Ministry of Health
Decree — Official Gazette n.253 of
Allocation of the fund for the strengthening of test di Next-Generation Sequencing di profiling genomics dei tumors dei quali evidence is recognized and appropriateness
THE MINISTER OF HEALTH
Having regard to Articles 3, 11, 32, 117 and 118 of the Constitution;
Having regard to the decree of the President del Council dei ministers 11
February 2014, No.59, bearing ‘Regulation di organization del
Ministry of Health’;
Having regard to the law of 23 December 1978, n. 833 bearing ‘Institution del
National Health Service’;
Having regard to the legislative decree 30 December 1992, n. 502 recante
«Reorganization of the discipline in health matters, pursuant to art. 1
of Law No 421 of 23 October 1992′;
Having regard to Legislative Decree No 517 of 7 December 1993 ‘Amendments
to Legislative Decree 30 December 1992, n. 502, bearing reordering
of the health regulation, a standard art. 1
Law No 421 of 23 October 1992′;
Having regard to Law no. 419 of 30 November 1998 «Delegation to the Government per la
rationalisation of the National Health Service e per the adoption
of a single text on organization e operation del
National Health Service.Modifications al decree legislative 30
December 1992, No 502′;
Having regard to art. 1, paragraphs 1, 2, 3, 7 and 8, del decree legislative 30
December 1992, n. 502, regulating, among the other, le mode
for la definition e disbursement dei levels essential di
assistance;
Having regard to the decree of the President del Council dei ministers, 12
January 2017 with ad subject: ‘Definition e update of
essential levels of assistance, referred to in art. 1, comma 7, del
decreto legislativo 30 dicembre 1992, n. 502′ determining the levels
essential di support ed in particular the ‘nomenclator
performance support specialist outpatient» di cui
in Annex 4 identifying the tests against the _- Service health
national;
Having regard to art.1, paragraph 684 of the law 30 December 2021, n. 234
‘State budget for the year financial 2022 e
multiannual budget for the three-year period 2022-2024″ that ha established
in the state of forecast del Ministry della health a fund,
named Next-Generation Test Fund Sequencing, with a
budget of EUR 5 million each degli years 2022 e
2023;
Having regard to the following paragraph 685 which allocates the aforementioned fund to
«enhancement of Next-Generation Sequencing profiling tests
genomics dei tumors dei quali are recognized evidence e
appropriateness’;
Seen, also, the paragraph 686 that predicts that ‘with decree del
Minister of Health, to be adopted within sixty days from date
of entry into force of this law, the criteria
and the modalities of allocation of the fund referred to in paragraph 684 are identified, as well as ‘ the
system for monitoring the use of sums’;
Considering that the above mentioned resources, equal to 5 million di euro
per year of the two-year period 2022-2023, are registered on
budget chapter 2307 management plan 1, called «Fund for i
Next Generation test Sequencing e provisions in matter di
laboratories», belonging to the responsibility center della Directorate
general of health prevention, and established per le Purpose
above as part of program di expense ‘Prevention e
promotion of human health and care sanitary al personnel
navigating and airfaring», della mission ‘Protection della health»
of the estimates of the Ministry of Health;
Having regard to the decree of the Minister economics e of finance 31
December 2021, concerning the division into chapters of Parliamentary voting units
relating to the budget of forecast per the financial year
2022 and for the three-year period 2022-2024;
Having regard to art.2, paragraph 109, of the law of 23 December 2009, n. 191,
recante provisions per la training del budget annual e
multiannual of the State, which starts from 1° January 2010, ha
repealed art. 5 of Law No 386 of 30 November 1989 on
Participation of the autonomous provinces ai funding recati from
any provision of law;
Whereas la possibility della profiling molecular,
mainly using Next Generation Sequencing (NGS) techniques,
and the possibility of accessing targeted therapies based on presence
of alterations molecular that need di test in degree of
identify them, represent important innovations in oncology;
Considering the need to identify a pathology oncology
for which it is possible to use tests per the sequencing
extended genomic (NGS) for molecular diagnosis and la which incidence
in the Italian population is such as to guarantee an adequate use
of the available fund, ensuring an equal possibility of access
to the test;
Having regard to the recommendations of ESMO (European Society for Medical
Ongology) for the use of NGS in patients with tumors metastatics
(F.Mosele et al, Ann Oncol 2020) that detect non  carcinoma; a
small cells, not scaly (adenocarcinoma) metastatic del
lung as a neoplasm for which it results widely documented
usage di test di NGS al end di an appropriate choice
therapeutic;
Having regard to the opinion of the Superior Council of Health (CSS) — Section
I, Session LII, of , expressed su request della
D.G. della ricerca e dell’innovazione in sanita’ del Ministerio of
health, which states about NGS tests that: ‘Evidence-recognised tests
are available e appropriateness, widely used
(also commercial) for all oncological diseases associate ad
actionable genetic alterations» and identifies i laboratories eligible
for performing these tests as «Structures that today have a
consolidated experience (>2 years) in performing NGS tests».
