ANALYSIS OF ALTERNATIVES SOCIO-ECONOMIC ANALYSIS - …
Transcript of ANALYSIS OF ALTERNATIVES SOCIO-ECONOMIC ANALYSIS - …
ANALYSIS OF ALTERNATIVES
&
SOCIO-ECONOMIC ANALYSIS
Legal name of Applicant(s): Diagnostica Stago
Submitted by: Diagnostica Stago
Substance: 4-(1,1,3,3-Tetramethylbutyl)phenol, ethoxylated
[covering well-defined substances and UVCB substances,
polymers and homologues]
Use title: Use-2
Industrial use of 4-tert-OPnEO in view of controlling the
amount of non-specific reactions in the production of in vitro
diagnostic reagents (STA® - Liatest® D-Di assays).
Use number: 2
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TABLES ............................................................................................................................................................. 4
FIGURES ........................................................................................................................................................... 5
LIST OF ABBREVIATIONS ................................................................................................................................... 6
1. SUMMARY ............................................................................................................................................... 7
2. AIMS AND SCOPE OF THE ANALYSIS ......................................................................................................... 9
2.1. Stago Group .................................................................................................................................................. 10 2.2. Scope of the AfA ........................................................................................................................................... 10
2.2.1. Taverny ............................................................................................................................................................. 11 2.3. Elements of context ..................................................................................................................................... 12
2.3.1. General elements of hemostasis ...................................................................................................................... 12 2.3.2. Physiologic origin of D-Dimer ........................................................................................................................... 14 2.3.3. Clinical use of D-Dimer assays .......................................................................................................................... 15
2.4. Products concerned...................................................................................................................................... 18 2.4.1. STA® - Liatest® D-Di product range .................................................................................................................. 18
2.5. Supply chain ................................................................................................................................................. 22 2.6. Elements of context ..................................................................................................................................... 23
2.6.1. General production process.............................................................................................................................. 23 2.6.2. Market .............................................................................................................................................................. 23
2.7. General methodology ................................................................................................................................... 25 2.7.1. Scope of the AfA ............................................................................................................................................... 26 2.7.2. Actualisation .................................................................................................................................................... 27
2.8. Substitution strategy .................................................................................................................................... 27 2.9. Presentation of the “applied for use” and “non-use” scenarios .................................................................. 28
2.9.1. “Applied for use” scenario ................................................................................................................................ 28 2.9.2. “Non-use” scenario .......................................................................................................................................... 28
3. “APPLIED FOR USE” SCENARIO ............................................................................................................... 29 3.1. Analysis of substance function ..................................................................................................................... 29
3.1.1. Functional properties ....................................................................................................................................... 29 3.1.2. Analytical performances................................................................................................................................... 30 3.1.3. Clinical performances ....................................................................................................................................... 30 3.1.4. Risks for human health and the environment .................................................................................................. 32
3.2. Market and business trends ......................................................................................................................... 33 3.2.1. Use of 4-tert-OPnEO ......................................................................................................................................... 33
3.3. Human health impacts of the “applied for use” scenario ............................................................................ 33 3.4. Impacts on the environment and monetised damage of the “applied for use” scenario ............................ 33
3.4.1. Environmental impacts and monetised damage .............................................................................................. 33 3.4.2. Environmental context of the impacts ............................................................................................................. 33 3.4.3. Environment impacts and monetised damage ................................................................................................. 40
4. SELECTION OF THE “NON-USE” SCENARIO ............................................................................................. 47 4.1. Substitution initiative ................................................................................................................................... 47 4.2. Resources ..................................................................................................................................................... 53 4.3. Assessment of shortlisted alternatives......................................................................................................... 54
4.3.1. Alternative 1: Brij L9 ......................................................................................................................................... 54 4.4. Substitution timeline .................................................................................................................................... 55 4.5. The most likely “non-use” scenario .............................................................................................................. 56
5. IMPACTS OF GRANTING AN AUTHORISATION ........................................................................................ 57
5.1. Economic impacts......................................................................................................................................... 57 5.1.1. Direct loss of revenues and profits ................................................................................................................... 58 5.1.2. Loss of markets ................................................................................................................................................ 59 5.1.3. Discussion: net impact for the Society .............................................................................................................. 59 5.1.4. General conclusion on economic impacts ........................................................................................................ 60
5.2. Social impacts ............................................................................................................................................... 60 5.2.1. Impact on patients health ................................................................................................................................ 60
5.3. Wider economic impact ............................................................................................................................... 65
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5.3.1. Negative impacts ............................................................................................................................................. 65 5.3.2. Positive wider economic impacts ..................................................................................................................... 66
5.4. Distributional impacts .................................................................................................................................. 66 5.4.1. Impact on employment .................................................................................................................................... 66
5.5. Conclusion of the socio-economic analysis .................................................................................................. 70 5.5.1. Synthesis of the impacts of the “non-use” scenario ......................................................................................... 70 5.5.1. Complementary element: cost-effectiveness ratio ........................................................................................... 71
5.6. Uncertainty analysis for both the “applied for use” and the “non-use” scenario ........................................ 71 5.7. Consumption cost-effectiveness ratio .......................................................................................................... 72 5.8. General conclusion on the impacts of granting an authorisation ................................................................ 72
6. CONCLUSION ......................................................................................................................................... 73 6.1. Comparison of the benefits and risks ........................................................................................................... 73 6.2. AoA-SEA in a nutshell ................................................................................................................................... 73 6.3. Information for the length of the review period .......................................................................................... 74 6.4. Substitution effort taken by the Applicants if an authorisation is granted .................................................. 74
7. References ............................................................................................................................................. 75
8. Annex – Justifications for Confidentiality Claims.................................................................................... 77
9. Appendixes ............................................................................................................................................ 78 9.1. ISO 9001:2015 certificate ............................................................................................................................. 78 9.2. ISO 14001:2015 certificate ........................................................................................................................... 81
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T A B L E S
Table 1. Uses of the Application for Authorisation ........................................................................ 9 Table 2. Negative predictive value, sensitivity and specificity of STA® - Liatest® D-Di (ref.00515) for
DVT exclusion and PE exclusion .................................................................................................. 21 Table 3. Precision of STA® Liatest® D-Di ...................................................................................... 22 Table 4. Supply chain of Diagnostica Stago’s IVD devices ............................................................. 22 Table 5. Selected Central Laboratory D-Dimer Assays .................................................................. 24 Table 6. Elements of demonstration that the benefits of continued us e outweigh the risk ........... 25 Table 7. Scope of the AfA ........................................................................................................... 26 Table 8. Impact periods for the two product ranges of Use-2 ...................................................... 26 Table 9. DIET study raw results - pulmonary embolism ................................................................ 31 Table 10. Sensitivity, specificity, negative & positive predicted values for STA® - Liatest® D-Di (ref.
00515) assays in the exclusion of pulmonary embolism ............................................................... 31 Table 11. DIET study raw results - deep vein thrombosis ............................................................. 31 Table 12. Sensitivity, specificity, negative & positive predicted values for STA® - Liatest® D-Di (ref.
00515) assays in the exclusion of deep vein thrombosis .............................................................. 32 Table 13. Consumption of IGEPAL® CA-630 over the 2014-2016 period under Use-2, in litres. ...... 33 Table 14. Seine River water quality analysis results for octylphenol ............................................. 35 Table 15. Seine-Normandie catchment area key figures .............................................................. 36 Table 16. Water quality for the Seine-Normandie catchment area, 2013 ...................................... 37 Table 17. Groundwater state for the Seine-Normandie catchment area ....................................... 37 Table 18. Seine-Normandie catchment area coastal water chemical quality ................................. 38 Table 19. Potential freshwater services in a catchment ............................................................... 41 Table 20. Detail of the global economic impact of recreational fishing in France .......................... 44 Table 21. Socio-economic situation for water-related activities in the Seine-Normandie catchment
area .......................................................................................................................................... 45 Table 22. Willingness to pay for the preservation of water quality at the Flathead River and Lake in
Montana United States of America ............................................................................................ 46 Table 23. Surfactants identified and tested ................................................................................. 50 Table 24. Surfactants selected for further investigation in Phase 2. ............................................. 50 Table 25. Surfactants selected for further investigation in Phase 2. ............................................. 52 Table 26. Results of reagent method analysis – functional criteria ............................................... 52 Table 27. Contributors involved in Stago’s substitution initiative for Use -2. ................................. 54 Table 28. Hazards identification for Brij L9 .................................................................................. 54 Table 29.General substitution timeline for Use-2 ........................................................................ 55 Table 30. Profits associated with D-Dimer assays per year ........................................................... 58 Table 31. Total profits loss over the impact period for Use-2 ....................................................... 58 Table 32. Alternative methods for the diagnostic of deep vein thrombosis .................................. 62 Table 33. Alternative methods for the diagnostic of pulmonary embolism ................................... 63 Table 34. Costs of tests for pulmonary embolism in Switzerland, the United States and Canada, in
USD (2003) ................................................................................................................................ 63 Table 35. Treatment costs for pulmonary embolism in Switzerland, the United States and Canada,
in USD (2003) ............................................................................................................................ 64 Table 36. Cost-effectiveness of various diagnostic strategies for deep vein thrombosis (2001) ..... 64 Table 37. Cost-effectiveness of various diagnostic strategies for deep vein thrombosis (2001) ..... 64 Table 38. Calculation of the social value of jobs lost via the default value methodology for Use -2 67 Table 39. Calculation of the value of output/wages lost during the period of unemployment for
one job, Use-2 ........................................................................................................................... 68 Table 40. Calculation of the value of Discounted value of lost output due to scarring for one job,
Use-2 ........................................................................................................................................ 68
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Table 41. Calculation of the value of output/wages lost during the period of unemployment for
one job, Use-2 ........................................................................................................................... 69 Table 42. Calculation of the recruitment costs for one job, Use-2 ................................................ 69 Table 43. Calculation of the value of benefits from leisure time related to unemployment for one
job, Use-2 .................................................................................................................................. 69 Table 44. Individual costs of unemployment, discounted ............................................................. 70 Table 45. Comparison of the characterisation of costs of unemployment using the default value
and the detail assessment methodologies .................................................................................. 70 Table 46. Synthesis of monetised impacts of the “non -use” scenario, Use-2 ................................ 71 Table 47. Synthesis of qualitative impacts of the “non -use” scenario, Use-2 ................................ 71 Table 48. Synthesis of the monetised impacts of the “non -use” scenario ..................................... 72 Table 49. Other impacts of non-use scenario .............................................................................. 72 Table 50. Justifications for confidentiality claims ........................................................................ 77
F IG U R E S
Figure 1. Taverny site ................................................................................................................. 11 Figure 2. Formation of the clot. .................................................................................................. 13 Figure 3. Synthetic coagulation process ...................................................................................... 14 Figure 4. Stago STA-R® ............................................................................................................... 19 Figure 5. Stago STA COMPACT MAX® 2 ....................................................................................... 19 Figure 6. Stago STA SATELLITE® .................................................................................................. 19 Figure 7. Interpretation of D-Dimer assay results ........................................................................ 20 Figure 8. General production process ......................................................................................... 23 Figure 9. STA R Max® ................................................................................................................. 30 Figure 10. Water courses nearby the Taverny site ....................................................................... 34 Figure 11. Delimitation of the Seine-Normandie catchment area ................................................. 36 Figure 12. Chemical state of coastal water bodies for the Seine-Normandie catchment area ........ 38 Figure 13. IF.3 hydrographical unit ............................................................................................. 39 Figure 14. Ecological state of the IF.3 hydrographical unit ........................................................... 39 Figure 15. Groundwater quality for the IF.3 hydrographical unit .................................................. 40 Figure 16. Spectrum of potential benefits of protected areas , ..................................................... 40 Figure 17. Fish population species in the Seine River ................................................................... 43 Figure 18. Detail of fishing expenditures, in € (2014), per year and per fisherman ........................ 44
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LIST OF ABBREVIATION S
AfA Application for Authorisation
B Billion (€)
CEA Cost-effectiveness analysis
DALY Disability-Adjusted Life Years
DAS Delivery and Acceptance Specification
HIT Heparin Induced Thrombocytopenia
IVD In vitro Diagnostic
k Thousands (€)
M Million (€)
PT Prothrombin Time
PV Present value
RIN1 or RIN2 Internal Standard Level 1 or 2
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1. SUMMARY
C ON T E XT
Stago is an in vitro diagnostic (IVD) detection kit manufacturer. Its activity is dedicated
to hemostasis disease.
