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WHO Drug Information Vol. 30, No. 4, 2016
Regulatory collaboration
Collaboration, not competition:
developing new reliance models
Exchange of assessment reports (ARs) with regulators outside the European Union (EU)1
At a time when modern medicines manufacture and distribution are
increasingly globalized, cooperation between medicine regulators has
become essential, and multiple models of regulatory collaboration are
being implemented in all regions of the world. The European regulatory
system for medicines is unique in the global regulatory environment and
may serve as a model for other countries or regions for building trust and
mutual reliance. The EU Medicines Agencies Network Strategy to 2020
highlights the strong international role that the EU network can play in
promoting reliance and work-sharing with other regulators.
This paper provides a discussion of the programmes and initiatives
in which medicines regulators rely on collaboration and on assessment
work carried out by other regulators while retaining responsibility for their
own regulatory decisions. It also proposes some tools and suggestions
to make these approaches more systematic. The paper concentrates
on assessment of applications for marketing authorization, but many
concepts expressed here can be applied to other regulatory areas such as
inspections and pharmacovigilance.
Although the focus is on exchange of documents produced by the
European Medicines Agency (EMA) and other agencies in the EU network
with regulators outside the EU, it is recognized that the EU regulatory
system also has much to gain by exchanging experience with, and
receiving information from, regulators in other regions of the world.
1
The 28 EU Member States plus Iceland, Liechtenstein and Norway form the European Economic Area
(EEA). Most of the EU rules, procedures and practices described in this article apply to all the EEA
countries.
Authors:
Riccardo Luigetti, European Medicines Agency (EMA)
Peter Bachmann, Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), Germany, and
Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh)
Emer Cooke, European Medicines Agency (EMA); since 15 November 2016: Department of
Essential Medicines and Health Products (EMP), World Health Organization
Tomas Salmonson, Läkemedelsverket (MPA), Sweden, and EMA Committee for Medicinal Products
for Human Use (CHMP)
Any feedback on ways to achieve or improve cooperation would be very much appreciated
by the EMA and the other agencies in the EU network, and can be addressed to EMA through
the mailbox: emainternational@ema.europa.eu.
558WHO Drug Information Vol. 30, No. 4, 2016 Regulatory collaboration
Introduction 1965. It has a long history of developing
effective cooperation within Europe and
Current regulatory challenges may serve as a model for other countries
Modern medicines manufacture and or regions for building trust and mutual
distribution are becoming more and reliance. The EU Medicines Agencies
more globalized. As a consequence the Network Strategy to 2020 (1), published in
manufacturing processes and supply December 2015, highlights collaboration
chains of pharmaceutical products, in the global regulatory environment as a
including generics, are increasingly strategic priority area and aims at further
complex. The same medicinal product developing a strong international role
is often distributed in several countries for the network by, among other things,
or world regions and used by patients capacity building and promoting reliance
all over the world. It is also common and work-sharing with other regulators.
that different manufacturing phases for A number of other countries and regions
the same product take place in different have also developed or are developing
countries, often very far away from formal and informal frameworks for
each other. At the same time more and cooperation and work-sharing, helping
more common elements are present avoid duplication and use resources
in the dossiers submitted in different efficiently. A few examples are given
jurisdictions. below; the list is far from being exhaustive.
In addition, new medicines coming to In the Region of the Americas, which
the market are often complex products comprises 55 countries, the Pan
such as biotechnology, gene therapy American Network for Drug Regulatory
or cell therapy products, or have Harmonization (PANDRH) is a forum of
sophisticated formulations involving national medicine regulatory agencies
e.g. micellar systems or nanoparticles. whose aim is to promote regulatory
Some regulators may lack the resources harmonization between them, including
or specific competences to carry out technical guidelines and regulatory
assessments of these products before processes, while the Caribbean
they are put on their markets. Community (CARICOM) is advancing a
In this environment, collaboration project to develop a regional regulatory
among regulators is essential to avoid system.
