EN    EN EN 
EN    EN  COMMISSION OF THE E UROPEAN 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 COMMI SSION TO THE COUNCIL,  
THE EUROPEAN PARLIAMENT AN D THE EUROPEAN ECONOMIC AND 
SOCIAL COMMITTEE AND THE CO MMITTEE OF THE REGIONS 
Pandemic Influenza A (H1N1) 2009  
{COM(2009) 481} 
{SEC(2009) 1188} {SEC(2009) 1189} {SEC(2009) 1190} {SEC(2009) 1192} 
EN 2   EN  
TABLE OF CONTENTS 
Executive summary and conclusions ......................................................................................... 3 
1. Types of marketing authorisa tions for medicinal products.......................................... 4 
2. authorised antiviral medication in th e EU to address the new influenza ..................... 4 
2.1. Authorised antiviral medicinal products ...................................................................... 4 2.2. Regulatory status of medicines cont aining Oseltamivir and Zanamivir ...................... 5 
2.3. Variation of Tamiflu® (Oseltamivir) and Relenza® (Zanamivir)............................... 5 3. Regulatory procedure for the authoris ation of new vaccines iN the EU...................... 6 
3.1. New vaccines .............................................................................................................. .6  
3.2. Authorised vaccines (under exceptional circumstances) ............................................. 7 3.3. Variations of authorised vaccines ................................................................................ 8 3.4. Specific considerations for specific population groups ............................................... 8 3.5. Specific legal provisions for th e distribution by Member States ................................. 9 
4. Accelerated procedures for the Influenza A (H1N1) vaccines)................................... 9 
4.1. Authorisation and variation of vaccines....................................................................... 9 4.2. Official Control Authority Batch Release (OCABR) ................................................ 10 5. Pharmacovigilance ..................................................................................................... 11 6. Cooperation with international partners..................................................................... 12 Annex 1: Scientific recommendations of the CH MP 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 au thorisation and variation of vaccines.................. 15 
Annex 4: Detailed requirements for pharmacovigilance.......................................................... 18 
EN 3   EN EXECUTIVE SUMMARY AND CONCLUSIONS  
On 11 June 2009 the WHO declared the infl uenza pandemic. Moreover the Strategic 
Advisory Group of Experts (SAGE) of the WHO recommended that healthcare workers 
should be vaccinated as a first pr iority to protect the essentia l 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 re sponsible for the definition and 
implementation of any strategy for vaccination, wh ile both the EU and th e Member States are 
carrying responsibilities for the authoris ation of vaccines and for the needed 
pharmacovigilance. On this basis, Member Stat es developed a shared approach for priority 
groups for vaccination, which was published on 25 August 2009.2 
The EU has already started ta ken action to tackle the pand emic. While various anti-viral 
medicines received approval for marketing in th e 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 au thorisations 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 pr ovides 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 proce ss, the central author isation process for 
marketing is mandatory. The national authorisation procedure is applicable to all other procedures and under certain condi tions there is a choice between  the two procedures. On the 
basis of these provisions, swift scientific assessment of Infl uenza A (H1N1) 2009 vaccines by 
the EMEA and a swift subsequent Commission Decision on the marketing authorisation will 
be ensured with the objec tive to have substantial amounts of safe vaccines available across the 
EU 27. 
Moreover, Community legislation has specific le gal provisions in th e case of a declared 
pandemic influenza. The Commission has underp inned legislation by regulatory guidelines 
and the EMEA has, through its scientific committees, adopted scientific guidelines including guidelines for pandemic vaccines. Specifically desi gned processes for the scientific evaluation 
of a variation of pandemic vaccin es are intended to allow for best  possible planning reliability 
in the case companies intend to start early pr oduction. In addition, the EMEA is in close 
contact on an exchange and sharing of stra tegies for drug development, assessment and 
scientific information with major internat ional partners, with which a confidentiality 
agreement exists (US, Canada, Japan). 
Scientific assessment of the risk-benefit balan ce of any vaccine to be authorised for the 
protection against Influenza A (H 1N1) 2009 will be important on the basis of available data in 
the current pandemic situation. In any case depe nding on the evolvement of the real situation 
the EU has all means at its dis posal to act as rapidly as need ed. Equally important for public 
trust and confidence is pharmacovigilance. Afte r an authorisation for marketing of vaccines 
                                                
