.
As a Member State she supports harmonisation in the
area of food supplements and health claims, which she
can especially appreciate working in the Federal Minis-
try of Health in Austria and hearing the issues in the
food industry. The main problem with food supple-
ments, she explained, is classification. “The lack of har-
monisation among Member States can make enforce-
ment by the Commission in the area of food supple-
ments difficult. In the case of classification, it could take
years to get the food off the market”.
She pointed out that although vitamins and minerals
are harmonised, the maximum amounts are not, which
causes a lot of issues. There is also no harmonisation of
botanicals and other substances, which makes it difficult
to enforce. She is also a strong supporter of the Health
Claims Regulation, as the presentation of a product af-
fects whether it is seen as a medicine or not.
As more and more claims are found on the internet ra-
ther than on the product, it is not easy for competent
Amire Mahmood
8
authorities to find these claims. The new Official Con-
trols Regulation (Regulation (EC) No 2017/625 on offi-
cial controls and other official activities performed to
ensure the application of food and feed law rules on
animal health and welfare, plant health and plant pro-
tection products, which replaces the old Regulation (EC)
No 2004/882) hands over more power to food authori-
ties and will come into force by the end of 2019.
It allows food inspectors from the ministry to perform
“mystery shopping”. Samples can be ordered from food
business operators by the competent authorities with-
out identifying themselves for the purposes of an offi-
cial control. The food business operator needs to be
informed that such samples have been taken, and must
have the right to a second expert opinion. In the case of
non-compliance there is a possibility for food inspectors
to cease the internet activities of the food business op-
erator for an appropriate period of time.
The European Commission recommendation on a coor-
dinated control plan on internet sales, which came out
in July 2017, asked Member States to look more at bone
and joint health supplements with medicinal claims and
four novel foods are listed as non-authorised: Agmatine
(4-aminobutyl) guanidine sulfate, Acacia rigidula,
Epimedium grandiflorum and Hoodia gordonii. The aim
was to strengthen the cooperation and administrative
assistance between Member States and practise using
RASFF (the Rapid Alert System for Food and Feed) and
AAC (AA) and AAC (FF) for a fast exchange. The AAC
(Administrative and Assistance Cooperation system) is
an IT system set up for EU countries to exchange data in
a structured manner regarding non-compliance with
food and feed legislation. Since August 2016, the sys-
tem has been split in two parts: a part dedicated
to Food Fraud and the Food Fraud Network, and a part
dedicated to every request for Administrative Assistance
and Cooperation which does not present health risks.
The intention was also to signal to food business opera-
tors that e-commerce control is taken seriously by the
competent authorities and to build experience and ca-
pacity with the enforcement of food law towards inter-
net sales of food.
“Each Member State looked at websites which offer
food in their official language. So far no mystery shop-
ping was required. There was a control period and now
the notification period is ongoing. Notifications were
made via RASFF or via AAC (AA)”. Dr Mahmood hopes
that this co-operation works and finds products which
should be removed from the market so that food busi-
ness operators can be adequately controlled.
Regulatory Gaps and Legal Uncertainty
Speaking from the consumer perspective, Ilaria Passa-
rani, Head of the food and health department, Europe-
an Consumer Organisation (BEUC), opened the discus-
sion with a metaphor of EU society at a crossroads for
many food policies issues. This ‘hesitation’, she ex-
plained, is at the expense of consumers’ rights to infor-
mation and consumer health and she is looking forward
to some action. She explained that while we wait for
decision makers to show us the way forward, consumers
remain confused over similar products and are exposed
to misleading claims and health risks.
She then described how consumers may feel confused
with the example of a botanical regulated as an herbal
medicinal product and a food supplement. St. John’s
Wort (Hypericium Perfortum), which is sold in Spain as a
Ilaria Passarani
9
Conference report
herbal medicine and in Belgium as a food supplement.
Both products make slightly different claims. For the
herbal medicine it is ‘the systematic treatment of fatigue
and loss of interest’, and for the food supplement claim
it is a ‘balancing effect on mood swings.’ The herbal
medicine warns against several interactions and side
effects while the food supplement does not. This dispar-
ity, she warned, can have an important impact on pa-
tient safety. Even if botanicals only make ‘minor claims’,
it is vital to guarantee that these claims are justified and
that these products live up to the promises they make.
She therefore believes botanical claims should be evalu-
ated by EFSA as all other claims, and should not be
granted special treatment.
Regarding the ongoing revision of the Health Claims
Regulation, the Consumer Association believes that, to
protect consumers from exaggerated and unsubstanti-
ated claims, if there is no evidence, there should be no
claim. However, if botanical claims are questioned, she
fears that all claims rejected by EFSA under Article 13
might be challenged, which the Consumer Association
do not want.
Commenting on the REFIT evaluation of the Health
Claims Regulation, she said “we are evaluating some-
thing that hasn’t been implemented and hasn’t yet pro-
duced an impact”. She believes this is a dangerous path
to take as it could extend to other legislation.
Another pending issue she reflected on is the lack of EU
harmonised maximum levels for vitamins and minerals.
The Stiftung Warentest test in Germany showed the risk
of too high doses of vitamins in food supplements (5
times greater than the levels recommended by BfARM).
The Consumentenbond test used in the Netherlands
found that 3 of the 5 food supplements examined con-
tain much more or much less iodine than the label indi-
cates. Some of these products were withdrawn while
others remain on the market. “Establishing maximum
and minimum limits as well as deviation margins for
vitamins and minerals is long overdue, so that consum-
ers are not exposed to either too low doses or too high
doses”, she explained.
She believes that more controls are needed for food
supplements sold online to protect consumers from
dangerous products, as information on interactions and
side effects is often not available. The Commission rec-
ommendation on official controls for products sold over
the internet is a welcomed step, as RAPID safety alerts
for food supplements have more than doubled since
2010.
As a consumer association, she hopes that decision-
makers will find the right direction and be guided by
key principles, putting consumers’ safety at the centre:
products should be safe, especially those used for
health, consumers should get value for money and
products should be effective, classification should be
coherent and based on the characteristics of the prod-
ucts and rather than the possibility to make health
claims, consumers should be informed and all claims
should be substantiated by good evidence. This applies
to all consumer products. If the EU wants to reconnect
with its citizens it needs to act quickly, she said. “If we
don’t act quickly, we risk losing consumer confidence in
these products, and this is no one’s interest”.
