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6.3 CTD 125
Figure 6.13 US application form FDA 356h. Source: FDA, 2022/U.S Department of Health
and Human Services/Public Domain.
126 6 Marketing Authorisation
Figure 6.13 (Continued)
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6.4 Submission and Review Process in the EU 127
Figure 6.13 (Continued)
6.4 Submission and Review Process in the EU
Depending on the type of medicinal product dierent procedures exist for obtaining
a marketing authorisation. ‘Union Authorisations’ are granted via a ‘centralised’
procedure in which applications are submitted to the European Medicines
Agency, whereas ‘National Authorisations’ may be obtained by applying to the
128 6 Marketing Authorisation
Competent Authorities of member states using either ‘decentralised’ or ‘mutual
recognition’ procedures.
6.4.1 Union Authorisation
The procedures for obtaining a Union authorisation (previously known as a
Community authorisation) to market a medicine are dened in EC Regulation No.
726/2004 as amended. The types of human-use medicinal products for which the
procedure may be used are shown in Figure 6.14. The applicant should submit an
eligibility request and notify the EMA of their intention to submit an application at
least seven months in advance of the planned submission date. This pre-submission
should contain a draft of the SPC, the grounds on which a Union Authorization
will be sought, a proposed invented name that will identify the drug throughout
the Union and other information relevant to the proposed application strategy.
Applicants are also encouraged to have a pre-submission meeting with the EMA
to discuss any aspects of the application in greater detail. The pre-submission
notication allows the Committee for Medicinal Products for Human Use (CHMP)
to verify that the product is suitable for authorisation via the centralised procedure
and to begin the process of appointing a rapporteur and co-rapporteur from among
its members. The rapporteurs are responsible for independently conducting the
scientic evaluation of the dossier and will assemble evaluation teams drawn from
the panel of scientic experts. In practice, they will rely heavily on the resources
available through their respective Competent Authorities. An EMA product team
is organised in parallel to deal with all procedural aspects of the application. The
Pharmacovigilance Risk Assessment Committee (PRAC) also appoints a rappor-
teur and co-rapporteur, who will focus upon assessing the applicant’s proposed
risk management plan. This plan describes ways any risks associated with the
Mandatory
● Biotech products based on recombinant DNA, gene expression, or hybridoma/
monoclonal antibody technologies.
● Biosimilar medicinal products developed by any of the above biotech processes
● Advanced therapy medicinal products (products based on genes, cells, or tissue
engineering)
● New active substances for treatment of AIDS, cancer, diabetes, neurodegenerative
disorders, autoimmune or other immunological disorders, and viral diseases.
● Orphan medicinal products.
Optional
● Other new active substances.
● Medicinal products that contribute signicant therapeutic, scientic or technical
innovation, or are in the interests of patient health.
● A generic copy of a centrally authorised product.
● Certain medicinal products for paediatric use.
Figure 6.14 Human medicinal products that may be authorised via the centralised
procedure.
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6.4 Submission and Review Process in the EU 129
medicine would be managed post-authorisation, and how additional information
will be obtained relating to safety/risk post-authorisation (see also Chapter 12).
For advanced therapy, medicinal products (Figure 6.4) (co) rapporteurs are also
appointed from members of the Committee for Advanced Therapies. The fee for a
complete application of a single-strength product (as of October 2021) is € 296,500.
6.4.2 Scientific Evaluation Process
The applicant must electronically submit a complete copy of dossier to the EMA
through the eSubmission Gateway. The EMA is allowed 14 days to validate the
application to ensure that it is complete and in accordance with the regulations,
after which the various rapporteurs can commence the scientic evaluation. The
review process involves considerable feedback between the rapporteurs, the CHMP,
and the applicant, central to which can be achieving agreement on the nal text
of the SPC, labels and leaet. The rapporteurs are required to deliver preliminary
assessment reports to the CHMP within 80 days of the start of the review process.