 
1 http://www.who.i nt/csr/disease/swineflu/notes/h 1n1_vaccine_20090713/en/index.html 
2 http://ec.europa.eu/health/p h_threats/com/Influenza/docs /HSC_EWRS_statement_en.pdf 
EN 4   EN 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 wide ning or a restriction of the scope of the 
marketing authorisation with respect to pa tient population, contra indications 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 ag ainst novel influenza, 
manufacturers depend on the isolation and suppl y of the relevant viru s strains by the World 
Health Organization, which pr ovided the Influenza A (H1N 1) 2009 strains in May 2009. In 
addition, the WHO may proceed to issue specif ic recommendations for the development of 
this vaccine and on the continued production of s easonal vaccines. 
Furthermore, after the declaration of the pandemic by WHO there ar e specific provisions 
which allow certain flexibility on the extent of data requirements to support a marketing authorisation applicatio n and variations thereof, and the subsequent timeframe for its 
regulatory assessment. In any case the risk-b enefit assessment has to be positive for each 
vaccine. 
1. T
YPES OF MARKETING AUTHORISATIONS FOR MEDICINAL PRODUCTS  
Anti-viral medication and vaccines are legally defined as medicinal products.3 
In the EU, medicinal products a nd 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 scien tific opinion coordinated by the European 
Medicines Agency EMEA (" central authorisation "). The latter is mandatory, inter alia,  
when a biotechnological process such as revers e 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 Co mmunity authorisation. The challe nge is to ensu re that both 
routes are providing for effici ent 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 auth orised 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 Mexi co were however found to be 
resistant to Amantadine and Rimantadine. Instead laboratory testing indicated that these viruses may be susceptible to Oseltamivir and Zanamivir.  
                                                
 
3 Article 1 of Directive 2001/83/EC 
4  
EN 5   EN Based on current information, the WHO evaluate s that cases of resi stance of Influenza A 
(H1N1) 2009 to neuraminidase inhibitors recently  reported appear to be sporadic. At this 
time, there is no evidence to indicate the deve lopment of widespread antiviral resistance 
against neuraminidase inhibitors. Therefore, th e WHO concluded that antiviral drugs remain a 
key component of the public health response when used as recommended.  
2.2. Regulatory status of medicines co ntaining Oseltamivir and Zanamivir 
A medicinal product with the active substance Oseltamivir  has been centrally authorised  as 
Tamiflu®  with a marketing authorisat ion valid since 20 June 2002. Oseltamivir  is indicated 
in the treatment of influenza in pa tients one year of age and older  who present with symptoms 
typical of influenza, when influenza virus is ci rculating in the Communit y. Oseltamivir is also 
indicated in post-exposure preventi on 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 pa tients above 5 years of age  who present with symptoms typical of 
influenza when influenza is circulating in th e community. Zanamivir is also indicated for 
post-exposure prevention in individu als 5 years of age or older. Za namivir 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 shel f 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 fo r Medicinal Products for Human Use (CHMP)6 
adopted scientific recommendations  to vary the marketing author isation for Tamiflu® with an 
update of the Summary of Product Characte ristics (SPC) and th e 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 Tamifl u® outweigh the risks and recommended the 
extension of the currently a pproved indication to include th is age group while providing 
specific dosing recommendations. 
• For pregnant and breastfeeding women, the CH MP recommended the use of Tamiflu® for 
treatment and post-exposure prophylaxis.  
The European Commission is currently evaluati ng these scientific r ecommendations in order 
to decide on the variation of th e relevant marketing authorisation. 
                                                 
5 Relenza® has been authorised via Mutual Recognitio n Procedure in all Member States except Romania 
and Bulgaria. 
6 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. 
7 http://www.emea.europa.eu/htms/human/pandemi cinfluenza/novelflu.htm#Updateon31July2009 
EN 6   EN 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 Proce dure. This approval needs to be followed by 
a formal decision by each Member State, in  which Relenza® has b een authorised. This 
process is still ongoing. 
In addition to scientific opinions  in preparation of a variatio n 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 v accines are described in Annex 2. 
The EU is working on several pos sibilities to tackle the H1N1 Influenza on the basis of the 
development of new vaccines, further developm ent 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 compre hensive 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 d ecide, 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 
                                                 