10
Session 2 The Real Implications of The New Medical
Device Legislation
Moderated by Gesine Meissner, Member, Committee
on Environment, Public Health and Food Safety (ENVI),
European Parliament, and shadow rapporteur for the
political group of the liberals during the legislative pro-
cess for the Medical Devices Regulation (so-called
‘MDR’), this session looked at the implications of the
new medical device legislation. Mrs. Meissner remarked
that the legislative process was difficult and alluded to
the challenges ahead with the implementation of the
legislation.
Novelties of The New Medical Devices Reg-
ulation - The Commission’s Perspective
Carlo Pettinelli, Director, Consumer, Environmental and
Health Technologies, Directorate General Internal Mar-
ket, Industry, Entrepreneurship and SMEs, European
Commission, opened the session by acknowledging the
crucial role of medical devices in self-care and as such
the sustainability of health systems. He thanked for the
commitment of all stakeholders that as of May 2017,
after 5 challenging years, the EU legislation for Medical
Devices has become law, and the EU now stands at the
forefront of innovation and progress in this field in the
world.
He firmly believes that the legislator has managed to
stick to the principles of balance and proportionality
and while the regulation will allow a uniform application
of its rules, the system will undergo a ‘deep evolution’
rather than a revolution. It will build on characteristics
of the older system, for example, the central role of no-
tified bodies in the certification process and the balance
between post and pre-market controls, while address-
ing the scandals arising in recent years, adapting the
rules to technological advances, and thereby increasing
patient confidence in the system.
Novelties introduced by the legislation include the pre-
market control for manufacturers of high risk devices
with the involvement of a pool of experts at EU level.
Another is the enforcement of the criteria for the desig-
nation and oversight of notified bodies. In particular the
new regulation reinforces the joint assessment of noti-
fied bodies, already introduced in 2013, a system
through which experts from Member States and the EU
Commission, jointly assess the competence and perfor-
mance of notified bodies. The medical device regulation
now also covers devices not used for a medical purpose,
which present the same characteristics and have an
analogous profile to an existing medical device, for ex-
ample, contact lenses used for aesthetic purposes. It
will increase transparency through the establishment of
a comprehensive database of the lifecycle of all medical
devices available on the EU market, which will be largely
publicly available. The regulation will also introduce a
stricter regime related to the use of hazardous sub-
stances and requirements for an implant card to be giv-
en to patients containing information about the im-
plant. It will reinforce the rules on clinical evaluations
and investigations, including an EU wide co-ordinated
procedure for clinical investigations taking place in
more than one Member State. It will also improve co-
ordination between Member State in the fields of vigi-
lance and surveillance. Obligations of economic opera-
tors have been specified and detailed and the roles and
responsibilities of authorised representatives are being
reinforced.
In respect of substance based medical devices, he ex-
plained that they will be subject to a new classification
Rule 21. Rule 21 was introduced to fill a legislative gap.
The old legislation on medical devices adopted 20 years
ago was not conceived with these products in mind.
Consequently, they generally fell in class I without a
consideration of their risk. This was later unanimously
Gesine Meissner
11
Conference report
seen as problematic, as some of these products are of-
ten used by vulnerable patient groups and are available
without prescription. The new legislation ensures that
the safety of these products is appropriately checked by
notified bodies. However, the strictest conformity as-
sessment procedure is only reserved for those products
which are systemically absorbed. He believes that, in
respect of substance-based devices, they succeeded in
negotiating a proportionate and risk-based approach.
In the context of the qualification and classification of
borderlines, there will be more legroom to take the
Commission’s decision on the regulatory status of prod-
ucts, as the Commission will now be able to initiate a
decision procedure of its own initiative.
In co-operation with the future Medical Device Co-
ordination group (MDCG), the Commission intends to
take initiative whenever needed to ensure that the inter-
nal market functions in an efficient manner and that
patients’ rights are guaranteed. At the same time, stake-
holders are always in a position to input their views and
opinions.
The effective and timely implementation of the legisla-
tion is crucial to ensure that expectations are properly
fulfilled and is a challenge which lies ahead. The Com-
mission is keen to ensure that the new system brings
added value for all stakeholders.
Anticipating questions AESGP has on whether the Com-
mission has enough resources to make all this happen
and to what extent stakeholders will be in a position to
inform the implementation process, he explained that
the Commission intends to allocate sufficient staff to
this task. The Commission services have already started
work on the secondary legislation, relevant guidance
and the Eudamed database since last year. On the sec-
ond question, he highlighted that not only does the
Better Regulation framework give stakeholders an in-
creased opportunity to comment, the new legislation
assigns a key role to stakeholders in expert groups.
Commission communication with stakeholders has al-
ready taken place. The Commission and the Competent
Authority for Medical Devices (CAMD) organised on the
9th
March 2016 the first stakeholder workshop with an
exchange of views on the workplan for the coming
years. The next workshop on 18 October 2017 will final-
ise the roadmap for the new medical device regulation.
The roadmap will set the timing and framework of fu-
ture deliverables for the Commission and Competent
Authorities mainly interpretative and operational guid-
ance for the medical devices regulation.
In light of this, he is confident that the ‘real implications’
offer concrete opportunities for EU medical devices pa-
tients and the health care system as a whole.
He remarked that the EU medical device regulation has
inspired other countries and a few days ago at the Inter-
national Medical Devices Forum (IMDF), the Australian
authorities declared that they will align their legislation
to match that of the EU. He is convinced that by work-
ing together we can make a successful transition and
further develop this important sector.
The Key Constraints to Implementation -
A Competent Authority View
John Wilkinson, Director of Medical Devices, Medicines
and Healthcare products Regulatory Agency (MHRA),
United Kingdom, stressed that the implementation of
the MDR should be consistent and fair which was a
problem with the old directives.
Carlo Pettinelli
John Wilkinson
12
New responsibilities have been given to competent au-
thorities. New products such as cosmetics and software
will now fall under the scope of the medical devices
regulation, which will present a challenge for everyone
in the system. The new legislation also calls for more
specific responsibility from actors in the supply chain,
which will present some challenges because this supply
chain is global. “How we’re going to manage that sup-
ply chain”, he added “is going to be critical going for-
ward”. Dealing with borderline substances and combi-
nation products in a practical and timely way is also cru-
cial going forward.
