Commission communication on the Community marketing authorisation procedures for medicinal products
Date: 1998-07-22
Institutions: European Commission
Subjects: approximation of laws, market approval, medicinal product, pharmaceutical legislation, pharmaceutical product

C  229/4

EN

Official  Journal  of  the  European  Communities

22.7.98

Commission  communication  on  the  Community  marketing  authorisation  procedures  for
medicinal  products

(98/C  229/03)

INTRODUCTION

A. SCOPE  OF  APPLICATION  OF  COUNCIL  REGU(cid:220)

LATION  (EEC)  No  2309/93

As  part  of  the  overall  strategy  for  building  a  single
market  for  pharmaceuticals,  a  series  of  new  procedures
for  granting  marketing  authorisations  were  introduced.
On  1  January  1995,  two  new  procedures  for  the  author(cid:220)
isation  of  medicinal  products  for  human  and  veterinary
use  came  into  effect.  Council  Regulation  (EEC)  No
2309/93  laid  down  procedures  for  a  Community  author(cid:220)
isation  of  medicinal  products  for  human  and  veterinary
use  (i.e.  the  "centralised’  procedure)  and  established  a
the  Evaluation  of  Medicinal
European  Agency 
Products  (EMEA)(cid:216)(˛).  In  addition,  three  Directives(cid:216)(ˇ)
amended  the  existing  Community  pharmaceutical  legis(cid:220)
lation  to  create  a  new  "mutual  recognition’  procedure  for
the  authorisation  of  human  and  veterinary(cid:216)(—)  medicinal
products  based  on  the  principle  of  mutual  recognition  of
national  authorisations,  with  binding  Community  arbi(cid:220)
tration  in  the  event  of  disagreement  between  Member
States.

for 

The  three  year  period  of  transition  for  the  mutual  recog(cid:220)
nition  procedure  which  was  foreseen  in  1995  ended  on
1(cid:217)January  1998.  Thereafter,  access  to  the  Community
market  follows  either  the  centralised  or  mutual  recog(cid:220)
nition  route.

Independent  national  procedures  will  continue,  but  are
strictly  limited  from  1  January  1998  to  the  initial  phase
of  mutual  recognition  (granting  of  the  marketing  author(cid:220)
isation  by 
to
medicinal  products  which  are  not  marketed  in  more  than
one  Member  State.

"reference  Member  State’)  and 

the 

Now  that  the  transition  period  for  mutual  recognition  is
over,  and  in  order  to  ensure  the  continued  successful
operation  of  the  new  Community  marketing  author(cid:220)
isation  systems,  examination  of  a  number  of  further
issues  is  due.  Therefore  the  Commission  wishes  to  clarify
its  position  on  certain  aspects  relating  to  the  implemen(cid:220)
tation  of 
recognition
the  centralised  and  mutual 
procedures.

According  to  Article  3(1)  of  Regulation  (EEC)  No
2309/93,  no  medicinal  product  referred  to  in  Part  A  of
the  Annex  may  be  placed  on  the  market  within  the
Community  unless  a  marketing  authorisation  has  been
granted  by  the  Community 
in  accordance  with  the
provisions  of  this  Regulation  (obligatory  use  of  the
centralised  procedure).

Article  3(2)  of  this  Regulation  provides  for  the  possibility
that  the  person  responsible  for  placing  on  the  market  a
medicinal  product  referred  to  in  Part  B  of  the  Annex
may  request  that  the  authorisation  to  place  the  medicinal
product  on  the  market  be  granted  by  the  Community  in
accordance  with 
this  Regulation
the  provisions  of 
(voluntary  use  of  the  centralised  procedure).

In  order  to  be  able  to  determine  the  scope  of  application
of  the  centralised  procedure,  it  is  essential  to  have  clear
criteria  to  determine  whether  a  medicinal  product  falls
under  the  category  of  products  for  which  a  Community
marketing  authorisation  is  obligatory  ("List  A  products’)
or  under 
the  centralised
procedure  is  optional  ("List  B  products’).

the  category 

for  which 

1.(cid:217)Part  A  of  the  Annex  -  biotechnology  derived

products

The  centralised  procedure  is  mandatory  for  medicinal
products  derived  from  the  biotechnological  processes
described  in  Part  A  of  the  Annex  to  Regulation  (EEC)
No  2309/93.  Initially  biotechnology  was  seen  as  an
opportunity  to  develop  new  medicinal  products  which
would  otherwise  not  be  possible.  Now,  however,
biotechnology  techniques  can  also  be  incorporated  into
the  manufacture  of  existing  medicinal  products  in  order
to  enhance  yields,  improve  quality  or  reduce  environ(cid:220)
mental  impact.

Part  A  of  the  Annex  to  the  abovementioned  Regulation
covers  medicinal  products  developed  by  means  of  the
following  biotechnological  processes:

(˛)(cid:217)OJ  L  214,  24.8.1993,  p.  1.
(ˇ)(cid:217)Council  Directives 

93/40/EEC 
93/41/EEC,  OJ  L  214,  24.8.1993,  pp.  22,  31  and  40.

93/39/EEC, 

and

-(cid:217)recombinant  DNA  technology,

the  references 

(—)(cid:217)For  the  readability  and  the  clarity  of  the  Communication,
to  Directives  concerning  medicinal
only 
products  for  human  use  will  be  made  in  the  text;  the
references  to  Directives  regarding  veterinary  products  will
be  given  in  footnotes.

-(cid:217)controlled  expression  of  genes  coded  for  biologically
in  prokaryotes  and  eukaryotes,

active  proteins 
including  transformed  mammalian  cells,

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-(cid:217)hybridoma  and  monoclonal  antibody  methods.

In  Commission  communication  94/C(cid:216)82/4(cid:216)((cid:209)), 
some
practical  examples  of  medicinal  products  covered  by  Part
A  had  already  been  given:

-(cid:217)products  intended  for  gene  therapy,

The  Commission  considers  that  the  definition  in  the
European  Pharmacopoeia  monograph  of  products  of
recombinant  DNA 
(monograph  No
is  already  part  of  Community
1997,784),  which 
in
to 
pharmaceutical 
Directive  75/318/EEC(cid:216)((cid:210)),  has  to  be  applied  in  this
context.

legislation  due 

technology 

references 

-(cid:217)vaccines  from  strains  developed  by  means  of  recom(cid:220)
binant  DNA  technology,  including  gene  deletion,

-(cid:217)any  medicinal  product  for  which  a  monoclonal
antibody  is  used  at  any  stage  in  the  manufacturing
process.

Thus  any  medicinal  product  in  the  composition  of
which  there  is  a  proteinaceous  constituent  obtained
by  means  of  recombinant  DNA  technology,  falls
under  the  scope  of  Part  A  of  Regulation  (EEC)  No
2309/93, 
the
constituent  is  an  active  substance  of  the  medicinal
product.

irrespective  of  whether  or  not 

(a) Medicinal  product  developed  by  means  of  recombinant

DNA  technology

(b) Products  intended  for  gene  therapy

Since  questions  continue  to  arise  in  respect  of  the
meaning  of  "medicinal  product  developed  by  means
of  recombinant  DNA  technology’,  the  Commission
wishes  to  clarify  its  interpretation  of  these  terms  and
thus  make  precise  the  scope  of  part  A  of  the  Annex
to  Regulation  (EEC)  No  2309/93.

the 

pharmaceutical 

As  a  preliminary  remark,  it  has  to  be  kept  in  mind
that  the  main  aims  of  the  creation  of  the  centralised
procedure  were  the  improvement  of  the  functioning
of  the  Single  Market  as  far  as  medicinal  products  are
concerned,  the  avoidance  of  duplication  of  scientific
reduction  of  administrative
evaluation  and 
burden  and  as  a  consequence,  the  promotion  of  the
European 
industry.  Medicinal
products  developed  by  means  of  biotechnological
processes  were  considered  to  be  an  appropriate  and
centralised
point 
promising 
procedure.  It 
that,
according  to  Community  pharmaceutical  legislation,
the  quality,  safety  and  efficacy  of  any  medicinal
product  have  to  be  equally  ensured  through  the
centralised  and  the  decentralised  procedures,  the
protection  of  public  health  being  the  ultimate  aim  of
Community  legislation  in  this  matter.

the 
to  stress 

important 

is  also 

starting 

for 

it 

is  particularly 

To  ensure  an  efficient  and  smooth  functioning  of
these  procedures, 
important  to
determine  which  categories  of  substances  developed
by  means  of 
technology
represent,  when  used  as  constituents  of  medicinal
products,  an  essential  element  of  a  medicinal  product
to  be  considered  in  the  choice  of  the  procedure  to  be
followed.

recombinant  DNA 

its 

to  human 

tissues  and 

Gene  therapy  corresponds  to  a  set  of  processes
aimed  at  the  transfer  of  a  gene,  basically  a  piece  of
subsequent
DNA, 
expression  in  vivo.  The  systems  for  therapeutic  gene
transfer  and  expression  involve  a  therapeutic  gene
and  an  expression  system  that  is  contained  in  a
delivery  system,  known  as  a  vector.  The  delivery
system  can  use  either  viral  vectors  (retroviral  or
adenoviral  vectors  for  example)  as  well  as  non(cid:220)viral
vectors  (such  as  cationic 
liposomes  or  molecular
conjugates).  The  vectors  themselves,  regardless  of
their  physical  nature,  have  to  be  considered  as  part
of  the  "product  intended  for  gene  therapy’  which  is  a
medicinal  product  in  the  meaning  of  the  Community
pharmaceutical 
vectors
represent  an  intrinsic  part  of  this  product  endowed
with  a  therapeutic  effect.

legislation. 