The applicant is also copied on the report. Over the next 40 days issues raised
in the reports together with the comments and feedback from the CHMP are
formalised into a list of questions that are ocially sent to the applicant. The CHMP
may additionally request that GMP/GCP/GLP inspections are conducted by the
Competent Authorities of the relevant Member States or that drug samples are
tested. The clock is then stopped until the applicant provides responses to these
questions. This rst clock-stop generally lasts three to six months. The rapporteurs
have another 30 days to prepare a joint report on these responses. A further 30 days
are allowed for the CHMP to issue a nal list of any outstanding issues and/or a
request for an oral presentation by the applicant. This second clock stop typically
lasts for one to three months. The applicant must also submit the nal draft of the
SPC, label, and leaet text in English. At this stage, the CHMP will adopt a formal
scientic opinion on the application, making a recommendation on whether or
not the medicinal product should be granted a marketing authorisation and, if so,
under what conditions of use. The committee will also agree on the nal permitted
wording of the product information for healthcare professionals and for patients
(i.e. the wording on the summary of product characteristics, labelling and package
leaets), as well as on any additional data the company is required to provide
subsequent to authorisation. The total time allowed to compete the scientic review
is 210 days, excluding the time taken for applicant responses (clock stops).
The CHMP usually reaches its decision by consensus, but if consensus cannot be
reached, the opinion of the majority of members stands. Assuming the outcome is
favourable, the agency must forward its opinion to the applicant, the EU Commis-
sion, and the Member States within 15 days, together with:
● A report describing the evaluation of the medicinal product and the reasoning
behind the conclusions drawn.
● Copies of the draft SPC (becomes Annex 1 to the decision).
130 6 Marketing Authorisation
● Manufacturing information and any proposed restrictions or conditions
(Annex 2).
● The draft text of the label and package leaet (Annex 3).
● The Assessment Report.
If the opinion is unfavourable, the applicant has 15days to notify the agency of its
intention to request a reexamination of the decision and a further 45 to submit the
grounds on which a review is requested. New rapporteurs are appointed to reexam-
ine the dossier, with the focus solely being upon the points raised by the application
in their grounds for appeal. The CHMP is allowed 60 days to deliver their opinion in
light of the reexamination.
6.4.3 Decision Making Process
The Commission is responsible for turning the agency opinion into a binding
legal decision for all Member states and ensuring that the marketing authorisation
is in compliance with the regulations. They must prepare a draft decision in
consultation with other relevant Directorates General within 15 days of receipt
of the opinion from the EMA. In the meantime, the EMA is responsible for
coordinating with the Member States, Norway and Iceland, a linguist review
of translations of the SPC, label and leaet into EU, Norwegian and Icelandic
languages, prepared by the applicant. Note: Norway, Iceland and Liechtenstein
through the European Economic Area (EEA) agreement have adopted the EU
system for drug regulation, even though they are not EU member states. The states
have 15 days to return linguist comments, so that the Commission may annex
nal text versions to the draft decision before it is forwarded to the members of
the Standing Committee for Medicinal Products for Human Use for consideration.
The Committee should return their comments and observations in writing to the
Commission within 22 days unless they raise serious objections on legal or public
health grounds that necessitate discussion in a plenary meeting of the Committee.
Once the Committee consultation stage has been completed, the Commission
has 15 days to adopt the nal decision. The decision is communicated to the
applicant and all member states, and published in the next issue of the Ocial
Journal of the EU, C series while the medicine is entered in a Union Register of
Medicinal Products. A European Public Assessment Report (EPAR), is prepared
by the CHMP and published on the EMA website. This is intended to inform the
general public in simple easy to understand language of the reasoning behind
the granting or refusal of a marketing authorisation. Excluding the time taken
for applicant responses or appeals, a Union marketing authorisation should be
granted within 277 days of the start of the review process. A ow diagram of the
authorisation process is shown in Figure 6.15 and a product case study is presented
in Box 6.1.