He explained that the Competent Authorities for Medi-
cal Devices (CAMD) network and the Commission will
start work over the next 18 months to map out the im-
plications of the implementation process and the EU
work plans which will extend over several years. He re-
minded that the roadmap will be revealed on the 18th
of
October at the next stakeholder meeting.
The MHRA has also been mapping the implementation
of the MDR, which is a lot of work for national authori-
ties. There are a number of key constraints to the imple-
mentation of the Medical Devices Regulation, such as
the dual regulatory system during the transition period,
and how people perceive the new CE mark versus the
old CE mark. The whole system will be underpinned by
guidance and it will evolve. The regulations are directly
applicable and Member States have less latitude to in-
terpret things. Eudamed is a critical building block of
the system. If Eudamed is late, he stressed, there need
to be provisions on how this can be handled.
Two groups are underpinning the work on implementa-
tion of the regulation and dealing with these con-
straints: the implementation Task force, an ad hoc
group recently reconstituted looking at what needs to
be done, and the transition subgroup. Work will also
need to be done by expert groups in different areas.
The transition subgroup mainly consists of regulators
and lawyers looking at interpretive legal issues with the
transitional provisions.
He explained that we are transitioning from an old to
new governance structure (the CAMD to the Medical
Device Coordination Group (MDCG)). The MDCG has a
broader role and is currently looking to reduce duplica-
tion in the roles.
On classifications under the new regulation, he ex-
plained that the focus should not be on up or down
classifications, but on the evidence to support clinical
claims. In respect of substance-based medical devices,
he too believes that the old legislation was inadequate.
On clinical evaluations he stressed the importance of
evidence to support risk assessments.
13
Conference report
In terms of challenges ahead, he explained that it is
about getting clarity through the legal text to give eco-
nomic operators clarity going forward.
MDR Implementation and Substance-Based
Medical Devices
Emiliano Giovagnoni, Regulatory Affairs Director, Abo-
ca, presented the industry’s perspective on the imple-
mentation of the MDR. Now that the regulatory frame-
work for medical devices has been defined, he believes
it is important to establish implementation rules able to
welcome the innovative character of substance-based
medical devices.
“We need to define the rules of the game, in order to
implement the provisions of the new regulation proper-
ly”, he explained. To do this, two main criteria need to
be taken into account: a European harmonized interpre-
tative system specifically designed for substance-based
medical devices, and ‘case by case evaluations.’ “We
need a regulatory approach specifically developed for
substance-based medical devices” he explained, “which
takes into consideration the differences with medicinal
products.” This, he explained can be achieved with a
systematic revision of the guidance documents
(Meddev, Common specifications etc.). “Once the gen-
eral interpretative context has been defined, it is neces-
sary that each product is evaluated according to its
characteristics which make it unique”. He stressed that
this is particularly relevant for medical devices made of
complex natural substances, whose composition cannot
be generalized and linked to homogeneous product
categories. He believes that the application of these two
criteria, combined with a constructive discussion be-
tween European and national regulatory authorities,
notified bodies, industrial associations and companies,
will allow us to face effectively the main criticalities of
the new regulation.
There are many aspects of the new regulation that will
have a significant impact on industry and that must be
taken into consideration. These include the definition
(article 2) of a “medical device”, the classification Rule 21
and defining the concept of “absorption”, clinical prod-
uct evaluations and the role of notified bodies. The solu-
tion, he explained, can be found by adopting a
‘harmonized European interpretative system’ based on a
"case by case" evaluation.
A principal intended action which is achieved by phar-
macological, immunological or metabolic means distin-
guishes a medicinal product from a medical device. He
explained that up to now, an approach “by exclusion”
has usually been followed at regulatory level and a
product is generally classified as a medical device only
when there are no medicinal products already regis-
tered, regardless of whether its mechanism of action is
14
by pharmacological, immunological or metabolic
means. He therefore believes it is necessary to reassess
all the mechanisms of actions and to assign each of
them either to the category of medicinal products or to
the category of substance-based devices, based on sol-
id scientific data and regardless of their historical classi-
fication. This would ensure a harmonised EU approach,
and avoid ‘inverse shopping legislation’, and attempts
to support historical classifications.
He gave examples of ‘inverse shopping legislation’ such
as an osmotic/ bulk-forming mechanisms of action for
laxatives, a mucoprotective action for cough syrups and
a bacterial anti-adhesion mechanism of action in prod-
ucts for cystitis. In Aboca’s view antacids should be con-
sidered as medical devices. Of interest is the osmotic
mechanism of action, a colligative property which de-
pends on the concentration of solute rather than the
structure of the molecule. As there is no receptor-ligand
interaction the mechanism of action should be regarded
as a medicinal product. The definition of
‘pharmacological means’ is crucial for the medical de-
vices sector. Meddev 2.1 provides a starting point, but
he believes it needs to evolve, and not introduce the
concept of indirect pharmacological action.
Rule 21 places absorption at the centre of the classifica-
tion system. When absorption is relevant for the intend-
ed purpose the classification is clear. However, all sub-
stance based medical devices, are somehow absorbed
by the human body. In the absence of a clear criterion, a
product containing substances generally recognized as
safe and other active substances absorbed in concentra-
tions not relevant for risk assessment would be classi-
fied in class III without any justification. He believes that
absorption should justify class III only when the sub-
stances absorbed are relevant for the risk assessment.
Aboca proposes for products containing natural sub-
stances to apply metabolomics techniques to evaluate
the extent of absorption. Manufacturers’ would be able
to assess on a case-by-case basis, if the substances is
absorbed in concentrations relevant for risk assessment,
and then whether the extent of absorption is such that
classification of the product in Class III is required. Oth-
erwise, it should fall into Class IIb.
Emiliano Giovagnoni
15
Conference report
Regarding the role of notified bodies, it is necessary to
ensure an efficient system of notified bodies able to
manage the huge number of requests they will receive,
within the timeline of the transitional period, given that
substance-based medical devices currently classified as
class I will seek Notified body certification, and a gen-
eral upgrade of the risk class is foreseen for many sub-
stance-based medical devices. And in Italy alone, more
than 2,000 substance-based medical devices are cur-
rently on the market. “A European system of notified
bodies highly specialized in the evaluation of substance-
based medical devices and able to ensure a smooth
transition from the current system to the new one is
critical,” he explained.