Indeed 

the 

(c) Cell  therapy

Cell  therapy  consists  of  the  administration  to  humans
of  autologous  living  cells  (i.e.,  emanating  from  the
patient  himself),  or  allogeneic  cells  (therefore  coming
from  another  human  being)  or  even  xenogeneic  cells
(coming  from  an  animal).  To  some  extent,  these
selected  cells  may  have  been  manipulated  or
processed  to  change  their  biological  characteristics,
prior  to  their  administration.  This  definition  includes
autologous
the 

activation  of 

expansion 

and 

((cid:209))(cid:217)OJ  C  82,  19.3.1994,  p.  4.

((cid:210))(cid:217)OJ  L  147,  9.6.1975,  p.  1,  Directive  as  last  amended  by
Directive  93/39/EEC.  For  veterinary  medicinal  products:
Directive  81/852/EEC  (OJ  L  317,  6.11.1981,  p.  16),  as  last
amended  by  Directive  93/40/EEC.

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cell  populations  ex  vivo  (adoptive 
immunotherapy,
for  example)  and  the  use  of  allogeneic  or  xenogeneic
cells  contained  in  microcapsules  for  protein  drug
replacement.

Cell  therapy  products  have  to  be  considered  as
medicinal  products  needing  a  marketing  author(cid:220)
isation  if  they  are  industrially  manufactured.  If  cell
therapy  products  are  the  result  of  any  biotechnology
process  referred  to  in  Part  A  of  the  Annex  to  Regu(cid:220)
lation  (EEC)  No  2309/93,  they  will  have  to  be  auth(cid:220)
orised  by  the  Community.

2.(cid:217)Part  B  of  the  Annex  -  high  technology  products  and

products  containing  new  active  substances

its 

legal  effects  and 

The  centralised  procedure  is  optional  for  the  medicinal
products  referred  to  in  Part  B  of  the  same  Annex.
Despite  the  optional  nature  of  the  procedure  in  such  a
context, 
legal
characteristics  of 
the  Community  marketing  author(cid:220)
isation  issued  are  developed  to  full  effect.  This  is  why  it
has  to  be  stressed  that,  once  granted  with  a  Community
marketing  authorisation  based  on  Part  B  of  the  Annex,  a
medicinal  product  can  no  longer  be  the  subject  of  a
subsequent  (or  previous)  national  marketing  author(cid:220)
isation.

in  particular  the 

(a) Conditions  of  implementation  of  Article  4(3)(8a)  of

Directive  65/65/EEC ((cid:211))

This  Article  grants  certain  derogations  to  applicants
relating  to  the  need  to  provide  the  results  of  pharma(cid:220)
cological  and  toxicological  tests  or  the  results  of
clinical  trials.  An  applicant  can  make  use  of  these
derogations  in  the  centralised  procedure  only  if  the
specific  conditions  set  out  in  the  relevant  provisions
are  fully  complied  with.

1. Abridged  applications

The  text  of  Article  4(3)(8a)(i)  and  (iii)  implies
that  the  abridged  application  can  only  be  lodged
with  the  authority  that  evaluated  and  authorised

((cid:211))(cid:217)OJ  22,  9.2.1965,  p.  369/5,  Directive  as  last  amended  by
Directive  93/39/EEC.  For  veterinary  medicinal  products  any
reference  to  this  Article  has  to  be  understood:  Article  5(3)
(10a)(i),  (ii)  and  (iii)  of  Directive  81/851/EEC  (OJ  L  317,
6.11.1981,  p.  1),  Directive  as  last  amended  by  Directive
93/40/EEC.

the  medicinal  product  which 

the  original  product  as  this  authority  holds  the
dossier  on 
is
essentially  similar  to  that  of  the  second  applicant.
This  means 
in  the  context  of  the  centralised
procedure  that  abridged  applications  can  only  be
lodged  with  the  EMEA.

-(cid:217)In  the  case  of  Article  4(3)(8a)(i)  ("informed
consent’),  the  product  to  which  essential  simi(cid:220)
larity(cid:216)((cid:212))  is  claimed  has  to  be  centrally  auth(cid:220)
orised  and  essential 
to  be
demonstrated  by  the  applicant.  Moreover,  the
consent  of  the  marketing  authorisation  holder
of  the  original  product  has  to  cover  the  use  of
the  references  being  used  for  examining  the
application  in  question.

similarity  has 

-(cid:217)In  the  case  of  Article  4(3)(8a)(iii)  ("generic
application’),  the  product  to  which  essential
similarity  is  claimed  has  to  be  authorised  by
the  Community  and  essential  similarity  has  to
be  demonstrated  by  the  applicant.  Moreover,
the  product  to  which  essential  similarity  is
claimed  has  to  be  marketed  in  the  Community
for  not  less  than  10  years.

stated  before, 

for  an  abridged  application
As 
concerning  a  medicinal  product  essentially  similar  to
one  already  covered  by  a  Community  authorisation,
in  all  cases.
the  centralised  route  must  be  used 
to
Therefore 
referring 
for
Community  marketing  authorisation  dossier 
medicinal  products  which  are  essentially  similar  to
Community  authorised  products  falling  under  the
scope  of  Part  B  of  the  Annex  to  Regulation  (EEC)
No  2309/93,  must  follow  the  centralised  procedure.

applications 

generic 

2. Bibliographical  applications

the  well  established  use  of 

In  the  case  of  Article  4(3)(8a)(ii)  ("bibliographical
application’) 
the
constituent(s)  of  the  medicinal  product  has  to
be  demonstrated  and  the  applicant  has  to  provide
the  EMEA  with  a  complete  set  of  detailed

((cid:212))(cid:217)The  exact  meaning  of  the  term 

"essential  similarity’,  as
described  in  of  the  "Notice  to  Applicants’  (Volume  2A  and
Volume  6A  of  "The  rules  governing  medicinal  products  in
the  European  Union’)  is:  "the  same  qualitative  and  quanti(cid:220)
tative  composition  in  terms  of  active  principles,  and  the
pharmaceutical  form 
is  the  same;  and  where  necessary,
appropriate  bioavailability  studies  have  been  carried  out;  by
extension,  the  concept  of  essentially  similar  also  applies  to
different  oral  forms  (e.g.  tablets  and  capsules)  with  the  same
active  substance  for  immediate  release’.

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to 
in 

scientific 

literature
published 
references 
presented 
with  Directive
accordance 
75/318/EEC(cid:216)((cid:213)).  It  also  has  to  be  stressed  that  all
requirements  laid  down  in  this  Directive  have  to  be
addressed  in  the  application.

(b) Medicinal 

same 
substance(s)  as  a  Community  authorised  product

containing 

products 

the 

active

that 

to  place  on 

In  order  to  maintain  coherence  and  transparency,
and  to  preserve  the  unity  of  the  Community  Single
Market,  where  the  same  marketing  authorisation
holder  wishes 
the  market  another
medicinal  product  with  the  active  substance  which  is
already  the  subject  of  a  Community  authorisation,
the  centralised
the  Commission  considers 
procedure  should  be  used,  in  particular  when  the
therapeutic  indication  is  within  the  third  level  of  the
ATC  code.  In  cases  where  the  applicant  does  not
apply  for  a  Community  authorisation  as  described
above,  the  therapeutic  indication(s)  authorised  by  the
Community  should  not  be  part  of  the  national  auth(cid:220)
orisation.  In  such  a  context,  the  Commission  will
consider  the  benefit  of  referring  the  case  to  the
in
EMEA 
accordance  with  Articles  11  or  12  of  Directive
75/319/EEC(cid:216)((cid:214))  in  order  to  preserve  the  abovemen(cid:220)
tioned  coherence  and  transparency.

arbitration  procedure 

through 

an 

shall 

authorisation  holder 

According  to  Community  pharmaceutical  legislation,  the
marketing 
the
competent  authorities  of  any  change  in  the  manufac(cid:220)
turing  process.  This  also  includes  the  introduction  of  a
biotechnology  manufacturing  step.  If  an  active  substance
from  the  same  supplier  is  common  to  more  than  one
marketing  authorisation,  combining 
these  cases  will
avoid  unnecessary  duplication  of  work.

inform 

The  Commission  considers  that  the  appropriate  rules  to
deal  with  these  cases  are  the  following:

1. The  constituent  concerned  by  the 

introduction  of
recombinant  DNA  technology  is  of  a  proteinaceous
nature

According  to  Regulation  (EEC)  No  2309/93  and  the
interpretation  already  mentioned  (see  point  A.1)  of
"medicinal  product  developed  by  means  of  recombinant
DNA  technology’,  a  medicinal  product  will  fall  under
Part  A  of  the  Annex  to  this  Regulation  if  the  constituent
concerned  by  the  introduction  of  this  recombinant  DNA
technology  step  is  of  a  proteinaceous  nature.  Therefore
this  product  has  to  be  authorised  through  the  centralised
procedure.