8 CMD(h):  Scientific Committee of the Me mber 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. 
9 Article 17 of Directive 2001/83EC; Article 6 (3) and 14 (9) of Regulation (EC) 726/2004 
10 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 me dicinal product – speci fically for vaccines it 
relates to the ability of inducing an immune response ( immunogenicity ); safety  relates to any adverse 
reactions. 
11 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. Th e vote is followed by a droit de regard of one 
month by the European Parliament; specific arrang ements 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  
EN 7   EN of the medicinal product, notifica tion to the competent authoritie s 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 em ergency 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 a nd 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 additiona l data and may be subject to specific obligations for 
collecting data on pharmacovigilance. 
For such emergency situations such as the pa ndemic 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 compa ny 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 accelera ted 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 define d 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.  
                                                
 
12 Article 14 (8) of Regulation 726/2004 
13 Article 14 (7) of Regulation (EC) 726/2004; Commission Regulation (EC) 507/2006  
14 http://www.emea.europa.eu/htms/human/pandemicinfluenza/guidance.htm 
15 http://www.emea.europa.eu/htms/hum an/pandemicinfluenza/vaccines.htm ; 
http://ec.europa.eu/enterprise/pharm aceuticals/register/alfregister.htm 
EN 8   EN 3.3. Variations of authorised vaccines 
Any adjustment of existing vaccines to includ e the strains to the Influenza A (H1N1) 2009 
will trigger a variation of the mock-up vaccine ma rketing 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 t ypical variation for seasonal vaccines  following the 
abbreviated scientific and regulatory assessmen t procedure may be started on the basis of 
quality data. However, the applicant is obliged to submit clinical data for the 
immunogenicity17 and safety  during and before completion of the process. The procedure 
takes approximately 70 days .18 
This procedure may exceptionally and temporar ily be further abbreviated in case of a 
pandemic situation  recognised by the WHO or the Comm unity, building on the basis of a 
significantly reduced package of data. These sp ecific provisions for variations of human 
influenza vaccines in a pandemic situation appl y for centrally authorised products and for 
nationally authorised products via MRP and DC P 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 formulati on would remain the same as for the mock-
up. Subsequently, competent authoritie s 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 comp ared to a variation of a seasonal vaccine, 
additional comprehensive clinical safety and ef ficacy 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 cons idered a major variation requiring additional scientific data to 
support the change.  
In addition, in the event of declared pande mic competent authorities strive to speed up 
processes significantly and utilis e various accelerated regulato ry 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, th ere is the need for a careful scientific 
assessment on risks and benefits for defined special population groups for all vaccines. The 
                                                
 
16 Type II variation as defined in Commission Regulation 1084/2003 and 1085/2003 
17 Immunogenicity  is the ability to provoke an immune response and is a key criterion for the efficacy  
of a vaccine. 
18 Article 7 of Commission Regulation (EC) 1084/2003 and of Commission Regulation 1085/2003 
19 Article 8 of Commission Regulation (EC) 1084/2003 and of Commission Regulation 1085/2003 
EN 9   EN outcome of this assessment should be reflected  in the Summary of Product Characteristics 
(SPC) which is part of the au thorisation 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 lin e with the objectives and provisions of the 
Paediatric Regulation.20 
Based on the Community paediatric legislatio n the EMEA has developed principles for a 
harmonised approach to be applied for the de velopment 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 us ing 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 un authorised medicinal 
product in response to the suspected or conf irmed spread of pathogenic agents. This 
encompasses pandemic situations, such as the Influenza A (H1N1) 2009 pandemic. In such a 
case marketing authorisation holders, manufacturer s 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 situa tion. This also applies when the use of an 
authorised medicinal product, such as an anti viral medicine and a vaccine, is recommended 
beyond authorised conditions (e.g. indications, age groups). These provisions apply independently whether a na tional or Community author isation 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) v accines is currently difficult to predict. For the 
time being, any timelines must be considered indicative. 
Several  mutually non-exclusive  options  for national and central auth orisations exist to allow a 
scientific development of a monovalent vaccine24 against Influenza A (H1N1) 2009 according 
to the pandemic situation and subsequent regulat ory 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 fl exibility to assign batches 
according to the specific need s in various Member States. 
                                                