duplication of work, release scarce In Africa, several regional communities
resources for more critical areas and and projects are in place to develop
speed up patients access to new and/or cooperation mechanisms, such as the
affordable products. East African Community (EAC) and
the Southern African Development
New models of cooperation Community (SADC), which are working
The growing awareness of the need for towards harmonization among the
regulators to work together has led to the participating authorities, and the
emergence of new models of cooperation. ZaZiBoNa project, which connects the
The European medicines system is regulatory systems of the four participating
probably the best-established example of countries (Zambia, Zimbabwe, Botswana
regulatory cooperation between medicines and Namibia) with a view to expanding
authorities, with a legal basis dating from the project to other countries. The African
559Regulatory collaboration WHO Drug Information Vol. 30, No. 4, 2016
Vaccine Regulatory Forum (AVAREF) is An alternative way to achieve
developing mechanisms and pathways cooperation and avoid duplication of work
for expedited regulatory review of clinical is what is often referred to as reliance.
trials for products being developed to Reliance is a broad concept and can be
address public health emergencies and achieved in real life in different ways. In
neglected diseases, including joint review general, reliance implies that the work
by regulators and ethics committees. A done is shared by the trusted authority
timeline for the establishment of an African (e.g. through assessment or inspection
Medicines Agency has been recently reports), while the receiving authority uses
established (2). this work according to its own scientific
The Association of Southeast Asian knowledge and regulatory procedures and
Nations (ASEAN), the Asia-Pacific retains its own regulatory responsibilities.
Economic Cooperation (APEC) and For example when an assessment report
the Gulf Central Committee for Drug for a medicine authorized in the EU is
Registration (GCC-DR) are among the shared with a regulatory authority in Africa,
regional initiatives in Asia working towards the receiving authority might still need to
harmonization for medicinal products. consider differences in conditions of use,
patient population and other parameters.
Collaboration and reliance In many cases reliance on the
Regulatory collaboration can be achieved assessment or inspection work carried out
in a variety of ways, including information by another trusted regulatory authority can
and/or work-sharing and mutual be the best way to cooperate effectively.
recognition of assessment and inspection Reliance can be unilateral, bilateral
results. (mutual) or multilateral.
Forms of cooperation such as mutual
recognition agreements, which require EU registration pathways
establishment of a strong legal framework, The EU regulatory model has evolved
are desirable and should be implemented significantly over time, particularly since
whenever possible. However, they take the creation of the European Medicines
a long time to set up, as the regulatory Agency (EMA), the Centralised Procedure
systems involved need to be mutually and the Mutual Recognition Procedure
assessed and shown to be equivalent in 1995. The various routes to medicines
before implementation. approval in the EU system (Table 1) are
Table 1. Routes to medicines approval in the EU system*
Centralised Procedure Assessment via EMA, resulting in a single marketing authorization
(CP) throughout the EU
Decentralised Procedure Assessment of a new (not previously authorized) medicine by a
(DCP) Reference Member State on behalf of a group of other Member States
Mutual Recognition Assessment of a medicine authorized in at least one Member State by a
Procedure (MRP) Reference Member State on behalf of a group of other Member States
National procedures Assessment by a Member State of a medicine for approval in its own
jurisdiction
*More information is available in the Notice to Applicants published by the European Commission at:
http://ec.europa.eu/health/documents/eudralex/vol-2/index_en.htm
560WHO Drug Information Vol. 30, No. 4, 2016 Regulatory collaboration
based on a single assessment system for marketing authorization. The receiving
so that any assessment report (AR) from authorities benefit from the information
any of the agencies in the EU network can in the EU ARs but maintain their own
be used as a basis for reliance by other regulatory responsibilities for decision-
regulators. making.