2. Other  cases

B. INTRODUCTION  OF  A  BIOTECHNOLOGY  MANU(cid:220)
FACTURING  STEP  AFTER  THE  GRANTING  OF  A
MARKETING  AUTHORISATION

-(cid:217)The  medicinal  products  are  not 

covered  by
Commission  Regulations  (EC)  No  541/95  or  (EC)
No  542/95(cid:216)(˛˝)  (i.e.  products  that  have  not  been
subject  to  any  Community  procedure).

The  new  Community  marketing  authorisation  system
foresees  that  the  centralised  procedure  has  to  be  used  for
for  medicinal  products  developed  by
applications 
biotechnology.  However, 
the  position  of  medicinal
products  already  on  the  market  and  authorised  by
Member  States,  where  one  or  more  biotechnology  steps
are  introduced  into  the  manufacturing  process  after  the
marketing  authorisation  has  been  granted  needs  to  be
clarified.  Hundreds  of  products  are  concerned  by  such  a
modification.

These  medicinal  products  have,  by  virtue  of  the  granting
of  a  marketing  authorisation,  demonstrated  quality,
safety  and  efficacy  and  are  being  used  by  patients,  in
many  cases  for  a  long  time.

((cid:213))(cid:217)For  veterinary  medicinal  products:  Directive  81/852/EEC.
((cid:214))(cid:217)OJ  L  147,  9.6.1975,  p.  13,  Directive  as  last  amended  by
Directive  93/39/EEC.  For  veterinary  medicinal  products  any
reference  to  these  Articles  has  to  be  understood:  Articles  19
or  20  of  Directive  81/851/EEC.

For  products  not  covered  by  Commission  Regu(cid:220)
lations  (EC)  No  541/95  or  (EC)  No  542/95,  the
marketing  authorisation  holders  should  just  notify
the  change  to  the  competent  authorities  of  the
concerned  Member  States  if  they  can  provide  these
authorities  with  a  certificate  of  suitability  from  the
the
European  Pharmacopoeia 
constituent  concerned  by  the 
introduction  of  the
biotechnology  step  still  complies  with  monographs
from 
this
constituent  does  not  comply  with  monographs  and  a
certificate  of  suitability  is  therefore  not  available,  the
marketing  authorisation  holder  should 
lodge  an
application  for  a  variation  to  the  original  marketing
authorisation  according  to  the  nationally  applicable
rules.

the  European  Pharmacopoeia. 

establishing 

that 

If 

However  when,  in  the  case  of  a  constituent  described
introduction
in  the  European  Pharmacopoeia,  the 
leave
of 

the  biotechnolgy 

liable 

step 

to 

is 

(˛˝)(cid:217)OJ  L  55,  11.3.1995,  pp.  7  and  15.

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impurities  not  controlled  in  a  monograph  from  the
European  Pharmacopoeia,  these  impurities  must  be
delcared  and  a  suitable  test  procedure  must  be
described.  If  a  certificate  of  suitability  from  the
European  Pharmacopoeia  is  available  which  specifies
the  supplementary  test(s),  the  notification  procedure
should  be  followed.

-(cid:217)The  medicinal  products  are  covered  by  Regulation
(EC)  No  541/95  (i.e.  products  covered  by  marketing
authorisations  which  have  undergone  a  Community
procedure)  or  by  Regulation  (EC)  No  542/95  (i.e.
products  covered  by  Community  marketing  author(cid:220)
isation).

(EEC)  NO  2309/93, 

For  products  covered  by  Regulations  (EC)  No
541/95  and  (EC)  No  542/95  which  fall  under  the
scope  of  Regulation 
the
marketing  authorisation  holders  must 
lodge  an
application  with  the  appropriate  competent  authority
(authorities  of  the  concerned  Member  States  or
EMEA).  Where  the  marketing  authorisation  holder
can  demonstrate  that  the  specified  conditions  of  a
Type  I  variation  are  met  and 
in  particular  can
provide  a  certificate  of  suitability  from  the  European
Pharmacopoeia  establishing 
the  constituent
concerned  by  the  introduction  of  the  biotechnology
step  still  complies  with  a  monograph  from 
the
European  Pharmacopoeia,  a  Type 
I  variation
procedure  within  the  meaning  of  the  abovementioned
Commission  Regulations  will  be  accepted.  If  these
conditions  are  not  met,  the  marketing  authorisation
holder  has  to  lodge  an  application  for  a  Type  II
variation  procedure  within  the  meaning  of  the  above(cid:220)
mentioned  Commission  Regulations.

that 

C. NAME  OF  A  MEDICINAL  PRODUCT

Member  States  grant  a  marketing  authorisation  to  a
single  authorisation  holder  who  is  responsible  for  placing
the  medicinal  product  on  the  market.  The  marketing
authorisation  includes,  when  available,  the  INN  (Inter(cid:220)
national  Non(cid:220)Proprietary  Name)  and  when  branded,  a
single  invented  name  (brand  name).  Only  one  brand
name  should  normally  be  approved  per  marketing  auth(cid:220)
orisation  granted.

This  also  applies  in  the  case  of  a  Community  author(cid:220)
isation  for  which  there  is  a  single  summary  of  product
characteristics  (SPC),  a  single  leaflet  and  a  single  label
is  advisable  for  applicants  using  the
approved(cid:216)(˛˛).  It 

centralised  procedure  to  identify  at  an  early  stage,  and
before  lodging  the  application,  one  brand  name  which
can  be  used  throughout  the  Community  while  keeping
fall(cid:220)back  options  (brand  name(s))  in  reserve.

However,  in  exceptional  cases,  in  particular  where  the
proposed  brand  name  has  been  cancelled,  opposed  or
objected  to  under  trade  mark  law  in  a  Member  State,  the
Commission  will  address  the  issue  in  order  not  to  disad(cid:220)
vantage  patients  and  their  access  to  the  concerned
medicinal  product  in  that  Member  State.  If  sufficient
evidence  is  given  by  the  marketing  authorisation  holder
that,  in  spite  of  all  its  efforts,  the  chosen  or  foreseen
trade  mark  cannot  be  used  in  a  Member  State,  the
Commission  will  -  exceptionally  -  authorise  the  use  of
a  different  trade  mark  in  that  Member  State.  Should  a
derogation  be  granted,  it  will  affect  neither  the  legal
obligations  of  the  marketing  authorisation  holder,  nor
the  validity  of  the  marketing  authorisation  throughout
the  Community  and  shall  not  be  used  to  introduce  any
partitioning  of  the  European  market,  i.e.  to  restrict  or
prevent  the  free  movement  of  the  concerned  medicinal
product.

D. PARALLEL  DISTRIBUTION  OF  COMMUNITY  AUTH(cid:220)

ORISED  MEDICINES

A  Community  marketing  authorisation  is,  by  definition,
valid  in  all  Member  States.  Therefore  products  put  on
the  market  of  one  Member  State  can  be  marketed  in  any
other  part  of  the  Community  by  a  distributor,  inde(cid:220)
pendent  of  the  marketing  authorisation  holder  ("parallel
distributor’).  In  such  circumstances,  the  marketing  auth(cid:220)
orisation  holder  remains  unchanged  and  retains,  of
course,  the  responsibility  incumbent  on  him/her  under
Community  law.

In  this  context,  which  is  very  different  from  the  parallel
importation  of  medicines  authorised  nationally  because
of  differences  which  can  exist  between  the  marketing
authorisation  granted  by  the  Member  State  of  origin  and
the  one  granted  by  the  Member  State  of  destination,  the
only  changes  to  the  product  which  can  be  required
in  order  to  allow  parallel  distribution  are  changes  in
the  language  of  the  labelling  and  package  leaflet  to
comply  with  Article  4(2)  and  Article  8  of  Directive
92/27/EEC(cid:216)(˛ˇ),  and/or,  more  rarely,  changes  in  the  size
of  the  package  (repackaging).

(˛˛)(cid:217)For  medicinal  products  for  human  use:  see  answer  given  by
Mr  Bangemann  on  behalf  of  the  Commission  to  a  Parlia(cid:220)
mentary  written  question  from  Mr  K.  Collins  (written
question  No  E(cid:220)2553/96;  OJ  C  83,  14.3.1997,  p.  26).

(˛ˇ)(cid:217)For  veterinary  medicinal  products:  Article  47  and  Article

48(1)  of  Directive  81/851/EEC.

