Commission staff working document - Regulatory process for the authorisation of antiviral medicines and vaccines in the protection against Pandemic Influenza (H1N1) 2009 - Accompanying document to the Communication from the Commission to the Council, the European Parliament and the European Economic and Social Committee and the Committee of the Regions : Pandemic Influenza A (H1N1) 2009 {COM(2009) 481} {SEC(2009) 1188} {SEC(2009) 1189} {SEC(2009) 1190} {SEC(2009) 1192}
Date: 2009-09-15
Institutions: European Commission
Subjects: disease prevention, epidemiology, health control, health risk, infectious disease, medicinal product, public health, vaccination, vaccine

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COMMISSION OF THE EUROPEAN COMMUNITIES 

Brussels, 15.9.2009 
SEC(2009) 1191 final 

COMMISSION STAFF WORKING DOCUMENT 

Regulatory process for the authorisation of antiviral medicines and vaccines in the 
protection against Pandemic Influenza (H1N1) 2009 

Accompanying document to the 

COMMUNICATION FROM THE COMMISSION TO THE COUNCIL,  
THE EUROPEAN PARLIAMENT AND THE EUROPEAN ECONOMIC AND 
SOCIAL COMMITTEE AND THE COMMITTEE OF THE REGIONS 

Pandemic Influenza A (H1N1) 2009 

{COM(2009) 481} 
{SEC(2009) 1188} 
{SEC(2009) 1189} 
{SEC(2009) 1190} 
{SEC(2009) 1192} 

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TABLE OF CONTENTS 

Executive summary and conclusions ......................................................................................... 3 

1. 

2. 

2.1. 

2.2. 

2.3. 

3. 

3.1. 

3.2. 

3.3. 

3.4. 

3.5. 

4. 

4.1. 

4.2. 

5. 

6. 

Types of marketing authorisations for medicinal products.......................................... 4 

authorised antiviral medication in the EU to address the new influenza ..................... 4 

Authorised antiviral medicinal products ...................................................................... 4 

Regulatory status of medicines containing Oseltamivir and Zanamivir ...................... 5 

Variation of Tamiflu® (Oseltamivir) and Relenza® (Zanamivir)............................... 5 

Regulatory procedure for the authorisation of new vaccines iN the EU...................... 6 

New vaccines ............................................................................................................... 6 

Authorised vaccines (under exceptional circumstances) ............................................. 7 

Variations of authorised vaccines ................................................................................ 8 

Specific considerations for specific population groups ............................................... 8 

Specific legal provisions for the distribution by Member States ................................. 9 

Accelerated procedures for the Influenza A (H1N1) vaccines) ................................... 9 

Authorisation and variation of vaccines....................................................................... 9 

Official Control Authority Batch Release (OCABR) ................................................ 10 

Pharmacovigilance ..................................................................................................... 11 

Cooperation with international partners..................................................................... 12 

Annex 1: Scientific recommendations of the CHMP concerning the use of Tamiflu® and of 

the CMD(h) concerning Relenza® ............................................................................ 13 

Annex 2: Special features of Influenza Vaccines..................................................................... 14 

Annex 3: Accelerated procedures for the authorisation and variation of vaccines .................. 15 

Annex 4: Detailed requirements for pharmacovigilance.......................................................... 18 

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EXECUTIVE SUMMARY AND CONCLUSIONS 

On  11  June  2009  the  WHO  declared  the  influenza  pandemic.  Moreover  the  Strategic 
Advisory  Group  of  Experts  (SAGE)  of  the  WHO  recommended  that  healthcare  workers 
should  be  vaccinated  as  a  first  priority  to  protect  the  essential  health  infrastructure.  SAGE 
suggested  the  following  order  of  priority  encompassing  the  whole  population:  pregnant 
women, those aged above 6 months with one or several chronic medical conditions, healthy 
young  adults  of  15  to  49  years  of  age,  healthy  children,  healthy  adults of  50  to  64  years  of 
age, and healthy adults of 65 years of age and above. WHO endorsed these recommendations 
on  11  July  2009.1  The  EU  Member  States  are  responsible  for  the  definition  and 
implementation of any strategy for vaccination, while both the EU and the Member States are 
the  needed 
carrying 
pharmacovigilance.  On  this  basis,  Member  States  developed  a  shared  approach  for  priority 
groups for vaccination, which was published on 25 August 2009.2 

the  authorisation  of  vaccines  and 

responsibilities 

for 

for 

The  EU  has  already  started  taken  action  to  tackle  the  pandemic.  While  various  anti-viral 
medicines  received  approval  for  marketing  in  the  past  and  are  available  for  treatment  of 
pandemic  influenza  in  the  EU,  new  measures  have  been  concentrated  on  an  accelerated 
assessment of new applications for marketing authorisations of Influenza A (H1N1) vaccines 
and  variations  thereof.  Both  the  European  Medicines  Agency  (EMEA)  and  Member  States 
have received or are expecting applications for market authorisations and variations thereof. 
Community  legislation  provides  for  a  sound  legal  framework  to  address  the  challenges  of  a 
pandemic  influenza.  For  defined  categories  of  medicinal  products,  such  as  vaccines 
manufactured  using  a  biotechnological  process,  the  central  authorisation  process  for 
marketing  is  mandatory.  The  national  authorisation  procedure  is  applicable  to  all  other 
procedures and under certain conditions there is a choice between the two procedures. On the 
basis of these provisions, swift scientific assessment of Influenza A (H1N1) 2009 vaccines by 
the EMEA and a swift subsequent Commission Decision on the marketing authorisation will 
be ensured with the objective to have substantial amounts of safe vaccines available across the 
EU 27. 

Moreover,  Community  legislation  has  specific  legal  provisions  in  the  case  of  a  declared 
pandemic  influenza.  The  Commission  has  underpinned  legislation  by  regulatory  guidelines 
and the EMEA has, through its scientific committees, adopted scientific guidelines including 
guidelines for pandemic vaccines. Specifically designed processes for the scientific evaluation 
of a variation of pandemic vaccines are intended to allow for best possible planning reliability 
in  the  case  companies  intend  to  start  early  production.  In  addition,  the  EMEA  is  in  close 
contact  on  an  exchange  and  sharing  of  strategies  for  drug  development,  assessment  and 
scientific  information  with  major  international  partners,  with  which  a  confidentiality 
agreement exists (US, Canada, Japan). 