Exchange of complete, unredacted Currently the pilot involves EU
ARs plays an important role in regulatory authorities as well as Health Canada,
cooperation. EU regulators share their Swissmedic, the Taiwan Food and
unredacted ARs with regulators outside Drug Administration (TFDA) and the
the EU in several established initiatives Therapeutic Goods Administration (TGA)
and other contexts, as described of Australia. Other members of the IGDRP
below. This exchange is often based on may decide to take part at a later stage.
confidentiality agreements, but in the spirit In January 2015, the information-sharing
of regulatory collaboration ARs can also pilot was extended to include applications
be exchanged where there is no such for generics submitted through the
agreement in place and the applicant Centralised Procedure, allowing EMA
for marketing authorization consents to to share its ARs relating to these
this sharing. This allows the extensive submissions with the collaborating non-EU
assessment work carried out by EU regulatory agencies in real time.
experts to be used by other international The EU is leading this initiative with
regulators for the benefit of patients. The the aim of strengthening the scientific
different means used to achieve such assessment, increasing consistency in the
sharing of ARs in practice are explained assessment of generics and saving global
later in this paper. assessment resources.
Information-sharing initiatives WHO collaborative registration pilot for
involving EU ARs stringently authorized products, including
through the EU’s Article 58 Procedure
IGDRP information-sharing pilots with The World Health Organization (WHO)
EU’s Decentralised and Centralised collaborative registration pilot for
Procedures medicines approved by a stringent
The information-sharing pilot of the regulatory authority (SRA)3 was initiated
International Generic Drug Regulators in 2015 as an extension of a WHO
Programme (IGDRP)2 was launched in procedure that facilitates and accelerates
July 2014 using the EU Decentralised the national registration of products
Procedure (DCP) as a model for already assessed and prequalified by
cooperation. It provides a mechanism for WHO. The pilot aims at facilitating the
sharing of information during the scientific registration of SRA-approved essential
assessment phases of the procedure. medicines in countries where regulatory
During Decentralised Procedures for
generics participating in the pilot, ARs are
3
Defined in WHO guidance (3) as a regulatory
authority in a country that is a member of the
shared by the EU agencies in real time International Conference on Harmonisation
with the participating non-EU authorities, (ICH) or an ICH observer country, or a
upon request from the company applying regulatory authority associated with an ICH
country through a legally binding mutual
2
https://www.igdrp.com/ recognition agreement
561Regulatory collaboration WHO Drug Information Vol. 30, No. 4, 2016
resources may be limited. Here as well, would for Centrally Authorised Products
the receiving competent authorities retain authorized for marketing in Europe, taking
their regulatory responsibilities and make into account possible different conditions
their own decisions.4 of use. Experts and observers from WHO
Since November 2014 EMA has or from WHO Member States (appointed
participated in the development and by WHO) are part of the assessment
implementation of the pilot. In this context, process. The CHMP, after consultation
EMA ARs are shared with regulators in with WHO, adopts a scientific opinion,
African countries by companies holding following the process in place for the
EU marketing authorizations who wish to Centralised Procedure.5
market their products in these countries. An Article 58 Procedure followed by
EMA confirms, upon request from the collaborative registration provides a useful
company, that it has no objections to the approach to speeding up patient access
sharing of its ARs and, in accordance to essential medicines, including new or
with WHO procedures, confirms that the improved therapies for unmet medical
Quality Information Summary provided by needs, without compromising on the
the company complies with the information quality of assessment.
in the dossier assessed by EMA. EMA can
provide the receiving authority with further Other uses of EU assessment
information or clarification on any aspect reports by non-EU regulators
of the assessment and promotes dialogue Non-EU regulators often request
between the receiving authority and the applicants to provide EU ARs in contexts
relevant EMA assessors as required. other than the information-sharing
At the time of writing, EMA participation initiatives described above. The use of
has involved three Centrally Authorized EU ARs in the receiving country may be
Products and one assessed under Article included in the legislation, guidelines or
58 (see below), for the treatment of HIV, procedures of these countries. Some
malaria or tuberculosis. examples are given below.