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In  the  context  of  medicinal  products  authorised  by  the
Community,  it  must  be  remembered  that,  by  definition,
the  Community  marketing  authorisation  encompasses  all
linguistic  versions  of  the  labelling  and  package  leaflet
and  all  available,  authorised  pack  sizes.

the  meaning  of  Article  16  of  Directive  75/319/
EEC(cid:216)(˛(cid:209))  (if  not  already  provided  to  the  authorities)
if  there  is  a  change  of  pack  size  in  conformity  with
the  already  authorised  pack  sizes;

In  any  case,  the  original  condition  of  the  product  inside
the  packaging  must  not  be  directly  or  indirectly  affected
and  any  changes  in  the  size  of  the  package  must  be  duly
justified, 
it  must  be  demonstrated  that  they  are
strictly  necessary  to  market  the  product  distributed  in
parallel  in  the  Member  State  of  destination  in  the  same
conditions  as  the  product  distributed  by  the  marketing
authorisation  holder.

i.e. 

is  required, 

further  authorisation 

Although  no 
the
Community  (in  practice  the  EMEA)  and  national  auth(cid:220)
orities  (authorities  of  the  Member  States  in  which  the
medicinal  product  will  be  distributed  in  parallel)  shall  be
informed  that  such  parallel  distribution  will  take  place  in
order  to  enable  the  EMEA  to  check  compliance  with  the
terms  of  the  Community  marketing  authorisation  and  the
national  authorities  to  monitor  the  market  (batch  identi(cid:220)
fication,  pharmacovigilance,  etc.)  and  to  carry  out  post(cid:220)
marketing  surveillance.

1.(cid:217)Information  to  be  submitted  by  the  parallel  distributor

The  parallel  distributor  must  send  to  the  competent  auth(cid:220)
orities  the  following  information:

(a)(cid:217)the  (brand  and  INN)  name(s)  of  the  medicine(s)
concerned  and  its/their  authorisation  number(s)  in
the  Community  register  of  medicinal  products;

(b) name  or  business  name  of  the  parallel  distributor;

(c) one  or  more  mock(cid:220)ups  of  the  medicines  as  they  will
be  marketed  in  the  Member  State  of  destination,
including  the  package  leaflets;

(d) a  copy  of  the  wholesale  distribution  authorisation
within 
the  meaning  of  Article  3  of  Directive
92/25/EEC(cid:216)(˛—)  (if  not  already  provided  to  the  auth(cid:220)
orities)  and/or  a  manufacturing  authorisation  within

(e) as  the  case  may  be,  a  comprehensive  justification  if
there  is  a  change  of  pack  size  in  conformity  with  the
already  authorised  pack  sizes.

2.(cid:217)Procedure

In  the  Commission’s  view,  any  objection  from  the
competent  authority  shall  be  notified  within  30  days  and
shall  state  in  detail  the  reasons  on  which  it  is  based.
Obviously,  a  parallel  distributor  has  to  fulfil,  as  a
wholesale  distributor,  the  obligations  incumbent  on  him
under  the  terms  of  Articles  5  and  8  of  Directive
92/25/EEC(cid:216)(˛(cid:210)).

According  to  the  current  case(cid:220)law  of  the  Court  of  Justice
of  the  European  Communities,  the  trade  mark  owner
must  be  given  advance  notice  by  the  parallel  distributor
that  the  repackaged  product  is  to  be  put  on  sale.  The
owner  may  also  require  the  parallel  distributor  to  supply
him  with  a  specimen  of  the  repackaged  product  before  it
goes  on  sale,  to  enable  him  to  check  that  the  presen(cid:220)
tation  after  repackaging  is  not  such  as  to  damage  the
reputation  of  the  trade  mark.

E. MUTUAL  RECOGNITION  PROCEDURE

Whilst  safeguarding  the  protection  of  public  health,  the
Community  procedure  of  mutual  recognition  in  the  new
system  has  as  one  of  its  main  objectives  the  harmon(cid:220)
isation  of  national  marketing  authorisations  and  the
avoidance  of  duplicative  evaluation.  In  addition, 
it
introduces  the  possibility  of  Community  referral  (the
arbitration  procedure) 
in  the  event  of  disagreement
between  Member  States.  Regardless  of  the  basis  for
harmonisation  (e.g.  mutual  recognition  at  the  request  of
the  company,  or  by  the  Member  State,  or  arising  from
divergent  decisions  between  Member  States  or  in  cases
of  Community 
interest),  once  this  harmonisation  has
been  achieved,  it  is  maintained  by  further  procedures
relating  to  variations  and  pharmacovigilance.

(˛—)(cid:217)OJ  L  113,  30.4.1992,  p.  1; 

for  veterinary  medicinal

(˛(cid:210))(cid:217)For  veterinary  medicinal  products:  Article  50a  and  Article

products:  Article  50a  of  Directive  81/851/EEC.

50b  of  Directive  81/851/EEC.

(˛(cid:209))(cid:217)For  veterinary  medicinal  products:  Article  24  of  Directive

81/851/EEC.

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1.(cid:217)Legal  provisions

(EEC)  No  93/39(cid:216)(˛(cid:211)) 
into  Community  pharmaceutical 

introduced
Council  Directive 
legislation
provisions 
the
which  determine 
application  modalities  of 
recognition
procedure.  The  provisions  which  are  most  relevant  for
determining  the  scope  and  the  operation  of  the  mutual
recognition  procedure  are:

the  scope  of  application  and 

the  mutual 

This  transition  period  ended  on  31  December  1997.
Therefore,  the  method  of  access  (other  than  by  the
centralised  procedure)  to  the  Community  market  is  now
by  mutual  recognition.  This  means  that  from  now  on,
any  medicinal  product  which  is  to  be  placed  on  the
market  of  more  than  one  other  Member  State  has  to  be
processed  through  the  mutual  recognition  procedure
only.

the  competent  authority. 

-(cid:217)Article  4(11)  of  Council  Directive  65/65/EEC(cid:216)(˛(cid:212))
which  imposes  an  obligation  to  provide  information
to 
this
provision  is  not  directly  linked  to  mutual  recognition,
it  has  a  particularly  important  role  for  the  mutual
recognition  procedure),

though 

(Even 

-(cid:217)applications 

for  products  already  authorised 

in
another  Member  State,  i.e.  mutual  recognition  at  the
request  of  an  applicant  (Article  9  of  Directive
75/319/EEC)(cid:216)(˛(cid:213))  and  obligatory  mutual  recognition
by  the  competent  authorities  of  the  Member  States
(Article  7a  of  Directive  65/65/EEC)(cid:216)(˛(cid:214)),

-(cid:217)simultaneous  applications  for  products  as  yet  not
in  a  Member  State  (Article  7(2)  of

authorised 
Directive  65/65/EEC)(cid:216)(ˇ˝).

2.(cid:217)End  of  the  transition  period

When  adopting  these  provisions,  a  transition  period  of
three  years  (1995  to  1998)  was  foreseen,  so  that  both
Member  States  and  industry  could  gradually  become
familiar  with  the  operation  of  this  new  system  before  it
became  obligatory.  Thus  applicants  wishing  to  access
more  than  one  Member  State  market  had  a  choice
inde(cid:220)
between  the  mutual  recognition  procedure  or 
pendent  national  applications.

(˛(cid:211))(cid:217)For  veterinary  medicinal  products:  Directive  93/40/EEC.
(˛(cid:212))(cid:217)For  veterinary  medicinal  products  any  reference  to  this
Article  has  to  be  understood:  Article  5(13)  of  Directive
81/851/EEC.

(˛(cid:213))(cid:217)For  veterinary  medicinal  products  any  reference  to  this
Article  has  to  be  understood:  Article  17  of  Directive
81/851/EEC.

(˛(cid:214))(cid:217)For  veterinary  medicinal  products  any  reference  to  this
Article  has  to  be  understood:  Article  8a  of  Directive
81/851/EEC.

(ˇ˝)(cid:217)For  veterinary  medicinal  products  any  reference  to  this
Article  has  to  be  understood:  Article  8(2)  of  Directive
81/851/EEC.

regarding 

consequence, 

from  1 
the 

January  1998,  any
As  a 
application(cid:216)(ˇ˛) 
a
authorisation  of 
medicinal  product  which  is  already  the  subject  of  an
existing  marketing  authorisation 
in  another  Member
State  will  have  to  follow  the  Community  mutual  recog(cid:220)
nition  procedure,  thus  guaranteeing  uniform  marketing
authorisation  decisions  throughout  the  single  European
market.

In  such  a  context,  it  is  worth  mentioning  the  particular
case  where  an  applicant  withdraws  an  application
regarding  a  medicinal  product  in  one  Member  State
during  a  mutual  recognition  procedure  in  order  to  avoid
an  arbitration  (according  to  Article  10  of  Directive
75/319/EEC(cid:216)(ˇˇ))  being  triggered  by  that  Member  State.
The  transitional  period  being  over,  this  applicant  no
longer  has  any  possibility  of  accessing  the  market  of  the
Member  State  where  the  application  has  been  withdrawn
with  the  concerned  product,  an  independent  national
marketing  authorisation  for  a  product  already  authorised
in  another  Member  State  being  illegal.

