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