GENOMIC MEDICINEFRANCE 2025

EDITORIAL
The France Genomic Medicine Plan 2025 fulfils
the commission entrusted by Prime Minister
Manuel Valls to Alliance Aviesan in April 2015 toinvestigate establishing access to genetic diagnosis
in France together with a prospective review
covering the first ten years.
Following the example of similar programs
launched in the United Kingdom in 2012, in the
USA in 2014 and in China, France aims throughthis Plan to construct a medical and industrial
system to introduce precision medicine into thecare pathway and develop a national frameworkin this matter.
The proposals in this Plan have been formulated
after a year of work with institutional representatives and multidisciplinary experts from thefields of science, health care, business, researchand health care agencies, Ministries, business asrepresented by Ariis, CNAM and HAS, CGI andthe École d’économie de Toulouse. The “French
Model” proposed here is a mixed one involving
prerogatives of health care and science in line with
our health care system, its link with research, theeconomic model of health care procedures andthe need to establish a process of integration ofscientific advances into health care to facilitate
access for everyone in the country to innovation.
This Plan also takes into account, in a concrete
fashion, technological progress from sequencing to
the storage and analysis of the resultant big data as
well as confidential reporting back to doctors andpatients. Big multinational companies appreciate
the strong potential represented by developing
digital health care and are investing heavily inthe sector. Businesses operating in biologicaldiagnosis, the digital sector and new sequencing
technology have worked together with otherinstitutions to draw up these recommendations.

The issues and challenges for France
A missed chance for patients

Four major challenges

In Europe, a number of countries have begun
assimilating genomic medicine into their healthcare system, including Estonia, the Netherlands
and Slovenia. If France fails to launch its own
initiative, the risk is one of medical tourism with
French patients going abroad to other countries on
the Continent that offer these high-value-added
medical services with the corollary of effect ofexacerbating the inequality of citizen access tohealth care.

The strong international competition in thefield of genomic medicine is explained by thechallenges it raises.

Strong international competition
Genomic medicine is no longer a promise—itis already a reality that will transform how we
prevent, diagnose, treat and predict the prognosis
of disease. It is also a stage for strong international
competition, each country wanting to develop
its own industry and attract scientific talent tobolster up its own advantages.

First and foremost, it is a public health issue.
Genomic medicine is revolutionizing the carepathway and therefore how the public health system is organized. A large number of patients withrare diseases or cancer will benefit from routine
sequencing of their genomes with more personalized diagnosis and treatment. Great progress has
already been made with more common diseases(metabolic, cardiovascular, neurological, etc.)
through genome sequencing, above and beyond
identification of the usual susceptibility-conferring
genes. With time and expansion to cover novel
clinically validated indications, all patients will
eventually benefit from improved care.

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To achieve this, the challenge is also scientificand clinical. This will involve reinforcing thechain going from the molecular investigation of
disease to therapeutic benefit to patients via theassembly and matching of multiple heterogeneous
databases, be they of biological data (sequences,
screens, imaging results, etc.), clinical data oreven environmental information.
And the technological challenge is no less pressing: information and communication sciences
and technologies are called on to converge withthe life sciences and health care information,
the capacity to acquire, store, distribute, matchand interpret such big data from diverse sources
being at the heart of said convergence. It represents a genuine focus of excellence in calculation
science and biological data that will emerge. In
addition to servers, cores and intensive calculation

methods, the development of software for data
mining and modelling will make it possible tomeet the challenge of genomic medicine and,more broadly, personalized medicine.
Finally and pre-eminently, the challenge is an
economic one both in terms of expenditure by
our health care system and also the chance todevelop new industrial infrastructure.
On the one hand, innovation in health care andquality of life is one of the drivers of growth indeveloped countries. And on the other hand,genomic medicine is more precise meaningsavings on health care due to fewer inappropriate, inaccurate and extensive examinations,faster turnover times, less prescription of uselessdrugs, fewer debilitating adverse reactions andgains in years of life.

Objectives of the France Genomic Medicine Plan 2025
To meet these challenges, we have proposed atransformative, ten-year Plan. Built up around
sequencing platforms covering the whole country,
a national data analysis center and a nationalreference center for technological innovationand transfer, the aim is to capitalize on the specificities of our health care system and bring yet
more closely together care, research, training
and innovation in the service of health care andquality of life.

Finally, the third target for 2025 is to set up anational genomic medicine framework capableof driving scientific and technological innovation,industrial capitalization and economic growth.
This Plan will create a dynamic in the matter ofinnovation in a number of fields: conservation,
the generation and mathematical processing of
big data, Web semantics and the Web of objects,
medical devices, dematerialization, digitizationand e-Health, etc.

A Plan structured by three targets

The involvement of relevant businesses together
with academic scientists and the public sector
is essential.

The first is to position France among the countries
leading the way in personalized and precision
medicine with export of the expertise derived
from the French medical and industrial genomic
medicine system.
Our second target is to prepare for integration of
genomic medicine into the care pathway and the
management of common diseases. This means
setting up a generic care pathway with accessfor all patients with cancer, a rare disease or acommon disease by 2025, with genomic medicine
available to all affected patients in the country.
By 2020, some 235,000 genomes will be being
sequenced each year. Beyond that, the system will
be expanded to cover common diseases.
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Ethical considerations at every step of the France Genomic Medicine Plan 2025
The ethical dimension is an integral part of thePlan. In this field too France has to construct a
new model—here too France will innovate.
It will not be possible to develop personalized
genomic medicine without at the same time
providing answers to the numerous questions
being asked by citizens and patient support
groups on consent in access to and exploitationof health data, the anonymization of data vis-àvis third parties, how secondary discoveries andunwanted incidents—inevitable when the entire
genomes of patients and their family members
are sequenced—are to be handled and the risk ofeven worse exclusion of people who are alreadybeing poorly served by the health care system.
Some developments would be difficult to put
up with. If we do not integrate all the necessary
ethical rigor into our collective approach, wewould risk traducing the democratic contract
between science and society.

Precise genomic medicine represents a revolution
in the fields of health care and prevention. It isfostering huge hopes—legitimately so—in people.
It is changing how we define disease and how
we help the sick.
France must give itself the resources needed tomake this revolution a success and take its place atthe vanguard. Growth is crucial, a major scale-up.
The France Genomic Medicine Plan 2025 willbring this and its success is now our collective
duty to both patients and society as a whole.

Yves Lévy
President of Aviesan

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SUMMARYIn an engagement letter on 17 April 2015, the Prime Minister commissioned Aviesan to examine
how to integrate large-scale sequencing into the care pathway. Four aims were specified:ne the place and importance of genome
challenges in terms of innovation,•Defi•Assesssequencing in medicine today and predict
capitalization and economic development,
developments that might be expected overthe coming ten years.

taking into account technological aspects,
how to handle big data and ethical issues.

the position of France in genomic•Establish
Develop a long-term medico-economic model
research, the place of this science in current •health care plans and priorities when it comesto ensuring consistency with national healthcare and research strategies.

integrating reimbursement by the healthinsurance system with development of anindustrial framework to sustain the initiative.

Under the presidency of Aviesan, a Steering Committee was convened with institutional
representatives, diverse experts from the fields of research, health care and business as well as
delegates from research and health care agencies, ministerial departments, and industrial enterprises
represented by Ariis, CNAM, HAS, CGI and the Toulouse École d’économie.This Committee has
been meeting every month since May 2015.
The Steering Committee set up four Working Groups to focus on the issues raised in the Prime
Minister's engagement letter. In these Groups, relevant experts—physicians, scientists, business
representatives, learned societies and patient support groups—meet up on a weekly or monthly basis.

The medical, economic and international background
Access to genomic medicine represents achallenge for public health: with the spread ofultra-high-throughput sequencing, significant
proportions of patients will ultimately benefit
from routine genomic investigation, not only
patients with rare diseases and cancer but also
those with certain common diseases. Higherresolution diagnosis will enhance care with shortertime frames as well as more effective therapeuticstrategies and fewer adverse reactions.
This domain represents an important economic
issue with tremendous savings on health careexpenditure and great expectations from thisnew channel. Reduced health care expenditure is
likely to be substantial by virtue of various factors:
a reduced number of expensive but spurious
diagnostic procedures; quicker test turnover;
avoidance of ineffective, potentially dangerous
drug treatments and the need to treat adverse
reactions; earlier treatment; and more effective
treatment leading to increased life expectancy.
In parallel, a new, innovative industrial framework will have to be constructed—a source ofeconomic development and employment. This
will support the system's expanding scope andprovide solutions to the numerous technologicalchallenges arising, in particular development of
the information technology capacity that will
be required.
Genomic medicine is a field of international
competition supported by national plans. The
United States, the United Kingdom and China
in particular are investing in this sector andhave mobilized their biggest companies to findinnovative technological solutions to the problems raised by large-scale ultra-high-throughput
sequencing and the handling of big data. France,with an annual capacity for just 20,000 exomes
and 10,000 genomes, is significantly lagging
behind these countries that can do several tensof thousands of runs a year. While an industrial
opportunity is growing in the field of genomic
medicine—an opportunity that is attracting
the interest of companies like Google, Apple,
Facebook, Amazon, Microsoft and Samsung
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(GAFAMS)—France must not miss this uniquechance to develop a national industrial frameworkof high strategic, medical, scientific and economic
value associated with the development of thisinitiative; the ultimate risk being technologicaldependence. Moreover, other European countries

including Germany, Estonia, the Netherlands
and Slovenia have already started integrating
genomic medicine into their health care systems
thereby increasing the risk of the French systemlosing ground resulting in domestic patients goingabroad for these services.

Targets of the 2025 France Genomic Medicine Plan
France among the leading big counbe capable by 2020 of sequencing 235,000•Totriesposition•Togenomes
in the field of genomic medicine within
a year, corresponding to 20,000 patientsthe next ten years, with the aim of exporting
expertise in the domain and developing a strong
medical and industrial framework based on
genomic medicine.
by 2025 a generic care pathway•Towithestablish
privileged, common access to genomic

with rare diseases together with their families(about 60,000 genomes) and 50,000 priority
patients with metastatic cancer or a cancer
that has proven refractory to treatment (about
175,000). Beyond 2020, the system's capacity
will be grown to cover common diseases.

medicine for all French people affected bycancer, a rare disease or a common disease(patients and, in some cases, their families).