Article 58 of Regulation (EC) No.
726/2004 (4) allows EMA’s Committee Switzerland
for Medicinal Products for Human Use The Swiss legislation (5) foresees that for
(CHMP) to give opinions, in co-operation a medicinal product which has already
with the WHO, on medicinal products for been granted an authorization in a country
human use that are intended exclusively with a comparable control system for
for markets outside the EU. This includes medicinal products, the assessment
vaccines used in the WHO Expanded by the reference authority will be taken
Programme on Immunization, medicines into account by Swissmedic during
used to treat public health priority the authorization procedure, provided
diseases, and medicines for WHO target that the applicant explicitly requests
diseases such as HIV/AIDS, malaria or Swissmedic to do so. The goal is to make
tuberculosis. Under Article 58 the CHMP medicinal products already authorized in
carries out a scientific assessment
according to the same standards as it 5
More information on Article 58 is available
at: www.ema.europa.eu/ema/index.
4
More information is available at http://apps.who. jsp?curl=pages/regulation/document_listing/
int/prequal/ under “Collaborative Registration”. document_listing_000157.jsp
562WHO Drug Information Vol. 30, No. 4, 2016 Regulatory collaboration
foreign countries available to patients in Singapore
Switzerland as rapidly as possible while Legislation in Singapore (7) allows for
ensuring a targeted, risk-assessed use of leveraging of foreign reports to grant
Swissmedic’s resources. marketing authorizations. The reference
Use of an existing EU AR in this way has agencies accepted by the Singapore
decreased the review time by up to about Health Sciences Authority (HSA) are
20%. In 2015, about 15% of medicinal EMA, U.S. FDA, Health Canada, TGA
products with known active substances and MHRA (for national products or
authorized in Switzerland were authorized Decentralised and Mutual Recognition
taking into account ARs produced by products where MHRA is the Reference
EMA or an EU Reference Member State.6 Member State). For applications that
In addition, there are products for which have obtained prior approval from these
the approval decision is not based solely reference agencies, HSA has a system
on shared EU reports. Applicants are that enables leveraging of assessments
encouraged to always submit any such performed by these agencies, called the
ARs as they are considered a valuable Verification Route (VR). To be eligible
source of information. for the VR, one of the criteria is that the
product is authorized for marketing in any
Canada two of the HSA’s reference agencies.
In Canada, a draft guideline was The VR takes 60 days (excluding
published in 2012 (6) which details how clock-stops) as opposed to the 270 days
information submitted by applicants on necessary for products not previously
reviews carried out by foreign authorities authorized by any other authority (Full
can be used by Health Canada during the Route) or to the 180 days for products
assessment of applications. The guideline authorized by at least one drug regulatory
recognizes that the Canadian law does authority (Abridged Route). 5% of the
not prevent Health Canada from using, products authorized in Singapore in 2015
where appropriate, foreign reviews to have been authorized via the VR using
perform part of the evaluation or to inform EMA assessment reports.7
Health Canada’s decision-making. Health
Canada however cannot grant (or refuse Mexico
to grant) marketing authorization based In 2012, EMA was approached by the
solely on the existence of a foreign review Mexican medicines regulator COFEPRIS
and its corresponding regulatory decision. to facilitate an assessment of legal
Different levels of reliance on foreign equivalence between the Mexican and
reviews are detailed in the guideline, EU pharmaceutical legislation. After
allowing for the possibility that a critical dialogue with EMA lawyers, the result
assessment of the foreign review is used was a unilateral agreement (“acuerdo”)
as a basis for the Canadian regulatory (8) through which Mexico uses the work
decision on the entire data package or on carried out at EMA during assessment
one or more of its components. of Centrally Authorised Products to
expedite approval of new medicines in
Mexico. Similar arrangements are in
place between Mexico and some other
6
Personal communication received from
Swissmedic 7
Personal communication received from HSA
563Regulatory collaboration WHO Drug Information Vol. 30, No. 4, 2016
countries, including the United States, in these cases confidential information is
Canada, Australia and Switzerland. redacted.