Under Use-2, Stago is downstream user of 4-tert-OPnEO (Igepal) for its detergent
properties in the production of in vitro diagnostic reagents (STA® - Liatest® D-Di
assays).
S U B S T A NC E F U N CT IO N
IGEPAL® CA-630 is a non-ionic surfactant with detergent properties. Its
substitution in the context of the production of STA® - Liatest® D-Di assays has to take
into consideration: possess physico-chemical properties that allow for the same or
better analytical and clinical performances compared to that of the IGEPAL®.
So as to play its role within the production process of STA® - Liatest® D-Di assays,
potential alternatives need to possess the following properties:
- Be a non-ionic surfactant, and therefore with limited sensitivity to both pH and
the ionic strength of the environment.
- Present an HLB (Hydrophilic-Lipophilic Balance) comprised between 13
and 15.
- Allow to significantly reduce plasma turbidity and maintain it constant over
time.
I DE NT IF I CAT IO N O F AL T E R NAT I V E S
The main problematics for Stago regarding this type of products are the sensitivity and
the stringent regulatory framework. So, any change in raw material or equipment in
the manufacturing process has to undergo a strict change management process. An
internal work of research led to identify one potential alternative process to 4-(1,1,3,3-
Tetramethylbutyl)phenol, ethoxylated for its surfactants activities. In addition, several
performances linked to the non-specific reaction are necessary. The timeline
obligations are linked to the change management process for the Use-2 products
(R&D, analytical tests, clinical tests and regulatory obligation).
“ A P P L IE D FO R U SE ” AN D “ NO N - U SE” SC E NA RIO S
Under the “applied for use” scenario, Stago will pursue the use of 4-tert-OPnEO in the
production of products concerned by Use-2 during the period of time necessary to
develop, implement and validate an alternative process, thereby securing both its
activity and the supply of IVD tests to laboratories and hospitals. The most likely “non-
use” scenario is the cease of manufacturing.
Taking into account the high level of requirement associated with Use-2, its
importance for Stago in terms of business, know-how and competitiveness, the cease
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of manufacturing of STA®-Liatest®D-Di assays will probably result to the global cease
of Stago activity.
So, since Use-2 concerns an important part of Stago’s current and future portfolios,
this scenario will have strong economic, social and wider impacts on Stago company
and the society in general.
I M P ACT S OF G RA NT I NG A UT HO RI S AT ION
No benefits/risks assessment can be performed considering the endocrine disrupters
properties of the substance.
The environment exposure is considered to be extremely low (below the water
framework directive threshold).
Compare to the monetised impact of the “non-use” scenario (loss of profits and loss
of employment) which is around [500M-5B](#1a)
Non-monetised impacts of the “non-use” scenario include the loss of markets linked
to a knock-off effect, relocation costs, and impacts on the society health system.
C ON C L U SI ON
Based on the arguments put forward, and in order to develop, implement and
qualify an alternative solution for Use-2, Stago apply for a twelve-year review
period.
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2. AIMS AND SCOPE OF TH E ANALYSIS
The aim of the present document is to provide a comprehensive analysis of both the
Analysis of Alternatives and Socio-Economic Analysis parts of Diagnostica Stago’s
Application for Authorisation of Use-2, i.e:
- to provide a comprehensive understanding of the context of the AfA;
- to describe Diagnostica Stago’s initiatives of research for alternatives,
potential alternatives and substitution strategy;
- to provide a cost - effectiveness assessment of the application.
For the sake of clarity, it is reminded that this document is part of a broader AfA
as Diagnostica Stago’s application comprises two uses:
Use-1
Industrial use of 4-tert-OPnEO for its detergent properties in the process of cell lysing for the production of in vitro diagnostic reagents (Asserachrom® HPIA, Asserachrom® HPIA–IgG and Asserachrom® PF4 and STA®-Néoplastine® R15 assays).
Use-2 Industrial use of 4-tert-OPnEO in view of controlling the amount of non-specific reactions in the production of in vitro diagnostic reagents (STA® - Liatest® D-Di assays).
Table 1. Uses of the Application for Authorisation Nota: Use-1 is detailed in a separate document
Diagnostica Stago is a downstream user of 4-(1,1,3,3-Tetramethylbutyl)
phenol, ethoxylated (4-tert-OPnEO) as a detergent in the control of
nonspecific reactions in the production of in vitro diagnostic kits. Under Use-
2, the substance is used as a commercial solution (IGEPAL® CA-630) on site in
France for the production of STA® - Liatest® D-Di assays.
4-tert-OPnEO provides key properties production of Diagnostica Stago’s in
vitro diagnostic kits, for which no alternatives are yet to be identified,
developed, validated and industrialised.
It is used in the production of several products of Diagnostica Stago’s portfolio
that constitute the core of the company’s offer; a ban on its use would
generate significant in terms of loss of revenues and profits, as well as loss of
employment and significant external impacts on patients health and
healthcare systems.
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2.1. Stago Group
Created in 1945, in France under the name “Laboratoire Stago” as a
pharmaceutical laboratory, Stago is today the only independent international
company on the In Vitro Diagnostic industry fully dedicated to exploring hemostasis
and thrombosis. Stago’s mission is to provide biologists and clinicians with reliable and
effective diagnostic tools that help understand, treat and monitor hemostasis related
pathologies.
A unique catalogue of tests covers all types of exploration, from primary
hemostasis, fibrinolysis, thrombophilia, anticoagulant therapy follow-up, and
thrombin generation to the study of platelets.
Stago Group has almost 2,200 employees, over half of whom are based in France
and develops, produces and sells the widest range of reagents and Hemostasis test
instruments throughout the world. Every single minute, nearly one thousand tests are
performed worldwide on Stago systems.
Diagnostica Stago’s portfolio comprises over 350 products with a representation
in over 110 countries via its affiliates and an extensive distribution network.
2.2. Scope of the AfA
4-(1,1,3,3-Tetramethylbutyl)phenol, ethoxylated [covering well-defined
substances and UVCB substances, polymers and homologues], referred to as 4-tert-
OPnEO in the present document, is classified under REACh as a Substance of Very High
Concern due to Endocrine disrupting properties for the environment (according to Art.
57(f)) of its degradation product (1,1,3,3-tetramethylbutyl)phenol).
4-tert-OPnEO was part of ECHA’s fifth recommendation of 6 February 2014 for the
inclusion of substances in Annex XIV of REACh. Latest Application Date for its use is 4
July 2019; Sunset Date was set to 4 January 20211.
Under Use-2, Diagnostica Stago uses 4-tert-OPnEO for its detergent properties in
the production of in vitro diagnostic (IVD) reagents. 4-tert-OPnEO is used in the
commercial product, IGEPAL® CA-630, supplied by Sigma-Aldrich, to manufacture a
key product range in Stago’s portfolio: STA® - Liatest® D-Di assays.
The main properties sought-after with 4-tert-OPnEO under Use-2 include:
- Being a non-ionic surfactant,
- Having an HLB (Hydrophilic-Lipophilic Balance) value comprised between 13
and 15,
- Allowing for a substantial reduction of plasma turbidity (OD540nm < 0.35) with
plasma diluted to 1/6th with STA®- Owren-Koller buffer,
- Providing a similar level of analytical performances to that of IGEPAL® CA-630
(reactivity, specificity, stability within systems, long-term stability),
1 COMMISSION REGULATION (EU) 2017/999 of 13 June 2017 amending Annex XIV to Regulation (EC) No 1907/2006 of the European Parliament and of the Council concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH)
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- Providing a similar level of clinical performances (diagnostic) to that of the
current reagent.
Under Use-2, 4-tert-OPnEO is used at one site of Diagnostica Stago in Taverny, France.
2.2.1. Taverny
Figure 1. Taverny site
The site is located 23-29 rue Constantin Pecqueur at Taverny. It has been in
operation since 1999. The building surface is 8,995 sqm; it comprises administrative
functions, production areas and technical installations. Zones dedicated to the
fabrication, filling and freeze drying of products are ISO 8 (Class D) cleanroom areas.
The site of Taverny is an Installation Classified for the Protection of the Environment
under prefectoral authorization. It is therefore subject to the technical requirements
of the prefectural order (“Arrêté préfectoral”) of 12 October 2005 and its update of 24
April 2009. These requirements concern:
- prevention of water pollution
- prevention of air pollution
- waste management
- prevention of noise pollution
- prevention of risks related to the infrastructures and special installations
(refrigeration / compression installations, accumulation, combustion, acid /
soda storage).