Specific measures in the 2025 France Genomic Medicine Plan
Transformative and innovative, directed andsupported by the State over a period of ten years,
this Plan provides an original, global responseto the Prime Minister's request. In contrast
to the initiatives launched elsewhere, notably
the United States and the United Kingdom, it
exploits particularities of our health care system
which covers patient care, training and research
with—especially in recent years—the developmentof broad-scope actions which strongly support
this approach (governmental plans, establishment of spaces for dialog between partners andcompanies, and definition of national health careand research strategies).
The Plan is organized to meet needs identified atthe various steps along the care pathway designed
around the patient/doctor pair from the orderingof genome analysis through the compilation of
conclusions. It is embodied in three main targets
with a series of measures to:

Establish genomic medicine instruments forthe care pathway with:setting up of a network of twelve sequencing•theservices covering the whole country by 2020,
to meet the stated quantitative objectives;of a National Center for Intensive•establishment
Calculation (CAD, Collecteur analyseur dedonnées) capable of processing and analyzing
the huge volumes of data that will be generated
and providing primary services for professional
health care providers in the framework of
their care pathways (in silico tests and aids todecision-making in diagnosis, establishingprognosis and designing therapeutic strategies);of standardized, interoperable•generalizationelectronic patient medical records—a step thatis indispensable when it comes to integratingand exploiting genomic and clinical data;of 2016, the execution of pilot projects on•ascancer,
rare diseases and common diseases
designed to overcome technological, clinicaland regulatory obstacles encountered along
the pathway;6

for changes in current regulatory Implement necessary changes throughout devel•preparation
frameworks according to Good Practices as opment of the Plan to ensure information andwell as judicial and ethical standards, notably by appointing a National Consultative
Ethics Committee (Comité consultatif nationald’éthique) to examine the various steps of thecare pathway vis-a-vis ethical aspects of thecollection, storage and processing of clinicaland genomic data as well as guaranteeing safe,
high-quality care.

involvement of the general public, users andpatient support groups, with:

Respond to the increasing scope of the systemwith technological and regulatory changes
integrated in the Plan's dynamics by:ulatory aspects of genomic medicine at theinternational level;

nition of a governance system that matches•defi
the Plan's requirements, and establishment ofspecial monitoring and steering mechanisms;
of a registry to monitor devel•establishment
opments in medical, technological and reg-of an economic registry to sponsor•creation
research on the Plan's economic consequences;of a system to assess and validate•establishment
new indications for access to genomic diagnosis
organizing the information, consultation•
ensuring development of the existing base withand involvement of everyone in society who
progressive integration into the care pathway;of a national Reference Center for•creation
Technology, Innovation and Transfer (centre deis concerned.

référence technologique, d’innovation, et de transfert, CRefIX1) turned towards the sequencing
service, CAD and companies;
nition of an economic model to ensure•defi
the durable integration of this new system
into the health care system linked to healthinsurance which should define costs andreimbursement conditions and promoting the
emergence of a "genomic medicine" channel
by offering companies not only an economic
logic but also an operating logic for the futuresystem guaranteeing its development in thelong term;of the activities of all those involved•orientation
to address industrial issues with support froma public/private sector task force;up special training programs in univer•setting
sities and schools to prime construction of amulti- and inter-disciplinary genomic healthsystem and foster new skills and personnel,
specifically capable of meeting the challengesof how to analyze and interpret the data.

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CRefIX: Centre de Référence, d’Innovation, d’eXpertise,et de transfert

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CONTEN
1 A BROAD-SCOPE NATIONAL PLAN TO ENSURE INTEGRATION OF GENOME
SEQUENCING INTO THE CARE PATHWAY ............................................................11
1.1 Introducing genome sequencing into the care pathway meets major
challenges in France ...................................................................................................... 11
1.1.1 Access to genomic medicine: a public health issue........................................................11
1.1.2 Genomic medicine: a matter of international competition...........................................121.1.3 A sector that represents a major economic issue with massive savings for Frenchhealth care system and repercussions of a new system ...........................................................13

1.2 France possesses many advantages when it comes to reaching the desired
objective but the necessary partners and investment can only be guaranteed withstrong governmental commitment................................................................................ 13

2 TARGETS OF THE PLAN ......................................................................................15
2.1 A paradigm shift in French health care system ........................................15
2.2 Operational targets for 2020 and 2025....................................................16
3 FRANCE GENOMIC MEDICINE ACTION PLAN 2025 ..........................................17
Target 1: establish instruments for a genomic care pathway .......................................18
Measure 1: Construct French capacity for ultra-high-throughput sequencing to meetthe defined targets .....................................................................................................................18
Measure 2: Develop the tools required to process and exploit the volume of datathat will be generated with creation of a central analysis service (collecteur analyseur
de données, CAD) .......................................................................................................................20
Measure 3: Foster the integration and exploitation of patient data into the care pathway .....22

Target 2: Ensure operational development and expansion of the system in asafe technical, ethical framework ................................................................................. 23
Measure 4: Establishment of a Reference Center for Innovation, Assessment andTransfer (Centre de référence, d’innovation, d’expertise et de transfert, CRefIX) to foster thetechnological developments and information technology required for implementation of
the pathway................................................................................................................................23
Measure 5: Overcome the technological, clinical and regulatory obstacles encounteredalong the path with respect to the three broad groups of disease concerned ........................25
Measure 6: Establish a system to assess and validate new indications for access togenomic diagnosis .....................................................................................................................26
Measure 7: Foster new skills and personnel capable of meeting the challenges of how toanalyze and interpret the data ..................................................................................................27
8

NTS
Measure 8: Integrate ethical aspects related to the collection, storage and processing ofclinical and genomic data and guarantee safe, high-quality care ...........................................28

Target 3: Establish monitoring and steering tools to make the adjustments required
throughout implementation of the Plan while ensuring public involvement.............. 31
Measure 9: Mobilize industrial entities implicated in the project to meet technological andindustrial needs at the various steps in the care pathway and promote the emergence of a"genomic medicine" channel ....................................................................................................31
Measure 10: Orientate the activities of all those involved to address industrial issues arisingalong the genomic care pathway ................................................................................................. 32
Measure 11: Monitor developments in the field of genomic medicine at theinternational level ......................................................................................................................33
Measure 12: Establish a research program dedicated to medico-economic aspects of
the Plan ......................................................................................................................................33
Measure 13: Organize the information, consultation and involvement of everyone insociety who is concerned...........................................................................................................35
Measure 14: Define a governance system for the Genomic Medicine Plan .........................35

GLOSSARY .................................................................................................................38
APPENDIX .......................................................................................................................................41
Appendix

Letter from the Prime Minister to the President of Aviesan .......................419

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1 A BROAD-SCOPE NATIONAL PLAN IS
NECESSARY TO ENSURE INTEGRATIONOF GENOME SEQUENCING INTO THE
CARE PATHWAY
The Prime Minister has commissioned thePresident of Aviesan to review how to set up
large-volume sequencing. The ultimate objective
is to reach all patients throughout the country
in whom such tests might be relevant with an
expectation of major impact on both diagnosis
and care (Appendix).
Under the auspices of the president of Aviesan,studies have been undertaken by various specialist
and multidisciplinary groups bringing together
experts (physicians and scientists), academics,
business, learned societies and patient support
groups which have expressed interest in the project.
These studies have led to identification of the
major issues that this project needs to address andhave shown that the medical, societal, economic,
scientific, technical, ethical and legal challenges tobe overcome are substantial (1.1). The challenge
raised by the development of genomic medicine
with integration of an ultra-high-throughput
sequencing system into the care pathway will
require significant resources and governmental

commitment to match the level of the issues atstake (1.2).
An ambitious, transformative Genomic Medicine
Plan to be implemented over a period of ten years
is being proposed (Parts 2 and 3). In response to
the Prime Minister's commission, it provides a
global response integrating patients, our systems
for health care, research and training, and thenational economic fabric. Elsewhere, similar
initiatives are being supported at the highest
level—by British Prime Minister David Cameron(the 100,000 Genomes Plan) and American
President Barack Obama—and several other
European countries have already committed tomaking genomic medicine part of their health caresystems in various ways (Germany, Estonia, theNetherlands and Slovenia). To position France inthis global competition and avoid losing important ground in terms of both French economy
and health care system, this multi-faceted Plan
(linking health care, industry and research) will
be coordinated, under the auspices of the Prime
Minister, by Aviesan working closely together
with all interested parties.

1.1 Introducing genome sequencing into the care pathway
meets major challenges in France
1.1.1 Access to genomic medicine: a public health issue
The benefits of new-generation sequencing technology (high-throughput and ultra-high-throughput) on panels2 of genes and exomes3, especially for the purposes of diagnosis, have now been
demonstrated in patients with a rare disease or cancer.