Scientific  assessment  of  the  risk-benefit  balance  of  any  vaccine  to  be  authorised  for  the 
protection against Influenza A (H1N1) 2009 will be important on the basis of available data in 
the current pandemic situation. In any case depending on the evolvement of the real situation 
the EU has all means at its disposal to act as rapidly as needed. Equally important for public 
trust  and  confidence  is  pharmacovigilance.  After  an  authorisation  for  marketing  of  vaccines 

1 
2 

http://www.who.int/csr/disease/swineflu/notes/h1n1_vaccine_20090713/en/index.html 
http://ec.europa.eu/health/ph_threats/com/Influenza/docs/HSC_EWRS_statement_en.pdf 

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has been granted, companies will  be subject to intensive pharmacovigilance monitoring and 
reporting  obligations.  When  deemed  necessary  from  a  risk-benefit  perspective,  competent 
authorities will take the necessary actions with respect to the marketing authorisation granted. 
This  may  include,  but  is  not  limited  to,  a  widening  or  a  restriction  of  the  scope  of  the 
marketing  authorisation  with  respect  to  patient  population,  contraindications  and  posology 
amongst others.  

The  Commission  will  facilitate  as  much  as  possible  cooperation  and  the  exchange  of 
information. 

Cooperation  with  WHO  is  crucial.  In  order  to  develop  vaccines  against  novel  influenza, 
manufacturers depend on the isolation and supply of the relevant virus strains by the World 
Health  Organization, which provided the Influenza A (H1N1) 2009 strains in May 2009. In 
addition,  the  WHO  may  proceed  to  issue  specific  recommendations  for  the  development  of 
this vaccine and on the continued production of seasonal vaccines. 

Furthermore,  after  the  declaration  of  the  pandemic  by  WHO  there  are  specific  provisions 
which  allow  certain  flexibility  on  the  extent  of  data  requirements  to  support  a  marketing 
authorisation  application  and  variations  thereof,  and  the  subsequent  timeframe  for  its 
regulatory  assessment.  In  any  case  the  risk-benefit  assessment  has  to  be  positive  for  each 
vaccine. 

1. 

TYPES OF MARKETING AUTHORISATIONS FOR MEDICINAL PRODUCTS 

Anti-viral medication and vaccines are legally defined as medicinal products.3 

In the EU, medicinal products and their variations are subject to authorisation for marketing 
either  at  a  national  level  ("national  authorisation")  or  at  Community  level,  through 
Commission  Decision,  on  the  basis  of  a  scientific  opinion  coordinated  by  the  European 
Medicines  Agency  EMEA  ("central  authorisation").  The  latter  is  mandatory,  inter  alia, 
when a biotechnological process such as reverse genetics techniques for the manufacturing of 
vaccines is involved. Otherwise, under certain conditions, the manufacturer is free to choose 
whether to go for national or Community authorisation. The challenge is to ensure that both 
routes are providing for efficient and fast solutions which respond to citizen's concerns. 

2. 

AUTHORISED ANTIVIRAL MEDICATION IN THE EU TO ADDRESS THE NEW INFLUENZA 

2.1. 

Authorised antiviral medicinal products 

There  are  presently  four  antiviral  drugs  authorised  and  available  for  treatment  and  post-
exposure  prevention  of  influenza4  and  these  belong  to  two  classes:  adamantane  (M2) 
inhibitors  (Amantadine  and  Rimantadine)  and  neuraminidase  inhibitors  (Oseltamivir  and 
Zanamivir).  

The  novel  influenza  viruses  first  detected  in  humans  in  Mexico  were  however  found  to  be 
resistant  to  Amantadine  and  Rimantadine.  Instead  laboratory  testing  indicated  that  these 
viruses may be susceptible to Oseltamivir and Zanamivir.  

Article 1 of Directive 2001/83/EC 

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Based  on  current  information,  the  WHO  evaluates  that  cases  of  resistance  of  Influenza  A 
(H1N1)  2009  to  neuraminidase  inhibitors  recently  reported  appear  to  be  sporadic.  At  this 
time,  there  is  no  evidence  to  indicate  the  development  of  widespread  antiviral  resistance 
against neuraminidase inhibitors. Therefore, the WHO concluded that antiviral drugs remain a 
key component of the public health response when used as recommended.  

2.2. 

Regulatory status of medicines containing Oseltamivir and Zanamivir 

A medicinal product with the active substance Oseltamivir has been centrally authorised as 
Tamiflu® with a marketing authorisation valid since 20 June 2002. Oseltamivir is indicated 
in the treatment of influenza in patients one year of age and older who present with symptoms 
typical of influenza, when influenza virus is circulating in the Community. Oseltamivir is also 
indicated in post-exposure prevention in individuals one year of age or older. Oseltamivir is 
approved as hard capsules and powder for oral suspension. 

A medicinal product with the active substance Zanamivir has been authorised nationally via 
the mutual recognition procedure as Relenza® since June 1999.5 Zanamivir is indicated for 
treatment of influenza in patients above 5 years of age who present with symptoms typical of 
influenza  when  influenza  is  circulating  in  the  community.  Zanamivir  is  also  indicated  for 
post-exposure prevention in individuals 5 years of age or older. Zanamivir is approved as oral 
inhalation powder administered through a diskhaler device. 

2.3. 

Variation of Tamiflu® (Oseltamivir) and Relenza® (Zanamivir) 

Tamiflu® 

In May 2009, the European Commission approved a variation of the marketing authorisation 
for Tamiflu® concerning the shelf life extension from 5 to 7 years on the basis of a scientific 
opinion by the CHMP. 

In addition, on 31 July 2009, the Committee for Medicinal Products for Human Use (CHMP)6 
adopted scientific recommendations to vary the marketing authorisation for Tamiflu® with an 
update of the Summary of Product Characteristics (SPC) and the package leaflet:7: 

•  For  children  aged  from  6-12  months,  the  CHMP  has  concluded  that  during  an  influenza 
pandemic  the  benefits  of  the  use  of  Tamiflu®  outweigh  the  risks  and  recommended  the 
extension  of  the  currently  approved  indication  to  include  this  age  group  while  providing 
specific dosing recommendations. 