Diagnostica Stago is ISO 9001:2015 certified; industrial activities of the site of Taverny
are ISO 14001:2015 certified as documented in Appendix.
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2.3. Elements of context
STA® - Liatest® D-Di assays that are concerned by Use-2 of the present application
for Authorization are used to test plasma D-Dimer level.
In what follows are detailed both the physiologic origin and clinical use of D-Dimer
assays.
2.3.1. General elements of hemostasis
Hemostasis is the body's normal physiological response for the prevention and
stopping of bleeding/haemorrhage. It results in the blocking of any vascular rupture.
Generally speaking, it helps ensure blood fluidity and blood vessel integrity.
Abnormalities in hemostasis can result in bleeding (haemorrhage) or blood clots
(thrombosis).
Hemostasis consists of:
- Primary Hemostasis: local vascular contraction (to reduce blood flow to the
injury site) and platelet plug formation
- Secondary Hemostasis: clotting of the plasma (secondary hemostasis),
involving interactions between numerous coagulation factors and inhibitors.
- Fibrinolysis: process for removing the clot once blood vessel integrity has
been restored.
Hemostasis is often characterised as a balance between coagulation (the process
by which blood forms clots) and fibrinolysis (the process by which blood clots are
dissolved). Pathologies may be associated with an imbalance between these two
processes.
When there is a rupture in a blood vessel, the first priority is to stop blood loss. The
main players in blood are the platelets and fibrinogen, which act to form a platelet
plug, as illustrated in Figure 2 below.
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Figure 2. Formation of the clot2. Bleeding at the site of the vascular injury is stopped by the formation of an extravascular
clot. An injury causes a transitory vasoconstriction of the small blood vessels reducing blood
flow. Platelets stick to the sub-endothelial tissue at the site of injury and finally they
aggregate together. Initiation of coagulation leads to the formation of fibrin, which helps
stabilize this clot and stop bleeding.
Following this first step, the formation of a clot stops any further bleeding. This
process consists of a series of chemical reactions involving various plasma
components. To date 10 major coagulation factors are known to be involved in this
process. These complex interactions lead to the transformation of fibrinogen to fibrin.
As part of the wound healing process, fibrinolysis dissolves the clot.
2 B. Boneu, J-P. Cazenave, Introduction à l'étude de l'hémostase et de la thrombose, 1997
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Figure 3. Synthetic coagulation process
2.3.2. Physiologic origin of D-Dimer
D-Dimer are the degradation product of fibrin, the final element of blood
coagulation, during the fibrinolysis process.
The specific degradation of fibrin (i.e., fibrinolysis) is the reactive mechanism
responding to the formation of fibrin3. Plasmin is the fibrinolytic enzyme derived from
the inactive plasminogen. Plasminogen is converted into plasmin by plasminogen
activators. The main plasminogen activators are the tissue plasminogen activator (tPA)
and the pro-urokinase which is activated into urokinase by, among others, the contact
system of coagulation4.
In the bloodstream, plasmin is rapidly and specifically neutralized by α2-antiplasmin
thereby restricting its fibrinogenolytic activity and localizing the fibrinolysis on the
3 Adam S.S., Key N.S., Greenberg C.S.: “D-dimer antigen: current concepts and future prospects”. Blood, 113, 13, 2009. 4 Bachmann., “Fibrinolysis” in “Thrombosis and Haemostasis”, Verstraete M., Vermylen J., Lijnen H.R., Arnout J., Leuven: International Society on Thrombosis and Haemostasis and Leuven University Press, 227-265, 1987.
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fibrin clot. On the fibrin clot, plasmin degrades fibrin into various products, called fibrin
degradation products. Plasmin can also act on fibrinogen, leading to the generation of
fibrinogen degradation products.
2.3.3. Clinical use of D-Dimer assays
The presence of fibrin degradation products, among which D-dimer is the terminal
product, is proof that the fibrinolytic system is in action in response to coagulation
activation.
D-Dimer levels notably increase in case of venous thromboembolism but can
increase in several other pathological or physiological condition such as trauma,
surgery, infections, cancer, disseminated intravascular coagulation (DIC), elderly and
pregnancy.
Venous thromboembolism (VTE)
Ž Venous thromboembolism is a common, lethal disorder that affects
hospitalized and non-hospitalized patients, recurs frequently, is often overlooked, and
results in long-term complications including chronic thromboembolic pulmonary
hypertension and the post-thrombotic syndrome5. Venous thromboembolism is the
third most common cardiovascular illness after acute coronary syndrome and stroke6.
Ž Venous thromboembolism is a disease that includes both deep vein
thrombosis and pulmonary embolism:
- Deep vein thrombosis (DVT)
DVT relates to the formation of a blood clot (thrombus) within a deep
vein, most commonly the legs. It is the most common disease of the
vascular system and up to one third of the patients experience a
pulmonary embolism, many of which are fatal7.
- Pulmonary embolism (PE)
PE is a dramatic and life-threatening complication of deep venous
thrombosis8. By occluding the pulmonary arterial bed, it may lead to acute
life-threatening but potentially reversible right ventricular failure9 with an
estimated annual incidence of 0.5–1.2 cases per 1000 individuals10. The
symptoms and signs of pulmonary embolism are nonspecific, making the
5 Ozaki, Bartholomew, Venous Thromboembolism (Deep Venous Thrombosis & Pulmonary Embolism), The Cleveland Clinic Foundation, December 2012 6 Goldhaber SZ: Pulmonary embolism thrombolysis: A clarion call for international collaboration. J Am Coll Cardiol 1992;19(2):246-247 7 Killewich et al Diagnosis of Deep Venous Thrombosis, Circulation Vol 79, No 4, April 1989 8 Kostadima, Zakynthinos - Pulmonary Embolism: Pathophysiology,Diagnosis, Treatment, Hellenic Journal of Cardiology 48: 94-107, 2007 9 Guidelines on the diagnosis and management of acute pulmonary embolism, European Heart Journal (2008) 29, 2276–2315 10 Mos IC, Douma RA, Erkens PM, Kruip MJ, Hovens MM, van Houten AA, et al. Diagnostic outcome management study in patients with clinically suspected recurrent acute pulmonary embolism with a structured algorithm. Thromb Res 2014; 133:1039–1044
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diagnosis highly challenging11. The consequences of a misdiagnosis can be
serious: a false-negative diagnosis is associated with an increased risk of
fatal outcome, whereas a false-positive diagnosis might lead to
unnecessary exposure to anticoagulant therapy12.
Venous thromboembolism (DVT and PE) has a mortality rate of 6 to 12 percent13.
D-dimer measurement is nowadays an unavoidable tool in the diagnosis strategy
for both DVT and PE.
When the likelihood of DVT is low or moderate (determined with a well-validated
prediction rule), a D-dimer level below a defined threshold can excludes safely VTE14:
no further workup is necessary in such cases, even in patients who have had a prior
VTE. D-dimer however cannot be used to diagnose VTE because of its low specificity,
due to the many other conditions that can arise d-dimer level (inflammation, cancer,
elderly…)1516.
Exclusion of VTE based on a negative d-dimer allows avoiding additional imaging
technics procedures (such as compression ultrasound for DVT and computed
tomography pulmonary angiography – CTPA - or ventilation-perfusion scan for PE).
Imaging techniques are usually expensive, not always available and are associated
with an extension of hospitalization stay.
Patients suspected of PE who escape exposure to imaging techniques avoid also
imaging techniques drawbacks and sides effects, such as the approximately 2%
probability of false-positive diagnosis and its associated risk of unnecessary
anticoagulation, radiation exposure, the 1% risk of immediate complication (such as
allergy) and the 15% probability of developing contrast-induced nephropathy.
Disseminated intravascular coagulation (DIC)
According to the subcommittee on DIC of the International Society on Thrombosis
and Hemostasis, “DIC is an acquired syndrome characterized by the intravascular
activation of coagulation with loss of localisation arising from different causes. It can
11 Hwang, Schulman, Respiratory review of 2013: pulmonary thromboembolism. Tuberc Respir Dis (Seoul) 2013; 75:89–94. 12 Pernod et al. Validation of STA-Liatest D-Di assay for exclusion of pulmonary embolism according to the latest Clinical and Laboratory Standard Institute/Food and Drug Administration guideline. Results of a multicenter management study, Blood Coagul Fibrinolysis. 2017 Apr; 28(3): 254–260. 13 Wilbur, Shian, Diagnosis of Deep Venous Thrombosis and Pulmonary Embolism, American Family Physician, Volume 86, Number 10, November 15, 2012 14 Wilbur, Shian, Diagnosis of Deep Venous Thrombosis and Pulmonary Embolism, American Family Physician, Volume 86, Number 10, November 15, 2012 15 Stein PD, Hull RD, Patel KC, et al. D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review. Ann Intern Med. 2004;140(8):589-602 16 Bounameaux H, de Moerloose P, Perrier A, Reber G. Plasma measurement of D-dimer as diagnostic aid in suspected venous thromboembolism: an overview. Thromb Haemost. 1994;71(1):1-6
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 17
originate from and cause damage to the microvasculature, which if sufficiently severe,
can produce organ dysfunction”17.
DIC corresponds to a multiple aetiologies process or syndrome (cancer, sepsis,
obstetrical complications, venomous snakebites, etc.) that includes, to variable
degrees:
- An abnormal coagulation activation with thrombin and fibrin formation
- A visceral intra-vascular fibrin deposition
- A consumption of coagulation factors (Factor V18) and cells (platelets)
- A secondary fibrinolysis
Epidemiologically, DIC is estimated to be present in as many as 1% of hospitalized
patients19.
DIC may occur in 30-50% of patients with sepsis with equal frequency in gram negative
and positive bacterial infections. In patients with severe trauma who have a systemic
inflammatory response syndrome, DIC can occur in 50-70% patients, particularly in
patients with neurotrauma. In obstetrical patients with abruptio placentae, septic
abortions and amniotic fluid embolism, DIC occurs in more than 50% patients. Cancer
patients with metastatic tumours have DIC in approximately 10-15% patients and it
occurs in 15% cases with acute leukaemia with highest frequency in acute
promyelocytic leukaemia)20.