Clinical Evaluations and the Equivalence
Approach
Bettina Funke, Head of Medical Devices, Scientific &
Regulatory Affairs, R&D Consumer Health Care, Merz
Consumer Care GmbH, presented the industry’s view on
the equivalence approach for clinical evaluations. The
new medical devices regulation introduces stricter re-
quirements for clinical evaluations. In that context, clini-
cal data, defined under article 2, as information con-
cerning the safety and performance of medical devices,
can be sourced either from the scientific literature on
similar devices, clinical investigations or post market
surveillance.
She explained that equivalence to another similar device
can be demonstrated from the scientific literature by
taking into consideration the technical, biological or
clinical characteristics of the product.
“Technical equivalence,” she explained “is the most fea-
sible to demonstrate especially when the device has a
similar design, similar conditions of use, similar specifi-
cations and properties and similar principles of opera-
tion and performance requirements. Next would be bio-
logical equivalence; having the same materials or sub-
stances in contact with the same human tissues or body
fluids for a similar kind and duration of contact and sim-
Bettina Funke
16
ilar release characteristics. Last would be the clinical
characteristics; having the same clinical conditions or
purpose, severity and stage of disease, same site in the
body and similar population.” There is also a require-
ment for manufacturers to have sufficient levels of ac-
cess to the data relating to devices with which they are
claiming equivalence in order to justify their claims.
However, what is deemed ‘sufficient’ needs to be clari-
fied.
She then gave examples of possible outcomes when the
equivalence approach is interpreted too strictly. One
example was of a nasal spray made from seawater,
where the source of the seawater in the formula was
changed. Another was a simethicone preparation, where
a flavouring excipient was changed. Although these
seem like minor changes the equivalence of both the
nasal spray and the simethicone preparation could be
questioned. However, she believes this general view
doesn’t really contribute to the safety and performance
of substance based medical devices. She believes that
instead, a thorough case by case evaluation would be
more meaningful. Moreover, if equivalence cannot be
established a huge number of additional clinical trials
will be required.
She then presented the challenges with performing clin-
ical trials. “You need to convince an ethical commission
about the need for a trial for a change in substance hav-
ing no impact on the principal mode of action or for a
longstanding product, and this could be judged as a
repetition of an already conducted trial which would be
unethical”. Financial concerns are also an issue. “We
may lose a number of good products since high invest-
ment in clinical trials may not be commercially viable for
each individual product.” The remaining transition peri-
od lasts for only two and a half years from now which is
extremely challenging for all parties to handle this huge
amount of trials. “Substance based medical devices are
at risk of requiring new clinical trials for formal reasons”,
she explained “and although the legal manufacturer
wants to comply with the new legislation, these safe and
effective products may disappear from the market”.
Session 3 Fostering Market Access for Substance-
Based Medical Devices
Moderated by Maud Perrudin, Legal and Regulatory
Affairs Manager, AESGP, this session explored the key
market access issues for manufacturers of substance
based medical devices and the views of representatives
from different notified bodies.
Regulatory Challenges for Notified Bodies
and Market Implications
Roberta Marcoaldi, Director of the Notified Body 0373
-Istituto Superiore di Sanità (ISS), Italy, presented the
challenges of the new Medical Devices Regulation for
notified bodies. She explained that in the last few years
the legislation for the medical devices sector has been
subject to a long and complex review process. The revi-
sion has become necessary to ensure a high level of
patient and user health protection. In 2013 the Commis-
sion implementing Regulation on the designation and
the supervision of notified bodies under the Medical
Devices Directives was published which proposed new
requirements for Notified Bodies.
The Regulation 920/2013 has involved a re-
accreditation process of Notified Bodies which has not
yet been concluded. Some Notified Bodies have been
unable to demonstrate their ability to respect the new
requirements and therefore the previous designation
obtained in accordance with the directive 93/42/EEC
was withdrawn. This has led to market problems as sev-
eral manufacturers have been forced, within a relatively
Roberta Marcoaldi
17
Conference report
short time, to identify an alternative Notified Body for
the CE Certification of medical devices.
In the Regulation 920/2013 some issues concerning the
role and obligations of Notified Bodies were in fact an-
ticipated, and include: the qualification of the personnel,
Quality management system (QMS), the definition of
conformity assessment procedures, demonstration of
the availability of personnel for clinical evaluations,
deepening of the qualification and classification assess-
ment procedures and deepening of the clinical data
assessment procedures including the Post-Market Clini-
cal Follow up (PMCF).
The entry into force of the new Medical Devices Regula-
tion (MDR 2017/745) emphasizes and shows more strin-
gent requirements for notified bodies, manufacturers,
the technical documentation produced by manufactur-
ers, Post-Market Surveillance (PMS) and Post-Market
Clinical Follow up (PMCF). New classification rules have
been introduced, such as the new approach for sub-
stance-based medical devices and medical devices
which contain medicinal substances. The Medical Device
Coordination Group (MDCG) now also plays a role in
the conformity assessment process and re-accreditation
process of notified bodies.
All Notified Bodies must be re-accredited in order to
carry out certification activities in accordance with the
MDR. The timeline for the application of the regulation
is 26 May 2020. All Notified Bodies will have to submit
their application for the new designation in the coming
months. She explained that the Italian competent Au-
thority has already asked the Italian Notified Bodies to
express their intention to re-designate and to indicate
the period during which the application will be submit-
ted.
A draft list of NBOG codes (types of devices for the pur-
pose of specifying the scope of the designation under
the Regulation (EU) 2017/745) has been published. A
draft application form (for designation as notified body
under the Regulation (EU) 2017/745) is expected to be
published by the end of November 2017. Then the Noti-
fied Bodies will be able to submit their application for
designation by December 2017 / January 2018.
“We are very concerned because the re-accreditation
process will be very articulate and surely quite long (up
to 20-24 months) for assessment purposes, because a
number of different assessments steps are required: a
preliminary assessment report of the authority responsi-
ble for notified body, assessment by the Commission
and the Medical Device Expert Group, appointment of
the joint assessment, audit on site (on site assessment
of applicant body), follow up activities (report of joint
assessment and authority responsible for notified body).
Then the MDCG will deliver its recommendation and a
decision will be taken on the designation of Notified
Body. The re-accreditation process will also be followed
by the notification of the designation (which might take
another 3 – 6 months).”