2
3

A panel is a set of genes (10-100) that have been shown to be involved in a disease.
The exome is the part of the genome (about 1.5%) made up of exons, i.e. the parts of genes that are transcribed into themessenger RNA that supports synthesis of the proteins, functional products that determine a cell's structure and activities.
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In the field of rare diseases, such technology ismaking it possible to identify rare single nucleotide
variations (SNVs) and genomic rearrangements
like copy number variations (CNVs) that cause
disease. It also makes it possible to compare
genomes from different family members which
is significantly enhancing diagnosis4.
In oncology, numerous sequences can be determined on any given patient, e.g. healthy tissue,
tumors at different stages, malignant cells in the
bloodstream, etc., and being able to consider setsof nosological, prognostic and theranostic markers5
together is dramatically expanding the range oftherapeutic choice to ensure maximum treatment
efficacy with a minimum of adverse reactions.
For common diseases in which complex genetic
factors are involved, sequencing is already shedding
light on associations between specific genetic
variations and differential responses to treatment,
the large number of genes involved in diseases
like diabetes (40-80, depending on the form)
and, more recently (in experimental studies), theinvolvement of rare SNVs in certain pathologies.
Large-scale high-throughput sequencing willassure access to this type of approach for all
patients who might benefit from it and provide
information about a patient's genome to bringabout considerable improvement in the qualityof diagnosis and therapeutic orientation.
For rare diseases, above and beyond improved
sequence information, genome analysis will identify guilty mutations that could not have been
detected in panels or exomes.
In oncology, combination of the information fromgenome analysis (detection of rearrangements,etc.), deep exome sequencing, transcriptomics6
and medical records will give a new dimension
to both diagnosis and therapeutic orientation. It
A CNV is a particular type of polymorphism inwhich the number of copies of a certain gene in the
genome varies between individuals.
5
A theranostic marker is one that helps guide apatient's treatment.
6
Transcriptomics is the study of the entire set ofmessenger RNA molecules in an organism.
4

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would seem that it will only be possible to realize
the Cancer Plan 3 objective of sequencing 60,000
tumors by 2019 in the framework of this initiative.
For common diseases, although sequencing is
confirming their complexity it is also opening theway to fuller understanding and better classificationof many such pathologies and, in consequence,
how to treat them. Thus, by making it possible todefine genetic signatures and biological markers,
genome analysis is emerging as a powerful tool torefine and redefine nosological frameworks andthe principles that orientate therapeutic choices.
Routinely using genomic data and understanding
how it relates to clinical manifestations will
ultimately have substantial impact on medical
practice with better-targeted, more effective
therapeutic strategies, fewer adverse reactions andtherefore improved patient care. Developing thesystem to make it accessible to a large numberof patients seems therefore to be fully justified.

1.1.2 Genomic medicine: a matter ofinternational competition
In the framework of national programs, theUnited States, the United Kingdom and China
in particular are investing in this sector andhave mobilized their biggest companies to findinnovative technological solutions to the problems raised by large-scale ultra-high-throughput
sequencing and the handling of big data.
So far in the field of genomic medicine, France
is behind these countries that already have infrastructure capable of tens of thousands of runs ayear (whereas French capacity is estimated tobe limited to just 20,000 exomes and 10,000
genomes a year). These centers are partners in
ambitious industrial collaborations (Amazon,
Illumina, pharmaceutical companies, etc.) toconstitute an industrial network of genomic
medicine in which businesses that specialize inbig data like Google, Apple, Facebook, Amazon,
Microsoft, and Samsung (GAFAMS) are gettinginterested, seeking to establish standards for the
resultant data and thereby procure for them major
competitive advantage. Against this background,
it is important that France does not waste thisunique opportunity to develop industrial channelsof high strategic, medical, scientific and economic
value associated with the development of thisinitiative (1.1.3); all the more so given the riskof technological dependence.

Other European countries including Germany,
Estonia, the Netherlands and Slovenia have alreadystarted integrating genomic medicine into theirhealth care systems thereby increasing the risk of
the French system losing ground with domestic
patients having to go abroad for these services.

1.1.3 A sector that represents a major economic issue with massive savings for Frenchhealth care system and repercussions of a new systemsavings for French health care system are expenditure. To date, there are no diagnostic•Thepotentially huge and should be accompanied criteria for common diseases based on genome
by social and economic benefits resulting
from a significant improvement in healthy
life expectancy.
For rare diseases, the expected impact is due tomore accurate diagnosis (fewer irrelevant, expensive investigations and faster test turnover times),
optimized treatment and improved strategies
to prevent the disease or limit its complications(especially for metabolic diseases).
In cancer, benefit will accrue on the one handfrom reduced costs (with fewer prescriptions ofineffective targeted therapies and fewer adverse
reactions to treat) and also the positive socio-economic impact of extra years of life. This shouldbe particularly significant for the novel targeted
immunotherapy products which are currently
effective in 30-40% of the patients treated. In any
case, identifying specific markers will enhance thetargeting of treatment and thereby reduce costsby eliminating inappropriate treatment modalities
with the corresponding possible adverse reactions.
Common diseases cause serious morbidity andmortality as well as entailing massive health caresequencing that lead to differential treatment eventhough responses can be highly disparate and thissometimes leads to a period of therapeutic failure.
The tools of genomic medicine should ultimately
shed light on the underlying causes of these diseases
and thereby help identify the most appropriate
treatment modalities. The impact will manifest in
the form of improved care, more accurate diagnosis
and better-targeted therapeutic strategy.
many technological challenges to be met—•The
to find solutions and assemble equipment, inparticular with respect to the unprecedented
computing power required in terms of storage
and calculation—necessitate construction ofa genuine industrial system, a new source ofeconomic development and employment thatcan meet needs in innovation and drive thesystem's growth. In addition to those traditionally involved in health care, pharmaceuticals, imaging, medical devices and scientificequipment, this concerns big players in theworlds of information technology, big data,
connected objects and E-medicine.

1.2 France possesses many advantages when it comes toreaching the desired objective but the necessary partners andinvestment can only be guaranteed with strong governmental
commitment
For realization of this goal, France can count on:
highly structured, top quality health care•asystem
together with established cohorts of
populations and diverse patient groups, includ-ing well-characterized cohorts of patients withvarious rare diseases, cancer and common
diseases. These cohorts represent an essential
instrument to support development of thisinitiative in various domains;13networks and specialist structures (a The development of infrastructure and acquisition•national
variety of structures for rare diseases, molecular of equipment (sequencing centers, storage facilities
diagnosis laboratories, the structured cancer carepathway and services based on the molecular
genetics of cancer) together with long experience in the implementation of Health Care
Plans7, e.g. those for Cancer, Rare Diseases
and Neurodegenerative Diseases;
longstanding link between clinical practice and•aresearch,
an integral element of how health careis organized in France and a great advantage
when it comes to developing genomic medicine;presence in France of world-leading man•theufacturers and innovative smaller companies.
Some fifty companies have been identified
as relevant to genomic medicine. Contacts
forged in the course of preparatory work withcertain companies have given a measure of
their very real interest in this initiative. Thisis particularly the case for companies working
on data processing and analysis, fields in which
France is particularly strong (Dassault Systèmes,Orange, Atos/Bull, CAP/SOGETI, etc.);competitive research sector•anthatinternationallywill be able to respond to many of thechallenges and issues raised by this projectin both its technological and clinical aspects(microfluids, data security, the processing andanalysis of big data, modeling, biological andmedical interpretation, clinical trials, etc.). In
addition, internationally reputed researchers
into the human and social sciences will beable to make important contributions to thisinitiative through dissection of the complex
ethical and societal issues that the growth anduse of this type of technology will soon pose.
Nevertheless, the success of this initiative depends
on coordination of all the above-mentioned players
and this can only be achieved with support fromthe State.

7

14

In the field of rare diseases, France was the first to
formulate initiatives in the form of Plans and thesehave been closely studied elsewhere; the same is truein cancer with broad-scope support from the National
Cancer Institute (INCa, Institut national du cancer
cancer).

and data analysis structures) will require massive
preliminary investment. State aid will be indispensable to creating a sufficiently powerful levereffect to mobilize interested industrial partners(sciences and information and communication
technologies—SICT—companies). Solid integration of this new instrument into the healthcare system will require the construction of an
economic model relying on reimbursement by
the health insurance system, taking into accountsavings expected by virtue of improved diagnosis, a lower incidence of adverse reactions andenhanced therapeutic efficacy resulting frombetter initial orientation.
The 100,000 Genomes Project launched by the
British government in December 2014 withfunding of £300 million has proven very attractive
to companies in the health care sector with many
partnerships already established.
Finally, when coupled with transparent coordination of all those involved, State funding andcommitment act as powerful drivers for theconfidence and involvement of patients, patient
support groups and the population as a whole.
A Plan that is supported and steered by the State,involving a broad range of different players, would
seem to be key when it comes to taking all thesevarious dimensions into account, consolidating
implementation of the system and positioning
France among the leaders in the field.

2 TARGETS OF THE PLAN
2.1 A paradigm shift in French health care system
The aim is to put France among the front runners in the field of genomic medicine within
ten years. The new model to be introduced isbased on sharing nationally collected data to thebenefit of as many people as possible with major
improvements expected in terms of diagnosis
and treatment.

and therapeutic monitoring, to the benefit ofpatients, with:base of validated indications on which to base•atheirprescriptions related to genomic analysis;of electronic medical records•generalization
including genomic data as well as all thepatient's clinical details;

Ultimately, it is planned that all French patientswith cancer, a rare disease or a common disease
will be afforded access to genomic medicine as
an integral part of their care pathway. This may
mean genome sequencing plus, when warranted,
exome and/or transcriptome analysis.

•special services to guarantee them access:of in silico genomic analysis•towiththetheresults
identification of genetic variations

In contrast to the projects in the United Kingdom
and the United States, this initiative relies on anovel approach with a unique ambition to combine
a number of complementary targets, here listed
as a function of the benefits that will accrue tothose affected, once the system is running.

aids for diagnosis and•decision-making
establishing prognosis;
instruments to help when ther•special
apeutic strategies are being formulated.

Patients:

that might be biologically significant in
the context of the disease in question;

Health care system:

and/or treatment integrating genomic•diagnosis
deployment of genomic services across the country,
data—supported by expert interpretation—with
all the traditional clinical data;
health care from the system in the•adaptedlight of the information, in line with all relevant ethical rules, including questions ofConsent, secondary discoveries of medical
interest, reporting of results, and data security
and sharing;
dialog with and via patient support•facilitatedgroups with commensurate consciousness-raising about genomic medicine and health at alllevels concerned.