Morbidity and mortality depend on the underlying disease and the severity of
coagulopathy. The mortality rates in different diseases complicated by DIC are21:
- Septic abortion with shock due to clostridial infection associated with severe
DIC has a mortality rate of 50%;
- In major trauma, the presence of DIC approximately doubles the mortality
rate;
- Idiopathic purpura fulminans associated with DIC has a mortality rate of 18%.
In DIC the fibrinolytic system is activated and therefore the D-dimer level increases. D-
dimer assays is crucial in the diagnosis of DIC, and in DIC patients’
17 Taylor Jr., Toh, Hoots, Wada, Levi - Scientific and Standardization Committee Communications: Towards a Definition, Clinical and Laboratory Criteria, and a Scoring System for Disseminated Intravascular Coagulation - Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis - 2011 18 Factor V is a protein of the coagulation system synthesised in the liver, that is able to bind to activated platelets and is activated by thrombin. 19 Matsuda T. Clinical aspects of DIC--disseminated intravascular coagulation. Pol J Pharmacol. 1996 Jan-Feb. 48(1):73-5 20 Furlong MA, Furlong BR. Disseminated Intravascular Coagulation. Jan 2007 21 Nair, Disseminated Intravascular Coagulation, Medicine Update Vol. 18, 2008
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management22,23,24,25. D-dimer is parts of all diagnosis scores that are used in practice
for DIC diagnosis. Three different guidelines are actually used, depending on local
practices. They have been issues by the following learning societies: International
Society of Thrombosis and Hemostasis (ISTH DIC score), Japanese Association of Acute
Medicine (JAAM score) and Japanese Ministry of Health and Welfare (JMHW DIC
score).
Activation States of Coagulation
The D-dimer level increases during the activation states of coagulation because
such states induce the increased production of thrombin which is followed by the
formation of fibrin and subsequently leads to enhanced fibrinolysis, the latter being
most frequently reactive.
Increased levels of D-dimer have been reported in the following cases:
inflammation, trauma, post-operative period, cancers, bleeding, severe infections26,27.
2.4. Products concerned
The use of 4-tert-OPnEO under Use-2 concerns a key family of products for
Diagnostica Stago’s portfolio: STA® - Liatest® D-Di product range.
2.4.1. STA® - Liatest® D-Di product range
STA® - Liatest® D-Di is a product range of immune-turbidimetric assays for the
quantitative determination of D-dimer in venous plasma, for use on STA-R®, STA
Compact® and STA Satellite® analyzers by professional laboratory personnel.
22 BAKHTIARI K., MEIJERS J.C.M., DE JONGE E., LEVI M.: “Prospective validation of the International Society of Thrombosis and Haemostasis scoring system for disseminated intravascular coagulation”. Crit. Care Med., 32, 12, 2004. 23 LEHMAN C.M., WILSON L.W., RODGERS G.M.: “Analytic Validation and Clinical Evaluation of the STA LIATEST Immunoturbidimetric D-Dimer Assay for the Diagnosis of Disseminated Intravascular Coagulation”. Am. J. Clin. Pathol., 122, 178-184, 2004. 24 ADAM S.S., KEY N.S., GREENBERG C.S.: “D-dimer antigen: current concepts and future prospects”. Blood, 113, 13, 2009. 25 BATES S.M.: “D-Dimer Assays in Diagnosis and Management of Thrombotic andBleeding Disorders”. Semin Thromb Hemost, 38, 673–682, 2012. 26 ADAM S.S., KEY N.S., GREENBERG C.S.: “D-dimer antigen: current concepts and future prospects”. Blood, 113, 13, 2009. 27 BATES S.M.: “D-Dimer Assays in Diagnosis and Management of Thrombotic andBleeding Disorders”. Semin Thromb Hemost, 38, 673–682, 2012.
Analysis of Alternatives – Socio-Economic Analysis
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Figure 4. Stago STA-R®
Figure 5. Stago STA COMPACT MAX® 2
Figure 6. Stago STA SATELLITE®
The STA® - Liatest® D-Di is intended for use in conjunction with a clinical pre-test
probability assessment model to exclude pulmonary embolism and as an aid in the
diagnostic of deep venous thrombosis in outpatients suspected of PE or DVT.
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A D-Dimer value that is lower than 500 ng/mL, determined using a method validated
in this indication, may be used to rule out the existence of DVT or of PE within the
previous week.
Figure 7. Interpretation of D-Dimer assay results
The power of the test may be improved if it is carried out after assessment of
clinical risk using a validated score suitable for the clinical setting (DVT or PE), such as
the Wells score. Use of such scores limits recourse to D-Dimer assay to situations
involving low or moderate clinical risk.
Medical imaging is routinely carried out as a first-line investigation where there is a
high clinical risk. For low or moderate clinical risk, a D-Dimer value below the exclusion
threshold is sufficient to rule out a diagnostic of DVT or PE within the preceding week.
However, due to the lack of specificity of high D-Dimer levels and to the low positive
predictive value (PPV) of the test, imaging must be carried out where the D-Dimer level
exceeds the exclusion threshold.
STA® -Liatest® D-Di has been the standard-of-care for quantitative, automated D-
Dimer assays in thousands of hospitals, medical centres and private laboratories for
more than 15 years with more than 2 million patient results reported worldwide.
STA®-Liatest® D-Di demonstrated best-in-class clinical specificity in the DiET (D-
Dimer for the Exclusion of Thromboembolism) study28. Higher specificity indicates
fewer false positive D-Dimer results and fewer unnecessary referrals for imaging
studies that may increase the cost of patient care, increase length of stay and increase
patient exposure to radiation and associated complications of imaging studies.
STA - Liatest® D-Di products concerned by Use-2 of the present application for
Authorisation are the following:
- STA® - Liatest® D-Di PLUS (ref. 00662)
- STA® - Liatest® D-Di (ref. 00968)
- TriniLIA D-Dimer II (ref. T3104)
28 5-year, multi-national, prospective management study, including pre-test probability assessment, objective imaging results and 3-month patient follow-up (US National Institutes of Health registration: NCT012218050). The study enrolled more than 2,000 outpatients with a suspicion of deep vein thrombosis (DVT) or pulmonary embolism (PE) in 16 sites in North America and Europe: United States (10), Canada (1), France (2), Italy (2) and Spain (2).
Patient D-Dimer level
≥500 ng/mL FEU(fibrinogen-equivalent units)
No diagnostic:
Pursue clinical investigation
<500 ng/mL FEU(fibrinogen-equivalent units)
Exclusion
of DVT / PE
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- STA® - Liatest® D-Di Chine (ref. 01071)
- STA® - Liatest® D-Di (ref. 00515 / 00515US)
Key characteristics of STA® - Liatest® D-Di (ref. 00515) include:
DVT PE
NEGATIVE PREDICTIVE VALUE 100% 99.7%
SENSITIVITY 100% 97.0%
SPECIFICITY 55.2% 75.5%
Table 2. Negative predictive value29, sensitivity and specificity of STA® - Liatest® D-Di (ref.00515) for DVT exclusion and PE exclusion
Other performance characteristics of STA® - Liatest® D-Di include:
- Limit of Detection
The limit of detection was assessed according to CLSI guideline EP17-A30. The limit of
detection on STA-R®, STA Compact® and STA Satellite® is 0.27 μg/ml (FEU).
- Assay Working Range
The assay working range is 0.27 - 4.00 μg/ml (FEU). However, in case of use of the
procedure with automatic dilution of the sample the corrected assay range is, in effect,
up to 20 μg/ml (FEU). If the procedure without sample dilution is used, the assay range
is 0.27 - 4.00 μg/ml.
- Dose-Hook Effect
No dose-hook effect has been observed. The D-dimer levels of all tested plasmas
containing D-dimer levels as high as 500 μg/ml (FEU) were found above the upper limit
of the assay working range of 4 μg/ml (i.e., > 20 μg/ml due to dilution).
- Analytical Specificity
The STA® - Liatest® D-Di is insensitive to fibrinogen and E fragment. A cross-reactivity
is observed with the D fragment. However, this has no effect because in in vivo
physiological conditions, the presence of α2-antiplasmin precludes the production of
FDP-D from fibrinogen.
- Precision
Precision studies were performed according to CLSI guideline EP05-A231 (20 days, 2
runs per day) on STA-R®. The following results have been obtained:
29 Proportions of negative results in statistics and diagnostic tests that are true negative results. Describes the performance of a diagnostic test or other statistical measure: a high result can be interpreted as indicating the accuracy of such a statistic. 30 CLSI Document EP17-A: “Protocols for determination of limits of detection and limits of quantitation; approved guideline”. First Edition, 24, 34, 2004. 31 CLSI Document EP05-A2: “Evaluation of precision performance of quantitative measurement methods; approved guideline”. Second Edition, 24, 25, 2004.
Analysis of Alternatives – Socio-Economic Analysis
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SAMPLE X̄
μg/ml
REPEATIBILITY BETWEEN-
RUN PRECISION
WITHIN-DAY
PRECISION
BETWEEN-DAY
PRECISION
WITHIN-LABORATORY
PRECISION
SD
μg/ml
CV
%
SD
μg/ml
CV
%
SD
μg/ml
CV
%
SD
μg/ml
CV
%
SD
μg/ml
CV
%
1 0.67 0.042 6.3 0.024 3.6 0.029 4.3 0.010 1.4 0.049 7.4
2 2.20 0.049 2.2 0.070 3.2 0.030 1.3 0.000 0.0 0.085 3.9
Table 3. Precision of STA® Liatest® D-Di SD = Standard Deviation; CV = coefficient of variation
STA® - Liatest® D-Di assays allow to reduce medical imaging in the diagnostic,
as it allows to identify situations involving low or moderate clinical risk that do
not require such investigation.
Being considered as routine tests, these assays constitute the backbone of
Stago’s portfolio.
2.5. Supply chain
The supply chain of Diagnostica Stago’s IVD devices can be described as follows:
SIGMA-ALDRICH Supplier of IGEPAL® CA-630
DIAGNOSTICA STAGO Downstream user of 4-tert-OPnEO
ANALYTICAL LABORATORIES End Users
Table 4. Supply chain of Diagnostica Stago’s IVD devices
As per Art. 56(3) of REACh, and according to the definition of SR&D activities
provided in ECHA’s guidance32, end-user analytical activities (use of kits) performed by
laboratories and hospitals are exempted from Authorisation.