When marketing authorization holders
Modalities for exchange of are requested by a non-EU authority to
information with non-EU regulators share EU ARs for their products, they may
ask the relevant EU agency to confirm
Sharing of assessment reports (ARs) in writing that it has no objection to the
EMA ARs (for both the Centralised and the sharing. Unless there are serious reasons
Article 58 procedures) and ARs from other to object, the EU agency indicates to
agencies in the EU network are shared the company concerned that it does not
with non-EU regulators directly or through object. A standard wording for responding
the marketing authorization holder. to such requests has been developed and
Although EU ARs include commercially published on the EMA website.9
confidential information, they can be
exchanged by EMA and the other Public ARs
agencies in the EU network with other Notwithstanding the measures identified
regulators when there is a Confidentiality above the EU assessment process
Arrangement8 in place between the EU is exceptionally transparent, and the
and the receiving authority. Through these possibility of taking advantage of what
arrangements the parties agree not to is made public on the websites of EMA
disclose confidential information. and the other agencies in the EU network
In the absence of such an should not be underestimated. The EMA
agreement, unredacted EU ARs can website, for example, is continuously
still be exchanged directly with non-EU updated with information on the quality,
regulators, provided that the marketing safety and efficacy of Centrally Authorised
authorization holder for the products Products. For every medicine, including
consents to the exchange. EMA is those with a positive opinion under
encouraging such direct exchanges as far Article 58, a European Public Assessment
as possible, and a template to be used Report (EPAR) is published,10 which gives
by companies to consent to exchange of a wealth of information on the product,
ARs has been made public on the EMA its use and its assessment. EMA also
website9. EU ARs can also be provided publishes information on medicines
by EU authorities without consent from which receive a negative opinion from the
the marketing authorization holder, but CHMP.
Similar public ARs are published by
other agencies in the European network.
8
Confidentiality Arrangements are in place Public ARs for products assessed through
between the EU and the following organizations:
US Food and Drug Administration (FDA); Health the Mutual Recognition Procedure are
Canada (HC); Japan Ministry of Health, Labour published in the MR Product Index on the
and Welfare (MHLW) and Pharmaceutical and Heads of Medicines Agencies website.11
Medical Devices Agency (PMDA); Swissmedic;
Australia Therapeutic Goods Administration
(TGA); World Health Organization (WHO) 10
More information on EPARs is available
9
Available in the EMA questions and answers on at: www.ema.europa.eu/ema/index.
pre-submission guidance, Question No. 68 at: jsp?curl=pages/medicines/landing/epar_search.
www.ema.europa.eu/ema/index.jsp?curl=pages/ jsp&mid=WC0b01ac058001d125
regulation/general/general_content_000157.jsp 11
Available at: www.hma.eu/mriproductindex.html
564WHO Drug Information Vol. 30, No. 4, 2016 Regulatory collaboration
Additional approaches Pharmaceutical Inspection Co-operation
Exchange or publication of ARs are not Scheme (PIC/S) and the International
the only ways in which cooperation on Generic Drug Regulators Programme
medicine assessment among regulators (IGDRP) among others provide excellent
can be achieved or information on platforms for working together to
assessment can be exchanged. Other overcome remaining difficulties.
possibilities are being explored, such
as allowing regulators from other Conclusion
jurisdictions to listen to, or participate The challenges faced by regulators
in, relevant product-specific meetings in an increasingly complex regulatory
and discussions. The possibility of environment are shared and recognized
post-authorization webinars, where the by the EU agencies network, and the
scientific rationale for the decisions taken need for cooperation is emphasized in the
by an agency is explained and discussed recently published EU network strategy
with other regulators, may also be (1). EMA and the other agencies in the
considered. EU network are willing to provide support
and to cooperate with other international
Remaining barriers regulators as much as possible, while
There are still barriers to overcome in at the same time benefiting from the
furthering the exchange of assessment work done by other authorities as far as
and inspection information among possible.