•  For pregnant and breastfeeding women, the CHMP recommended the use of Tamiflu® for 

treatment and post-exposure prophylaxis.  

The European Commission is currently evaluating these scientific recommendations in order 
to decide on the variation of the relevant marketing authorisation. 

5 

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7 

Relenza® has been authorised via Mutual Recognition Procedure in all Member States except Romania 
and Bulgaria. 
CHMP: Scientific Committee of the European Medicines Agency (EMEA) responsible for adopting a 
scientific  opinion  on  the  evaluation  of  an  application  for  a  central  marketing  authorisation  and 
variations thereof. 
http://www.emea.europa.eu/htms/human/pandemicinfluenza/novelflu.htm#Updateon31July2009 

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Relenza® 

In May 2009, a variation to extend the shelf life of Relenza® from 5 to 7 years was approved 
by Member States via Mutual Recognition Procedure. This approval needs to be followed by 
a  formal  decision  by  each  Member  State,  in  which  Relenza®  has  been  authorised.  This 
process is still ongoing. 

In addition to scientific opinions in preparation of a variation the CHMP and the Coordination 
Group  for  Mutual  Recognition  and  Decentralised  Procedures  –  Human  CMD(h)8  adopted 
scientific recommendations for Tamiflu® and Relenza® respectively. For details see Annex 
1. 

3. 

REGULATORY PROCEDURE FOR THE AUTHORISATION OF VACCINES IN THE EU 

Special features of Influenza vaccines are described in Annex 2. 

The EU is working on several possibilities to tackle the H1N1 Influenza on the basis of the 
development  of  new  vaccines,  further  development  of  mock  up  vaccines  or  variations  of 
mock up vaccines. 

3.1. 

New vaccines 

The procedure for assessing an application and preparing a marketing authorisation of a new 
vaccine is subject to legal timelines: 210 days both for national and central authorisations9 
covering  the  scientific  assessment  of  comprehensive  data  for  quality,  safety  and  efficacy10. 
For those applications for a central authorisation, which are of major interest from the point 
of view of public health, this process can be further accelerated and the period reduced to 150 
days. Furthermore, competent authorities may decide, on a case-by-case basis, to accelerate 
their  assessment  and  approval  procedures  depending  on  the  urgency  compared  to  the  legal 
timelines.11 

In exceptional circumstances and for objective, verifiable reasons, a central authorisation 
may be granted subject to certain requirements, e.g. specific procedures concerning the safety 

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11 

CMD(h):  Scientific  Committee  of  the  Member  States  tasked  with  the  preparation  and  adoption  of  a 
scientific  opinion  on  the  evaluation  of  an  application  for  a  national  marketing  authorisation  and 
variations thereof. 
Article 17 of Directive 2001/83EC; Article 6 (3) and 14 (9) of Regulation (EC) 726/2004 
Quality  is  defined  by  the  inherent  product  characteristics  (e.g.  nature  of  the  active  ingredient, 
manufacturing  process,  results  of  analytical  testing,  formulation,  dosage  form,  stability,  level  of 
impurities); efficacy relates to the clinical effects of a medicinal product – specifically for vaccines it 
relates to the ability of inducing an immune response (immunogenicity); safety relates to any adverse 
reactions. 
Note:  For  national  procedures  Member  States  have  to  ensure  that  the  procedure  for  granting  the 
marketing  authorisation  is  completed  within  a  maximum  of  210  days  after  submission  of  a  valid 
application.  For  central  authorisations  the  CHMP  is  obliged  to  provide  its  scientific  opinion  within 
210  (or  150)  days.  In  preparation  of  a  Commission  Decision  with  reference  to  the  Comitology 
procedure  (Decision  1999/468/EC)  the  European  Commission  submits  the  draft  opinion  for  a  vote  to 
the Standing Committee representing Member States. The vote is followed by a droit de regard of one 
month  by  the  European  Parliament;  specific  arrangements  are  being  agreed  with  the  newly  elected 
Parliament,  on  the  basis  of  the  Inter-institutional  agreement  between  the  Parliament  and  the 
Commission on procedures for implementing the Council decision 1999/468/EC to reduce this period 
for reasons of public health 

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of the medicinal product, notification to the competent authorities of any incident relating to 
its  use  and  action  to  be  taken.  Continuation  of  the  authorisation  is  linked  to  an  annual 
reassessment of these conditions.12 

For medicinal products used in emergency situations in response to public health threats, duly 
recognised either by the WHO or the Community (including the declaration of a pandemic), a 
central conditional marketing authorisation13 may be granted when there is sufficient proof 
of a positive risk-benefit balance on the basis of less comprehensive data for the safety and 
efficacy compared to a regular authorisation and when unmet medical needs will need to be 
fulfilled. Conditional marketing authorisations are made subject to specific obligations. They 
have  a  limited  validity  of  one  year  and  can  be  renewed.  Furthermore,  the  applicant  must 
provide  comprehensive  additional  data  and  may  be  subject  to  specific  obligations  for 
collecting data on pharmacovigilance. 

For such emergency situations such as  the pandemic influenza a  "rolling  review  procedure" 
has  been  developed  to  accelerate  the  review  of  any  applications  received.  This  means  that 
during the phase of data development the company exchanges scientific data with the EMEA, 
as soon as available.  

The  procedures  for  application  by  companies  and  assessment  by  competent  authorities  are 
underpinned  by  specific  technical  guidelines  developed  by  the  EMEA,  also  covering  the 
special aspects related to pandemic vaccines.14 

In addition, it is possible to submit a new vaccine for a national authorisation by Member 
States who may also apply accelerated review timetables to speed up availability of authorised 
vaccines. 

3.2. 

Authorised vaccines (under exceptional circumstances) 

To  date,  the  Commission  has  centrally  authorised  one  non-adjuvanted  and  three 
adjuvanted monovalent influenza vaccines as pandemic mock-up dossiers under exceptional 
circumstances.15 These vaccines have been authorised for the prophylaxis of an influenza in 
an officially declared pandemic situation. 

The adjuvant enhances the immunogenic effect of a vaccine and thereby allows a reduction in 
the amount of virus antigen in a given dose. This has an impact on the number of doses which 
can be produced with a defined amount of virus-antigen.  