Nevertheless, through this AfA, Stago wishes to cover the entire life cycle of the
substance, including thus downstream users’ activities linked to the use of Stago’ kits
containing the substance. In this purpose, quantities of substance contained in the kits
and supplied to end-users and their conditions of use are described in the Chemical
Safety Report, while substance function in the final kit is specified in the section 3.1.
These elements thus tend to justify the application of the SR&D exemption through
the demonstration of the implementation of controlled operating conditions, as well
as the importance of using 4-tert-OPnEO for the efficiency and the good realization of
the IVD test.
32 ECHA, Guidance on Scientific Research and Development (SR&D) and Product and Process Orientated Research and Development (PPORD), Version 2.0, November 2014
Analysis of Alternatives – Socio-Economic Analysis
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2.6. Elements of context
2.6.1. General production process
The general production process of IVD reagents concerned by the application for
Authorisation is synthetized as follows:
Figure 8. General production process
In addition to production operations, several industrial steps are required for
conditioning and validating the quality of the products. A large volume of facilities and
human resources is therefore conditioned to the production of reagents for IVD kits
of Use-2.
2.6.2. Market
Several competitors offer D-Dimer dosage solutions, as illustrated below:
Reagents Manufacturing
Quality Control
Filling
Capping and Labelling
Quarantine
Packaging
ASSAY NAME MANUFACTURER METHODOLOGY MANUFACTURER
CUT-OFF
FDA APPROVAL / CLEARANCE FOR VTE
EVALUATION
Advanced D-Dimer Dade Behring Diagnostics Quantitative, latex enhanced immunoturbidimetric
immunoassay Instrument dependent
Aid in diagnostic
AQT90 FLEX D-dimer Radiometer Medical ApS Quantitative, time-resolved fluorometry 500 mg/L NA
Auto Blue 400 Auto Red 700 D-Dimer
Helena Biosciences Latex enhanced immunoturbidimetric immunoassay 200 ng/mL NA
Diazyme D-Dimer Assay Diazyme Laboratories Latex enhanced immunoturbidimetric immunoassay < 0.5μg/mL Aid in diagnostic
HemosIL AcuStar D-Dimer Instrumentation Laboratory Emzyme immunoassay, chemiluminescence 500 ng/mL Exclusion
HemosIL D-Dimer HS Instrumentation Laboratory Latex enhanced immunoturbidimetric immunoassay 243 ng/mL Exclusion
INNOVANCE D-Dimer Siemens AG Quantitative, latex enhanced 500 ng/mL Exclusion
MDAW D-Dimer bioMerieux SA Quantitative, latex enhanced NA Aid in diagnostic
Nordic Red D-dimer Nordic Biomarker AB Quantitative, latex enhanced immunoturbidimetric
immunoassay 200 ng/mL NA
Nordic Blue D-dimer Nordic Biomarker AB Quantitative, latex enhanced immunoturbidimetric
immunoassay 200 ng/mL NA
STA® - Liatest® D-Di Diagnostica Stago, Inc. Quantitative, latex enhanced immunoturbidimetric
immunoassay < 0.5μg/mL Exclusion
Tina-quant D-Dimer BM F. Hoffman-La Roche Ltd. Quantitative, latex-enhanced immunoturbidimetric
immunoassay < 0.5μg/mL Exclusion
TriniLIA D-Dimer Tcoag Ireland Ltd. Polystyrene microparticle agglutination assay NA NA
VIDAS D-Dimer bioMerieux SA Quantitative, ELISA, sandwich type 500 ng/mL Exclusion
Table 5. Selected Central Laboratory D-Dimer Assays33
33 Roger et al., Widely Used Types and Clinical Applications of D-Dimer Assay, Laboratory Medicine 47:2:90-102
Analysis of Alternatives – Socio-Economic Analysis
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These solutions cannot, however be considered as direct substitutes to STA® -
Liatest® D-Di, as:
- They offer diverse levels of methods and sensitivity;
- They require dedicated detection equipment and cannot be directly used on
Stago’s automated equipment;
- Given Stago’s market share for these assays, it is very unlikely that one actor
will be able to upscale its production so as to cover Stago’s uses, as the
production of antibodies requires a significant period of time (approx. 18
months).
These elements are further detailed in section 5 of the present document.
2.7. General methodology
Endocrine disrupting properties of 4-tert-OPnEO degradation product make it
difficult to derive a dose-response relationship that would quantitatively link
substance release and environmental impacts.
In these conditions, ECHA identified three elements required in order to conclude
that the benefits of continued use outweigh the risk34. These elements, along with a
comment regarding where they have been developed in the present document as
follows, are:
ELEMENT COMMENT
Monetised estimate of the benefits of continued use
Monetised costs as well as qualitative
impacts of the “non-use” scenario are
detailed in section 5.
Quantified release estimates accompanied with a
qualitative description of where the releases occur
Release estimates are detailed in the
Chemical Safety Report; a detailed
description of the potentially receiving
medium is provided in section 3.6.1
Qualitative description of the potential impacts
A qualitative description of the
potential impacts is detailed in section
3.6/2
Table 6. Elements of demonstration that the benefits of continued use outweigh the risk
In addition to these elements and by analogy with ECHA’s approach regarding the
evaluation of restriction reports and applications for authorisation for PBT and vPvB
substances35, a cost-effectiveness analysis will be provided.
Cost-effectiveness analysis (CEA) as a decision supporting methodology aims at
determining the most (economically) efficient way to achieve a regulatory objective.
34 ECHA, SEA-related considerations in applications for authorisation for endocrine disrupting substances for the environment, specifically OPnEO and NPnEO (SEAC/37/2017/03), Helsinki, 30 November 2017 35 ECHA, Evaluation of restriction reports and applications for authorisation for PBT and vPvB substances in SEAC, 2016
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In the context of an application for Authorisation under REACh, and since there are
great difficulties to characterise the relationship between volume of effluents and
environmental impacts, it will be assessed:
- Costs per reduced unit emission, i.e 𝐶𝑜𝑠𝑡𝑠 (€)
𝑘𝑔 𝑒𝑚𝑖𝑠𝑠𝑖𝑜𝑛 𝑎𝑣𝑜𝑖𝑑𝑒𝑑
- Costs per reduced unit consumption, i.e 𝐶𝑜𝑠𝑡𝑠 (€)
𝑘𝑔 𝑒𝑚𝑖𝑠𝑠𝑖𝑜𝑛 𝑎𝑣𝑜𝑖𝑑𝑒𝑑
Costs per reduced unit emission will be used as a primary cost-effectiveness
characterisation ratio; costs per unit consumption will also be calculated as a
sensitivity analysis in view of providing a broader perspective regarding the overall
potential impacts of the application.
2.7.1. Scope of the AfA
Key elements of the scope of the AfA are provided in Table 7 below:
SCOPE COMMENT
Temporal
boundary
Twelve years post-sunset date: 2021 – 2033. See table below for a
description of the triggering period for each impact.
Geographic
boundaries
Direct impacts concern France.
Indirect impacts for Diagnostica Stago’s supply chain customers cover
a worldwide scope.
Economic
boundaries
Direct economic impacts for Stago (loss of profits)
Indirect impacts for Stago’s value chain (end-users)
Table 7. Scope of the AfA
Impact periods for these two scenarios are as follows:
CATEGORY IMPACT IMPACT PERIOD
Economic
impacts
Direct impacts: loss of profits 12 years
Indirect impacts: loss of markets Variable: 3 to 10 years depending on
the frequency of tenders
Social
impacts
Impacts on employment 2 years
Medical impacts Several months to years depending
on medical and market situations
Wider
economic
impacts
Negative impacts related to market
disruption
Several months to years depending
on market situations
Opportunities for competitors Several months to years depending
on market situations
Table 8. Impact periods for the two product ranges of Use-2
Analysis of Alternatives – Socio-Economic Analysis
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2.7.2. Actualisation
All final monetised results of this document are expressed in present value (PV).
2.7.2.1. Discounting
Comparing costs and benefits during different periods of time to present values
requires the use of discounting technique to translate future costs and benefits into
present-days values to account for the time value of money
The choice of discount rate is important since it can affect the cost-benefit results of
the analysis. The higher the discount rate is the lower the future benefits and costs
values will be, as compared to present values.
In our methodology, we deliberately chose to use two different discount rates
depending on the type of future impacts evaluated.
Thus, future human health costs described in the “applied for use” scenario of this
dossier will be evaluated using a lower discount rate that the one used to consider
economic impacts in the “non-use” scenario. This difference is related to the different
“nature” of these impacts and aims to reflect the society’s rate of time preference with
respect to health risks.
As per ECHA’s guidelines, the calculation of discounted values is performed on an
annualised basis, with the following formula:
𝑃𝑉 = ∑ 𝐹𝑛(1 + 𝑟)−𝑛
𝑛=𝑡
𝑛=1
= 𝐹1
(1 + 𝑟)+
𝐹2
(1 + 𝑟)2+ ⋯ +
𝐹𝑡
(1 + 𝑟)𝑡
Considering:
- 𝑃𝑉 = present value
- 𝐹𝑛 = future costs at year 𝑛
- 𝑟 = annual discount rate
- 𝑡 = last annuity of the discount period
Based on ECHA’s recommendation36, a 4% discounting rate is used to assess the
future cost/benefits values for impacts not related to health matters.
2.8. Substitution strategy
A significant work of research for the substitution of IGEPAL® CA-630 in the
production process of STA® - Liatest® D-Di assays led to identify one potential
alternative: Brij L9.
This alternative, however, has yet to be further investigated, implemented and
qualified and will therefore not be available before the sunset date of 4-tert-OPnEO.
36 ECHA, Guidance on the preparation of socio-economic analysis as part of an application for
Authorisation, 2011
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Use-2 Diagnostica Stago 28
2.9. Presentation of the “applied for use” and “non-
use” scenarios
2.9.1. “Applied for use” scenario
Under the “applied for use” scenario, Stago will pursue the use of 4-tert-OPnEO
in the production of products concerned by Use-2 during the period of time necessary
to develop, implement and validate an alternative process, thereby securing both its
activity and the supply of IVD tests to laboratories and hospitals.
Environmental risks and impacts of the “applied for use” scenario are respectively
detailed in section 3.4.
2.9.2. “Non-use” scenario
The most likely “non-use” scenario for Use-2 is following: with the ban on the use
of 4-tert-OPnEO, Stago will have to cease the production of STA - Liatest® D-Di assays.