 
20 Regulation 1901/2006 
21 http://www.emea.europa.eu/pdfs/human/paediatrics/40577909en.pdf 
22 Regulation 1901/2006 
23 Article 5 of Directive 2001/83/EC 
24 monovalent vaccine – vaccine against one virus strain 
EN 10   EN 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 cons idered key for preparing a scientific opinion on 
the variation of such mock-up vaccines wi ll 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 au thorisation 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) for the variation  of centrally  authorized pandemic mock-up  dossiers for a strain 
update, 
(2) for a central  conditional marketing authorisation  in emergency situations 
(3) for the national  authorisation of new vaccines  
4.2. Official Control Authorit y 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 Of ficial 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 spec ifications as laid down in the marketing 
authorisation.
26. This system also applies to immunologi cal medicinal products used in public 
health immunisation programmes, such as ag ainst 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 se rve to objective to evaluate the robustness of 
the manufacturing process, including quality control. 
In the case of vaccines against Influenza A (H 1N1) 2009 OMCLs of the Member States strive 
to accelerate the process of the above menti oned Official Control Au thority Batch Release 
and to complete it coincidently wi th the authorisation for marketing. 
                                                
 
25 http://www.emea.europa.eu/pdfs/human/press/pr/46856809en.pdf 
26 It covers at least the assessment of documents, including control reports by the qualified person, and 
may also include a re-testing by Official Medicina l Control Laboratories established by the Member 
States. Medicinal Products perform the re-testing in line with procedures and guidelines published by the European Directorate for the Quality of Medicines (EDQM); 
(http://www.edqm.eu/en/Human_Biologicals_OCABR-611.html) 
27 Article 112-114 of Directive 2001/83/EC 
EN 11   EN 5. PHARMACOVIGILANCE  
The European Union has in place a comprehensiv e and effective safety monitoring system for 
the reporting and assessment  of the safety and efficacy of a medicinal product af ter 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 pharm acovigilance system in the EU. 
When Member States launch an Influen za A (H1N1) vaccination campaign, it will be 
therefore essential to monitor closely any unexpected serious a dverse 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 requi red by competent authorities to propose 
additional pharmacovigilance activities. Marketi ng authorisation holders also have to submit 
Periodic Safety Update Reports (PSURs) doc umenting all adverse reactions including a 
scientific evaluation of the risk-benefit bala nce. 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 be tween all competent aut horities is therefore 
important.  
In the case of centrally authorised pandemi c 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 encomp assing a minimum sample of 9000 subjects 
involving all age groups from 2 months up. For rare events, such as the Guillain-Barré 
syndrome
31 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 vi ew is taken that  the risk-benefit 
balance of the vaccine is not positive under nor mal 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 speci fic conditions of the au thorisation, such as 
recommendations of use for specific age groups or patient populations.32 
Furthermore, the Commission will support studi es on establishing a cross-border vaccine 
monitoring system for Influe nza 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 deliver ables is the development of a reliable 
methodology which can be routinely applied to the investigation of other rare adverse events. 
                                                 