The  intention  of  the  mock-up  concept  is  to  have  an  approved  model  which  can  be  swiftly 
changed to include the actual influenza virus strain identified for the pandemic and provided 
by the WHO. A pandemic vaccine can only be marketed in the case of a declared pandemic 
by WHO or the Community.  

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15 

Article 14 (8) of Regulation 726/2004 
Article 14 (7) of Regulation (EC) 726/2004; Commission Regulation (EC) 507/2006  
http://www.emea.europa.eu/htms/human/pandemicinfluenza/guidance.htm 
http://www.emea.europa.eu/htms/human/pandemicinfluenza/vaccines.htm; 
http://ec.europa.eu/enterprise/pharmaceuticals/register/alfregister.htm 

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3.3. 

Variations of authorised vaccines 

Any  adjustment  of  existing  vaccines  to  include  the  strains  to  the  Influenza  A  (H1N1)  2009 
will trigger a variation of the mock-up vaccine marketing authorisation. Legislation stipulates 
for accelerated procedures both for the variation of seasonal vaccines and for the variation of 
vaccines in a pandemic situation. 

A  regular  procedure  for  major  variations  takes  approximately  100  days.16  Building  on  the 
experience  of  previous  seasons,  a  typical  variation  for  seasonal  vaccines  following  the 
abbreviated  scientific  and  regulatory  assessment  procedure  may  be  started  on  the  basis  of 
quality  data.  However, 
the 
immunogenicity17  and  safety  during  and  before  completion  of  the  process.  The  procedure 
takes approximately 70 days.18 

to  submit  clinical  data  for 

the  applicant 

is  obliged 

This  procedure  may  exceptionally  and  temporarily  be  further  abbreviated  in  case  of  a 
pandemic  situation  recognised  by  the  WHO  or  the  Community,  building  on  the  basis  of  a 
significantly  reduced  package  of  data.  These  specific  provisions  for  variations  of  human 
influenza  vaccines  in  a  pandemic  situation  apply  for  centrally  authorised  products  and  for 
nationally  authorised  products  via  MRP  and  DCP  procedure  (see  chapter  1).  Its  application 
for  purely  national  variation  procedures  is  at  the  discretion  of  the  Member  States.19  Such 
variation procedures normally address changes to the virus strains included in the vaccine, as 
with the exception of the virus strain the formulation would remain the same as for the mock-
up.  Subsequently,  competent  authorities  may  exceptionally  and  temporarily  consider  the 
variation  accepted  after  receipt  of  the  application  before  the  full  procedure  of  scientific 
and regulatory assessment has been completed. This concept builds on the fact that pandemic 
mock-up  vaccines  have  been  authorised  on  the  basis  of  a  certain  amount  of  quality  and 
clinical  data  for  safety  and  immunogenicity  of  the  proposed  formulation  of  the  mock-up 
vaccine.  Therefore,  to  expedite  the  process  compared  to  a  variation  of  a  seasonal  vaccine, 
additional  comprehensive  clinical  safety  and  efficacy  data  from  adults  and  children  can  be 
submitted after the variation has been authorised by the competent authority. Changes to the 
formulation  and  inclusion  of  adjuvants  to  such  vaccines  would  go  beyond  these  specific 
variation procedures and be considered a major variation requiring additional scientific data to 
support the change.  

In  addition,  in  the  event  of  declared  pandemic  competent  authorities  strive  to  speed  up 
processes  significantly  and  utilise  various  accelerated  regulatory  options  available  for  the 
development of a vaccine. 

3.4. 

Specific considerations for specific population groups 

The overall risk-benefit balance of any vaccine authorised for protection against Influenza A 
(H1N1) 2009 and any variation to an authorised mock-up vaccine has to be positive. Taking 
the  above  mentioned  priorities  into  account,  there  is  the  need  for  a  careful  scientific 
assessment on risks and benefits for defined special population groups for all vaccines. The 

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19 

Type II variation as defined in Commission Regulation 1084/2003 and 1085/2003 
Immunogenicity is the ability to provoke an immune response and is a key criterion for the efficacy 
of a vaccine. 
Article 7 of Commission Regulation (EC) 1084/2003 and of Commission Regulation 1085/2003 
Article 8 of Commission Regulation (EC) 1084/2003 and of Commission Regulation 1085/2003 

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outcome  of  this  assessment  should  be  reflected  in  the  Summary  of  Product  Characteristics 
(SPC) which is part of the authorisation of each vaccine.  

Should new data be generated over time, the SPC may be further limited or widened through 
further  variations.  These  principles  are  in  line  with  the  objectives  and  provisions  of  the 
Paediatric Regulation.20 

Based  on  the  Community  paediatric  legislation  the  EMEA  has  developed  principles  for  a 
harmonised  approach  to  be  applied  for  the  development  of  Paediatric  Investigation  Plans 
(PIP) outlining the generation of scientific data for use of a Influenza A (H1N1) Vaccine in 
the paediatric population during a pandemic.21 Each PIP is subject to a scientific assessment 
by  the  Paediatric  Committee  and  a  decision  by  the  EMEA.22This  should  help  national 
authorities when recommending or using vaccines notably for children 

3.5. 

Specific legal provisions for the distribution by Member States 

As a general rule, marketing authorisation holders are subject to liability for the use of their 
products as long as they are used within the terms of the marketing authorisation. 

Member  States  may  temporarily  authorise  the  distribution  of  an  unauthorised  medicinal 
product  in  response  to  the  suspected  or  confirmed  spread  of  pathogenic  agents.  This 
encompasses pandemic situations, such as the Influenza A (H1N1) 2009 pandemic. In such a 
case marketing authorisation holders, manufacturers and health professionals are not subject 
to  civil  or  administrative  liability  for  any  consequences  resulting  from  the  use  of  a  vaccine 
when  such  use  of  an  unauthorised  vaccine  is  recommended  or  required  by  a  competent 
authority  in  response  to  the  pandemic  situation.  This  also  applies  when  the  use  of  an 
authorised  medicinal  product,  such  as  an  antiviral  medicine  and  a  vaccine,  is  recommended 
beyond  authorised  conditions  (e.g.  indications,  age  groups).  These  provisions  apply 
independently whether a national or Community authorisation has been granted.23  

4. 