Among the arguments that make it impossible to consider an alternative “non-use”
scenario (performance degradation, relocation or sub-contracting outside the
European Union) are the intrinsic characteristics of the production process of STA® -
Liatest® D-Di, that:
- requires an extremely high level of know-how and a major human factor
- follows a complex qualification process for raw materials
- presents difficulties in the sourcing of antibodies, due to the very high
level of quality requirements
- requires an extremely low level of batch-to-batch variability.
Given these specificities on the production processes of D-Di parameters and
the strategic place of products of Use-2 products without which Stago cannot
participate to call of tenders, the cease of production of STA-Liatest® D-Di assays is
likely to bring about the definitive cease of the Stago’s activity.
A comprehensive description of these elements is provided in the following section.
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 29
3. “APPLIED FOR USE” SCENARIO
3.1. Analysis of substance function
IGEPAL® CA-630 is a non-ionic surfactant with detergent properties. Its
substitution in the context of the production of STA® - Liatest® D-Di assays has to take
into consideration: possess physico-chemical properties that allow for the same or
better analytical and clinical performances compared to that of the IGEPAL® CA-630
as well as present a lower level of risk for human health and the environment.
3.1.1. Functional properties
So as to play its role within the production process of STA® - Liatest® D-Di assays,
potential alternatives need to possess the following properties:
- Be a non-ionic surfactant, and therefore with limited sensitivity to both pH and
the ionic strength of the environment. This characteristic is necessary to
eliminate issues related to the proteins denaturation in the absence of
electrostatic interactions between proteins and ionic surfactants.
- Present an HLB (Hydrophilic-Lipophilic Balance) comprised between 13
and 15. HLB, the proportion between the weight percentages of hydrophilic
head and the lipophilic tail in a surfactant molecule is an indication of the
behaviour that may be expected from a surfactant. An emulsifier that is
lipophilic in character is assigned a low HLB number and an emulsifier that is
hydrophilic in character is assigned a high number. The midpoint is
approximately ten and the assigned values have ranged from one to forty37.
- Allow to significantly reduce plasma turbidity (OD540nm < 0.35 using plasma
diluted to 1/6th with STA®- Owren- Koller buffer) and maintain it constant
over time. OD540nm stands for Optical Density for a 540 nm of wavelength.
In spectroscopy, the optical density (also called absorbance) of a material is a
logarithmic ratio of the radiation falling upon a material, to the radiation
transmitted through a material.
37 Gadhave, Determination of Hydrophilic-Lipophilic Balance Value, International Journal of Science and Research, Volume 3 Issue 4, April 2014
Under Use-2, Stago use 4-tert-OPnEO as a detergent in the manufacture of
reagents for in vitro diagnostic haemostasis assays.
The main functional properties sough-after by Stago with 4-tert-OPnEO
include: non-ionic surfactant properties, defined HLB (Hydrophilic-Lipophilic
Balance) value, reduction of plasma turbidity and similar level of analytical
and clinical performances to that obtained with IGEPAL® CA-630.
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Use-2 Diagnostica Stago 30
3.1.2. Analytical performances
STA® - Liatest® D-Di assays are conducted in automatic instruments such as
illustrated on Figure 9 below:
Figure 9. STA R Max®
In this context, specifications regarding analytical performances have been
established for the validation of a potential alternative so as to ensure its compatibility
with Stago analysis instruments.
These include:
- Provide the same mean reactivity ratio than that obtained with IGEPAL® CA-
630
- Guarantee a stability of reagents within instruments of 15 days with reducers
- Long-term stability (shelf-life) of (#2a) at temperatures of 2 to 8°C
- Ensuring a pH value for D-Dimer reagents buffers of (#2b)
3.1.3. Clinical performances
So as to be validated, diagnostic reagents produced with the potential alternative
have, in fine, to provide the same diagnosis than those currently produced with
IGEPAL® CA-630 when tested against plasma from actual patients.
The clinical performance framework of reference for STA® - Liatest® D-Di (ref.
00515) assays has been established in the DIET (D-Dimer for the Exclusion of
Thromboembolism) study. The DIET 5-year study was conducted on a multi-national
scale to demonstrate the reliable performance of STA® - Liatest® D-Di assays in the
exclusion of pulmonary embolism and deep vein thrombosis.
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 31
The results obtained are provided in what follows:
Pulmonary embolism
DIET study results, out of 1,130 plasmas studied:
1,130 plasmas analysed
MEDICAL IMAGING
(reference method)
Positive Negative Total
D-DIMER
(positive if
[D-Di] > 0.50 µg/ml)
Positive 98 252 350
Negative 3 777 780
Total 101 1,029 1,130
Table 9. DIET study raw results - pulmonary embolism
Associated characterisation results are the following:
2 RESULTS
SENSITIVITY 97.0%
(91.6-99.4%)
SPECIFICITY 75.5%
(72.8-78.1%)
NEGATIVE PREDICTED VALUE 99.7%
(99.2-100.0%)
POSITIVE PREDICTE VALUER 25.5%
(23.5-27.7%)
Table 10. Sensitivity, specificity, negative & positive predicted values for STA® - Liatest® D-Di (ref. 00515) assays in the exclusion of pulmonary embolism
Deep vein thrombosis
DIET study results, out of 980 plasmas studied:
980 plasmas analysed
MEDICAL IMAGING
(reference method)
Positive Negative Total
D-DIMER
(positive if
[D-Di] > 0.50 µg/ml)
Positive 85 401 486
Negative 0 494 494
Total 85 895 980
Table 11. DIET study raw results - deep vein thrombosis
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 32
Associated characterisation results are the following:
2 RESULTS
SENSITIVITY 100.0%
(95.8-100.0%)
SPECIFICITY 55.2%
(51.9-58.5%)
NEGATIVE PREDICTED VALUE 100.0%
(99.3-100.0%)
POSITIVE PREDICTE VALUE 17.5%
(14.2-21.2%)
Table 12. Sensitivity, specificity, negative & positive predicted values for STA® - Liatest® D-Di (ref. 00515) assays in the exclusion of deep vein thrombosis
3.1.4. Risks for human health and the environment
To be valid, a potential alternative has to present a lower level of risk for human
health and the environment than that of IGEPAL® CA-630. Candidate alternatives have
not to be classified as a SVHC under the REACh regulation.
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 33
3.2. Market and business trends
3.2.1. Use of 4-tert-OPnEO
The quantity of 4-tert-OPnEO used under Use-2 is provided in Table 13. below:
litres 2014 2015 2016 2017* 2018* 2019* 2020*
IGEPAL® CA-630 7.168 8.598 8.870 8.365 8.616 8.875 9.415
Table 13. Consumption of IGEPAL® CA-630 over the 2014-2016 period under Use-2, in litres. * = Forecasts @ 3% annual growth
The average 4-tert-OPnEO consumption over the 2014 – 2016 period is 8.212
litres. This consumption, assuming a density of 1,056 and a 100% concentration of
IGEPAL® CA-630 corresponds to 8.67 Kg.
3.3. Human health impacts of the “applied for use”
scenario
4-tert-OPnEO was included on Annex XIV of REACh for the impacts on the
environment of its degradation products; as a consequence, impacts on human health
are excluded of the context of the present application.
3.4. Impacts on the environment and monetised
damage of the “applied for use” scenario
3.4.1. Environmental impacts and monetised damage
A direct causal link between exposures to 4-tert-OPnEO and impacts on the
environment is difficult to establish in a robust manner, especially in the case of the
present application for Authorisation where substance releases are already reduced
to a minimum (near zero).
However, and in view of providing a better understanding of the situation, several
elements of context will be provided in what follows, that pertain to:
- The environmental context of the impacts – hydrographical situation
around Stago’ sites and characterisation of the receiving medium
- Elements of qualitative environmental impact characterisation – use
and non-use value
3.4.2. Environmental context of the impacts
Water courses nearby the site of Taverny are identified on the map below:
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 34
Figure 10. Water courses nearby the Taverny site38
The total annual wastewater discharges for the site of Taverny are estimated to
30,000 m3/yr. Wastewater discharges from the site of Taverny are treated in Achères’
municipal water treatment plan.
These sites are located in an industrial area and do not comprise protected
species.
Surrounding remarkable natural environment include39:
- The Montmorency forest
- The Montubois valley
- The Bessancourt sablonnière (sandy area)
The industrial zone, upon which Diagnostica Stago’ sites are located, is not in a
flood zone.
The closest river stream, the Seine, is located at around 5.5 km north and 4.5 km
west from the site. The Seine is the second largest navigated river in Europe. It is
navigable by larger vessels and comprises several commercial ports and activity zones.
According to the Seine Normandie water agency, the water quality as Andrésy (the
location where the water from the Oise River meets the Seine River) is characterised
as “hors classe” (out of category), despite of significant water pollution. Parameters
considered in the assessment are: dissolved O2, O2 saturation percentage, COD
(chemical oxygen demand), BOD5 (biological oxygen demand during 5 days of
incubation) and ammonium content.
38 https://www.geoportail.gouv.fr/ 39 Source : Inventaire National du Patrimoine Naturel – National Inventoru of the Natural Heritage - inpn.mnhn.fr
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 35
A regular wastewater and rain waters monitoring is performed following technical
recommendations of the prefectoral decree related to facilities classified for
environmental protection.
The Seine Normandie Water Agency (Agence de l’Eau Seine Normandie) publishes
monitoring data for the control of water quality of the Seine River. Octylphenol results
in the city of Poissy (downstream from Stago’s facilities) are the following for the years
2016 and 2017:
YEAR NUMBER OF
SAMPLES ANALYSED RESULTS
2016 36 All samples below quantification limit
2017 16
Table 14. Seine River water quality analysis results for octylphenol40
On a broader scope, the Seine River water quality is qualified as “Correct” for all
of the 878 parameters tested each year.
Groundwater quality, on the other hand, is characterised as “Mediocre” but no
detailed information on the presence of 4-tert-OPnEO has been found in various
sampling sites nearby Stago’s facilities.