28 Title IX of Directive 2001/83/EC, Chapter 3 of Regulation 726/2004; Eudralex Volume 9 
(http://ec.europa.eu/enterprise/pha rmaceuticals/eudralex/vol9_en.htm) 
29 http://www.emea.europa.eu/pdfs/human /pandemicinfluenza/35938109en.pdf 
30 CHMP Recommendations for the Pharmacovigilance Plan as part of the Risk Management Plan to be 
submitted with the Marketing Authorisation A pplication for a Pandemic Influenza Vaccine 
(EMEA/359381/2009);http://www.emea.europa.eu/pd fs/human/pandemicinfluenza/35938109en.pdf  
31 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.  
32 Article 116 and 177 of Directive 2001/83/EC 
EN 12   EN For further details concerning legal and opera tional pharmacovigilance provisions see Annex 
4. 
6. COOPERATION WITH INTE RNATIONAL 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. 
Furthermore, the Commission and the EMEA  concluded bilateral confidentiality 
arrangements with regulatory agen cies of three third countries for the regulatory and scientific 
collaboration, in particular ex change of information between the parties as part of their 
regulatory and scientific processes, both befo re and after a medicine has been approved.33 The 
exchange encompasses information related to applications for mark eting authorisations, 
pharmacovigilance data and impending regulator y 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 Phar maceuticals and Medicinal Devices Agency 
(PMDA). 
In the current situation these arrangements are be ing 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 a nd further close cooperation on this issue. 
                                                 
33 http://ec.europa.eu/enterprise/pharm aceuticals/international/intercoopbi.htm 
EN 13   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 thre at after the first cases of Influenza A (H1N1) 
2009 have been reported the CHMP adopted scien tific 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 contex t of the Influenza A 
(H1N1) 2009 outbreak Tamiflu® may be used in children below on e year of age under 
medical supervision. The recommendation also referenced to data suggesting that using 
Tamiflu® and Relenza® in pregnant and breas t-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 s hould not be discarded where the expiry date 
has already passed and a further period of 2 year s could be added to the stated expiry date 
when stored below 25°C. 
(2) Scientific recommendations of the CM D(h) (Coordination Group for Mutual 
Recognition and Decentralised Procedu res – 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 Influen za 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 di stribution in th e absence of a 
specific authorisation of this  additional device during the pa ndemic by making reference to 
specific legal provisi ons (see Section 3.5). 
                                                
 
34 http://www.emea.europa.eu/humandocs/ PDFs/EPAR/tamifl u/32609509en.pdf 
35 Article 5 (3) of Regulation 726/2004 
36 See the CMD(h) meeting report for more information:  
http://www.hma.eu/fileadmin/dateien/Human_Medic ines/CMD_h_/cmdh_pressreleases/2009_07.pdf 
EN 14   EN ANNEX 2: SPECIAL FEATURES OF INFLUENZA VACCINES  
Influenza vaccines may be developed for the pr otection against seasonal influenza or for the 
protection against a pandemic with a specific infl uenza virus. For the protection in the case of 
an upcoming or recognised pandemic, two con cepts have been developed in the European 
Union: pre-pandemic vaccines and pandemic "m ock-up" vaccines. Currently, such vaccines 
have been approved against Influenza A (H5N1). 
Vaccines may be monovalent or polyvalent, whic h 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 manufacturing
37 of an influenza vaccine: a classical 
reassortant technique38 and a biotechnological process invo lving a reverse genetics technique. 
Vaccines may be manufactured wi th 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 Using hen eggs or cells fo r the growth of the virus 
38 Reassortment: mixing of genetic material of viruses 
39 Adjuvants used include aluminium phosphate and hydrated aluminium hydroxide, MF 59, AS03 
EN 15   EN ANNEX 3: ACCELERATED PROCEDURES FOR THE AUTHORISATION AND VARIATION OF 
VACCINES  
(1) Variation of centrally authorized pandemi c mock-up dossiers for a strain update 
As for the assessment of the variation of pa ndemic mock-up vaccines to include the actual 
pandemic virus strain, specific accelerated proc edures 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 applicatio n for such a variation on the basis of data 
generated within the following timelines: 
 