ACCELERATED PROCEDURES FOR THE INFLUENZA A (H1N1) VACCINES) 

4.1. 

Authorisation and variation of vaccines 

In a situation, where the disease continues to evolve, the outcome of the assessment and the 
date of authorisation of Influenza A (H1N1) vaccines is currently difficult to predict. For the 
time being, any timelines must be considered indicative. 

Several mutually non-exclusive options for national and central authorisations exist to allow a 
scientific development of a monovalent vaccine24 against Influenza A (H1N1) 2009 according 
to the pandemic situation and subsequent regulatory approval. Regardless whether national or 
Community  authorisation  is  chosen,  it  is  important  to  ensure  the  efficient  use  of  limited 
manufacturing  capacities  inside  and  outside  the  EU  and  for  flexibility  to  assign  batches 
according to the specific needs in various Member States. 

20 
21 
22 
23 
24 

Regulation 1901/2006 
http://www.emea.europa.eu/pdfs/human/paediatrics/40577909en.pdf 
Regulation 1901/2006 
Article 5 of Directive 2001/83/EC 
monovalent vaccine – vaccine against one virus strain 

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A variation of centrally authorised mock-up dossiers is expected to allow fast assessment 
and  authorisation  and  subsequent  availability  of  vaccines  for  the  market.  Currently,  it  is 
expected that the majority of quality data considered key for preparing a scientific opinion on 
the  variation  of  such  mock-up  vaccines  will  be  available  from  September  2009  onwards 
allowing a Commission Decision on the variation to the terms of the marketing authorisation 
shortly thereafter.25  

The development of relevant data by interested companies and the scientific assessment for a 
new  vaccine  is  more  comprehensive.  Therefore,  in  the  case  of  applications  for  central 
authorisations it is expected that the scientific assessment will take longer. The Commission 
will  swiftly  take  a  Decision  on  the  marketing  authorisation  after  adoption  of  a  scientific 
opinion.  In  the  case  of  a  national  authorisation  it  is  up  to  Member  States  to  decide  on  the 
acceleration of the regular procedure. 

Specific information is detailed in Annex 3 on the application of an accelerated procedure:  

(1) 

(2) 

(3) 

for  the  variation  of  centrally  authorized  pandemic  mock-up  dossiers  for  a  strain 
update, 

for a central conditional marketing authorisation in emergency situations 

for the national authorisation of new vaccines  

4.2. 

Official Control Authority Batch Release (OCABR) 

On the basis of Community provisions and in the interest of public health Member States have 
put in place a system according to which Official Medicinal Control Laboratories (OMCLs) 
examine  batches  of  specific  medicinal  products  before  the  competent  authority  will  allow 
those batches to be released onto the market (Official Control Authority Batch Release) after 
a  medicinal  product  has  been  authorised.  The  examination  is  intended  to  determine  the 
conformity  of  a  batch  with  the  approved  specifications  as  laid  down  in  the  marketing 
authorisation.26. This system also applies to immunological medicinal products used in public 
health  immunisation  programmes,  such  as  against  Influenza  A  (H1N1)  2009  independently 
whether they have been authorised centrally or at a national level.27 Through this system it is 
intended  to  verify  whether  the  quality  control  testing  of  the  manufacturer  is  capable  of 
ensuring the quality of the product. It may also serve to objective to evaluate the robustness of 
the manufacturing process, including quality control. 

In the case of vaccines against Influenza A (H1N1) 2009 OMCLs of the Member States strive 
to  accelerate  the  process  of  the  above  mentioned  Official  Control  Authority  Batch  Release 
and to complete it coincidently with the authorisation for marketing. 

25 
26 

27 

EN 

http://www.emea.europa.eu/pdfs/human/press/pr/46856809en.pdf 
It  covers  at  least  the  assessment  of  documents,  including  control  reports  by  the  qualified  person,  and 
may  also  include  a  re-testing  by  Official  Medicinal  Control  Laboratories  established  by  the  Member 
States. Medicinal Products perform the re-testing in line with procedures and guidelines published by 
(EDQM); 
Quality 
the 
(http://www.edqm.eu/en/Human_Biologicals_OCABR-611.html) 
Article 112-114 of Directive 2001/83/EC 

Directorate 

Medicines 

European 

the 

for 

of 

10 

   EN 

                                                 
5. 

PHARMACOVIGILANCE 

The European Union has in place a comprehensive and effective safety monitoring system for 
the reporting and assessment of the safety and efficacy of a medicinal product after it has been 
authorised.28  These  provisions  sufficiently  address  the  situation  of  pandemic  influenza 
vaccines.  In  addition,  the  EMEA  has  published  specific  guidance.29  As  with  all  medicinal 
products  for  pandemic  vaccines  and  anti-viral  medicines,  public  confidence  will  depend  on 
the proper functioning of the pharmacovigilance system in the EU. 

When  Member  States  launch  an  Influenza  A  (H1N1)  vaccination  campaign,  it  will  be 
therefore  essential  to  monitor closely  any  unexpected  serious  adverse  reactions  to  allow  the 
risk/benefit  to  be  reassessed  scientifically  if  necessary.  Marketing  authorisation  holders  are 
obliged  to  have  procedures  in  place  for  adverse  event  reporting  as  part  of  their 
pharmacovigilance  system.  They  may  be  required  by  competent  authorities  to  propose 
additional pharmacovigilance activities. Marketing authorisation holders also have to submit 
Periodic  Safety  Update  Reports  (PSURs)  documenting  all  adverse  reactions  including  a 
scientific  evaluation  of  the  risk-benefit  balance.  In  addition,  the  results  of  further  post 
authorisation  safety  studies  in  adults  and  children  will  be  systematically  required.  Close 
cooperation  and  the  exchange  of  information  between  all  competent  authorities  is  therefore 
important.  

In  the  case  of  centrally  authorised  pandemic  vaccines,  the  CHMP  has  adopted  scientific 
recommendations  on  the  expected  requirements  which  will  be  imposed  on  marketing 
authorisation  holders  as  part  of  the  marketing  authorisation.30  These  include  an  earlier  and 
more frequent submission of PSURs compared to the usual procedure. In addition, companies 
will  be  obliged  to  launch  prospective  epidemiological  cohort  studies  for  each  authorised 
vaccines  with  a  focus  on  safety  and  encompassing  a  minimum  sample  of  9000  subjects 
involving  all  age  groups  from  2  months  up.  For  rare  events,  such  as  the  Guillain-Barré 
syndrome31  marketing  authorisation  holders  will  be  obliged  to  investigate  the  possibility  of 
collecting data through participation of specialist centres or clinics. 