She believes that the harmonization of conformity as-
sessment procedures has not yet been achieved, in par-
ticular for: unannounced audits (are notified bodies
forced to submit a three year plan and not five as per
the MDR?), clinical evaluations (are notified bodies
forced to apply the guideline that underlines the princi-
ple of equivalence; MEDDEV 2.7.1 rev. 4?), personnel for
clinical evaluation (are notified bodies forced to demon-
strate a clinical expertise for personnel that carry out the
clinical evaluation?) and medical devices containing me-
dicinal substances .
The MDR 2017/745 establishes the qualification of sub-
stance-based products and defines a special classifica-
tion rule: 21. MDR requirements also define a more
stringent approach to assess such medical devices. This
represents a new challenge for Manufacturers and Noti-
fied Bodies. “Substance-based medical devices will no
longer be classified in class I.” “This will mean an in-
creasing number of medical devices requiring the evalu-
ation of a Notified Body, and the development of spe-
cific know-how will be necessary, in particular for Noti-
fied Bodies.”
Rule 21 introduced the concept of substances absorp-
tion. In this respect, she believes it is necessary to define
a correct interpretation of rule 21 and understand the
term “absorption” of substances, as the absorption of
substances can determine the classification of medical
devices.
In addition, the quality and safety of devices that are
composed of substances or of combinations of sub-
stances that are intended to be introduced into the hu-
man body via a body orifice or applied to the skin and
that are absorbed by, or locally dispersed in, the human
body, shall be verified where applicable and only in re-
spect of the requirements not covered by this Regula-
tion, in accordance with the relevant requirements laid
down in Annex I to Directive 2001/83/EC for the evalua-
tion of absorption, distribution, metabolism, excretion,
18
local tolerance, toxicity, interaction with other devices,
medicinal products or other substances and potential
for adverse reactions.. The notified body shall seek a
scientific opinion from one of the competent authorities
designated by the Member States in accordance with
Directive 2001/83/EC or from the EMA on the compli-
ance of the device with the relevant requirements laid
down in Annex I to Directive 2001/83/EC. The opinion of
the medicinal products authority consulted shall be
drawn up within 150 days of receipt of all the necessary
documentation. The notified body then has to consider
the views expressed in the scientific opinion. Manufac-
turers will therefore have to provide documentary evi-
dence in the product technical documentation for Sub-
stance based medical devices.
All manufacturers are also required to establish and up-
date a clinical evaluation plan to demonstrate conformi-
ty with safety and performance requirements. Clinical
evaluations may be based on clinical data from an
‘equivalent medical device.’ However, the demonstra-
tion of equivalence is very difficult for manufacturers.
As a notified body, she plans to support the manufac-
turer during the transitional period. The manufacturer is
also required to proactively collect and evaluate clinical
data (Post-market Clinical Follow up (PMCF)) to confirm
the safety and performance of the medical device
throughout its expected lifetime. It is a continuous pro-
cess which updates the clinical evaluation and should be
addressed in the manufacturer's post-market surveil-
lance plan.
Rule 14 on medical devices incorporating a medicinal
substance requires that the quality, safety and useful-
ness of the substance be verified with the methods
specified in Annex I to Directive 2001/83/EC. Notified
bodies must then verify the usefulness of the medicinal
substance and seek a scientific opinion from a compe-
tent authority or EMA on the quality and safety of the
substance including the benefit or risk of the incorpora-
tion of the substance into the device. Under the old
Medical Device Directive, the notified body could take
the updated scientific opinion into account in reconsid-
ering its assessment of the conformity assessment pro-
cedure. Under the new medical device regulation, the
notified body cannot deliver the certificate if the scien-
tific opinion is unfavourable and shall convey its final
decision to the medicinal products authority consulted.
She concluded by describing how Notified Body 0373
are preparing themselves for the application of the
MDR. “We will submit our application in the first three
months of next year, then we will carry out the new
qualification of personnel taking into account new Noti-
fied Body Operations Group (NBOG). We will also review
our quality management system and conformity assess-
ment procedures. The certification process will also be
reviewed considering the change of the MDR (role of
Medical Device Expert Group, new consultation proce-
19
Conference report
dures with the competent authority for medicinal prod-
ucts).” Notified Body 0373 will also organize information
and training events for manufacturers.
On the next steps forward, she explained that there
should be discussions with the authority responsible for
Notified Bodies on a harmonised approach to imple-
mentation. Updates should be shared between the No-
tified Bodies and manufacturers to foster closer collabo-
ration, and discussions at European level (Medical De-
vice Coordination Group, common specifications, imple-
menting acts) should be followed.
“Getting Ready for The New Medical Device
Regulation”
Jeff Vest, Principal Scientist at TÜV SÜD UK, a notified
body in Germany, began his presentation by giving an
overview of the timelines of the MDR since the Commis-
sion consultation on the medical devices framework in
2008. Eudamed will need to be functional by March
2020. There are confidentiality requirements which ap-
ply by May of 2018. A lot of manufacturers don’t have
the information to meet the MDR. Some class 1 medical
devices will be up-classified. Annex 4 of the Active Im-
plantable Medical Devices Directive (AIMDD) and Annex
4 of the Medical Devices Directive (MDD) (for the self-
certification by manufacturers) will become void by 27
May 2022. Certificates issued from May 25 2017 shall
become void at latest on 27 May 2024, although devices
may continue to be made available or put into service
until the 27th
May 2025. From May 2020, there should
be no significant changes in the design and intended
purpose of the device. The reporting of serious adverse
events and device deficiencies as per the MDR also ap-
plies from May the 26th
2020. Finally, the co-ordinated
assessment procedure on clinical investigations shall
apply from May the 26th
2027.
The labelling system and whether this will be similar to
the FDA approach has yet to be defined. “UDI (Unique
Device Identification system) is a costly process.” he ex-
plained, “We need to implement an acceptable model
and in the regulatory world there isn’t enough time to
do this”.
Consultancy services cannot be offered by notified bod-
ies but TÜV SÜD can do mock reviews and offer Gap
analysis services. Ultimately though, it is up to industry
to fill those gaps. In-house trainings offered by TÜV
SÜD are generic and can’t be tailored for companies.
TÜV SÜD also organise workshops and throughout the
transition period they anticipate a high demand for clin-
ical workshops. They can also offer mock audits, clinical
audits etc. They can review the manufacturer’s clinical
evaluation report, technical documentation, Periodic
Safety Update Reports (PSURS), and they will consider
justifications for not doing a PMCF (Post Market Clinical
follow-up).