In the context of the Water Framework Directive, water quality is managed in
France at the catchment area (basin) level. The relevant catchment area for Stago’s
facilities is the “bassin Seine-Normandie” (Seine-Normandie basin/catchment area):
40 Qualit’eau, Agence de l’eau Seine Normandie, http://qualiteau.eau-seine-normandie.fr/
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 36
Figure 11. Delimitation of the Seine-Normandie catchment area41
Catchment area; Stago facilities
Key figures for the Seine-Normandie catchment area include:
Catchment area surface 94,500 km2
Population 18.3 million inhabitants
Typology of territories
- Agricultural area 63.8%
- Forests 25.3%
- Artificial surface 9.5%
- Water surface 1.4%
Water courses linear distance 55,000 km
Seafront 640 km
Table 15. Seine-Normandie catchment area key figures
Water quality (considering biological, physico-chemical and specific pollutants
criteria) for the Seine-Normandie catchment area is characterised as follows:
41 Eau Seine Normandie, Etat des lieux du bassin de la Seine et des cours d’eau côtiers normands, Decembre 2013
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 37
Table 16. Water quality for the Seine-Normandie catchment area, 201342
The state of groundwater for the Seine-Normandie catchment area is the following:
Table 17. Groundwater state for the Seine-Normandie catchment area
The issue of octylphenol at the scale of the Seine-Normandie catchment area is
characterised as follows43:
- Octylphenol is a priority in the context of the Water Framework Directive;
- Octylphenol tonnages released in the basin are estimated at 10 to 100 kg/yr;
- Its global pressure indicator (that characterises the pressure exerted by
industrial and urban releases considering the intrinsic toxicological properties
of substances) is set to 4 (on a scale of 1 to 5, with five being the higher-
pressure indicator level)
42 Eau Seine Normandie, Etat des lieux du bassin de la Seine et des cours d’eau côtiers normands, Decembre 2013 43 Eau Seine Normandie, Etat des lieux du bassin de la Seine et des cours d’eau côtiers normands, Decembre 2013
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 38
Coastal water chemical quality is characterised as follows:
Table 18. Seine-Normandie catchment area coastal water chemical quality
It has to be noted that the downgrade of water quality status (from good to bad state)
is, for three of the 26 coastal water bodies concerned, due to threshold overrunning
for 4-tert-OPnEO as identified below:
Figure 12. Chemical state of coastal water bodies for the Seine-Normandie catchment area
Coastal water bodies quality downgrade due to 4-tert-OPnEO threshold overrun
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 39
Water quality for the hydrographical unit upon which Stago’s facilities are located
can be characterised as follows44:
- General map of the IF.3 hydrographical unit:
Figure 13. IF.3 hydrographical unit
Stago facilities
- Ecological state:
Figure 14. Ecological state of the IF.3 hydrographical unit
44 Eau Seine Normandie, Le SDAGE 2016 – 2021, Programme de mesures du bassin de la Seine et des cours d’eau côtiers normands, 18 novembre 2015
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 40
- Quality of groundwater:
Figure 15. Groundwater quality for the IF.3 hydrographical unit
- Good; - Mediocre- Stago facilities
The stago’ sites are localised in the good area.
3.4.3. Environment impacts and monetised damage
3.4.3.1. General assessment framework
A spectrum of potential benefits of protected areas has been proposed by Pinfold
that is structured as follows:
Figure 16. Spectrum of potential benefits of protected areas45,46
In this framework,
- Direct use refers to benefits derived from goods and services provided by
the Protected Area: this might include hunting, forest products, fishing,
as well as agriculture and industrial uses;
45 Socio-Economic Analysis for the Protected Areas Strategy, Gardner Pinfold Consulting Economists Limited - July, 2000 46 EVRI (2009) in Nimmo-Bell (2009) Biodiversity Valuation Manual. A technical manual for MAF
BNZ.
Potential benefits
Directuse
Indirectuse
Optionvalues
USEVALUES
NON-USEVALUES
Existencevalues
Bequestvalues
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 41
- Indirect use refers to functional benefits such as ecosystem services
(nutrient cycles, carbon storage & sequestration), and commercial
navigation;
- Option value is the value society places on having a good quality
freshwater available for possible future uses (recreation, scenic,
property), as opposed to current uses;
- Bequest value is the value attached to the ability to bequeath the
Protected Area to future generations; which includes species, habitats as
well as spiritual and cultural values;
- Existence value refers to the value society places on having the
freshwater areas whether or not people ever use the area for any human
activity; this includes aesthetic values or educational / scientific
information.
In what follows, it is proposed to base the analysis of the ecosystemic value of the
receiving environment (aquatic compartment) on this categorisation.
General freshwater services can be summarised as follows:
CATCHMENT SERVICE DESCRIPTION
Water quality
improvement
Bioremediation, such as reducing phosphorus and nitrogen through
biological processing
Biodiversity maintenance Provide habitat for indigenous flora and fauna
Erosion control Vegetation cover preventing soil erosion
Water supply Supply water for industrial and agricultural usage
Recreational opportunity Offer places for human enjoyment
due to the natural and artificial scenes
Raw material supply Supply fish for human and produce plants for livestock
Existence value Maintain wetlands for future generations
Table 19. Potential freshwater services in a catchment
Of these services, impacts of a potential release of 4-tert-OPnEO may concern
both biodiversity maintenance and raw material supply due to its endocrine properties
for the environment. Data put forward in what follows aim at characterising the scope
and the extent of such impacts in the context of Stago’s production site.
Direct use
The main direct use value of aquatic environment potentially impacted by Stago’s
use of 4-tert-OPnEO in the context of the application for Authorisation seems to be
related to fishing.
Direct impacts on commercial fishing appear extremely limited, given that the closest
fishery identified (Pisciculture de la Villette - 3 Rue de Rosay, 78930 Villette) is located
at around 50km from the Stago site. In addition, this fishery is not directly linked to
the seine river.
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 42
Elements of context for the direct impacts on recreational fishing can be provided as
follows:
- The main fish species found in Île-de-France river include47: wels catfish (Siluris
Glanis), Large-mouth bass (Micropterus salmoides), pike (Esox lucius), roach
(Rutilus rutilus), pike perch (Stizostedion lucioperca), carp (Cyprinus carpo),
common rudd (Scardinius erythrophtalmus), tench (Tinca tinca), perch (Perca
fluviatilis)
- A detailed inventory of fish species in the Seine River is provided in the table
below, for the counting campaigns of 2009 to 2016:
POPULATION, PER COUNTING YEAR
FISH SPECIES 2009 2010 2011 2012 2013 2014 2015 2016
Bleak 17 7 56 352 233 183 397 174
Flower barbeau 1 6 12 12 49 24 2
Black bass 2
Bouvière 6 3 4 2 3
Bremen sp. 11 2 4 19 6 3 4
Pike 2 2
Chabot 170 93 330 226 235 270 213 18
Chub 31 141 207 300 155 214 169 160
Roach 27 248 656 136 32 996 89 15
Stud 12 16 32 28 29 123 38 11
Ruffe 30
Hotu 1 35 1 5 123 80
Ide melanote 1
Loche franche 2
Common Perch 76 37 88 30 75 11 73 13
Sun Perch 18 5 1
Rudd 51 32 19 32 21 8 12 1
Sandre 2 1 1 3
Catfish 4 3 1
Catfish 1 1
Tench 1
Minnow 1
Vandoise 1 16 1 3 5 14
47 Fédération Interdépartementale de Pêche 75 92 93 94 – Interdepartmental Fishing Association 75 92 93 94
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 43
Figure 17. Fish population species in the Seine River48
- Most of fishing spots in the Île-de-France region are located upstream from
the Stago facilitiy49
- Water quality of the Seine river has been significantly improving over the last
decades. As an illustration, 32 fish species have been identified during the
latest fish counting study whereas the same study, carried out in 1990 only
identified 14 different fish species50.
- The Île-de-France recreational fishing federation51 brings together around
7,000 fishing enthusiasts that are members of 16 associations fishing
associations (AAPPMA52).
- Fishing in the Île-de-France region is subject to the possession of a fishing
permit that costs € 75 for an adult person and is valid for one year.
- Key figures of recreational fishing in France in 201653 include:
→ 1,527,490 fishermen
→ 1,032,731 holders of a fishing card
→ 3,700 certified fishing associations
→ 1,000 employees
→ 40,000 volunteers (3,500 full-time equivalent)
Economical elements regarding the fishing situation in the Seine River are scarce
but global data can be provided:
- The global economic impact of the recreational fishing in France is estimated
to € 2B:
IMPACT DESCRIPTION VALUE
Direct impact Fishing material, boating, memberships, aquaculture,
fish-farming € 790M
Indirect impact All suppliers of fishing activities € 340M
Induced impact Expenditures related to salaries employees of direct
and indirect fishing activities € 510M
48 opendata.hauts-de-seine.fr 49 Fédération Interdépartementale de Pêche 75 92 93 94 – Interdepartmental Fishing Association 75 92 93 94 50 La pêche et les poissons, 32 espèces de poissons dans la seine en idf - https://www.peche-poissons.com/news/32-espces-de-poissons-dans-la-seine-en-idf 51 Fédération de Paris, Hauts-de-Seine, Seine-Saint-Denis, Val-de-Marne pour la pêche et la protection du milieu aquatique 52 Associations Agréées de Pêche et de Protection du Milieu Aquatique - Certified associations for fishing and protection of aquatic environments 53 Fédération Nationale De La Pêche En France, Rapport annuel d’activité 2016
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 44
Catalytic impact Economic activity related to other expenditures € 390M
Table 20. Detail of the global economic impact of recreational fishing in France54
- On average, fishing expenditures amount to € 681 per year per fisherman:
Figure 18. Detail of fishing expenditures, in € (2014), per year and per fisherman55
- A study of the economic impact of the black bass fishing in France has been
carried out in 2016 by the Black Bass France fishing association56. According to
this study, the cumulated expenses related to black bass fishing in France
amount to € 4,838 per fisherman per year. This amount comprises gear &
equipment, boat and boat accessories as well as services expenses. The
representativeness of this value for the situation of the present application for
Authorisation is relatively low, as a very low proportion of black bass fishers
(<1%) has been identified in the Île-de-France region.
- The freshwater recreational fishermen population for the Seine-Normandie
catchment area is estimated to 330,000 individuals (2011); expenditures
associated with fishing activities are estimated to € 94M (2011)57.