If,  after  an  assessment  of  these  data  and  information,  the  view  is  taken  that  the  risk-benefit 
balance of the vaccine is not positive under normal conditions of use, competent authorities 
are expected to suspend, revoke, withdraw or vary a marketing authorisation or prohibit the 
supply. These measures may also be taken for specific conditions of the authorisation, such as 
recommendations of use for specific age groups or patient populations.32 

Furthermore,  the  Commission  will  support  studies  on  establishing  a  cross-border  vaccine 
monitoring  system  for  Influenza  A  (H1N1)  vaccines  based  on  a  common  protocol  or  the 
pooling of a critical set of validated data for rare and severe neurological adverse events from 
Member  States.  One  of  the  expected  deliverables  is  the  development  of  a  reliable 
methodology which can be routinely applied to the investigation of other rare adverse events. 

28 

29 
30 

31 

32 

Title  IX  of  Directive  2001/83/EC,  Chapter  3  of  Regulation  726/2004;  Eudralex  Volume  9 
(http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol9_en.htm) 
http://www.emea.europa.eu/pdfs/human/pandemicinfluenza/35938109en.pdf 
CHMP Recommendations for the Pharmacovigilance Plan as part of the Risk Management Plan to be 
submitted  with  the  Marketing  Authorisation  Application  for  a  Pandemic  Influenza  Vaccine 
(EMEA/359381/2009);http://www.emea.europa.eu/pdfs/human/pandemicinfluenza/35938109en.pdf  
Guillain  Barré  Syndrome  is  a  disorder  in  which  the  body's  immune  system  attacks  part  of  the  peripheral 
nervous system. Vaccinations have been reported to trigger the syndrome. 
Article 116 and 177 of Directive 2001/83/EC 

EN 

11 

   EN 

                                                 
For further details concerning legal and operational pharmacovigilance provisions see Annex 
4. 

6. 

COOPERATION WITH INTERNATIONAL PARTNERS 

For  the  preparation  of  strategies  for  the  assessment  and  authorisation  of  vaccines  the 
European Commission and the EMEA are in close contact with the WHO and via the WHO 
also with other regulatory authorities worldwide. 

the  Commission  and 

the  EMEA  concluded  bilateral  confidentiality 
Furthermore, 
arrangements with regulatory agencies of three third countries for the regulatory and scientific 
collaboration,  in  particular  exchange  of  information  between  the  parties  as  part  of  their 
regulatory and scientific processes, both before and after a medicine has been approved.33 The 
exchange  encompasses  information  related  to  applications  for  marketing  authorisations, 
pharmacovigilance  data  and  impending  regulatory  actions.  Such  arrangements  have  been 
concluded  with  the  US  Food  and  Drug  Administration  (FDA),  the  Health  Products  and 
Food Branch of Health Canada, and for Japan with the Japanese Ministry of Health, Labour 
and  Welfare  (MHWLW)  and  the  Japanese  Pharmaceuticals  and  Medicinal  Devices  Agency 
(PMDA). 

In the current situation these arrangements are being used for an exchange of information and 
views concerning the scientific assessment and the regulatory procedure for the authorisation 
of vaccines against Influenza A (H1N1) 2009 and further close cooperation on this issue. 

33 

http://ec.europa.eu/enterprise/pharmaceuticals/international/intercoopbi.htm 

EN 

12 

   EN 

                                                 
ANNEX  1:  SCIENTIFIC  RECOMMENDATIONS  OF  THE  CHMP  CONCERNING  THE  USE  OF 

TAMIFLU® AND OF THE CMD(H) CONCERNING RELENZA® 

(1) 

Scientific  recommendations  of  the  CHMP  regarding  the  use  of  Tamiflu®  and 
Relenza® in an influenza pandemic34 

As an early response to a potential health threat after the first cases of Influenza A (H1N1) 
2009 have been reported the CHMP adopted scientific recommendations independently of any 
preparation for a variation of the marketing authorisation35  

In  case  of  a  pandemic  influenza  is  declared  by  the  WHO  in  the  context  of  the  Influenza  A 
(H1N1)  2009  outbreak  Tamiflu®  may  be  used  in  children  below  one  year  of  age  under 
medical  supervision.  The  recommendation  also  referenced  to  data  suggesting  that  using 
Tamiflu® and Relenza® in pregnant and breast-feeding women may outweigh the risks in the 
context  of  an  Influenza  A  (H1N1)  2009  in  a  pandemic  situation.  Finally,  the  CHMP 
recommended that boxes of Tamiflu® capsules should not be discarded where the expiry date 
has  already  passed  and  a  further  period  of  2  years  could  be  added  to  the  stated  expiry  date 
when stored below 25°C. 

(2) 

Scientific  recommendations  of  the  CMD(h)  (Coordination  Group  for  Mutual 
Recognition  and  Decentralised  Procedures  –  Human)  regarding  the  national 
distribution of Relenza® during influenza pandemic36 

In July 2009, the Coordination Group for Mutual Recognition and Decentralised Procedures – 
Human (CMD(h)) concluded that a distribution of an additional device would be appropriate 
as a temporary measure during the Influenza A (H1N1) 2009 pandemic, considering limited 
production capacity of the approved diskhaler. Following this assessment it is now up to the 
national competent authorities to take a decision on temporary distribution in the absence of a 
specific  authorisation  of  this  additional  device  during  the  pandemic  by  making  reference  to 
specific legal provisions (see Section 3.5). 

34 
35 
36 

EN 

http://www.emea.europa.eu/humandocs/PDFs/EPAR/tamiflu/32609509en.pdf 
Article 5 (3) of Regulation 726/2004 
See 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/cmdh_pressreleases/2009_07.pdf 

CMD(h) 

meeting 

report 

more 

the 

for 

information:  

13 

   EN 

                                                 
ANNEX 2: SPECIAL FEATURES OF INFLUENZA VACCINES 

Influenza vaccines may be developed for the protection against seasonal influenza or for the 
protection against a pandemic with a specific influenza virus. For the protection in the case of 
an  upcoming  or  recognised  pandemic,  two  concepts  have  been  developed  in  the  European 
Union:  pre-pandemic  vaccines  and  pandemic  "mock-up"  vaccines.  Currently,  such  vaccines 
have been approved against Influenza A (H5N1). 