He indicated that TÜV SÜD is looking forward to the
joint audits by the competent authorities. An uncertain-
ty that remains is whether notified bodies can cope with
the flood of applications. When will notified bodies be
appointed? All in May of 2020, or will it be a staggered
appointment? The MDR is untested so some changes
can be expected from unintended consequences or in-
terpretations of the legislation. There are still uncertain-
ties remaining relating to UDI, and common specifica-
tions (which have not yet been published).. “There are a
number of key elements that are still missing,” he ex-
plained. He concluded by inviting industry to discuss
updates and meet early with their notified body, so they
can advise manufacturers on what needs to be done to
meet the requirements of the MDR.
The Medical Device Regulation and The
Uncertainties That Lie Ahead
Jörg Wilke, from Zertifizerungsgesellschaft fur Mediz-
inproduckte Europa (ECM), opened his presentation
with an introduction of his notified body, CE 0481. ECM
0481 is a notified body under the Medical Devices Di-
rective (MDD) since 1995. They lack laboratory capaci-
ties and focus on quality assurance and access. Their
scope is limited to mainly non-active medical devices
covering sterile products, animal tissue products and
Jeff Vest
20
pharmaceutical active substances. They have experience
with substance based medical devices. They are the
third notified body to undergo joint assessments.
He explained that notified bodies are facing an increas-
ing number of applications due to the decreasing num-
ber of notified bodies and reclassification due to the
new MDR. In this respect, he welcomed input from in-
dustry. He then described the extent of assessment ac-
tivities carried out by the notified body. There are audit
activities at the premises of the legal manufacturer and
critical suppliers, if necessary, and due to the reclassifi-
cation there will be increased technical file assessments.
A scrutiny and consultation process is now required de-
pending on the nature and classification of the medical
device. Physical product testing during notified body
audits is required, and for certain products there are
periodic review obligations, not covered by the current
legislative framework. All classes apart from sterile class
I or class I a measuring function will require technical file
assessment activities. These are case driven for class III,
but for the other classes it will be based on a repre-
sentative sample. However, currently there are no crite-
ria in the MDR of what a representative sample means.
The NBOG guidance for audits and testing of repre-
sentative samples will no longer be applicable, and
there may be a potential implementing act by the Com-
mission concerning the legal requirements for the test-
ing of samples.
He explained that clarity is needed for the classification
rule 14 for medical devices with medical substances an-
cillary to the device, replacing the current rule 13, rule
19 for nanomaterials and rule 21 on substance-based
medical devices.
Rule 14 refers to medicinal substances with an ancillary
action to a medical device but have no clear action on
the human body. The rule has led to discussions over
whether the function as a preservative would affect its
classification. Clarification is also required on whether
rule 19 for nanomaterials is based on the nanomaterial
or its intended use.
For rule 21 on substance-based medical devices, does it
apply to the all substances or those achieving the princi-
pal intended action of the product? There is no defini-
tion of ‘substance’ in the medical device legislation, and
the legislation doesn’t refer to definitions in the legisla-
tion for pharmaceutical products. In respect of Rule 21,
there are different perspectives on what is ‘inside the
body.’ “From a biological perspective”, he added the
stomach is outside the body. Moreover, absorption re-
quires crossing a barrier to be distributed locally or sys-
temically-therefore the terms locally dispersed and sys-
temically absorbed need to be clarified and are mislead-
ing”.
He stressed that requirements/guidance is required for
the new classification rules, which the current guidance
doesn’t address. At national level, NAKI in Germany, a
co-ordination group has been established located at the
ministry of health, to address these questions. They are
mirroring the competent authority meetings quite well,
and some of its subgroups might be present in the
forthcoming Medical Device Co-ordination Group
(MDCG) which has not been established yet. “We need
more consensus at EU wide level to allow a homoge-
nous interpretation of fundamental questions so that
manufacturers can apply properly the classification rules
and notified bodies can check these procedures.”
Jörg Wilke
21
Conference report
A Business Perspective to Foster Market
Access for Substance-Based Medical Devices
Maikel Hendriks, CEO of Medical Brands, began by
giving an overview of the history of his company, look-
ing at dental products before moving to the self-care
sector. Their product portfolio includes feminine prod-
ucts, cough and cold products, footcare etc. and many
different formulations are marketed. Although their first
product ‘Freeze off your Wart’ was seen as a medical
device by notified bodies and the competent authority,
when it came to market, concerns were raised by the
competent authority because it involved bringing home
treatment people received at the doctor. He firmly be-
lieves that “innovation should come before regulation.”
He alluded to the blue guide book which was created to
remove technical barriers to EU trade and to enable the
free movement of safe goods. He now believes that
technical barriers to innovation, particularly in self-care
are being created.
Today healthcare is moving closer to the user with mo-
bile apps, the internet, on-line pharmacies, wearables
etc. which will lead to less interaction with GP’s and con-
venience for products.
Regarding substance-based medical devices, although a
physical mode of action was described for Simethicone
in the reputed opinion by the competent authority, the
product was subsequently classified as a medicinal
product. He asked what the sense of this reclassification
was and whether there had been an impact analysis.
Indicating that his company had carried out its own im-
pact assessment, he presented the results that a third of
OTC medical devices on the EU market could be subject
to such reclassification.
Eudamed, the lack of guidance and clinical equivalence
are issues which industry faces going forward. On Noti-
fied bodies, he explained that “we now have 58 notified
bodies; when we started, there were 85. In the mean-
time, 16 were withdrawn, 9 expired and 2 were suspend-
ed. Further reduction can be expected with the designa-
tion procedure.” “After discussions with the Commis-
sion, the first notified body will set the standard and
there is a risk that other notified bodies will not pass”
The first MDR audits start in May 2020.
Maikel Hendriks
22
He also alluded to the change in the role of the author-
ised representative from a mailbox function to responsi-
bility for parts of the manufacturers’ dossier. On adver-
tising, Neprofarm, the self-care association in the Neth-
erlands, have developed an advertising code of conduct
for medical devices, which, through the work of PAGB,
will be mutually recognised by the UK.
“Authorities should go through the manufacturer’s dos-
sier, rather than group products based on opinions from
EMA.” He calls for case-by-case reviews of products.