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6.4 Submission and Review Process in the EU 131
Pre-submission meeting
– 7 months Pre-submission Notification (Applicant)
Rapporteurs appointed (CHMP/PRAC)
Dossier Submitted (Applicant)–14 days
Dossier validation (EMA)
Day 0 Dossier Validation Completed (EMA)
Scientific Review (Rapporteurs)
Day 80
Comments/ feedback from CHMP
Day 120 List of questions issued to applicant (CHMP/EMA)
Prepare response (Applicant)Clock stopped
Inspections (CA)
Day 121
Response review (Rapporteurs)
Day150
Comments/feedback from CHMP
Day 180 List of outstanding issues or oral hearing (CHMP)
Oral hearing if necessaryClock stopped
Day 181
Day 210 Adoption of Opinion and Assessment Report (CHMP)
Prepare to transfer opinion (EMA)
Linguist review
Day 225
Prepare draft decision (Commission)
Day 229
Standing Committee consultation
End of consultationDay 261
Prepare final decision
Day 277
Preliminary Assessment Reports (Rapporteurs)
GMP/GCP/GLP
Response and revised SPC and labelling submitted (Applicant) Sample testing
Joint report on responses (Rapporteurs)
Final draft of English SPC, labelling and insert (Applicant)
Opinion transferred to Commission (EMA)
Product info (MS)
Draft decision to Standing Committee + multilingual Annexes
Decision formally adopted by the Commission
Figure 6.15 Union marketing authorisation process.
132 6 Marketing Authorisation
Box 6.1 Case Study: EU Evaluation and Approval Process for the Medicinal Prod-
uct Verquvo
Verquvo (vericiguat) is a medicine used to treat chronic heart failure. The
company (Bayer AG) submitted an application for marketing authorization
to the EMA on 27 May 27 2020. Bayer had previously sought and received
scientific advice from the EMA pertaining to various aspects of the product’s
development in 2016. In 2019, it received confirmation from the EMA of the
product’s suitability to be considered for authorization under the centralized
evaluation process. The CHMP appointed a rapporteur and co-rapporteur
and the evaluation process began in mid-June 2020. The rapporteur and
co-raporteur’s first assessment reports were circulated to all CHMP members in
September 2020. In parallel, a PRAC rapporteur was appointed and submitted
a first assessment report to the PRAC in September. After consideration, the
CHMP sent a consolidated list of questions to the applicant in October 2020,
with the applicant submitting responses in January 2021. The rapporteurs
considered the responses and circulated a joint assessment report on those
responses to all CHMP members in March 2021. That same month, the CHMP
sent a list of outstanding issues to the applicant and received responses from
the applicant in April 2021. The CHMP then considered the application and
all applicant responses and issued a positive opinion for granting a marketing
authorization for Verquvo on 20 May 2021. The EMA transmitted its opinion
to the European Commission, which issued marketing authorisation for the
product, valid throughout the European Union, on 16 July 2021.
6.4.4 National Authorisations
Outside of the products that come within the scope of Union Authorisations, all
other products can only be licensed via application to the Competent Authorities
of individual Member States. However, through the use of either decentralised
or mutual recognition procedures it is possible to obtain authorisations on the
basis of a dossier assessment conducted by a single member state. Although these
procedures are operated via national competent authorities, both the decentralised
and mutual recognition procedures are themselves organized by the EU-wide
coordination group for mutual recognition and decentralized procedures – human
(CMDh). CMDh also serves as a forum through which any issues arising during
operation of the procedures may be discussed.