Vaccines may be monovalent or polyvalent, which means they may include antigens of one or 
several  virus-types.  While  vaccines  for  seasonal  influenza  are  typically  polyvalent,  existing 
concepts  for  vaccines  for  use  in  a  (pre)-pandemic  situation  are  currently  based  on  a 
monovalent composition.  

Two  routes  are  possible  for  the  manufacturing37  of  an  influenza  vaccine:  a  classical 
reassortant technique38 and a biotechnological process involving a reverse genetics technique. 
Vaccines  may  be  manufactured  with  or  without  an  adjuvant.39  The  adjuvant  enhances  the 
immunogenic  effect  of  a  vaccine  and  thereby  allows  a  reduction  in  the  amount  of  virus 
antigen in a given dose. This has an impact on the number of doses which can be produced 
with a defined amount of virus-antigen.  

37 
38 
39 

Using hen eggs or cells for the growth of the virus 
Reassortment: mixing of genetic material of viruses 
Adjuvants used include aluminium phosphate and hydrated aluminium hydroxide, MF 59, AS03 

EN 

14 

   EN 

                                                 
ANNEX  3:  ACCELERATED  PROCEDURES  FOR  THE  AUTHORISATION  AND  VARIATION  OF 

VACCINES 

(1) 

Variation of centrally authorized pandemic mock-up dossiers for a strain update 

As  for  the  assessment  of  the  variation  of  pandemic  mock-up  vaccines  to  include  the  actual 
pandemic virus strain, specific accelerated procedures can be applied. The evaluation of the 
CHMP, under which conditions a vaccine is expected to have a positive risk-benefit balance 
and the assessment of the benefit to public health of its immediate availability to fulfil unmet 
medical needs, will be of key importance. The Commission will act immediately and swiftly 
after receipt of a positive scientific opinion by the CHMP. 

Currently,  three  companies  foresee  reference  to  this  procedure.  Marketing  authorisation 
holders  are  expected  to  submit  an  application  for  such  a  variation  on  the  basis  of  data 
generated within the following timelines: 

ESTIMATED DATA AVAILABILITY FOR THREE MOCK-UP MAS via VARIATION 

Jul 09 

Aug 09 

Sep 09 

Oct 09

Nov 09

Dec 09

Jan 10 

Feb 10

March 10

Quality data 

First/ interim adult clinical data 

First/ interim paediatric data 

Range of quality data submission times 

First/  interim  adult  clinical  data  (to  document  efficacy, 
ie. immunogenicity, and safety) 

First/ interim paediatric data (children) 

The timelines given cover the range of submission dates proposed 
by the companies concerned as of 08/2009 and are still estimates 
as  further  discussion  is needed  with  these  companies  concerning  
the precise submission dates and data packages. 

All vaccines are monovalent A(H1N1)v vaccines 

The extent of safety and efficacy data should correlate to the evolution of the influenza and 
pandemic  situation,  which  will  have  to  be  taken  into  account  throughout  the  process. 

EN 

15 

   EN 

 
 
 
Currently,  it  is  expected  that  the  majority  of  quality  data  considered  key  by  the  CHMP  for 
preparing a scientific opinion will be available from September 2009 onwards.40 During the 
phase of data development the company exchanges scientific data with the EMEA to allow a 
"rolling  review".  Following  this  procedure,  both  EMEA  and  Commission  –  pending 
unforeseeable  situations  -  strive  to  expedite  their  scientific  and  regulatory  review  processes 
compared to normal procedures: the EMEA estimates an accelerated formal variation review 
process  of  approximately  5  working  days.  This  procedure  will  be  followed  by  the  formal 
process of authorisation through Commission Decision, for which the Commission estimates 
an expedited period of 10- 20 working days which is intended to be further reduced to a bare 
minimum.  

(2) 

Central conditional marketing authorisation in emergency situations 

This procedure will require a new marketing authorisation and therefore more data compared 
to the above mentioned variation procedure within the mock-up concept, thereby necessitating 
a  more  extensive  scientific  assessment.  Currently,  two  companies  foresee  reference  to  this 
procedure. Marketing authorisation holders are expected to submit an application on the basis 
of data generated within the following timelines: 

ESTIMATED DATA AVAILABILITY FOR TWO NEW CONDITIONAL MAAS  

Jul 09 

Aug 09 

Sep 09 

Oct 09

Nov 09

Dec 09

Jan 10 

Feb 10

March 10

Quality data

First/ interim adult clinical data 

First/ interim paediatric data 

Range of quality data submission times 

First/  interim  adult  clinical  data  (to  document  efficacy, 
ie. immunogenicity, and efficacy) 

First/ interim paediatric data (children) 

The timelines given cover the range of submission dates proposed 
by the companies concerned as of 8/2009 and are still estimates as 
further discussion is needed  with these companies concerning the 
The timelines are still estimates as we need to further discuss with  
precise submission dates and data packages.  

All vaccines are monovalent A(H1N1)v vaccines 

MAA: Market Authorisation Application 

40 

http://www.emea.europa.eu/pdfs/human/press/pr/46856809en.pdf 

EN 

16 

   EN 

                                                 
 
The  extent  of  clinical  data  required  will  correlate  to  the  evolution  of  the  influenza  and  the 
pandemic situation, which will have to be taken into account throughout the process. During 
the  phase  of  data  development  the  company  exchanges  scientific  data  with  the  EMEA  to 
allow a  "rolling  review". Following this procedure, both EMEA  and Commission -  pending 
unforeseeable  situations  -  strive  to  expedite  their  scientific  and  regulatory  review  processes 
compared to normal procedures: the EMEA estimates an accelerated formal review process of 
approximately  one  month.  This  procedure  will  be  followed  by  the  formal  process  of 
authorisation through Commission Decision. For this process, which involves application of 
the  Comitology  procedure  and  an  adoption  by  the  Standing  Committee41,  the  Commission 
estimates an expedited period of 25- 40 working days followed by an additional review by the 
European Parliament of one month pending further arrangements after recent elections.42 This 
period is intended to be further reduced to a bare minimum. Use of this procedure will ensure 
the authorisation of marketing of vaccines in 27 Member States, which will also be recognised 
by  the  Members  of  the  European  Economic  Area.  Considering  the  need  to  adjust  to  any 
evolving situation these timelines are indicative. 