3.(cid:217)Application 

of  Article 

of  Directive
65/65/EEC  in  the  context  of  the  mutual  recognition
procedure 
the
applicant)

submitted  by 

(documents 

4(3)(11) 

to  be 

In  order  to  place  a  medicinal  product  on  the  market,  an
applicant  must  submit  an  application  for  a  marketing
authorisation  to  the  competent  authorities  of  each  of  the
Member  States  where  the  product  is  to  be  marketed.  The
provisions  of  Directive  65/65/EEC  apply  in  respect  of
the  data  to  be  supplied  to  demonstrate  the  quality,  safety
and  efficacy  of  the  product  and  the  administrative  data.
Further,  to  ensure  the  availability  of  the  necessary
information  upon  which  mutual  recognition  is  based,
applicants  are  required  to  comply,  at  the  time  of
submission  and  with  regular  updates,  with  the  provisions
of  Article  4(3)(11)  of  Directive  65/65/EEC.

(ˇ˛)(cid:217)To  be  more  precise,  any  application  validated 

from

1(cid:217)January  1998.

(ˇˇ)(cid:217)For  veterinary  medicinal  products  any  reference  to  this
Article  has  to  be  understood:  Article  18(13)  of  Directive
81/851/EEC.

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This  Article  lists  the  particulars  and  documents  that  have
to  accompany  any  application  for  a  marketing  author(cid:220)
isation  (be  it  an  application  for  a  central  authorisation  or
for  a  national  authorisation  or  for  the  mutual  recog(cid:220)
this
nition  of  a  national  authorisation).  However, 
provision  has  a  particularly  important  role  for  the  mutual
recognition  procedure.  Its  point  11  imposes  an  obligation
on  any  applicant  to  provide  the  following  information:

are  needed.  The  Commission  considers  that  this  wording
has  to  be  taken  to  encompass  any  medicinal  product
which  has 
same  qualitative  and  quantitative
composition  in  active  substances  (i.e.  the  same  strength)
and  the  same  pharmaceutical  form  as  the  product  for
which  a  marketing  authorisation  is  sought.

the 

-(cid:217)copies  of  any  authorisation  obtained 

in  another
Member  State  or  in  a  third  country  to  place  the
relevant  medicinal  product  on  the  market,  together
with  a  list  of  those  Member  States  in  which  an
application  for  authorisation  submitted  in  accordance
with  the  Directive  65/65/EEC  is  under  examination,

-(cid:217)copies  of  the  summary  of  the  product  characterstics
the

the  applicant  or  approved  by 

proposed  by 
competent  authorities  of  the  Member  State,

all  other 

However,  applicants  are  strongly  advised  to  forward  to
the  competent  authority  -  pursuant  to  Article  4(3)(11)
of  Directive  65/65/EEC  - 
available
information  on  similar  or  related  marketing  authoris(cid:220)
ations  they  have  been  granted  or  applications  they  have
lodged  in  other  Member  States  or  in  third  countries.  The
transmission  of  such  information  will  help  the  competent
authority  to  establish  that  legislative  requirements  are  not
circumvented.  The  transmission  of  such  information  to
the
the  competent  authority 
therefore  also 
applicant’s  own 
it  will  contribute  to  a
smooth  and  swift  procedure.

is 
interest  and 

in 

-(cid:217)copies  of  the  package  leaflet  proposed  in  accordance
with  Article  6  of  Directive  92/27/EEC  or  approved
by  the  competent  authorities  of  a  Member  State  in
accordance  with  Article  10  of  the  same  Directive(cid:216)(ˇ—),

(a) Normal  procedure

4.(cid:217)Mutual 

recognition  procedure 

triggered  by 

the

applicant  (Article  9  of  Directive  75/319/EEC)

-(cid:217)details  of  any  decision 

to  refuse  authorisation,
whether  in  the  Community  or  in  a  third  country,  and
the  reasons  for  such  decision.

to  avoid  circumvention  of 

According  to  Article  4(3)(11)  the  applicant  shall  submit
"copies  of  any  authorisation  obtained’.  Legislation  does
not  require  the  applicant  to  provide  information  on  auth(cid:220)
orisations  which  have  been  granted  to  other  persons.
However, 
this
in  order 
provision,  applicants  belonging 
the  same  mother
company  or  group  of  companies  have  to  be  taken  as  one
entity.  Applicants  which,  without  belonging  to  the  same
mother  company  or  group  of  companies,  have  concluded
agreements  (e.g.  "licensees’)  or  which  exercise  concerted
practices  concerning 
the  market  of
in  different  Member
the(cid:217)relevant  medicinal  product 
States,  also  have  to  be  taken  as  one  for  the  purpose  of
Article(cid:217)4(3)(11).

the  placing  on 

to 

In  such  particular  context,  criteria  to  determine  the
meaning  of  the  terms  "the  relevant  medicinal  product’

(ˇ—)(cid:217)For  veterinary  medicinal  products:  Article  48  of  Directive

81/851/EEC.

Article  9  of  Directive  75/319/EEC  refers  to  the
mutual  recognition  by  Member  States  ("concerned
Member  States’)  of  a  national  marketing  author(cid:220)
isation  previously  granted  by  a  first  Member  State
("reference  Member  State’),  the  applicant  having
the
this  procedure  when  applying 
launched 
concerned  Member  States.  It  explicitly  covers  only
cases  in  which  a  marketing  authorisation  has  already
been  issued  in  another  Member  State.  Cases  in  which
identical  applications  are  pending 
in  different
Member  States  and  in  which  an  earlier  authorisation
was  not  yet  granted  in  another  Member  State  are  not
covered  by  this  Article.

in 

In  accordance  with  the  provisions  of  Article  9,  the
applicant  must  fulfil  the  following  conditions:

-(cid:217)the  application  for  marketing  authorisation  must
conform  to  the  requirements  of  the  pharma(cid:220)
ceutical  legislation,  i.e.  be  a  valid  application  and
be 
the
information  and  particulars  referred  to  in  Articles
4,  4a  and  4b  of  Directive  65/65/EEC,

accompanied, 

appropriate, 

by 

as 

-(cid:217)the  applicant  must  certify 

the  dossier
submitted  is  identical  to  that  accepted  by  the  first
Member  State  and  he  shall  certify  that  the
summary  of  the  product  characteristics  proposed

that 

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by  him  is  identical  to  that  accepted  by  the  first
Member  State.  Moreover  he  shall  certify  that  all
the  dossiers  filed  as  part  of  the  procedure  are
identical.

Where  an  applicant  fulfils  these  conditions  the  first
marketing  authorisation  has  to  be  recognised, 
in
particular  the  SPC  as  approved  by  the  first  Member
State.  In  cases  where  a  Member  State  cannot
recognise  the  marketing  authorisation  of  the  first
Member  State,  then  the  matter  is  referred  for  arbi(cid:220)
tration  (Article  10  of  Directive  75/319/EEC)(cid:216)(ˇ(cid:209)).

(b) Identical  SPC  and  identical  dossiers

to  that  accepted  by  the  first  Member  State,  or  shall
identify  any  additions  or  amendments 
it  may
contain’.  Identical  products  with  an  identical  SPC
should  be  based  on  identical  dossiers  because  any
variation  introduced  between  the  granting  of  the  first
marketing  authorisation  and  an  application 
for
mutual  recognition  should  at  least  have  been  notified
to  the  competent  authority  and  should  already  be
taken  up  in  the  existing  dossier  for  the  product.  In
order  to  make  sure  that  a  full  harmonisation  is
achieved  in  the  mutual  recognition  procedure,  legis(cid:220)
lation  explicitly  addresses  this  issue  and  asks  the
applicant  to 
identify  any  need  for  updating  the
dossier  on  the  occasion  of  a  planned  mutual  recog(cid:220)
nition.

(c) Content  of  the  dossier

Article  9  requires  explicitly  that  the  "summary  of  the
product  characteristics  proposed  by  the  applicant  in
accordance  with  Article  4a  of  Directive  65/65/EEC
is  identical  to  that  accepted  by  the  first  Member
State’.  This  provision  states  clearly  that  the  SPCs  of
medicinal  products  undergoing  the  mutual  recog(cid:220)
nition  procedure  have  to  be  identical.  The  only  parts
of  the  SPC  which  need  not  be  identical  are:

-(cid:217)the  "name  of  the  medicinal  product’(cid:216)(ˇ(cid:210))  (because
the  name  constitutes  a 
formal  and  not  a
substantive  element  of  the  identity  of  a  product),
and

-(cid:217)the  "name  of  the  marketing  authorisation  holder’
(because  applicants  belonging  to  the  same  mother
company  or  group  of  companies  and  applicants
having 
exercising
concerted  practices  concerning  the  placing  on  the
market  of  the  relevant  medicinal  product  have  to
be  taken  as  one  entity).

concluded  agreements  or 

Applicants  should  be  aware  however  that  normally
an  identical  name  should  be  chosen  for  an  identical
product,  unless  there  are  compelling  reasons  not  to
do  so.