This will allow self-care to grow, and allow innovative
products to remain on the market. Otherwise, he ex-
plained, we can create a road-block if we see patients as
incapable of managing their own health.
AESGP’s Priorities and Ongoing Work
Maud Perrudin, Legal and Regulatory Affairs Manager
at AESGP, presented AESGP priorities with the imple-
mentation of new Medical Devices Regulation. “The leg-
islation is a great achievement,” she remarked “however,
the implementation will be a challenge”. “We are a sci-
ence based industry”, she explained, and hopes that the
implementation will be science based. In implementing
the text, she calls for transparency and a proportionate
and uniform approach. AESGP’s key priorities include
transitional measures, the regulatory status of products,
the quality and safety evaluation of substance based
medical devices, and the resource/capacity of notified
bodies.
A number of Class I devices will be “up-classified” to
class IIb or from class IIb to class III and there will be
many new requirements to comply with notably for the
up-classification to class III (including new clinical inves-
tigations). In this regard, she believes that reclassifica-
tion should start with a case by case assessment of all
the characteristics of the product. She believes medical
devices should be regarded holistically, and should they
contain substances known to have pharmacological,
immunological and metabolic properties, the only way
to rule out the medical device classification is to scien-
tifically establish that the substances do exert such
properties in the product as formulated and that such
properties plays a role in achieving the principal intend-
ed action of the product. Core to the business of AESGP,
is proper definitions of pharmacological, immunological
and metabolic means which is still on the Commission’s
agenda.
The so-called ‘rule of doubt’ set in Article 2.2 of the Me-
dicinal Products Directive 2001/83 applies, provided
that the concerned product meets both definitions of a
medicinal product and of medical devices, and results in
the product’s classification under the medicinal prod-
ucts directive. Oftentimes, she remarked, if a product
looks like a medicinal product it is classified as such.
When there is certainty that the product is classified as a
medicine in the first place, she believes that national
authorities must still demonstrate scientifically that the
product is medicinal by function (which means that it
achieves its action by pharmacological, immunological
or metabolic means in line with the Hecht Pharma Court
Case, C-140/07, §29). Therefore, proper definitions of
pharmacological, immunological or metabolic means
are critical.
She highlighted the issues with determining regulatory
status under the medical devices regulation, such as the
transparency of the Helsinki procedure, which is mainly
dedicated to the national competent authorities with
input from stakeholders far too late in the process. She
is hoping this will improve under the new legislation,
and that AESGP can provide data before a classification
decision is taken. Although Article 4 under the MDR will
be useful to clarify the regulatory status of Medical de-
vices, she calls for a clarification of the consultative role
of EMA, EFSA and ECHA in the determination of the
product’s regulatory status, the proper involvement of
notified bodies and concerned manufacturers at an ear-
ly stage and a call for data on a category of products
published on the Commission website prior to the
launch of the procedure.
In respect of substance-based medical devices, she indi-
cated that AESGP is doing its homework developing
Maud Perrudin
23
Conference report
guidance on the implementation of Rule 21, including a
decision tree to help manufacturers in borderline cases
also with Rules 4, 5 and 19. For quality and safety evalu-
ations, she stressed that concept of “generally consid-
ered as low-risk” should apply to substances with a long
history of safe use (e.g. as foodstuffs) or that have been
scientifically reviewed by European scientific bodies/
committees.
“The implementation of Rule 21 should be proportion-
ate and risk-based.” She stressed that the classification
must always be justified by the intended purpose and
the inherent risk. The interpretation of Rule 21 also
needs to take into account the various linguistic ver-
sions and the overall context of the medical device reg-
ulation.
Referring to the previous presentations, she highlighted
the concern of the self-care industry regarding contin-
gencies with the notified body designation process and
their capacity to meet the new requirements of the reg-
ulation. She believes that we should organise collabora-
tion with Notified Bodies and foster dialogue with na-
tional competent authorities and Commission to devel-
op guidance for Notified Bodies and authorities and
share good practices and expertise. “AESGP is happy to
share its experience and knowledge with notified bodies
and competent authorities”.
She concluded by emphasising that the implementation
needs to make the MDR and its Rule 21 useful in order
to achieve its objectives.
24
Session 4 Creating a Proportionate Regulatory
Environment for Herbal Medicinal Products
‘Herbal Medicines Are Widely Appreciated
By European Citizens’
Karin Kadenbach, Member of the European Parliament
Committee for environment, public health and food
safety (ENVI) (MEP) since 2009, presented her views on
herbal medicinal products in a video message. “Herbal
medicines are widely appreciated by European citizens”,
she explained. “80% of the population have used herbal
medicines, according to various surveys”. “The European
Parliament was instrumental in the establishment of the
Herbal Medicinal Products Committee (HMPC) at the
European Medicines Agency (EMA), as part of the Di-
rective on Traditional Herbal Medicinal products adopt-
ed in 2004,” she explained. Since then the committee
has delivered notable results, in particular with regard to
establishing monographs for herbal medicinal plants,
benefiting both patients and manufacturers. She be-
lieves that the work of the HMPC will be important in
the future, in light of the interest of European citizens in
these products. She also hopes that the work of the
HMPC will not be negatively affected by Brexit and the
relocation of the EMA. Manufacturers of herbal medi-
cines operate in a competitive environment, and many
products have a lower turnover rate and higher admin-
istrative costs than comparable products. She concluded
by welcoming the timely discussions on creating a pro-
portionate regulatory environment for herbal medicinal
products.
Challenges With ‘Traditional Use’ Registra-
tions
Agnès Mathieu-Mendes, Deputy Head of Unit, Direc-
torate Health and Food Safety, European Commission,
shared her reflections on the challenges with ‘traditional
use registrations’ for Herbal Medicinal Products
(THMPs) Herbal medicines can be authorised on the
basis of a full marketing authorisation application, a bib-
liographic one or registered on the basis of safety and
plausible level of efficacy attested by a long history of
use (30 years including 15 years in the EU) under the
Traditional Herbal Medicinal products Directive
2004/24/EC. The Commission endorses the EMA scien-
tific assessment with regard to the list of herbal sub-
stances, preparations and combinations thereof for use
in traditional herbal medicinal products (Commission
Decision 2008/911/EC). The list has recently been en-
riched with two new list entries: Sideritis herba and Va-
lerianae radix.