Physicians:
Information and tools to help them refine theircapacities for diagnosis, establishing prognosis

By 2020, the selected logistics will allow thefulfilling specific quality and security criteria
and covering a significant proportion of patients
before expansion through 2025 (2.2).
These pragmatic logistics will allow:

deployment of diagnostic services in the•localform of patient care and sample processing
centers, in line with regulations and security
rules;of these centers through a centralized•linking
data collation system (CAD) that fulfills all the
relevant technological imperatives of security,storage capacity and calculating power.
This organization could generate significant
savings for the health care system on top of its
socio-economic benefits.
15

Research:

Economy:expansion of the volume of data
creation of an integrated industrial network•considerable•theand analytical power to establish, on the one
dedicated to production of the instruments andhand, genetic signatures and biomarkers relevant to diagnosis and establishing prognosis
and, on the other, identifying genes and othermolecular entities involved in pathologicalprocesses, resistance to treatment and adverse
reactions;links between patient care and the scientific•newcommunity based on permanent dialog feeding

information technology required for genomic
medicine that could drive growth in otherfields of health care;pharmaceutical and biotechnology com•forpanies,
services that define companion tests
and better-targeted therapeutic trial design
by virtue of the analytical power developed
coupled with more effective pharmacovigilance.

the generation of knowledge and clinical validation. Analysis of the approaches adopted in
the United Kingdom, Estonia, the Netherlands
and the United States clearly shows that thedevelopment of genomic medicine depends
on a hybrid research/care system.

2.2 Operational targets for 2020 and 2025
The aim is to construct, by 2020, an operational
chain with an enlarged base of indications andsequencing capacity across a dozen centers commensurate with processing the following volumesof target patients:
diseases: at least 20,000 patients•rare
per annum plus their families, i.e. 60,000
genome-equivalents8;
priority will be given to those with cancer•cancer:that has metastasized or proven refractory totreatment, i.e. about 50,000 patients a year or
175,000 genomes9.

8
9

16

Testing of parents-child trios.
Volumes of exome and transcriptome sequences are
expressed in terms of genome-equivalents.

Beyond 2020 with the momentum generated,
steady growth is expected in both indications andpatient numbers, notably through extension tocover common diseases. The aim is to be able tofulfill the needs of a large proportion of affectedpatients in France by 2025.

3 FRANCE GENOMIC MEDICINE ACTION
PLAN 2025
The Plan is based on investment and involvement on the part of a large number of different
players. Its main measures are presented hereafter.
Simultaneously targeting cancer, rare diseases
and common diseases, the goal is to establish
a generic care pathway in genomic medicine,common to all patients whatever their disease.
The Plan articulates around three main objectives
with a series of measurements to:

1: the physician's order is issued following•Step
an interview with the patient, with the latter'sInformed Consent in writing.
2: samples are taken and then processed•Step
to isolate and qualify its nucleic acids.
3: the processing of samples for sequenc•Step
ing is followed by a preliminary comparison
based on the alignment of read-outs on areference genome to identify and qualify
sequence variants.

instruments for a genomic care path•establishway (Target 1);
4: in silico analysis of the data generated•Step
ensure operational deployment and expansion
by the services is carried out using classifica•of the system in a safe and ethical technical tion, modeling and interpretation tools withframework (Target 2);
monitoring and steering tools to•establish
make the adjustments required throughout
implementation of the Plan while ensuring
public involvement (Target 3);
The Plan's core generic care pathway (figure
below) is formulated around the pair of patientand doctor from the ordering of a test throughreturn of the conclusions. This pathway can be
broken down into five main functional steps asshown in the diagram below.

help from an expert biologist who defines
the biological, physiological and pathologicalsignificance of the findings before the report
is compiled.
5: results are sent to the physician who•Stepordered the test. Depending on the prescription's stipulations (diagnosis, establishingprognosis, theranostics), the ordering physician
can rely on in silico analysis and complementarydecision-making aids with input from CAD
to refine the conclusions to be communicatedto the patient.

Generic pathway: ordering, pre-testing, testing, biologic interpretation, report
Order
AgreementInterview
patient/doctor
Mutual decisionHelp withdecision-making

National Clinicobiological
Metadatabase

Sample-taking
Pre-testing

Help with ordering
Sequencing
AnalysisInterpretation andbiological validation17

Target 1: establish instruments for a genomic care pathway
Measure 1: Construct French capacity for ultra-high-throughput sequencing to meetthe defined targets
This measure aims to establish sequencing services throughout the country with expansion
throughout the Plan's lifetime.
Measure 1
Sampletransfer
Sampling

Transfer of the Variant
Call File (VCF)
Sequencing

CAD

standardized
proceduresand processes
Reference
platform(CRefIX)

ActionBuild a network of 12 ultra-high-throughput sequencing facilities by 2020 to provide all the services
associated with Pathway Step 3. Specifications for establishment of these facilities will be compiledin Spring 2016 and sites will be selected in September 2016. The schedule plans three installations
from the end of 2016 and then three a year between 2017 and 2019.

Description
This network of facilities—set up with an industrial configuration—will have a production capacityof the order of 20,000 genomes per annum per facility by 2020. A typical facility will have some
fifteen employees with:sequencing environment: whole genome, exome, RNA-Seq (the technology deployed•awillspecial
be preliminarily tested and validated on a reference platform at CRefIX , Measure 3);
10

11

10
11

18

RNA sequencing, transcriptome sequencing.
In 2015, the reference standard for ultra-high-throughput whole genome sequencing techniques corresponds to the HiSeq Xten platform from Illumina which can generate 10 x 1.8 Tbases in 3.5 days, i.e.
18,000 human genomes per annum (30x). Complete Genomics (a subsidiary of BGI) has announced thelaunch of a competitor ultra-high-throughput platform called Revolocity specially designed for clinicalapplications (exome, genome, RNA-Seq), capable of sequencing between 10,000 (50x) and 30,000 genomes
per annum. In the coming 4-5 years, new, third-generation technologies will likely have become robust
and reliable enough to replace these for clinical and diagnostic applications. Very long direct read-outs
without amplification (a single molecule) will probably yield higher-resolution information (epigenomics)
and structural information (haplotypes) from minute quantities of material. Reading will be in real time
and will therefore probably be very fast (also see Measure 3).

calculation resources (estimated at 2,000 cores and some 10 To of active memory )•associatedwith software to manage and control all sequencing-related procedures (management and mon12

itoring systems for samples and sequences, sequence quality control, circuits management andcontrol) and first-line bioinformatic analysis with identification of variants (comparison with areference genome and analysis of variants to identify SNVs, CNVs and SVs). These data willthen be systematically sent to CAD (Measure 2).

and archiving of all data generated in duplicate. The volume of data generated will depend•storageon analysis type but can be estimated at an average of 3.5 Pb/year per acquisition center. For
13

the archives, this figure is double (for security reasons).

Questions related to the normalization and standardization of processes and protocols, safety andethical problems will also be taken into account with a matching regulatory environment (Measures
8 and 9).

Schedule
Compilation of specifications for the facilities and site selection
Installation of the first three facilities
2016

Selection of sequencing technologies, definition of storage and calculationarchitecture (shared memory calculator, cluster calculation, etc.), specificationof software (purchasing of licenses, software compatibility)
Deployment of material solutions and specified software at the first
three facilities
Installation of alignment and automatic variant flagging software (preliminary
data analysis)

2017

Installation of CAD-compatible softwareFirst data transfer to CAD (to be set up in parallel)
Certification of the platform as a host for health-related data
Start of production with CAD

2017-2020

Establishment of nine more platforms

Calculation capacity is measured in terms of the number of processors/cores and active memory capacity
for large-scale matrix calculations.
13
2.5 Pb (Peta=1015) for cancer (160,000 patients x 500 Gb per patient x 3.2 whole-genome-equivalents-30X)
and 1 Pb for rare diseases (60,000 patients x 1 whole-genome-equivalent-30X x 150 Gb per patient). It
is too soon to specify the common diseases at this point.
12

19

Measure 2: Develop the tools required to process and exploit the volume of data thatwill be generated with creation of a central analysis service (collecteur analyseur de données,
CAD)
Measure 2
Interconnection
with clinicaldatabases
Transfer of the
Variant Call File
(VCF)
Sequencing

Expert annotationand variant validation
CAD

Methods, tools
and services (clinical,
research, industrials)
Standardized
proceduresand processes

CRefIX

Step 4 of the care pathway depends on capacity
for the processing, analysis and exploitation of
unprecedented volumes of data. Confronting
this challenge means assembling instruments
to afford access—in a highly secure storage
and archiving environment—to the whole setof a patient's genomic and clinical data, andintegrating the information into services for thephysician and all other concerned professional
health care providers (Step 5). This measureconsists of establishing a national data storage
center endowed with intensive calculation infrastructure in line with regulatory and security
imperatives. As the system grows, the build-up of
special services for scientists and health-related
businesses will make it possible to exploit theenormous potential represented by the data andinformation to be accumulated in coming years,
in line with confidentiality rules.

pathway. CAD will be based in Paris and will be
associated with a university to facilitate provisionof the training necessary (Measure 7).

Description
This Center is an essential component of the
project which will act as a hub around which
the above-mentioned network of facilities will
be coordinated (Measure 1).
CAD will provide a variety of services:of data generated by the production•Hosting
facilities (identified and automatically flagged
variants). Nominal storage capacity at CAD
will be of the order of 70 Pb/year.
and interfacing with national•Interconnection
databases (DMP , DCC ) for data matching
14

15

and interconnection with international databases.

ActionInstallation of a national intensive calculation
capability with commissioning by the end of2017 to offer the first services for professional
health care providers in the context of the care
20

14
15

Personnel medical file.
Oncology communication file.

capacities (partnership established with
•Massivea center [TGCC, the CEA Très Grand Centre
de Calcul
Calcul) for intensive calculation16, analysis,
data mining and data interpretation make itpossible to interpret data from different services
and partnerships: for professional health careproviders (validation in silico and by a networkof experts [Step 4]; for search, comparison
and ad hoc interpretation tools, depending on
the stipulations of the prescription [Pathway
Step 5]); for research (bioinformatics, biology,

clinical, public health), industry (clinical trial
feasibility studies, design of more targeted trials,
assistance with patient recruitment throughthe identification of genetic signatures andmarkers, pharmacogenetics).
CAD's regulatory framework (dealt with inMeasure 9) will bring together the public sector
with patient support groups and industrial concerns in a private-public partnership model. An
interface will be established to help industrial
players participate in services.