According  to  Article  9,  the  applicant  for  mutual
recognition  "shall  testify  that  the  dossier  is  identical

(ˇ(cid:209))(cid:217)For  veterinary  medicinal  products  any  reference  to  this
Article  has  to  be  understood:  Article  18  of  Directive
81/851/EEC.

(ˇ(cid:210))(cid:217)At  the  end  of  the  mutual  recognition  procedure,  there  will
be  only  one  brand  name  approved  per  marketing  author(cid:220)
isation  granted  (national  marketing  authorisations)  which  is
consistent  with  the  current  provisions  of  Community  law  as
underlined  under  point  C.

legislation 

procedure 

recognition 

required  by 

The  fact  that  the  applicant  for  mutual  recognition  is
explicitly 
submit  an
to 
application  together  with  all  relevant 
information
and  particulars  illustrates  a  general  principle  of  the
mutual 
for  medicinal
products:  "every  concerned  Member  State  shall  have
a  complete  dossier  at  its  disposal’.  A  situation  in
which 
just  one  Member  State  has  the  complete
dossier  while  other  concerned  Member  States  merely
rely  on  the  dossier  in  another  Member  State,  is
therefore  not  the  situation  envisaged  by  legislation.
This  fact  has,  as  will  be  addressed  below,  important
repercussions  particularly  for  the  mutual  recognition
of  generic  medicines.

As  previously  underlined,  the  holder  of  the  author(cid:220)
isation  shall  submit  -  together  with  the  application
for  mutual  recognition  -  all  the  information  and
particulars  referred  to 
in  Articles  4  and  4a  of
Directive  65/65/EEC.

certain  derogations 

Article  4(3)(8a)  grants 
to
applicants  concerning  the  need  to  provide  the  results
of  pharmacological  and  toxicological  tests  or  the
results  of  clinical  trials.  According  to  the  principle
established  above  that 
"every  concerned  Member
State  should  have  a  complete  dossier  at  its  disposal’,
an  applicant  may  make  use  of  these  derogations  in
the  mutual  recognition  process  only  if  the  specific
conditions  outlined  in  Article  4(3)(8a)(cid:216)(ˇ(cid:211))  are  also
met  in  the  Member  State(s)  in  which  mutual  recog(cid:220)

(ˇ(cid:211))(cid:217)It  has  to  be  pointed  out  that  these  specific  conditions  have
remained  unchanged  in  spite  of  the  setting  out  of  the
mutual  recognition  procedure  (and  of  the  centralised  one).

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nition 
State(s)).  This  means  specifically:

is  applied 

for 

(the  concerned  Member

automatically  met 
States  when  demonstrated 
Member  State.

in 

the  concerned  Member
reference
the 

in 

-(cid:217)In 

in  which  the 

the  case  of  Article  4(3)(8a)(i)  ("informed
consent’),  the  product  to  which  essential  simi(cid:220)
larity  is  claimed  has  to  be  authorised  both  in  the
reference  and  the  concerned  Member  State(s)
and  essential  similarity  has  to  be  demonstrated  by
the  applicant  in  all  these  Member  States  (except
"original  product’  has
for  cases 
in  the
already  undergone  mutual  recognition 
concerned  Member  States.  In  such  cases  the
criteria  of  essential  similarity  are  automatically
met).  Moreover,  the  consent  of  the  marketing
authorisation  holder  of  the  original  product  has
to  cover  the  use  of  the  pharmacological,  toxico(cid:220)
logical  or  clinical  references  contained  in  the  file
of 
in  each
the  original  medicinal  product 
Member  State  concerned  by  the  procedure.

-(cid:217)In 

the  applicant  has 

to  published 
in 

the  case  of  Article  4(3)(8)(a)(ii)  ("biblio(cid:220)
to
graphical  application’) 
provide  the  Member  State  involved  in  the  mutual
recognition  procedure  with  a  complete  dossier
including  the  proof  of  the  well(cid:220)established  use  of
the  constituent(s)  of  the  product  through  detailed
literature
references 
scientific 
presented 
accordance  with  Directive
75/318/EEC.  It  must  also  be  stressed  that  all
requirements  laid  down  in  this  Directive  have  to
be  addressed  in  the  application.  The  applicant
had  of  course  the  choice  of  the  bibliographical
data  on  which  it  based  the  application  in  the
reference  Member  State.  The  acceptance  of  these
bibliographical  data  by  the  reference  Member
State  gives  the  framework  for  the  issuing  of  the
marketing  authorisation 
to
mutual  recognition.  According  to  the  abovemen(cid:220)
tioned  Article,  the  data  submitted  have  to  prove
recognised  efficacy  and  an  acceptable  level  of
safety  as  far  as  the  constituent(s)  of  the  medicinal
product  on  evaluation  is  concerned.  Applications
filed  in  this  context  are  and  have  to  stay,  by  defi(cid:220)
nition,  complete  and  independent  ("stand  alone
applications’).

later  on 

subject 

in 

Moreover,  the  product  to  which  essential  similarity  is
claimed  must  have  been  authorised  within 
the
accordance  with  Community
Community, 
provisions  in  force  for  not  less  than  six  (or  10)  years.
If  the  protection  period  is  equal  in  all  the  concerned
Member  States,  no  problem  will  arise;  if,  however,
the  protection  period  in  the  concerned  Member  State
is  longer  than  in  the  reference  Member  State,  mutual
recognition  in  the  concerned  Member  State  is  not
possible  before  the  expiry  of  the  10(cid:220)year  period.

(d) Specific  cases  regarding  generic  products

Community  legislation  has  not  foreseen  any  kind  of
derogation  as  regards 
the  eligibility  of  generic
products  to  the  mutual  recognition  procedure  and
the  implementation  of  this  procedure  as  far  as  they
are  concerned.

to 

the  peculiarities  of 

Due 
the
Commission  would  like  to  emphasise  the  following
points.

these  products, 

For  applications  for  mutual  recognition  of  marketing
authorisations  of  generic  medicinal  products 
in
Member  States  in  which  the  summary  of  product
to  which
the  original  product 
characteristics  of 
essential  similarity 
is  not  harmonised,
is  claimed 
essential  similarity  has  to  be  demonstrated  by  the
is
applicant 
particularly  required  that  all  the  indications  in  the
SPC  proposed  by  the  generic  application  (as  auth(cid:220)
orised  by  the  reference  Member  State)  must  be  in  the
SPC  of  the  original  product,  which  may  have,  at
in  some  of  the  concerned  Member  States,
least 
additional  ones.

in  all  concerned  Member  States.  It 

-(cid:217)In 

the  case  of  Article  4(3)(8a)(iii)  ("generic
application’),  the  product  to  which  essential  simi(cid:220)
larity  is  claimed  has  to  be  authorised  both  in  the
reference  and  the  concerned  Member  State(s)
and  essential  similarity  has  to  be  demonstrated  by
the  applicant  in  all  concerned  Member  States,
except  for  cases  in  which  the  "original  product’
has  already  undergone  a  Community  procedure;
in  such  cases  the  criteria  of  essential  similarity  are

produce 

appropriate 

bioavailability 

The  proof  of  essential  similarity  can  include  the  need
to 
studies.
However,  even  in  cases  where  the  original  products
(or,  to  be  more  precise:  the  SPCs  of  the  original
products)  are  not  (yet)  harmonised,  Member  States
have  to  take  into  account  -  as  far  as  possible  and
relevant  -  the  results  of  bioavailability  studies  used
in  the  reference  Member  State.

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in 
in 

"essential  similarity’ 

Difficulties  could  be  encountered  arising  from  the
mutual  recognition  of  a  "generic’  medicinal  product’s
some  cases
marketing  authorisation  because 
mutual  recognition  would  result 
(horizontal)
harmonisation  across  Member  States  of  the  SPC  of  a
generic  product  but  (vertical)  disharmony  within
individual  Member  States  between  the  harmonised
generic  SPC  and  the  SPC  of  the  original  product  in
the  same  Member  States.  This  is  due  to  the  fact  that
the  "original’  product,  i.e.  the  first  marketing  author(cid:220)
isation  granted  to  the  inventor  company,  and  against
which 
is  claimed,  does  not
always  have  the  same  summary  of  product  charac(cid:220)
teristics  across  all  Member  States.  This  situation  can
be  tolerated  insofar  as  it  does  not  lead  to  a  public
health  problem.  In  cases  where  it  presents  a  serious
risk  to  public  health  (mainly  as  regards  contra(cid:220)indi(cid:220)
cations,  undesirable  effects,  precautions  of  use,  etc.),
the  matter  will  have  to  be  referred  to  arbitration
pursuant  to  Article  10  of  Directive  75/319/EEC  as
far  as  the  generic  product 
is  concerned  and  a
procedure  based  on  Article  11  of  the  same  Directive
will  ensure  a  parallel  harmonisation  of  the  national
SPCs  of  the  original  product.