Having regard to the decree of the Director General of Health Prevention
del , with which e’ state instituted the Table di
work, in which they participate experts national di proven experience,
aimed at identifying within the oncological care path
the method of prescription, execution, use and monitoring di
test di Next Generation Sequencing (NGS) with warranty di
appropriateness of use and cost analysis of performance in
object in view of an economic health policy effective ed
efficient;
Tenuto account della distribution demographic sul territory
national, based on data supplied from ISTAT referenced al 1°
January 2022;
Noted the identification of a quota for non  tests; higher
a euro 1.150,00;
Held necessary, therefore, proceed alla definition
criteria and methods of distribution between regions;
Acquired, also, the Understanding within the Permanent Conference for
the relations between the State, the regions and the autonomous provinces of Trento
e of Bolzano on (rep.acts no. 207/CSR);
Decree:
Art. 1
Purpose and object
1.This decree establishes i criteria e le modalities di
allocation of the fund established pursuant to art. 1, comma 684, della
Law No 234 ‘Budget of forecast dello Status
for financial year 2022 and multiannual budget per the three-year period
2022-2024″, as well as the system di monitoring employment of the
resources concerned.
Art. 2
Criteria, resource allocation and monitoring
1.For each of the years 2022 e 2023, le resources di which al
previous art. 1, are broken down between le regions sulla base del
number of eligible patients, calculated from estimate dei cases di
carcinoma not a small cells (adenocarcinoma) non squamous
metastatic of the lung, up to the amount of available resources
annually, second la table di cui in the Annex 1, that
is an integral part of this decree.
2. The modalities and requirements for access ai test di NGS In
patients with metastatic non-squamous non-small cell carcinoma
of the lung, are indicated in the Annex 2 that constitutes Part
integral to this decree.
3.For the year 2022, by 30 November, the regions send to the
Ministry of Health a resolution of commitment to adopt all
acts necessary for the implementation of the indications of the Annex 2,
relative alle modalities organizational per la prescription,
the execution, use, monitoring, as well as the execution and the
evaluation of NGS test results, with a view to an appropriate treatment choice for patients with non-a  cancer; small
metastatic nonsquamous cells of the lung.
4. Within thirty days from term fixed per la transmission
of the resolutions referred to in paragraph 3, the Ministry, acquired the favourable opinion
in favour of the Coordination Committee of which art. 3, disburse
to the regions the financing referred to in paragraph 1, relative per year
2022.
5.By , the regions transmit al Ministry
of health the report of the first twelve months of activity according to
the criteria set out in the abovementioned Annex 2.
6. The Ministry of Health, having obtained the opinion of Committee di
coordination referred to in the following art. 3, dispenses alle regions The
funding referred to in paragraph 1, relating to the year 2023. Failure to o
incomplete presentation of the report referenced ai first Twelve
months of activity involves the recovery total o partial delle
resources transferred e preclude the transfer of Resources
of the year 2023 to defaulting regions.