6.4.5 Decentralised Procedure
The decentralized procedure can be used in cases where the product has never
been authorised in any of the Member States, and the applicant wishes to obtain
a license in a number of states simultaneously. The applicant must submit an
application with the complete dossier using the Common European Submission
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6.4 Submission and Review Process in the EU 133
Portal (CESP) to the Competent Authorities of each of the member states where
authorisation is desired. A single Member State should be chosen as the ‘reference’
state to undertake the scientic assessment of the complete dossier, while the other
states are designated as ‘concerned’ states. The review process has many parallels
with the centralised procedure, in that similar time lines exist, the reference state
plays the role of the rapporteur and the concerned states replace the CHMP. Once
all states have validated that the dossiers are complete, the reference state is allowed
70 days to review the dossier and prepare a preliminary assessment report, which
is circulated to the concerned member states and the applicant. Comments from
the concerned member states and applicant responses are collected so that by day
120 the reference state may issue a draft assessment report together with draft
SPC, label and leaet texts. The clock may be stopped until requested responses
from the applicant are received. The application then enters the second step in the
assessment process, during which all the concerned member states consider the
draft assessment report and the product information. During this phase further
ne-tuning of the SPC, leaet and package insert may be required depending on
feedback from the member states. At the end of 90 days the member states must
approve the assessment report, SPC, leaet, and package insert, after which they are
allowed a further 30 days to enact national legislation granting the authorisations.
If there is a failure to reach agreement between the member states the issues can be
referred to the EMA/CHMP for arbitration. The procedure is outlinedin Figure 6.16.
–14 days
Dossier validation (CA's)
Day 0
Day 70
Comments from Concerned CA's
Responses from applicant
Day 120 Draft assessment report, SPC, Labels, leaflet (Reference CA)
Comments/feedback from CA's
Fine-tuning SPC
Day 210 Approval of assessment report, SPC, Labels, leaflet (CA's)
Authorisation (member states)Day 240
Dossier Submitted to CA's (Applicant)
Start of Assessment Step 1 (Reference CA)
Preliminary Assessment Reports (Reference CA) Stage 1
Stage 2
Figure 6.16 Decentralised marketing authorisation process (CA = (national) competent
authority).
134 6 Marketing Authorisation
6.4.6 Mutual Recognition Procedure
An applicant must use the mutual recognition procedure to obtain marketing
authorisations in other Member States, once an authorization has been granted
by a Member State. The applicant must submit the dossier using CESP to each of
the concerned member states where authorisation is requested and identify the
reference member state that granted the original authorisation. Before starting the
process, the applicant is advised to ensure that the existing Member State dossier is
fully up to date based on marketing experience. The applicant is also encouraged to
engage in dialogue with the reference Member State on adjustments to the approved
product information so as to ensure a smooth recognition procedure by the other
member states. The reference Member State has 90 days to update the original
assessment report based on dossier updates and forward itto the concerned Member
States together with the SPC, label and leaet text that it has approved. Within
90 days of the receipt of these documents, the concerned Member States shall
recognise the decision of the reference Member State and the approved summary
of product characteristics, package leaet and labelling by granting a marketing
authorisation with a harmonised summary of product characteristics, package
leaet and labelling. During this phase adjustments to the product information may
be agreed, with the reference Member State acting as the coordinating interface with
the applicant. If there is disagreement between Member States regarding the grant-
ing of an authorisation, the issue is referred to a coordinating group, consisting of
Member States’ representatives, and if it cannot be resolved there, then it is referred
to the CHMP for review and possible authorisation via the centralised procedure.
6.4.7 Plasma Master Files and Vaccine Antigen Master Files
Documentation providing detailed information on the characteristics, collection
and control of human plasma used as the starting material for blood-derived
products, or the production of antigens for vaccine products manufacture can be
submitted as stand-alone Plasma Master Files/Vaccine Antigen Master Files. This
is intended to simplify the tasks for both the applicant and the authorities where
the starting materials become constituents of many dierent products. Rather than
reviewing the quality and safety of the starting materials as part of each individual
marketing application, the lescan be centrally submitted tothe EMA for evaluation
and issue of certicates of compliance. 90 days are allowed to compete for the review
process. The certicates can be used to support marketing applications through
either centralised or national procedures. Certicates must be renewed annually.
6.5 Submission and Review Process in the US
Applications to market drugs for human use in the US are invariably assessed by
either the FDA’s Centre for Drug Evaluation and Research or the FDA’s Centre
for Biologics Evaluation and Research (CBER). ‘Chemical’-based drugs invari-
ably describe those whose active substance is manufactured by direct chemical
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