regulators worldwide. Such barriers can As demonstrated by examples from
be legal (e.g. lack of legal framework, other regions of the world, the EU
confidentiality issues), technical (e.g. lack authorities are not alone in favouring
of secure IT platforms for information- and promoting sharing of ARs and other
sharing), and non-technical (e.g. political regulatory documents (e.g. inspection
issues, lack of trust). However, none of reports). However, such cooperation is
them should be big enough to prevent currently mainly carried out at regional
cooperation and sharing of information level. It makes little sense that the work
among regulators, given the benefits it can carried out by regulators in one part of the
bring to patients worldwide. world is not shared with regulators in other
EMA and the other agencies in the EU regions. The cooperation and sharing
network are committed to finding ways to need to be more global in order to be
overcome such barriers wherever they more effective.
exist. For example, in the absence of a It has become increasingly clear that
globally accepted secure IT platform, they forms of cooperation requiring a strong
share unredacted ARs through the EU legal framework often require a very
secure email system, Eudralink, which long time to be achieved. An alternative
is encrypted and password-protected. approach is that of reliance, in which
Multilateral cooperation forums such regulatory authorities make use of shared
as WHO groups and committees, the information but retain their decision-
International Conference of Drugs making responsibilities. Reliance can be
Regulatory Authorities (ICDRA), the unilateral, bilateral or multilateral, can be
International Coalition of Medicines achieved in a short timeframe, does not
Regulatory Agencies (ICMRA), the require a heavy legal framework, and can
565Regulatory collaboration WHO Drug Information Vol. 30, No. 4, 2016
be the prelude to more formalized forms 3 WHO. Procedure for prequalification of
pharmaceutical products. Annex 10. In:
of cooperation such as mutual recognition WHO Expert Committee on Specifications
agreements. for Pharmaceutical Preparations. Forty-fifth
To promote reliance and work-sharing in report. Geneva: World Health Organization;
line with the EU network strategy to 2020, 2011 (WHO Technical Report Series No.
EMA and the other agencies in the EU 961).
network will continue to share unredacted 4 European Commission. Regulation (EC)
EU assessment and inspection reports No 726/2004 of the European Parliament
and of the Council of 31 March 2004 laying
with other regulators worldwide as much down Community procedures for the
as possible, and will actively develop new authorisation and supervision of medicinal
and better ways to facilitate cooperation products for human and veterinary use and
and exchange of information to realize the establishing a European Medicines Agency.
greatest possible benefits for patients. 5 Swiss Confederation. Federal Act on
Medicinal Products and Medical Devices
References (Therapeutic Products Act, TPA) of 15
December 2000. Article 13, Medicinal
1 EMA. EU Medicines Agencies Network products authorised in foreign countries,
Strategy to 2020. Working together and Ordinance of 17 October 2001
to improve health. London: European concerning Medicinal Products (Medicinal
Medicines Agency; 17 December 2015. Products Ordinance), Articles 5a - 5d.
Available at:
6 Health Canada. The Use of Foreign Reviews
2 AMRH. 2nd Task Team meeting to facilitate by Health Canada. Draft guidance document.
the establishment of African Medicines Published by authority of the Minister of
Agency (AMA) successful. AMRH Health. Draft Date: 2012/09/11.
Newsletter January–June 2016: pp. 5-6.
7 Health Sciences Authority (HSA). Guidance
on medicinal product registration in
Singapore. Effective 1 April 2011.
8 Government of Mexico. Diario oficial.
Tercera secciòn. Secretaría de Salud.
(Official gazette. Section Three.
Department of Health). 5 October 2012. å
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