Schedule
Feasibility study (IT architecture, organizational and regulatory aspects,
security) to size CAD and draw up specifications
2016

Definition and refinement of choices for storage architecture, calculation,
hosting protocols, anonymization, standards and data security. Definitionof protocols for exchange with the platforms, organization chart, statutes,
governance, economic modeling, identification of the various CAD users,
qualification of expert networks and CAD assessment modalities.
Deployment of specified material and software solutions

2017

Industrialization of specifications for the software to be installed at production centers, automatic flagging software (first data analysis services), CAD
certification and accreditation (as a host for health-related data), integration
into CAD of data from platforms, CAD accessibility for the first users.
Commissioning of first certified software for variant analysis

2018

16

Establishment of a dynamic exchange path between CAD and identified
sources of clinical data, first matching with clinical data to start analyses
integrating clinical data

2019

Implementation of new phenotypic annotation protocols according toestablished indications

2020

Data matching and mining for genetic and phenotypic annotations

A preliminary feasibility study will establish required calculation capacities and technology choices. An initial
capacity of 4096 cores and 16To followed by substantial expansion over the subsequent five years.
21Measure 3: Foster the integration and exploitation of patient data into the care pathway
A patient's clinical and genomic data should be
included in a virtual record available and usablefor everyone along the care pathway. This should
start from existing patients' medical records (PMR)
as well as the communication file currently usedin oncology. These instruments are still being
deployed, one of the challenges being how toensure interconnection of medical records at
CAD: files that are spread around health careestablishments, in most cases in non-interoperable

22

formats. Implementation of this Measure is a priority when it comes to integrating and exploiting
patient data which is in itself indispensable toconsolidating the care pathway.

ActionGeneralize and standardize personal medical
records and the oncology communication file
to ensure interconnection and the matching ofgenomic data from CAD with data from healthcare establishments.

Target 2: Ensure operational development and expansion of
the system in a safe technical, ethical framework
Measure 4: Establish a Reference Center for Innovation, Assessment and Transfer(Centre de référence, d’innovation, d’expertise et de transfert, CRefIX) to foster thetechnological developments and information technology required for implementationof the pathway
Achieving Target 1 (which is essential for consolidation of the care pathway) depends on thetwo central units stipulated in Measures 1 and
2: a network of ultra-high-throughput sequencing platforms interacting with a national data
analysis facility.
Operational implementation of these units and thesystem in general will ensure an operational carepathway that is capable of integrating innovation
in a dynamic and reactive fashion and developing
expertise in data exploitation. This depends ona number of interdependent factors:
nition and validation of instruments and•defi
procedures to ensure that the platforms andthe CAD can work properly together withappropriate interfaces for their deployment;
projects (Measure 5) designed to identify•pilotand overcome technological obstacles, in particular those associated with the huge volumesof information involved as well as treatment
and exploitation of the data generated;

ActionCreation of a national Reference Center forTechnology, Innovation and Transfer (centre deréférence technologique, d’innovation, et de transfert, CRefIX) to meet the various requirements
identified at the beginning of the project, integrating all the key actions mentioned with all
the necessary players.
It will itself constitute an important componentof the system with respect to its national reference and assessment roles. It will help prepare
for changes and technological innovations in
the future, develop processes and harmonize
protocols and methods before overseeing their
set-up and commissioning. Innovative projects
will accrue from public-private partnerships
in the framework of constitution of the newchannel. The deployment and integration ofnovel practices are favored by specific training
programs together with the necessary regulatory
and ethical changes (Measures 7 and 8).

of innovative potential from aca- Description•integration
demic research to guarantee high-level researchand development;of the background art and inno•consideration
vative perspectives of companies operating inthis evolving field;of strategic partnerships with•establishment
emerging players and leading international
companies (as has been done in the United
Kingdom considering the massive implantationof certain high-throughput technologies).

CRefIX will have a reference function withtransfer to sequencing platforms and CAD ofprocedures, new tools and technologies developedin the context of standardization of processes
and protocols of which it will oversee the implementation and commissioning, guaranteeing thetraining of staff working at the platforms and all
the way along the care pathway.
CRefIX will be implemented from academic
centers of excellence and through public-private
partnerships with key national players (Measures
7, 9 and 10). Organized across two sites, aspects
associated with sequencing will be based at the
Genopole in Évry and at CEA; digital aspects will23

be based in Paris with input from Inserm, Inria(Institut national de recherche dédié au numérique,
National Institute for Digital Research), universities, STIC companies, etc.
For R&D, it will help with the development andintegration of innovations all along the chain fromsample-taking through sample preparation andsequencing and up to analysis and interpretationof the results. It will oversee compilation andstandardization of the processes and protocols
to be deployed at the platforms and CAD.
CRefIX will host a reference sequencing platform
as of 2016. In line with its aims, this will carryout sequencing for the proposed pilot projects(Measure 5) in order to identify possible obstacles,
test-run solutions and ensure the technologicaldevelopments necessary at every relevant levelof the chain in the pathway. Subsequently, theexpertise thus acquired will be sequentially trans-ferred to the sequencing platforms together withassociated regulatory specifications.
Its activity will develop in a dynamic, adaptive
way making it possible to integrate new technologies and avoid risks of obsolescence and lossof competitiveness at the same time as smoothing over transitions without compromising thequality of services provided for patients along
the care pathway.
With respect to expected partnerships, it will havea transfer function, the conditions of which—inparticular with respect to capitalization—will bedefined at a later stage in concert with partneringbusinesses. It will also contribute to innovation invarious fields at the interface between the ethical,
social and regulatory issues raised by the need tointegrate genomic medicine into French existing
health care system (Measure 9).

Schedule

2016

Establishment of CRefIX: installation of a prototype platform at the National
Genotyping Center (Centre national de génotypage, CNG) at CEA in Évry,
choice of standards (sequencing) to apply, help compiling standards for theexchange of information with European and international Plans, software testing2017

Prototyping, testing and standardization of the first variant annotation
programs on the basis of solutions available from the academic environment
for routine clinical use in the care pathway, compliance with the life cycle ofnon-NGS data
Optimization of CAD storage (new models of specific database management
systems for the storage, indexing and searching of flagged variants)

2018

Definition of interoperability standards for matching data with other types
and sources of data
Commissioning of the first software for matching genomic and clinical data
Commissioning of first certified software for variant analysis

2019-2020

24

Implementation of new phenotypic annotation protocols according toestablished indications

Measure 5: Overcome the technological, clinical and regulatory obstacles encounteredalong the path with respect to the three broad groups of disease concerned
The main steps along the care pathway are
explained in the introduction to Part 3. They
involve sets of interacting links around the main
components, namely the network of sequencing
platforms and CAD (Measures 1 and 2).

Certain obstacles and areas of uncertainty havealready been identified along the main steps ofthe care pathway as described above:

Installing an ultra-high-throughput sequencing
capability across France raises a number of novel
technological and scientific challenges. Measures
1, 2 and 3 address these tightly interlacing issues
and, at the same time, the adaptation and development of a large number of instruments andprotocols, as identified at the preliminary stage.
Nevertheless, to reveal unexpected obstacles, toidentify constraints that need to be mitigated, andto develop and implement appropriate solutions,
it is indispensable to test how the care pathway
is working and its consistency in situ, including
high-throughput sequencing runs on selectedcohorts of patients.

of indications for which sequencing might
be relevant. Centers where the order can be
executed should be listed together with theiraccreditation vis-a-vis pathology-specific criteria (skills, protocols, etc.) and status (public
or private). This to investigate patient care indifferent parts of the country, ensure provisionof suitable medical training and test the content
and modalities of management of the Informed
Consent procedure (related to Measure 9).

1: To help doctors considering submit•Step
ting an order, they should be given a panel

2: At the sampling phase, the type of sam•Step
ple required (biopsy, blood sample, etc.) should
be stipulated according to disease and type ofsequencing (exome, genome or transcriptome).
How the sample was treated before dispatch
for sequencing. The type of structure capableof taking the sample (laboratory, hospital,
public, private) can be analyzed in the lightof the relevant requirements, standards andprotocols with a view to the standardization ofprocedures according to orders and accreditationof those involved. Conditions and proceduresfor transport to sequencing centers should also
be examined (haulier, temperature, SOPs17,
deadlines…).

ActionSet up four pilot projects on cancer, rare diseases,
common diseases and a sample of the general
population to detect and test technological, clinicaland regulatory obstacles—already identified or
not—at various steps along the care pathway.

Description
Focusing on the three broad groups of diseases
addressed in the Plan, these need to be scheduled
as a matter of priority. These will shed light on
specificities and provide answers with a view toconstructing a standardized care pathway that is
as consistent as possible, independently of any
specific disease.
These pilot projects will depend on existingskills and strengths (CNG for sequencing) as
well as the activities of the Reference Center forTechnology, Innovation and Transfer (centre deréférence technologique, d’innovation, et de transfert
transfert,
CRefIX, Measure 4) and a registry to be set up
by Aviesan (Measure 11).

3: Sample preparation and sequencing•Stepwith a preliminary comparison based on thealignment of read-outs on a reference genome
to identify and qualify sequence variants. The
obstacles to be tested at this stage will showwhether the centers ought to be generic ormore specific, qualify any input from private
partners (partners, sub-contractors, etc.?), checkthe standardization of procedures by having
replicate samples treated by different players,
test calculation, storage and data archiving
procedures, etc.
17Standard Operating Procedures25

4: Transfer to CAD (or the equivalent,•Step
simpler prototype during the transition phasein 2016) for processing and in silico exploitation of the resultant data. The obstacles to betested at this stage will confirm that transfer
and flow management capacities are adequate
and that CNIL authorizations concerning data
exploitation and exchange are being correctly

applied with effective, operational data sharing.
[CNIL: Commission nationale de l’informatiqueet des libertés, National Information Technology& Privacy Commission]
5: At this stage of submission of the report•Step
to the ordering physician, testing will focus
on the first aids to decision-making.

Schedule
2016-2017

Pilot studies on cancer and a rare disease.

2016

Working groups to set up pilot studies on diabetes and the general population

2017-2018

Pilot studies on diabetes and the general population

Measure 6: Establish a system to assess and validate new indications for access togenomic diagnosis
The growth through 2025 in the Plan will dependon expansion of the existing list of indications.
This relies on transfer of research to care withvalidation of indications derived from scientificprogress. New indications will be successively
added as they are validated. These indications will
be in the three broad sectors, i.e. rare diseases,
cancer and common diseases.