7. The regions may use the resources referred to in art.1, for
the performance of the activities referred to in the Annex 2, within the 31
March 2026. The regions shall transmit to the Ministry of health, by
30 October each year, an annual report, according to i Criteria
set out in Annex 2. The Committee of coordination
of art. 3, assess the conformity of the annual reports. The
missed or incomplete submission of reports annuals comporta
il recovery total o partial of resources Previously
transferred.
Art.3
Coordination Committee
1. Con decree del Director della Management general della
health prevention e’ instituted a Committee di coordination,
composed of three representatives of the Ministry of Health e da three
representatives of the regions and autonomous provinces.
2. The task of the Coordination Committee shall be to evaluate the deliberate
e interim and final reports on activities turns Transmitted
by the Regions, in the terms referred to in art.2, in order to evaluate la
the requirements for the disbursement of funds are met.
3. The Coordination Committee shall operate without new or major new members Charges
to be borne by public finances.
This decree is transmitted to the organs di control ed e’
published in the Gazzetta Ufficiale della Repubblica italiana.
Rome,
The Minister: Hope
Registered at the Court of Auditors on
Office for the Control of the Acts of the Ministry del work e of
policies social, del Ministry education, del Ministry
of University and Research, Ministry della culture, del
Ministry of Health, n.2698
&_ — Annex 1
Fund breakdown table
Part of the measure in graphic format
— &_ — Annex 2
Modality per indication, prescription, execution, use e
Next Generation Sequencing (NGS) test monitoring in scope
of the course of care oncology with warranty di appropriateness
d’uso
I.Introduction
The number of biomarkers to be evaluated in the practice clinic in
oncology per i treatments a target molecular sta
progressively increasing. This evolution della medicine di
precision requires careful selection of technologies di analysis
for ensure that esse come run second criteria di
appropriateness, in times appropriate to clinical needs e with Le
often limited amounts of biological material available.
The introduction of a technology in molecular diagnostics di
sequencing genomic extended, better known as Next
Generation Sequencing (NGS), represents a important contribution
technological to cope a these new needs clinics. The NGS techniques in practice clinic must be applied in
selected late-stage neoplasms, in function del number di
molecular da detect, della they complexity e della
percentage di patients with biomarkers approved dagli entities
regulators and national and international guidelines.
In this regard, the Superior Council of Health (CSS) — with opinion
of Section I, Session LII, 15 February 2022, su request
of the Directorate-General for Research and Innovation in health
of the Ministry of Health, states regarding NGS tests that: «I am
available test recognized per evidence e appropriateness,
widely used (also commercial) per all le pathologies
oncologic associate ad alterations genetic actionable» e
identifies the laboratories suitable for performing these test such as
«Structures that have a  today; consolidated experience (>2 years)
in NGS testing’.
Alla light del above opinion si e’ identified il
carcinoma not a small cells not scaly (adenocarcinoma)
metastatic of the lung as a pathology per la which ci si can’
avail immediately di technology di sequencing genomic
extended (NGS) for molecular diagnosis, in order to a appropriate
therapeutic choice for patients with it.
Ii.NGS for the choice of therapy in carcinoma not a Small
metastatic nonsquamous cells (adenocarcinoma) of the lung.
In Italy in 2020 41,650 have been estimated new diagnosis di
lung cancers. Di these, the 40-50% are represented da
adenocarcinomas. The tumor del lung represents la second
neoplasm more frequent in males (15%) e la third in women
(6%), with 34,000 deaths in 2020 (males = 23,400; females = 10,600)
(Source AIRTUM).
The distribution by region of these cases e’ reported in the
Table in Annex 1.
Based on these epidemiological elements and in consideration
of levels di evidence clinic dei molecular e of
recommendations of the European Society For Medical Oncology (ESMO)
for the use of NGS technology in patients with tumors metastatici
(Mateo et al, Ann Oncol 2018; Mosele et al, Ann Oncol 2020), e’
individuated the carcinoma not a small cells non squamous
(adenocarcinoma) metastatic of the lung as la neoplasm per la
which can be used immediately for tests in NGS per Multigenic analysis
Multigenic with therapeutic relapses.