5.(cid:217)Mutual  recognition,  procedure  triggered  by  a  Member

State  (Article  7a  of  Directive  65/65/EEC)

Article  7a  of  Directive  65/65/EEC  (which  became
binding  as  of  1  January  1998)  creates  an  obligation  on
Member  States  to  initiate,  each  time  it  is  applicable,  a
mutual  recognition  procedure 
the
course  of  action  chosen  by  an  applicant.  This  binding
provision  refers  to  all  applications  validated  as  of  1
January  1998.  Therefore,  from  1  January  1998  onwards,
any  application  regarding  a  medicinal  product  which  is
already  covered  by  an  existing  marketing  authorisation
in  another  Member  State  will  have  to  be  considered  in
the  context  of  the  mutual  recognition  procedure.

independently  of 

This  procedure  has  thus  to  be  considered  as  a  "catch(cid:220)all’
provision  given  to  the  Member  States  in  order  to  secure
of  Community 
an 
law
the  mutual  recognition  of
provisions  dealing  with 
national  marketing  authorisations.

implementation 

efficient 

this 

In 
that
differences  between  the  SPC  already  approved  in  one

the  Commission 

considers 

context, 

Member  State  and  the  proposed  SPC,  part  of  the
application  under  consideration 
in  another  Member
State,  do  not  automatically  prevent  the  latter  from  trig(cid:220)
gering  a  mutual  recognition  procedure(cid:216)(ˇ(cid:212)).  If 
these
differences  have  no  therapeutic  implications(cid:216)(ˇ(cid:213)),  i.e.  both
products  have  the  same  qualitative  and  quantitative
composition  in  active  substances  (i.e.  the  same  strength)
and  the  same  pharmaceutical  form,  they  have  to  be
considered  as  being  the  same  and  a  mutual  recognition
procedure  has  to  be  followed.

However,  in  the  case  of  a  medicinal  product  with  a  well(cid:220)
established  use  demonstrated  in  accordance  with  Article
4(3)(8)(a)(ii)  of  Directive  65/65/EEC  ("bibliographical
application’),  this  well(cid:220)established  use  being  based  on
data  referring  to  an  existing  group  of  products  with
different  SPCs  in  the  Member  States,  national  inde(cid:220)
pendent  procedures  could  continue  to  be  followed  as  far
as  no  Community  harmonisation  of  the  use  of  the
constituent(s)  of  the  said  product  exists;  the  purposes  of
Article  7a  of  Directive  75/319/EEC  being  not  to  provide
harmonisation  of  an  entire 
therapeutic  class  or  a
complete  group  of  products.  In  any  case,  Article  11  of
the  same  Directive  remains,  of  course,  applicable.

6.(cid:217)Simultaneous  applications  (Article  7(2)  of  Directive

65/65/EEC)

Article  7(2)  of  Directive  65/65/EEC  offers  Member
States 
to  start  a  mutual  recognition
procedure,  where  an  application  lodged  in  one  Member

the  possibility 

(ˇ(cid:212))(cid:217)This  of  course  applies  if  the  applicant  is  the  same  in  the
concerned  Member  States.  However  applicants  belonging  to
the  same  mother  company  or  group  of  companies  have  to
be  taken  as  one  entity.  Applicants  which,  without  belonging
to  the  same  mother  company  or  group  of  companies,  have
concluded  agreements  (e.g.  "licensees’)  or  which  exercise
concerted  practices  concerning  the  placing  on  the  market  of
the  relevant  medicinal  product  in  different  Member  States,
also  have  to  be  taken  as  one  (see  also  point  E.3).

(ˇ(cid:213))(cid:217)The  same  approach  has  been  followed  already  by  the  ECJ
in  the  context  of  parallel 
if  the
imported  product  is  the  same  as  the  one  already  marketed
in  the  country  of  import  and  thus  can  be  covered  by  the
same  marketing  authorisation  (e.g.  see  Case  C(cid:220)201/94  The
Queen  v. 
the  Medicines  Control  Agency  ex  parte
Smith(cid:216)&(cid:216)Nephew  Pharmaceuticals  Ltd  [1996(cid:129)  ECR  I(cid:220)5846).

imports  to  determine 

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State  is  already  under  active  examination  in  another
Member  State.

7.(cid:217)Maintenance  of  achieved  harmonisation

This  provision  explicitly  covers  only  cases 
in  which
identical  applications  are  pending  in  different  Member
States  and  in  which  an  earlier  authorisation  was  not  yet
granted  in  another  Member  State.  Cases  in  which  a
marketing  authorisation  has  already  been 
in
another  Member  State  are  not  covered  by  this  Article.  In
such  cases  Article  7a  of  Directive  65/65/EEC  applies.

issued 

"may’ 

in  Article  7(2) 

submitted  after  1 

implies  that  the
The  wording 
concerned  Member  State  has  an  option 
to  choose
whether  to  suspend  the  authorisation  procedure  and
await  the  assessment  report  prepared  by  the  other
Member  State  or  to  proceed  with  the  application.  This
provision  is  applicable  and  remains  applicable  for  all
applications 
January  1995.  The
entering  into  force  of  Article  7a  on  1  January  1998  has
no  direct  effect  on  the  applicability  of  this  provision.
in
Different  Member  States 
parallel  with  simultaneous  and 
identical  applications
under  Article  7(2)  even  after  1  January  1998.  However,
this  possibility  is  only  theoretical,  because  as  soon  as  one
of  the  two  Member  States  actually  grants  a  marketing
authorisation,  Article  7a  of  Directive  65/65/EEC
becomes  applicable  and  the  Member  State  which  has  not
yet  granted  an  authorisation  must  start  a  mutual  recog(cid:220)
nition  procedure  in  accordance  with  this  Article.

"may’  therefore  go  on 

Since  the  application  must  be  under  active  examination
in  the  other  Member  State,  this  mechanism  requires
Member  States  to  actively  cooperate.  Having  determined
that  the  application  is  under  active  examination,  the
Member  State  which  has 
its  evaluation
informs  the  other  (reference)  Member  State  and  the
applicant  of  its  decision  to  suspend  detailed  examination
of  the  application  in  question.

suspended 

Within  90  days  of  the  receipt  of  the  assessment  report
which  has  been  prepared  during  the  examination  of  the
application,  the  Member  State  which  suspended  the
examination  shall  either  recognise  the  decision  of  the
other  (reference)  Member  State  and  the  summary  of  the
product  characteristics  as  approved  by 
it
considers  that  there  are  grounds  for  supposing  that  the
authorisation  of  the  medicinal  product  concerned  may
present  a  risk  to  public  health, 
it  shall  apply  the
procedures  set  out  in  Articles  10,  11  and  12  of  Directive
75/319/EEC  ("arbitration  procedure’).

it,  or, 

if 

As  already  stressed  above,  the  mutual  recognition  of
marketing  authorisations  for  medicinal  products  is  based
on  the  principle  that  the  SPCs  for  products  that  have
undergone  the  mutual  recognition  procedure  shall  be
identical  and  remain  identical  in  all  concerned  Member
States.  This  principle,  enshrined 
in  Article  15  of
Directive  75/319/EEC,  clearly  covers  all  marketing
authorisations  which  have  been  granted  following  the
procedures 
of  Directive
75/319/EEC  and  Articles  7  and  7a  of  Directive
65/65/EEC.

in  Article 

foreseen 

9 

The  principle  that  achieved  harmonisation  has  to  be
maintained  is,  however,  not  limited  to  products  which
have  undergone  mutual 
already
mentioned  above,  it  also  covers  all  other  cases  in  which  a
through  any
SPC  was 
Community  procedure.

fully  or  partly  harmonised 

recognition.  As 

The  following  list  indicates  the  cases  in  which  authoris(cid:220)
ations  have  to  be  considered 
in  any  case  as  being
harmonised  in  all  the  concerned  Member  States:

-(cid:217)medicinal  products  which  have  been  considered
scope  of  application  of  Directive

within 
87/22/EEC(cid:216)(ˇ(cid:214))  (ex(cid:220)concertation  products),

the 

-(cid:217)medicinal  products  which  have  benefited  from  the
procedures  of  mutual  recognition  foreseen  in  Articles
7  and  7a  of  Directive  65/65/EEC,

-(cid:217)medicinal  products  authorised  according  to  Article

9(4)  of  Directive  75/319/EEC,

-(cid:217)medicinal  products  which  have  been  the  subject  of  a
referral  to  the  procedures  foreseen  by  Articles  11  and
12  of  Directive  75/319/EEC(cid:216)(—˝).

(ˇ(cid:214))(cid:217)OJ  L  15,  17.1.1987,  p.  38, 

repealed  by  Directive

93/41/EEC.

(—˝)(cid:217)For  veterinary  medicinal  products  any  references  to  this
Article  has  to  be  understood:  Article  19  or  20  of  Directive
81/851/EEC.