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.  Jul 09 
Quality data 
First/ interim adult clinical data 
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  
Range of quality data submission times 
First/ interim adult clinical data (to document efficacy, 
ie. immunogenicity, and safety) 
First/ interim paediatric data (children) ESTIMATED  DATA AVAILABILITY FOR THREE MOCK-UP MAS via VARIATION 
Aug 09 Sep 09 Oct 09 Nov 09 Dec 09 Jan 10 Feb 10
First/ interim paediatric data March 10
EN 16   EN Currently, it is expected that the majority of  quality data considered key by the CHMP for 
preparing a scientific op inion will be available from September 2009 onwards.40 During the 
phase of data development the company exchange s scientific data with the EMEA to allow a 
"rolling review". Following this proce dure, both EMEA and Commission – pending 
unforeseeable situations - strive to expedite th eir scientific and regul atory review processes 
compared to normal procedures: the EMEA estimat es an accelerated formal variation review 
process of approximately 5 working days. This  procedure will be followed by the formal 
process of authorisation through Commission D ecision, 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 aut horisation and therefore more data compared 
to the above mentioned variation procedure with in the mock-up concept, thereby necessitating 
a more extensive scientific assessment. Curren tly, two companies foresee reference to this 
procedure. Marketing authorisati on holders are expected to subm it an application on the basis 
of data generated within the following timelines: 
MAA: Market Authorisation Application 
                                                 
40 http://www.emea.europa.eu/pdfs/human/press/pr/46856809en.pdf Quality dataJul 09 
First/ interim adult clinical data 
The timelines are still estimates as we need to further discuss with   
Range of quality data submission times 
First/ interim adult clinical data (to document efficacy, 
ie. immunogenicity, and efficacy) 
First/ interim paediatric data (children) ESTIMATED DATA AVAILABILITY FOR TWO NEW CONDITIONAL  MAAS  
Aug 09 Sep 09 Oct 09 Nov 09 Dec 09 Jan 10 Feb 10
First/ interim paediatric data 
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 
precise submission dates and data packages.  
All vaccines are monovalent A(H1N1)v vaccines March 10
EN 17   EN The extent of clinical data required will correla te 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 ex changes scientific data with the EMEA to 
allow a "rolling review". Following this pr ocedure, both EMEA a nd Commission - pending 
unforeseeable situations - strive to expedite th eir scientific and regul atory review processes 
compared to normal procedures: the EMEA estima tes an accelerated formal review process of 
approximately one month. This procedure will be followed by the formal process of authorisation through Commission Decision. For th is process, which involves application of 
the Comitology procedure and an adoption by the Standing Committee
41, the Commission 
estimates an expedited period of 25- 40 working days followed by an additional review by the European Parliament of one month pending fu rther 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 tim elines 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 s tipulating 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 reduce d further upon the initiative of the national 
competent authority. Some companies have decide d 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 Articles 10, 35 of Regulation 726/2004, Decision 1999/468/EC 
42 See footnote No. 21 
EN 18   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 specifi c obligations for pharmacovigilance reporting 
after application of Infl uenza 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 la ter than 15 days fo llowing 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 reacti ons and including a sc ientific evaluation 
of the risk-benefit balan ce of the medicinal produc t, 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 re quest 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 market ing authorisation or variati on. Following EMEA guidance for 
pandemic vaccines, the first report shoul d be submitted on day 45 after approval and 
monthly thereafter for at least the first 6 months. 
• to submit  complete clinical safety and effica cy (including immunogenicity) data, 
including for the paediatric population, in the case of excep tional 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 effi cacy 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 authorities
46: 
• to ensure, by means of repeated inspections , compliance with the legal requirements; 
                                                 
43 Title IX of Directive 2001/83/EC, Chapter 3 of Regulation 724/2006 
44 Serious adverse reaction: results in death, is lif e-threatening, requires inpatient hospitalisation or 
prolongation of existing hospitalisation, results in pers istent or significant disability or incapacity, or is 
a congenital anomaly/ birth defect. 
45 Regulation 1084/2003 and 1085/2003 
46 Title IX, Article 111 of Directive 2001/ 83/EC, Chapter 3 of Regulation 724/2006 
EN 19   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 a nd PSURs and take appropriate measures; 
• to exchange information and cooperate th rough the working gr oups 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 th e view is taken that the pr oduct 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 Stat es are expected to inform each other, the 
EMEA and the Commission and to ensure ap propriate 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 requir ed 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 appr oved risk management 
plan, to launch prospective epidemiological cohort studies  for each authorised vaccine 
with a focus on safety and involving a mini mum 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 A pplication for a Pandemic Influenza Vaccine 
(EMEA/359381/2009);http://www.emea.europa.eu/pd fs/human/pandemicinfluenza/35938109en.pdf