In this neoplasm the use of NGS technology allows:
1) optimization employment del sample biological
available which has been shown to represent, in particular for
biopsies, an important limit for determinations made by
individual tests performed at a later time;
2) the detection of molecular alterations actionable, that
may not even be detected by other methods of analysis,
for which active drugs are available refunded from SSN O
However accessible with different procedures.
I results di one study duct in reality hospital
italiane and referred to the use of NGS for la profiling in patients
with non-a  lung cancer; small cells highlight a
cost for NGS tests di euro 1.150,00 allo state current of
genomic alterations investigated, against a cost of euro 1.780,00
for standard methods (Pinto et al, Health Economics 2021).
Iii.Indication
The prescription of a test NGS e’ indicated nei patients with
carcinoma not a small cells not scaly (adenocarcinoma)
metastatic of the lung susceptible to anticancer treatment e
taking into account the preferences expressed from patient appropriately
informed at the time of choosing the former line di therapy, e
can’ be repeated nei patients with alterations molecular
actionable undergoing therapies a molecular when Disease progression is shown
.
Si predicts usage di panels that are in degree di
analyze at least the molecular alterations below al end
to identify alterations genes that allow a intervention
therapeutic or that in any case may have a role for the definition
di choices therapeutic, with benefit clinical della therapy
prescribed on the basis of profiling molecular in terms di
efficacy, toxicity and impact sulla quality di life del
patient.
The NGS tests used must identify at least le following
molecular alterations for which they are already accessibility drugs:
KRAS mutation G12C, EGFR mutations, BRAF mutations, ALK
rearrangements, ROS1 rearrangements, NTRK rearrangements, RET
rearrangements, MET mutations with loss exon 14 (exon
skipping), HER2 mutations.
Genomic tests are not indicated in cases where the patient
correctly informed has denied consent to treatment, ne’
when, in the clinical judgment of the oncologist, le features e the patient’s clinical conditions exclude
clinical conditions of the patient to exclude la Possibility
of further therapeutic interventions indicated by the results of test.
It is necessary to request further consent if the Result
of the test has oncogenetic implications.
Iv.Prescription
The prescription of the test NGS comes carried out from center di
oncology, public o private accredited, that ha in load the
patient, following multidisciplinary evaluation e in context
del path diagnostic therapeutic welfare (PDTA) ove
existing.
The oncology center in charge of prescribing must fill in
a computerized form/request that shows, in addition to the master data and
the parameters that allow you to identify the level of risk del
patient, also the next result del test e the path
therapeutic undertaken. Such card shall, Also, Be updated with annual follow-up data.
Al center di oncology compete also’ la verification della
availability of an appropriate biological sample to be addressed to a
laboratory anatomy pathological/pathology molecular between those
identified at regional level.
The regions identify in their respective deliberative acts i centers
di oncology e i laboratories di anatomy pathological/pathology
molecular that will perform the prescription and i , respectively; test
NGS.
Laboratories di anatomy pathological/pathology molecular that
can execute i test NGS are identified between those with
experience consolidated, top ai two years, di profiling
genomics by NGS on tissue samples and liquid biopsy, as
reported in the cited opinion expressed by CSS in data 15 February
2022.
In fulfillment of functions di competence, i centers di
oncology prescribers are required al respect of European and national data protection provisions
; relative alla
health and genetic data, such as data personal belonging alle
special categories di which art. 9 del regulation EU n.
2016/679 of the European Parliament and of the Council of 27 April 2016.
V.Execution
The execution and subsequent interpretation of the test should not
result in a delay in the initiation of therapy that could potentially compromise the effectiveness of treatment
.
The anatomical-pathologist is responsible for the evaluation of the suitability del
tissue sample (primary tumor or metastasis) sul which it will have to
be executed the test, as well as ‘ della dissection del Fabric
Required to optimize test results.