(3) 

National authorisation of new vaccines 

An  application  for  such  an  authorisation  is  combined  with  the  full  data  requirement  for 
quality,  safety  and  efficacy  of  the  vaccine  stipulating  longer  development  and  assessment 
times  as  compared  to  the  other  options.  The  legal  timeline  for  the  assessment  follows  the 
regular  scheme  of  210  days  and  may  be  reduced  further  upon  the  initiative  of  the  national 
competent authority. Some companies have decided to submit a national application. It is at 
the discretion of the Member States to decide on any procedure to accelerate the assessment 
and authorisation process. 

41 
42 

Articles 10, 35 of Regulation 726/2004, Decision 1999/468/EC 
See footnote No. 21 

EN 

17 

   EN 

                                                 
ANNEX 4: DETAILED REQUIREMENTS FOR PHARMACOVIGILANCE 

In detail, Community legislation includes specific pharmacovigilance obligations  

for marketing authorisation holders43: 

•  to appoint a qualified person responsible for pharmacovigilance; 

•  to  introduce  and  maintain  a  pharmacovigilance  plan  as  part  of  the  risk  management 
system, which will be assessed as part of the evaluation of the application for a marketing 
authorisation and which could include specific obligations for pharmacovigilance reporting 
after application of Influenza A (H1N1) vaccines; 

•  to  maintain  detailed  records  of  all  suspected  adverse  reactions  occurring  either  in  the 

Community or in a third country; 

•  to promptly report suspected serious adverse reactions44, to the competent authority or 
European Medicines Agency (EMEA) (but no later than 15 days following the receipt of 
the information); 

•  to prepare and submit, to the competent authority or EMEA periodic safety update report 
(PSUR), documenting reports of all adverse reactions and including a scientific evaluation 
of the risk-benefit balance of the medicinal product, immediately upon request or at least 
every  six  months  during  the  first  two  years  following  the  initial  placing  on  the  market. 
Competent authorities will be allowed to request a PSUR any time when deemed necessary 
from a public health perspective. The timing of submission of the PSUR will be specified 
as a condition of the marketing authorisation or variation. Following EMEA guidance for 
pandemic  vaccines,  the  first  report  should  be  submitted  on  day  45  after  approval  and 
monthly thereafter for at least the first 6 months. 

•  to  submit  complete  clinical  safety  and  efficacy  (including  immunogenicity)  data, 
including  for  the  paediatric  population,  in  the  case  of  exceptional  and  temporary 
authorisation of a variation of a vaccine (in particular in the case of conditional marketing 
authorisations  and  varied  mock-up  pandemic  influenza  vaccines)  on  the  basis  of  quality 
and  limited  clinical  or  safety  data.45  Clinical  safety  and  efficacy  are  of  the  foremost 
importance  in  the  case  of  the  Influenza  A  (H1N1)  vaccines,  including  information 
regarding population subgroups such as pregnant women and children. 

for competent authorities46: 

•  to ensure, by means of repeated inspections, compliance with the legal requirements; 

43 
44 

45 
46 

Title IX of Directive 2001/83/EC, Chapter 3 of Regulation 724/2006 
Serious  adverse  reaction:  results  in  death,  is  life-threatening,  requires  inpatient  hospitalisation  or 
prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is 
a congenital anomaly/ birth defect. 
Regulation 1084/2003 and 1085/2003 
Title IX, Article 111 of Directive 2001/83/EC, Chapter 3 of Regulation 724/2006 

EN 

18 

   EN 

                                                 
•  to  make  available  through  a  data-processing  network  the  reports  of  suspected  serious 
adverse  reactions  to  the  agency  and  the  Member  States  at  the  latest  within  15  days  after 
their notification; 

•  to assess the adverse reaction reports and PSURs and take appropriate measures; 

•  to  exchange  information  and  cooperate  through  the  working  groups  of  the  EMEA  on 

pharmacovigilance; 

•  to suspend, revoke, withdraw or vary a marketing authorisation and or to prohibit the 
supply of a medicinal product if the view is taken that the product is harmful or the risk-
benefit balance is not positive under normal conditions of use or in the case of a lack of 
therapeutic efficacy; in such a case Member States are expected to inform each other, the 
EMEA  and  the  Commission  and  to  ensure  appropriate  coordination  between  Member 
States. 

The scientific Committee for Medicinal Products for Human Use (CHMP)47 of the EMEA 
has defined specific commitments, which should be systematically required in the marketing 
authorisation  as  part  of  the  risk  management  plan  for  a  pandemic  influenza  vaccine.  These 
include, inter alia, the following: 

•  specific  recommendations  and  formats  for  reporting  of  adverse  events  by  health  care 

professionals to the marketing authorisation holder; 

•  requirement of a submission of a simplified PSUR on Day 45 after shipment of the first 
batch of vaccine and thereafter monthly at least for the first 6 months, in the format defined 
by the CHMP; 

•  obligation for marketing authorisation holders, as part of their approved risk management 
plan,  to  launch  prospective  epidemiological  cohort  studies  for  each  authorised  vaccine 
with a focus on safety and involving a minimum sample of 9000 subjects involving all age 
groups (from 2 months up); 

•  Specific  consideration  should  be  given  to  document  the  safety  of  vaccines  in  pregnant 

women and immunocompromised subjects; 

•  For rare events such as Guillain-Barré syndrome, marketing authorisation holders should 
investigate the possibility of collecting data through the participation of specialist centres 
or clinics. 

47 

CHMP Recommendations for the Pharmacovigilance Plan as part of the Risk Management Plan to be 
submitted  with  the  Marketing  Authorisation  Application  for  a  Pandemic  Influenza  Vaccine 
(EMEA/359381/2009);http://www.emea.europa.eu/pdfs/human/pandemicinfluenza/35938109en.pdf  

EN 

19 

   EN