Herbal products can be marketed as medicine or food
and the responsibility of the classification lies with
Member States based on the presentation and claimed
effect. This has led to disparity at national level with the
uptake of the traditional use registration scheme. On
this note, she referred to the on-going REFIT evaluation
for the Regulation on health claims legislation; the out-
come of which is needed before to take any steps to-
wards a potential change of the herbal legislation which
is for the moment seen as fit for purpose.
Karin Kadenbach
Agnès Mathieu-Mendes
25
Conference report
Traditional and Herbal Medicinal Products:
Harmonisation and Globalisation
The work of the EMA Committee on Herbal medicinal
products was illustrated by Werner Knöss, Head of Di-
vision, complementary and Alternative Medicines and
Traditional medicines, Federal Institute for Drugs and
Medical Devices (BfArM) as well previous Chairman of
the EMA Committee for Herbal Medicinal Products
(HMPC). One thousand six hundred registrations were
granted over the past years but recently a couple of
new herbal medicinal products were authorised based
on a full Marketing Authorisation Application (MAA):
Episalvan through the centralised procedure and a
green tea extract (Veregen) and Cannabis extract via the
decentralised procedure (DCP). The outputs of the
HMPC fostered harmonisation and mutual understand-
ing of authorities paving the ways to these DCP and
centralised authorisations.
Global harmonisation is also key for companies which
seek to export due to the diversity of the regulatory
frameworks across the world. The EMA released a Ques-
tion and Answer document for companies outside the
EU want to meet EU regulatory requirements for
(traditional) herbal medicinal products.
The International Regulatory Cooperation for Herbal
Medicines (IRCH) now under the harbour of WHO; has
been an important step towards promotion of best reg-
ulatory practices on herbal medicines, although it will
take some time to develop this platform and find ways
how to converge the different regulatory systems.
Werner Knöss
26
Contribution of The European Pharmaco-
poeia to A Proportionate Regulatory Envi-
ronment for Herbal Medicinal Products
After the safety and efficacy pillars addressed by the
previous speakers, Susanne Keitel, Director, European
Directorate for the Quality of Medicines & Healthcare
(EDQM), addressed the quality one and the important
role the European Pharmacopoeia and its general chap-
ter and monographs play in that regard.
There are 6 general monographs and 294 individual
monographs dedicated to herbals. The EDQM has also a
number of specific monographs dedicated to Tradition-
al Chinese Medicine (TCM) to prevent severe quality
issues (false identification, adulteration, contamination
with pesticides).
She described some current challenges in the TCM field
such as the availability of samples which are required for
monograph elaboration. These include commercial
samples, authentic reference samples (to confirm that
commercial samples are both genuine and of an ac-
ceptable quality) and reference samples of substitute/
adulterant herbal drugs (for exclusion tests) are re-
quired.
Although processing may reduce toxicity and improve
the stability of TCM drugs, does it lead to an enhance-
ment of activity? There are no uniform processing
methods. Regional differences exist in China, for exam-
ple.
Finally, the choice of markers for assays may not always
be indicative of quality, stability or activity. A pilot phase
using semi-quantitative HPTLC has started. This allows
for the determination of one or more markers and the
possibility to use reagents instead of reference stand-
ards.
She also addressed the very controversial issue of pyr-
rolizidine alkaloids (PAs) contamination detected in
herbal medicinal products and food. PAs have been
isolated from 350 plant species, including a number of
weeds. According to HMPC investigations the problem
cannot be solved by simply focusing on Good Agricul-
tural and Collection Practices. EDQM has been given a
mandate to draft a general methods chapter in the field
of pyrrolizidine alkaloids, and maintain a list of PAs
which may be covered by the general chapter.
The Views of Industry on Herbal Medicinal
Products
Finally the views of the herbal medicinal products indus-
try were presented by Christelle Anquez-Traxler, Reg-
ulatory and Scientific Affairs Manager, AESGP, who
highlighted that the Directive 2004/24/EC and the crea-
tion of the HMPC within the EMA were milestones in the
regulatory system for herbals. The EU herbal mono-
graphs foster harmonisation and facilitate registrations.
However, industry would like an increased acceptance
of well-established use and paediatric use indications in
EU monographs and more entries making it to the list.
The threshold for acceptable genotoxicity data should
not become so high that no further list entries can be
finalised. In respect of paediatric use indications, paedi-
atric research in herbals should be stimulated, encour-
aged and rewarded in Europe. Research is very costly
and it is difficult to recoup investment but clinical trials
may not always be needed. Registries, real-world data
or extrapolation may provide opportunities. To improve
the functioning of the system and the sustainability of
the herbal medicinal products’ sector, the following are
needed by the industry:
▪ Respect of community monographs. A survey con-
ducted by AESGP in 2015 found that more than half
of granted marketing authorisations/registration
(based on monograph) deviate from the monograph
for various reasons. The acceptance and relevance of
EU Monographs is still very heterogeneous across
Member States. Generally there is a higher ac-
ceptance of THMPs monographs compared to well
established use (WEU) monographs. The main areas
of deviation are the indications, age limits, and pre-
clinical safety data.
Susanne Keitel
27
Conference report
At the end of the conference, AESGP Director General, Dr Hubertus Cranz, invited participants to attend the next
AESGP meetings in Lisbon on the 26th
-27th
of February 2018, with the Heads of EU Medicines Agencies, and the 54th
AESGP Annual Meeting in Amsterdam on the 5th
-7th
of June 2018.
▪ Assessment time in line with legislation. Currently
review timelines for THMPs are still extremely long,
taking up to 3 years (based on an AESGP internal
survey).
▪ Fees proportionate to work going into the evalua-
tion. Fees should distinguish between Marketing au-
thorisations with or without a monograph as the pre-
clinical/clinical assessment would already be done by
the HMPC.
▪ Resources and expertise on herbal medicines needed
within national agencies.
▪ Simplified maintenance of herbal medicines taking
into account their known safety profile (simplified
variations). Currently any manufacturing change for a
herbal is considered a major variation. AESGP recent-
ly presented a proposal to the Regulatory Optimisa-
tion Group (ROG), a HMA subgroup focused on reg-
ulatory/business optimisation, on the simplification
of the variation classification for herbal medicines.
This will ensure that the herbal medicinal products’ sec-
tor can remain competitive and safeguard innovation in
herbal medicines.
Christelle Anquez-Traxler
Invitation to the Next AESGP Meetings
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