In cases in which not sia possible have di a sample
tissue, the test could be executed su sample Blood
(liquid biopsy). La biopsy liquid can’ have dei limits di
sensitivity Related alla quantity di DNA tumor circulating
(ctDNA), and therefore should be limited to cases where there is non sia fabric
suitable available and/or the biopsy not can be repeated. The
patient must be informed dei limits del test executed su
blood sample in case it is necessary to use it.
The unit operative di anatomy pathological/laboratory di
molecular pathology in which the test will be performed NGS use la
identification statement «NGS test for non-small cell carcinoma
non scaly (adenocarcinoma) metastatic del lung
cyto/histologically diagnosed’ for registration on system
local operating system (SIL).For traceability purposes only, the unit
operative unit of pathological anatomy/pathology laboratory molecular
sending the sample per execution del test in other seat
register the submission with the item «Sending by sample per Test NGS for
carcinoma not a small cells not scaly (adenocarcinoma)
metastatic of cyto/histologically diagnosed lung’.
As regards i panels genes, are available tests
commercially recognized by evidence e appropriateness, widely
used for many associated oncological diseases ad alterations
actionable genes.
It is necessary to use CE-IVD or CE-IVDR  marked tests; or, in
alternative, carrying out internal validation procedures del
test for purpose of diagnosis clinic da part del Laboratory
User.
In public procedures for the purchase of NGS tests,
le regions must use criteria di evaluation based SU
Up-to-date scientific evidence and technologies validated for use
clinical.The financing will be used per the refund of
performance, allocating a quota for test not top a euro
1.150,00.
VI. Usage
The use of NGS test results is guaranteed by the center di
oncology that ha in load the patient per the indication,
the execution and follow-up of any therapies indicated.
If the test NGS individuals alterations genomic that non
result susceptible di treatment with i drugs a
molecular already recognized e available, interpretation del
result must be entrusted a a group multidisciplinary
including, in addition to the oncologist, at least one pathologist/molecular biologist and
a geneticist.
For the safekeeping and security of data and samples biological
are adopted precautions dictated in the provision n. 146 del 2019,
adopted by the Guarantor for the protection of personal data, ai Senses
of art.21, paragraph 1, of the legislative decree 10 August 2018, n.
101, also relatively alle information from provide Concerned
, acquisition del consent e alla Counselling
genetics.
VII. Monitoring
Reporting, both for the purposes del monitoring the use
of the fund both for the purpose of checking appropriateness and of clinical outcomes
clinical results obtained using NGS tests in addition to parameters
clinical-pathological, e’ insured, second le indications
organizational of each region, from each center di oncology
detected using la next name: ‘Test NGS for
carcinoma not a small cells not scaly (adenocarcinoma)
metastatic of cyto/histologically diagnosed lung’.
For patients belonging to treatment centres located outside the
region of residence, the benefit is considered to be dependent of
region to which it belongs, by means of economic compensation between region
provider and region of residence, that takes place via billing
direct.
Le regions provide a report usage del fund
within and with the modalities of the usual statements and with cadence
annual; in addition, they communicate to the Ministry a relationship detailed
regarding the number of NGS tests performed, appropriate use,
clinical outcomes and changes in use of resources obtained
with employment dei test NGS in addition ai parameters
clinical-pathological.
The regions shall use this report by the regions; dei data press releases
from cancer centers prescribers dei test, as well as ‘ di analysis
secondary data of administrative health data, in form aggregate e
anonymous.The annual report must include:
the number of NGS tests performed;
the moment of enforcement del test (first determination
performed for the definition of the first line of therapy; second
determination performed at disease progression in patient already’
subjected to molecular therapy);
the sample used to perform the test (sample di
tumor tissue primitive; sample di tissue di metastasis;
liquid biopsy);
the type of panel used and the number of genes evaluated;
the identified actionable molecular alterations;
therapy a molecular prescribed e practiced from
patient based on NGS test results.
Other information will also be collected, such as:
the duration of treatment of molecular therapy;
the outcomes della therapy in terms di answer objective
obtained, time to therapy failure and adverse events;
overall survival;
the number of inpatient/outpatient accesses.
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