ActionEstablish a system for the assessment and validation of new indications. Possible indications
will be discussed with partners or may be dictatedby Government or the Supreme Health Agency(HauteHaute autorité de santé
santé, HAS) which may commission specific studies to validate new guidelines
on access to genomic diagnosis.

Description
Work on the assessment and validation of new
indications will proceed in partnership with
the qualified agencies and institutions (learned
societies, HAS, patient support groups, General
Health Directorate [Direction
Direction générale de la santé
santé,
DGS], Social Security Directorate [Direction de laSécurité sociale, DSS]). These will take the form ofstudies on patient cohorts (phenotypes of common
26

diseases, rare diseases and cancer) and will aim at
validation of entry of the indication concerned
into a reimbursement process. CRefIX will be
consulted for treatment of innovative aspects of
set-up of the proposed studies.
The Plan will therefore have a major role inexamining, overseeing and including new indications in the health care system with thesesuccessive validations. The growth provided forin the Plans of Barack Obama and the 100,000
Genomes Plan in the United Kingdom is also
based on this same approach.
In parallel and above and beyond regulatory
aspects related to execution of the Plan (Measure9), this Measure will have a dimension related tothe human and social sciences. This will make itpossible to acquire the empirical data required tofacilitate the sharing of experiences between players
and on the other hand, conduct high-resolution
analysis of the experiences of all those concerned,
especially patients and their families with the
involvement of the relevant patient support groups.
Taking this dimension into account will drive
the development of Good Practices.

Measure 7: Foster new skills and personnel capable of meeting the challenges of how
to analyze and interpret the data
New skills and jobs are required to meet thechallenge of how to exploit and interpret theresults. The skills required at the various stagesof the pathway—at the new sequencing centers,
CAD, laboratories and platforms—cover several
multidisciplinary fields, mainly genetics andmolecular biology with sequencing technologies,
bioinformatics, bioanalysis and biostatistics. In
addition, these needs will broaden to specificaspects of the pathway concerning information,
Consent and the reporting of results.
These skills correspond to several levels of training
from technician to engineer and covering medical
practitioners and laboratory test specialists whowill have to master a number of them. A preliminary assessment of the jobs and skills to be
developed has been made and compared withcorresponding identifiable training programs. This
exercise together with complementary interviews
has shown that the skills needed are rare (ornon-existent) because they traverse relatively
unrelated disciplines—something that current
training programs rarely address and, if they do,
address poorly. Nevertheless, such skills are indispensable when it comes to ensuring an effective
care pathway and success of the proposed Plan.

ActionRapid establishment of specific training programs
at universities and colleges to prime construction of an industrial framework dedicated togenomic medicine, establish job descriptions
in collaboration with the General Directorate
for Care Provision (Direction générale de l’offre
de soins, DGOS), the General Directorate forHigher Education & Employment (Direction
générale de l’enseignement supérieur et de l’insertion
professionnelle, DGESIP) and the Conference ofUniversity Presidents (Conférence des présidents
d’université, CPU).
d’université

Description

initial training, it will first be necessary•Forto make a precise definition, as a function ofneeds, of the skills that will have to be acquiredby the various categories of personnel at theplatforms and CAD, as well as those that
doctors and other professional care providers
will have to acquire. These will have to be
added to job descriptions, e.g. in biostatistics
or data mining and analysis. On these bases,
a detailed inventory of current resources atnational training centers (IUT, universities,
schools of engineering) will be made.
help from DGESIP for the establishments•Withconcerned and Communities of Universities
and Establishments (Communautés d’universités
et d’établissements, Comue), existing training
programs (in particular for engineers, Master'sin Bioinformatics) will have to be adapted orreinforced, especially programs on bioinformatics, biostatistical genetics and data analysis.
Initial training of the professional health careproviders concerned—who do not currently
know much about genomic medicine—should
also be reviewed with a view to introducing therelevant ideas. In parallel, new transdisciplinary
training built on defined job descriptions will
have to be implemented in the form of vocational degrees and Master's qualifications.
already exist for ongoing training•Programs
and specific training for practicing laboratory
specialists, under the aegis of various learned
societies and professional groups. These structures could be built upon by helping them meeta demand for training that will considerably
grow in coming years.
of a training structure with ade•Creation
quate resources (a special school or as part ofa public health educational institution) could
be envisaged to afford genuine national andEuropean visibility for this novel interdisciplinary system. French participation in
EBI (European Bioinformatics Institute) and27

Elixir (European infrastructure for life sciences
information) will help with the developmentof European partnerships on training.
The development of such a system will eventuallycreate a scientific and industrial community thatbrings together clinicians, geneticists, medical

test specialists, epidemiologists, biostatisticians,computer experts and mathematicians. This willfurther enhance acceptance of this novel dimension
to medicine (Measure 13). Updated teaching ofmodern genetics in school would also help. A
ten-year perspective to guide the initiatives tobe put in place over the time frame.

Schedule
2016

2017

High-resolution review of skills and jobs
National mapping of relevant training programs and resources
Compilation of new job descriptions, formulation of novel transdisciplinary
training programs, adaptation and reinforcement of existing programs

Measure 8: Integrate ethical aspects related to the collection, storage and processingof clinical and genomic data and guarantee safe, high-quality care pathway
The availability and exploitation of genomic
data representing whole populations raises many
ethical questions, at both the individual andsocietal levels. In terms of regulations, a strict
framework ought to guarantee safe, high-quality
care pathway. The regulatory framework to
be developed or adapted is vast, concerning
most of those involved in the care pathway
in its manifold technical and logistic aspects.
Regulatory changes may go from the amendment of Good Practices (HAS, BioMedicine
Agency [[Agence de la biomédecine, ABM]) to theneed for new legislation (the Bioethics Law).
The Parliamentary Office for the Evaluationof Scientific and Technological Choices (Officeparlementaire d’évaluation des choix scientifiques
et technologiques, OPESCT), national, European
and international learned societies and groupsof geneticists, and experts working on European
projects (FP7, H2020) have already started posing
solid bases for deliberations. Finally, recent andongoing national and European legislation needs
to be closely examined from a perspective of the
impact of various recent texts on the steps ofgenomic medicine.

28

ActionExamine and, if necessary amend the regulatory
framework in the light of legal and ethical standards to adapt it to specific issues raised and theGood Practices that need to be established toguarantee safe, high-quality care pathway. An
Informed Consent model tailored for genomic medicine will be proposed. The National
Consultative Committee on Ethics (Comité
consultatif national d’éthique, CCNE) will have to
be convened to go into these aspects more deeply
at the national level. Given the importance of
these challenges and their scale, they now need
to be considered at the international level.

Description
At the individual level, before Consent, patientsought to be given information about all the issues
and conditions associated with the exploitation
and use of their personal medical data with
control based on access to medical records andprotections guaranteeing the confidentiality of all
such data. Two issues warranting special attention
are at the heart of this Measure:order to protect the patient, it will be necsequencing generates massive•inessary•genomic
to develop and apply advanced coding
amounts of data above and beyond theand anonymization techniques for intrinsically identifiable sequences. Nevertheless,cross-referencing different types of personal
data—even small datasets—with theoreticallyanonymized genomic data might elicit a riskof re-identification, especially since the storageof sequence data—or at least part of it—forlong periods is necessary to generalization of
their use in clinical and scientific applications.
Therefore, hermetic anonymization of sequence
data cannot be absolutely guaranteed and theinformation given to the patient ought to beaccordingly transparent. Anonymization cannot
therefore be the one and only cornerstone
for protection: above and beyond the mosttechnically advanced anonymization measures,
data will have to be protected with a whole setof other measures, commitments and vigilancewith tightly controlled access and stringent
restrictions on permitted uses;

information sought in the context of theorder which raises the question of secondary discoveries. In particular, discovery ofpresymptomatic pathology in a situation inwhich neither prevention nor cure are possible
would become commonplace. Against thisbackground, the question of whether to tell thepatient or not
not—respecting the individual's rightnot-to-know and parents' rights—representsa challenge, as well as questions of when to
make the announcement and how to do it.
Similarly, another question that will arise isthat of retesting capacity in the long term as
deeper understanding expands the possibilities
of interpretation.

From a collective point of view, adherence to these requirements has to be reconciled with thegeneral interest that is inciting this project in which capitalization on these data—for everyone's
benefit—assumes broad sharing and exploitation by the many players in the health care system,
scientific world and the economic tissue who will be involved18. Ultimately, a large number of fields
representing other societal challenges that it is as yet difficult to estimate will be affected and will
have to be managed, assurances for everyday acts, but also dietary, social and cultural practices
and habits.

18

See the conclusions of the Secretariat-General of the Council of the European Union on "personalized
medicine for patients", summarizing the Council's conclusions from 7 December 2015 (n° doc. prec.
14393/15) aimed at delegations.
29

revised Directive on diagnostics and medical•thedevices;
Law on modernization of the health care•thesystem in December 2015;•new European Union regulations of data pro- •the Digital Republic Law.

Concerning the regulatory framework, recent
and ongoing national and European legislationneeds to be closely examined from a perspectiveof the impact of various recent texts on the stepsof genomic medicine. In particular:
tection (General Rule on Data Protection)
finalized in December 2015 and to be publishedin the first half of 2016;

We intend to break this Measure down between
the main steps in the care pathway.

Schedule
Propose an Informed Consent model tailored for genomic medicine.
Assess patients' practical needs for information (time, modalities).
Compile a regulatory inventory taking stock of all applicable texts and identify
obstacles and needs for consistency at different levels of Standards in the lightof legislative schedules.
2016-2018

Convening of CCNE concerning secondary discoveries in the context ofclinical application and seeking new-generation sequencing, prior to revisionof the Bioethics Law.
Working together with CNIL and other concerned agencies on the implications of new European data protection regulations in the field of sequencing
in clinical practice as envisaged in the Plan.
Organize a national conference on regulatory aspects with all concerned
institutional players.
Establish a special registry for practices and experience sharing tools, especiallywith respect to secondary discoveries (related to Measure 11).
Involve France in international harmonization processes on secure data sharing
for genomic medicine.