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8.(cid:217)Fixed  combination  of  products

Member  States, 
it  would  clearly  not  be  possible  to
exclude  such  a  case  from  the  scope  of  application  of  the
mutual  recognition  procedure.

Questions  may  arise  concerning  the  procedure  applicable
for  the  authorisation  of 
"combination  products’  (i.e.
products  containing  two  or  more  medicinal  products  -
like  vaccines  -  in  a  fixed  combination)  when  the  SPCs
of  one  or  more  products  contained  in  the  combination
product  are  already  harmonised.  Strictly  speaking,  any
combination  product  is  a  separate  and  unique  product,
requiring  a  separate  authorisation  and  separate  SPC.  The
combination  product  can  therefore  never  be  seen  as  "the
to  a  product
same’  or  as  an 
combination.  Nevertheless,  a
encompassed 
competent  authority 
the  situation
in 
described  above  -  to  take  into  account  and  to  respect
the
the  harmonisation  already  achieved  as 
assessment  of  one  or  more  parts  of  the  combination
product  is  concerned.  Otherwise  there  would  be  a  clear
case  for  making  use  of  the  provision  of  Article  12  of
Directive  75/319/EEC  in  order  to  maintain  harmon(cid:220)
isation.

"identical  product’ 
the 

is  obliged  - 

far  as 

in 

9.(cid:217)Application  of  the  mutual  recognition  provisions  to
"line  extensions’  of  non(cid:220)harmonised  national  marketing
authorisations

Some  fundamental  changes  (e.g.  changes  to  the  thera(cid:220)
peutic  indications  or  changes  to  strength,  pharmaceutical
form  and  route  of  administration)  to  a  marketing  auth(cid:220)
orisation  require  an  application  for  a  new  marketing
authorisation  to  be  made.

the 

through 

The  fact  that  applications  for  such  changes  have  to  be
made 
evaluation  procedure
scientific 
normally  required  for  new  applications  and  not  through
a  more  simplified  procedure  ("variations  procedure’)
must  not  disguise  the  fact  that,  from  the  point  of  view  of
the  Commission,  the  applicant,  in  such  cases,  applies  for
a  change  to  an  existing  marketing  authorisation  and  not
for  a  completely  new  one.  When  such  changes  regard
new  strengths,  new  pharmaceutical  forms  or  new  indi(cid:220)
cations,  they  are  called  deliberately  line  extensions  of  an
existing  marketing  authorisation.

It  is  worth  mentioning  in  this  context  the  case  where  an
applicant  initially  was  granted  for  the  same  medicinal
product  two  different  and  purely  national  authorisations
in  different  Member  States.  If,  afterwards,  the  same
applicant  wished  -  by  lodging  applications  for  changes
or  variations  of  the  national  marketing  authorisations  -
to  obtain  harmonised  national  authorisations  in  different

In  such  a  case,  the  application  for  the  relevant  change  or
variation  will  have  to  be  considered  as  an  application  for
an  authorisation 
the
meaning  of  Article  9  of  Directive  75/319/EEC  with  the
resulting  legal  consequences.

the  same  product  within 

for 

It  goes  without  saying  that  -  as  in  any  other  case  of
mutual  recognition  -  the  criteria  concerning  the  identity
of  the  product  and  the  identity  and  completeness  of  the
dossier  have  to  be  fulfilled.  In  other  terms,  prior  to  any
mutual  recognition  procedure  for  "line  extensions’,  the
applicant  will  have  to  harmonise  the  already  approved
national  SPC  in  order  to  support  his  applications  in  all
the  concerned  Member  States  with  the  same  dossier.
This  a  priori  harmonisation  can  be  achieved  either
through  a 
coordinated  national  variation
procedures(cid:216)(—˛)  or  through  the  Community  procedure
foreseen  in  Article  11  of  Directive  75/319/EEC.  If  the
applicant  chooses  to  submit  a  completely  new  dossier
without  any  cross(cid:220)references  to  the  dossiers  supporting
the  existing  national  authorisations,  such  prerequisite
harmonisation  is,  of  course,  not  needed.

set  of 

CONCLUSION

The  new  Community  system  for  marketing  authoris(cid:220)
ations  was  set  out  in  1993  to  provide  harmonisation  and
coherence  in  a  very  specific  market,  which  was  still
deeply  heterogeneous  and  partitioned  in  spite  of  nearly
30  years  of  elaboration  of  common  technical  standards
and  criteria.  Since  1995  and  even  more  since  1  January
1998  with  the  end  of  the  transitional  arrangements  in  the
mutual  recognition  procedure,  a  new  European  legal
environment  exists  which  has  to  be  used  to  ensure  a
gradual,  continuous  and  sustained  harmonisation  of  all
medicinal  products  accessing  the  Community  market.

the 

such 

providing 

harmonisation, 

While 
new
Community  system  for  marketing  authorisation  serves
three  separate  interests.  To  the  citizens  of  Europe,  it
guarantees  that  new  medicinal  products  marketed  in  the
Community  have  been  independently  evaluated  to  a  high
scientific  standard  of  quality,  safety,  and  efficacy  and  it
aims  at  assuring  that  the  same  medicinal  products  will  be
the
used  under 
European  Union.  To  the  pharmaceutical 
it
offers  fast  access  to  the  Single  European  Market,  either
through  a  single  Community  authorisation  or  through

throughout 

conditions 

industry, 

same 

the 

(—˛)(cid:217)Commission  Regulation  (EC)  No  541/95  is  not  applicable
independent  national  marketing  authorisations  which

to 
have  not  benefited  from  any  Community  procedures.

22.7.98

EN

Official  Journal  of  the  European  Communities

C  229/17

the  effect  of  mutual  recognition.  Lastly,  but  not  least,  it
makes  for  more  rational  use  of  the  resources  needed  for
authorisation  and  monitoring  of  medicinal  products  by
eliminating  the  duplication  of  evaluation  that  charac(cid:220)
terised  the  former  system.

level 

However,  the  role  of  public  authorities  at  national  and
Community 
is  confined  to  creating  appropriate
economic  and  regulatory  conditions,  and  it  is  therefore
up  to  economic  operators  to  make  the  most  of  the  Single
Market.  In  such  a  context  it  is  of  the  utmost  importance
that  the  pharmaceutical  companies  become  fully  inte(cid:220)
grated  into  the  new  legal  and  regulatory  environment
and  duly  take  into  account  in  their  different  projects  and
commercial  strategies,  the  new  "rules  of  the  game’.

The  Member  States  have  been  diligent  in  putting  into
place  Single  Market  legislation  and  applying  Community
guidelines  on  the  development  of  medicinal  products.

However,  divergent 
interpretations  within  national
administrations,  a  certain  unwillingness  to  rely  on  other
Member  States’ 
scientific  evaluation  and  additional
lengthy  national  administrative  procedures  (issuance  of
administrative  decisions)  have  prevented  the  full  benefit
of  the  new  procedures  from  being  realised.  These  delays
at  national  level  continue  to  limit  the  Single  Market’s
positive  contribution  to  public  and  patient  access  to
medicinal  products.

In  order  to  remedy  this  situation  and  more  generally  to
improve  the  functioning  of  the  procedures,  modifications
of  the  current  legal  texts  could  be  needed  and  this  will
have  to  be  addressed  in  the  course  of  the  overall  review
of  the  new  system  which  is  due  to  take  place  in  the  year
2000.  In  order  to  prepare  this  exercise,  the  Commission
looks 
the
national  administrations,  from  the  EMEA  and  all  other
interested  parties  (consumers’  and  patients’  associations,
pharmaceutical  companies,  industry  federations,  etc.).

to  receiving  contributions 

forward 

from 

Non(cid:220)opposition  to  a  notified  concentration

(Case  No  IV/M.1218  -  Packaging  International  BV/NV  Koninklijke  KNP  BT)

(98/C  229/04)

(Text  with  EEA  relevance)

On  3  July  1998,  the  Commission  decided  not  to  oppose  the  above  notified  concentration  and
to  declare  it  compatible  with  the  common  market.  This  decision  is  based  on  Article  6(1)(b)  of
Council  Regulation  (EEC)  No  4064/89.  The  full  text  of  the  decision  is  only  available  in
English  and  will  be  made  public  after  it  is  cleared  of  any  business  secrets  it  may  contain.  It  will
be  available:

-(cid:217)as  a  paper  version  through  the  sales  offices  of  the  Office  for  Official  Publications  of  the

European  Communities  (see  list  on  the  last  page),

-(cid:217)in  electronic  form  in  the  "CEN’  version  of  the  CELEX  database,  under  document  number
398M1218.  CELEX  is  the  computerised  documentation  system  of  European  Community
law;  for  more  information  concerning  subscriptions  please  contact:

EUR(cid:220)OP,
Information,  Marketing  and  Public  Relations  (OP/4B),
2,  rue  Mercier,
L(cid:220)2985  Luxembourg.
Tel.  (352)  29(cid:216)29(cid:220)42455,  fax  (352)  29(cid:216)29(cid:220)42763.