2018-2020

Launch research projects in human and social sciences to conduct inquiries
and gather empirical data on different players' points of view on the ethicalchallenges of NGS.
Mobilize and consult with the various players—especially patient support
groups—on educational initiatives and Consent Forms and modalities.

30

Target 3: Establish monitoring and steering tools to make theadjustments required throughout implementation of the Plan
while ensuring public involvement
Measure 9: Mobilize industrial entities implicated in the project to meet technologicaland industrial needs at the various steps in the care pathway and promote the emergenceof a "genomic medicine" channel
This Plan constitutes a unique opportunity tofoster dynamic innovation in many areas, e.g.
conservation, the mathematical processing of
big data in the health care field, Web semantics
and the Web of Objects, medical devices, etc.
To find the necessary solutions and equipment, it
would seem essential to integrate this initiative into
an ambitious industrial development plan. This
will make it possible to construct a real system tosupport growth of the sector while constituting
a new source of economic development andemployment. The involvement of businesses isessential in the context of international competition (1.2). It is therefore indispensable tomobilize them as soon as possible after launchof the project to drive emergence of a genuine"genomic medicine" system.

Action
Propose companies a logic of how the system
will work as well as an economic logic allowing
its implementation, functioning and sustainable
development. It will therefore be important tostipulate the value chain and associated economic
model as well as modeling of the investments
required, key financial flows and expected results.

Description

involving patient care and covering entities•one
capable of performing the procedure as wellas the services and products aimed at allowing
performance;other focused on the exploitation of•theaggregated data.
If both of these value chains generate immediate
value linked to the hoped-for results of ultra-highthroughput sequencing (improved health care,in particular patient treatment, longer survival,etc.) and depending on technologies, solutions
and services possibly implemented by different
types of company, delayed, evolving value related
to data exploitation is also identified. This delayed
value will gradually lead to more precise medical
procedures resulting in enhanced therapeutic
efficacy, fewer adverse reactions, progressive
diminution of treatment mistakes, etc.
The medico-economic reflection should therefore
simultaneously consider a possible rise in costs
due to increased use of sequencing services and(ultimately) a reduction in patient treatment
costs (better treatment selection, limitation of thetreatment of non-responders, etc.). The medico-economic model should therefore cover theduration by including a possible investment
period before the results phase.

Such mobilization should in particular incite adescription and analysis of the business model
underlying this action (flow, value creation, costof investments, savings) within which everyone
will be able to take a position.
Analysis of how the future system will work
should take into account two interconnectedvalue chains:31

Schedule
2016-2018

Stipulate how the future industrial system will work and the economic logic
of its implementation and durable operation by accompanying the reflection
by a consultant.

2018-2020

Integrate pilot projects (Measure 5) and the high-resolution understandingof the care pathway that results in order to discern specific economic models
with differential flows.

Measure 10: Orientate the activities of all those involved to address industrial issues
arising along the genomic care pathway
Implementation of the Plan and the emergenceof a national industrial framework of genomic
medicine depend on simultaneously defining a
number of industrial tools at the various stages
related to the pilot projects (Measure 5), theactivities of CReflIX (Measure 4) and in thelonger term CAD. This will rely on the necessary
technological and medico-economic demonstrators(reagents, automatic sample preparation, data
integration, storage and interpretation, etc.).

In addition, normalization and standardizationof procedures and data from the various stages
will have to be addressed and envisaged from theoutset at the European level. Elements of anindustrial strategy also need to be developed
with, in particular, establishment of a databaseof relevant patents submitted in France in thefields concerned and definition of a strategy for
acquiring foreign patents.

Measure 10, CRefIX
ReferencecenterR&D

Standardized
proceduresand processes

Industrializationof procedures
and deployment
CAD

Ethics andregulations
Training

32

Networkof platforms

ActionAddress as soon as possible industrial issues related
to genomic medicine, not only technologicalissues but also regulatory and ethical aspects,
with adequate human resources to develop thenecessary innovations, products and services
through establishment of a public-private task
force.

Description
The public-private task force will be organizedaround the five think tanks already in place.
Specifically focusing on technical and practical aspects of setting up an industrial genomic
medicine framework, this task force will provide
another State-sponsored forum for dialog between
public-sector and private-sector partners(CSIS/CSF19, industrial solutions, diverse
Ministerial and InterMinisterial groups). The
work of this task force will yield proposals forthe next CSIS extended to companies involvedin the field of digital health care.
All the recommendations so far published by thistask force have been assimilated into the various
corresponding Measures.

ScheduleWork by the five groups that already constituted this task force for preparation of the Plan will
carry on and bolster the various Measures and Actions to be implemented.
This Measure therefore constitutes a transition phase. It is intended that it should disappear
as the industrial framework becomes operational.

Measure 11: Monitor developments in the field of genomic medicine at theinternational level
Against a background of international competition,
it is important to follow developments in the fieldof genomic medicine at the international level
to be ready for any adaptations or reorientations
required to implement the Plan and guarantee top
quality service for patients, at the same time aspreserving the competitiveness of national players
in the industrial framework thus constructed.

Description
This long-term genomic medicine registry will be
under the aegis of Aviesan. With all the relevant
expertise, one of its roles will be to monitor all
aspects of this rapidly evolving sector, be they
medical, scientific or societal, in particular tointegrate new validations. It will also provide aforum for the exchange of experiences.

ActionEstablish a monitoring system to follow the fieldof genomic medicine at the international level.

33

Measure 12: Establish a research program dedicated to economic aspects of the Plan
The introduction of economic calculation into
public-sector decision-making will ensure thatavailable resources are optimally allocated withinsociety. Empirical studies by the Organization
For Economic Co-operation & Development(OECD) confirm that health care system performance (as measured by life expectancy) is better
served by improving resource allocation than byincreasing health care expenditure.
In France, two pieces of legislation address theplace of economic calculation in the definitionof the scope of reimbursement in health care.
Firstly, the health care budget is voted on every
year by Parliament in line with the Finance &Social Security Law and secondly an efficiency
criterion has been integrated into assessment of
the price of health care goods and services since
October 2013. The efficiency of the system will
have to undergo a medico-economic efficiency
assessment (with input from professional healthcare providers) throughout the research program.
Increasing use of economic calculations in decision-making in health care meets a demand
for rationalization of government expenditure:
it guarantees optimum allocation of collective
resources. Any arbitration concerning collective
resources—which everyone expects to be expended
in the public interest—has to be justified andevery party (political decision-makers in concert
with professional health care providers) has tobe able to vet how they are being used.

34

ActionCreate a research program, as soon as the Planis launched, to study medico-economic aspectsof the integration of genomic medicine into
medical practice. The aim is to seek answers to
a complicated question, namely how to designa model that helps the population benefit fromprogress in genomic medicine at the same time
as guaranteeing a sustainable national economic
model based on optimization of the allocationof collective resources.

Description
Before validation, the Measure means that the
medico-economic implications—both qualitativeand quantitative—of every indication being
considered for ultra-high-throughput sequencing
should be assessed. This will take into accountthe medical (and societal) benefits of implementation, economic repercussions (including
societal and economic capitalization) and theconsolidated costs of deployment in the carepathway framework. This will cover benefits
accruing from more judicious prescription ofcomplementary examinations and treatments aswell as the economic consequences of being able
to replace current examinations with sequencing.
Since the system will cut down the incidenceof adverse reactions (that currently have to betreated), such savings will also be assessed. This
Action will be conducted under the aegis of the
Toulouse École d’économie (School of Economics)
with identified partners.

Measure 13: Organizing the information, consultation and involvement of everyone
in society who is concerned
A national Genomic Medicine Plan can only berealized with the involvement, understanding andcommitment of the general public as well as ofthose who are directly concerned. In parallel withmeasures pertaining to ethical and regulatory
aspects, some countries already committed togenomic medicine have undertaken wide-reaching
exercises of communication, consultation anddialog with their peoples, in particular Estonia
and the United Kingdom.

ActionUndertake broad-scope actions across the country
exploiting different media, different methods
for consultation targeting all levels from schools(because genomic medicine also concerns children)
to broad populations throughout the country.

Description
Sustainable actions have to set up to publish
regularly updated information and foster dialog
on how the Plan is being implemented in thegeneral population as well as those more directly

involved (patient support groups, users' groups,
youth, schoolchildren, etc.).
Education: define and organize how to establish
dialog with people (with more details after examination of the models in the United Kingdom,
Belgium and Estonia); set up an annual meetingon genomic medicine with large-scale educationaland consultation sessions for the general public;
posting of a Web site.
Research: launch research and research/action
projects in the human and social sciences togather information and monitor developments.
At the European level: France should support
the European Commission's Eurobarometer
initiative (2018) on genomic medicine to establish
its position vis-a-vis other European countries
and adapt the French Plan to match the European
framework; get involved in its conduct and analysis.
Training: with reference to Measure 8, investigate
the need for training and implement training
actions with charities, schoolchildren, teachers
and journalists.

Measure 14: Governance of the Genomic Medicine Plan
The governance proposed for the Genomic
Medicine Plan will be inclusive, based on multiple partners, involving all users in coordinationof its launch and achievement of a series ofactions over coming years. This coordination
will be organized at the political level which isessential to successful realization of the Plan's
objectives and will guarantee commitment overthe full ten years.
This governance will frame steering of the Plan,
monitoring of its implementation and assessment(notably medico-economic), dialog with those
involved as well as users, and education of thegeneral public.

Steering of the Genomic Medicine Plan
Steering of the Genomic Medicine Plan will be
under the responsibility of an InterMinisterial
Committee and the authority of the Prime
Minister. It aims to oversee implementation of
the Plan according to a realistic preset schedule.
It will ensure coordination between the nationaland regional levels. Steering will depend on
monitoring and assessing implementation of
the Plan.

35

Interministerial Genomic Medicine Plan
Steering Committee
The Steering Committee will be composed of the
Ministers of Research, Health and Industry with
Directors of these ministries' administrations andother involved ministries, the Director-Generalof Cnamts, the President of HAS, representatives of the Directorates-General of regional
health agencies, the President of Aviesan andrepresentatives from patient support and healthcare system users' groups.
The Steering Committee oversees implementationof the Plan through mobilization of partners andresources, and directing its orientations. As thesituation evolves, the Committee may propose
adaptation of the Plan.
It will meet at least once a year. It reports to
the Prime Minister on progress of the Plan andcompiles an Annual Report.
Monitoring and evaluating the Plan
The Genomic Medicine Plan is to be monitored
by a special operational Committee that helps
with its guidance. For each Action, the Plan
identifies a Pilot with a suitable schedule towork together with all the partners involved toperform the Action, monitor its implementation
and report on its results.
Monitoring Committee
Aviesan will coordinate monitoring of the
Genomic Medicine Plan and evaluate outcomes.
It will run the Monitoring Committee with all
the Pilots supervising Actions. It will schedulethe implementation of Actions and check theirconduct against said provisional schedule. It willassess outcomes through specific indicators andmonitor expenditure with respect to the allocatedbudget. It will compile an Annual Report on
the Genomic Medicine Plan. The Monitoring
Committee will meet three or four times a year.
Evaluation of the Genomic Medicine Plan
Implementation of the Genomic Medicine Plan
will be continuously evaluated by the Steering
Committee on the basis of success indicators andthe outcomes of specific Actions.

36

It will only be possible to evaluate impact of
the Plan on health targets (e.g. efficacy gains
in targeted cancer treatment by virtue of thecontributions of genomic medicine to improved
therapeutic orientation) after some time andeconomic impact constitutes a specific Measurein the Plan (Measure 12).
Indicators to be used to monitor and evaluate theachievement of targets will be proposed by theSteering and Monitoring Committees and thenprecisely defined together with the Pilots of the
Actions. These indicators will be validated at thePlan Steering Committee's first meeting in 2016.
The Genomic Medicine Plan will be evaluatedindependently—notably on the basis of said
indicators—by organizations and institutions
appointed by the Government, namely France
Stratégie, the Haut Conseil de la santé publique(HCSP, Supreme Public Health Council) andthe Haut Conseil de l’évaluation de la recherche etde l’enseignement supérieur (HCERES, Supreme
Council for the Evaluation of Research & Higher
Education). Medico-economic evaluation of thePlan will be conducted by the Toulouse Écoled’économie (School of Economics), a specificMeasure in the Plan.
Dialog between those directly involved in
implementation of the Plan and users
Health care professionals and users of the healthand research systems are to be implicated in
implementation of the Genomic Medicine Planin a globally democratic strategy.
Above and beyond the presence of users andpatient support groups on the Steering Committee,
Aviesan will organize consultations on implementation of the Genomic Medicine Plan withthose involved and users, in collaboration with theSteering Committee at annual meetings between
players, industrial partners and institutions.
Regional consultation
Through local meetings, regional health careagencies will organize consultations on the
Genomic Medicine Plan in their own region
between those who are directly involved, local
communities and users.

Keeping the public informed
To publicize how the Genomic Medicine Planis being implemented and its results, the Annual
Report on the Plan will be published. A special

Web site will be set up to broadcast full information
about the Genomic Medicine Plan, including
how it is progressing and its achievements.

37

GLOSSARY
ABM
ANSSI
ARIIS
AviesanCAD
CCNE
Cnamts
CNG
CNIL
CNV

Agence de la biomédecine
Agence nationale de la sécurité des systèmes d’information
Alliance pour la recherche et l’Innovation des Industries de Santé
Alliance pour les sciences de la vie et la santéCollecteur analyseur de données
Comité consultatif national d’éthique
Caisse nationale de l’assurance maladie des travailleurs salariésCentre national de génotypage (CEA à Evry)
Commission nationale de l’informatique et des libertés
Copy Number Variations. Number of copies of a given gene in the genome(which varies between different people)
Comue
Communautés d’universités et d’établissements
CPU
Conférence des présidents d’université
CRefIX
Centre de référence, d’innovation, d’expertise et de transfert
CSIS/CFS
Comité stratégique des industriels de la santé/Comité stratégique de filière santé
DCC
Dossier communicant de cancérologie
DGESIP
Direction générale de l’enseignement supérieur et de l’insertion professionnelle
DGOS
Direction générale de l’offre de soins
DMP
Dossier médical personnel
DSS
Direction de la Sécurité sociale
EBI
European Bioinformatics Institute
ElixirEuropean infrastructure for life sciences information
Exome
The totality of gene segments that are transcribed into the messenger RNA
molecules that code for proteins—the functional products that determine acell's structure and activities
FP7
EU's Seventh Framework Program
GAFAMS
Google, Apple, Facebook, Amazon, Microsoft, Samsung
GB
Giga base = 106 bases
H2020
European Horizon 2020 Research Program (2014-2020)
HAS
Haute autorité de santé
HCERES
Haut Conseil de l’évaluation de la recherche et de l’enseignement supérieur
HCSP
Haut Conseil de la santé publique
ICGC
International Cancer Genome Consortium
IGAENR
Inspection générale de l’administration de l’éducation nationale et de la recherche
INCa
Institut national du cancer
ITMO
Instituts thématiques multi-organismes d’Aviesan
LEEM
Les Entreprises du médicament
NGS
Next-Generation Sequencing, ultra-high-throughput sequencing
OECD
Organization of Economic Co-operation & Development
OPESCT
Office parlementaire d’évaluation des choix scientifiques et technologiques
PNMR
Plan national maladies rares
Pb
Peta bases = 1015 bases
RNA-Seq
RNA sequencing, sequencing of the transcriptome
SNIIRAM
Système national d’information inter-régimes de l’Assurance maladie
SNV
Single Nucleotide Variations
STIC
Sciences et technologies de l’information et de la communication
Transcriptome The whole set of RNA molecules resulting from transcription of the genome
38

The President of Aviesan expresses sincere thanks to all those whose contributions have been
essential in the construction of this Plan.
are due to all the representatives of central administrations, research institutions, higher•Thanks
teaching and research organizations, hospitals and health care establishments and private-sector
companies who have made important contributions at every stage of preparation of this Plan,
and also for the work of the Steering Committee and the thematic and cross-disciplinary groups
with special acknowledgment of those who have agreed to act as Pilots and coordinate groups'
activities.

•Foreign experts who have agreed to contribute to the work or provide evidence.
learned societies and patient support groups who have made contributions or expressed•Thetheir support.
•IGAENR for its help compiling this document.
and CVT Aviesan for logistic coordination of the work and support in preparing and•Aviesanproducing this document.

39

40

APPENDIXLETTER FROM THE PRIME MINISTERTO THE PRESIDENT OF AVIESAN

41

42

INSERM
DIRECTORATE-GENERAL
21 APRIL 2015
RECEIVED

Office of the Prime Minister
20017
Monsieur Yves Levy
President of AVIESAN
Biopark
8 rue de la Croix-Jarry
75013 PARIS
Paris, 17 April 2015 1236
Dear M. President,
Recent technological progress in molecular biology and the development of new ultra-highthroughput sequencers mean that it is now possible to sequence whole human genomes faster andmore cheaply. Analysis of whole genomes is taking an ever-more important place in medical practicein the areas of diagnosis, establishing prognosis and treatment in a framework of precision medicine.
A number of countries, including Great Britain and the United States of America have implemented
unprecedented measures to meet this challenge. To preclude our losing ground and dependence on
foreign countries, France too needs to acquire ultra-high-throughput sequencing capability
commensurate with its needs.
In 2013, about 3,000 patients needed whole genome sequences. These were sequenced at publicsector and private-sector facilities but because of a national lack of adequate capacity, some had tobe sent abroad. Most of this sequencing were paid for with funds from the Hospital Clinical Research
Program, the Cancer Institute or charities. The health insurance system does not currently reimburse
genome sequencing but the number of patients needing it is going to rise considerably in the near
future. These major changes in medical practice and organization of the health care system cannot
be separated from innovation and will require close coordination with the world of research.
Against this background, I am asking you as President of the Alliance Nationale pour les Sciences dela Vie et de la Santé (AVIESAN) to determine, within three months, what measures need to be taken
to make whole genome sequencing routine as soon as possible.
Your work should:

431) review the place of whole genome sequencing and whole exome sequencing in therapeuticstrategy. Please establish a qualitative and quantitative appraisal of current indications and,in the light of research underway, possible changes over the next ten years;2) establish France’s position in the research, analyze the place of these new technologies in
the context of National Health Plans (cancer, neurodegenerative disease, rare diseases, etc.)
and propose priorities in line with national research and health care strategies;3) evaluate challenges related to innovation and potential impact in terms of capitalization andeconomic development, taking stock of both technological aspects and how to handle theanalysis of massive databases, including the ethical issues;4) propose medico-economic and industrial models to guarantee a financially stable system,
including proposals concerning reimbursement by the Social Security system for wholegenome sequencing procedures.
I expect from you recommendations on how to organize appropriate infrastructure for sequencing
and data acquisition, handling and analysis. In particular, please consider whether a national
platform or a series of specialized or deconcentrated platforms would be the best option. Pleaselook at alternative set-ups to guarantee priority use in medical practice as well as in research. Pleasealso formulate recommendations on the need for the equipment and skills to ensure functioning of
the proposed infrastructure.
To fulfill this commission, exploit the expertise of:• the various divisions of AVIESAN, notably the Multi-Organism Thematic Institutes and thevarious experts who have already conducted investigations on the topic;• the Director-General of CNAMTS for medico-economic aspects;• the Ministry of Industry for questions about industrial channels.
Get in touch with relevant business spokespeople and potential partners in this project to talk aboutdeveloping public-private partnerships. It might be useful to establish a relationship with theStrategic Health Care Industry Council (Conseil stratégique des industries de santé, CSIS) whichorganizes all aspects of health-related businesses—health care, pharmaceuticals, medical devices, invitro and e-Health—around the theme of innovation.
Please report regularly to the Ministry of Social Affairs, Health and Women’s Rights, the Ministry of
Education, Higher Learning and Research, and the Ministry of the Economy, Industry andInformation Technology before remitting your conclusions to me at the end of this three-month
period.
Yours sincerely,
Manuel VALLS

44

75013 Paris

www.aviesan.fr

Graphics: Myriem BELKACEM – Inserm, Disc – February 2016

8, rue de la Croix-Jarry