- The socio-economic situation for water-related activities in the Seine-
Normandie catchment area is the following:
54 Fédération Nationale De La Pêche En France, Rapport annuel d’activité 2016 55 Synthèse des résultats de l’étude “Impacts socio-économiques de la pêche de loisir en eau douce en France”, Fédération Nationale de la Pêche en France et de la protection du milieu aquatique, February 2014 56 Résultats de l’étude d’impact économique de la pêche du black bass en France par BBF, esoxiste.com, 19 June 2017 57 Eau Seine Normandie, Etat des lieux du bassin de la Seine et des cours d’eau côtiers normands, Decembre 2013
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 45
Table 21. Socio-economic situation for water-related activities in the Seine-Normandie catchment area58
58 Eau Seine Normandie, Etat des lieux du bassin de la Seine et des cours d’eau côtiers normands, Decembre 2013
Uses that may have an impact on the aquatic environement
Uses that depend on a good water quality and/or activities with a low impact on
the aquatic environment
Sewage systems – costs for households: Expenses: € 1.2B; 18.3M inhabitants
Agriculture:Revenues: € 12B; 118,000 jobs
Commercial navigation:Revenues: € 124M; 3,000 jobs
Hydroelectricity:Revenues: € 39M; 170 jobs
Alluvial granulates extraction:Revenues: € 245M; 830 jobs
Industry:Revenues: € 313B; 1.2M jobs
Households drinking water consumpation: € 1B expenses; 18.3M inhabitants
Bathing-related tourism:€ 840M expenses; 23M bathers
River tourism and maritime boating:7M passengers; € 140M expenses; € 230M
revenues; 1,000 jobs
Nautical activities:€ 118M expenses; 1,400 jobs
Recreational fishing:400,000 fishermen; € 113M expenses
Aquaculture:Revenues: € 111M; 2,700 jobs
Profesisonal maritime fishing:Revenues: € 150M; 1,700 jobs
Analysis of Alternatives – Socio-Economic Analysis
Diagnostica Stago Use-2 46
- On a regional level (Normandie region), professional marine fishing is responsible for59:
→ 2,100 fishermen jobs (2013)
→ 28,900 tons of fishery products (2015)
Indirect use
Indirect use of the aquatic environment may relate to ecosystemic services such as biodiversity
support or the protection of endangered species.
Option values, existence values and bequest values
Willingness to pay for the preservation of water quality at the Flathead River and Lake in Montana
United States of America was characterised by Sutherland and Walsh (1985) as follows:
VALUE CATEGORY WILLINGNESS TO PAY
Option value $8
Existence value $30
Bequest value $35
Table 22. Willingness to pay for the preservation of water quality at the Flathead River and Lake in Montana United States of America 60
59 CCI Normandie, La Normandie en chiffres et en cartes, Panorama économique, 2017 60 Sutherland, RJ & Walsh, RG 1985, 'Eect of Distance on the Preservation Value of Water Quality', Land Economics, vol. 61, no. 3, pp. 281-291.
Analysis of Alternatives – Socio-Economic Analysis
Diagnostica Stago Use-2 47
4. SELECTION OF THE “NO N-USE” SCENARIO
4.1. Substitution initiative
Stago substitution initiative was structured as a five-phase project:
- Phase 1 – Screening of surfactants
- Phase 2 – Confirmation of analytical performances with selected
surfactants
- Phase 3 – R&D validation of the selected surfactant in the substitution of
IGEPAL® CA-630
- Phase 4 – Industrial validation of the substitution
- Phase 5 – Multicentric clinical testing
The content of these phases is detailed in what follows.
Product of Use-2 are classified as Class C in the context of the new CE IVD
regulation, meaning that risks for individuals are high in case of erroneous result. As a
consequence, any substitution in its production process has to undergo an extra-
constraining validation.
Indeed, a device may only be placed on the market or put into service if it complies
with Regulation (EU) 2017/746 at the time it is duly provided and when it is properly
installed, maintained and used in accordance with its intended purpose61. This
regulation lays down a series of obligations incumbent on the manufacturers of in vitro
diagnostic devices in Article 10. These obligations relate in particular to the need to
comply with certain performance characteristics set out in the annex I of that same
regulation.
The characteristics of the IVD devices such as analytical or clinical performances
shall be maintained during the lifetime of the device as indicated by the manufacturer
in respect of his obligations62.
61 https://eur-lex.europa.eu/legal-content/EN/TXT/HTML/?uri=OJ:L:2017:117:FULL&from=EN 62 https://eur-lex.europa.eu/legal-content/EN/TXT/HTML/?uri=OJ:L:2017:117:FULL&from=EN
A significant work of research and testing of potential alternatives to IGEPAL®
CA-630 in the context of Use-2 was carried out by Stago.
As a result of this initiative, one potential alternative has been identified that
is foreseen to meet the functional requirements laid out in the previous
section.
This potential alternative, however, has yet to undergo further empirical
investigation, quality validation and industrialisation; it will therefore not be
available to Stago before the sunset date of 4-tert-OPnEO.
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 48
At European level, any in vitro diagnostic medical device placed on the market or
in use including imported ones must have a CE marking. This CE marking may be affixed
to an in vitro diagnostic medical device only if it complies with the essential
requirements and has been the subject of the evaluation procedures applicable to it.
All of the essential requirements and conditions for compliance are described in
Regulation (EU) No.2017/746 of 5 April 2017 on in vitro diagnostic medical devices
repealing Directive 98/79 EC and Commission Decision 2010/227/EU. It was published
in the Official Journal of the European Union of May 5, 201763.
So, the modification of a component or a parameter necessarily implies the
reassessment of the conformity of the device concerned and its regulatory
requalification. The substitution of the detergent will therefore require a new
registration.
In addition to the process outlined in what follows, the following constraints will
apply:
- Other substitutions will have to be carried out together with that of 4-
tert-OPneO, that will significantly impact the process as such
substitutions have to be carried out in a sequential manner;
- A change in the process of antibodies production is expected;
- Products of Use-2 are liquid and therefore require a long-term (2 years)
stability testing before its recognition by regulatory bodies;
- According to the criticality of these products, full-scale production
batches will have to be carried out, which will impact the overall
production schedule.
Phase 1 – Screening of surfactants
A primary selection of non-ionic surfactants has been made via a bibliographic
research on considering their non-ionic nature and Hydrophilic-Lipophilic Balance
(HLB) values. In addition, safety data sheets have been analysed for each
contemplated surfactant so as to identify and rule out hazardous substances.
The following surfactants meeting those criteria have been tested:
63 http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32017R0746&from=EN
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 49
SURFACTANT SUPPLIER STATUS COMMENT
Croduret 40 CRODA
Overestimate of plasma control level (RIN2).
Overestimate confirmed by a method of
comparison with actual patients’ plasma.
Croduret 50 CRODA Idem Croduret 40
Brij L9 CRODA ✓ Closest performances to that of IGEPAL but weak
underestimate of normal controls
Laureth 9
CRM
(Cosmetic
Raw
Materials)
/ Same molecule as Brij L9
Brij CS 12 CRODA Poor dispersion and solubilisation during buffer
preparation Crodesta F 160 CRODA
Tergitol TMN 6 DOW
Underestimate of plasma control level 1 (RIN1).
Underestimate confirmed by a method of
comparison with actual patients’ plasma.
Tergitol TMN 10 DOW
Underestimate of plasma control level 1 (RIN1).
Underestimate confirmed by a method of
comparison with actual patients’ plasma
Mix of Tergitol TMN 10 and
Tergitol TMN 6 (70/30) DOW
Underestimate of plasma control level 1 (RIN1).
Underestimate confirmed by a method of
comparison with actual patients’ plasma
Tween 21 Sigma-
Aldrich
Poor results with normal controls and
underestimate of plasma control level 2 (RIN2)
Tween 20 Sigma-
Aldrich
Poor results with normal controls and
underestimate of plasma control level 2 (RIN2)
Tween 40 Sigma-
Aldrich Does not allow to neutralise the plasma turbidity
Tween 80 Sigma-
Aldrich
Slight overestimate of plasma control level 2
(RIN2) and underestimate of normal controls.
Without Tween 20, the turbidity is not controlled.
Tween 20 / Tween 80 and
Tween 20 / Tween 40
mixtures
Sigma-
Aldrich Underestimate of normal controls
Mix of Tween 20 / Brij L9 Sigma-
Aldrich ? Under consideration
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 50
Crodasol AC - LQ Croda
Very low reactivity and underestimate of normal
controls and plasma control level 1 (RIN1) Glycerox 767 HC Croda
Cithrol 4ML LQ Croda
Pluronic F127 Sigma Does not allowed to neutralise the plasma
turbidity
Sodium Deoxycholate Sigma Does not allowed to neutralise the plasma
turbidity
Table 23. Surfactants identified and tested ✓ = selected; = ongoing/non-evaluated = rejected
These surfactants have undergone a series of preliminary testing (neutralisation
of plasma turbidity, reactivity, coherence with control solutions and specificity dosage)
that allowed to identify the most promising options.
At the end of this phase, and following testing, the following surfactants have
been selected for further investigation under Phase 2:
RESULTS OF PHASE 1: ANALYTICAL PERFORMANCE COMPARED
TO REFERENCE SOLUTION
2 REACTIVITY SPECIFICITY
BRIJ L9 ≈ ≈
CRODURET 40 + ≈
TWEEN 20 - -
TERGITOL TMN 10 and
TERGITOL TMN 6 ≈ -
Table 24. Surfactants selected for further investigation in Phase 2. Analytical performances:
≈ similar, + increased, - decreased compared to that of reference solution
The surfactant Croduret 50 has not been selected because its behaviour is very
similar to Croduret 40.
The surfactants:
- Brij CS 12
- Crodesta F160
- Tween 21
- Croduret AC-LQ
- Glycerox 767 HC
- Cithrol 4ML LQ
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 51
- Pluronic F127
- Sodium Deoxycholate
- Tween 40
- Tween 80
have not been selected for at least one of the following reasons:
- Too low level of reactivity
- Too low level of plasma turbidity neutralization
- Too low level of compliance with the results obtained with the control
solution
- A large number of chemical compounds are present in these solutions,
which may be chemically active; this may significantly influence the
reagent performances throughout their life and add variability to the
assay.
Phase 2 – Confirmation of analytical performances of selected
surfactants
The goal of Phase 2 is to confirm analytical performances of the surfactants
selected during Phase 1, in view of their potential integration in Stago’s production
process.
To this end, a larger scale production was carried out with each of the selected
surfactants. Performances of the reagents obtained have then been compared to
those of a reference solution produced with IGEPAL® CA-630. Each reagent is
characterised by its pre-calibration equation.
The accuracy of quality controls, as well as the dosage of specificity have been
validated with each buffer solution and compared to results obtained with the
reference buffer solution containing IGEPAL® CA-630.
The testing repeatability has been evaluated for each buffer solution. Repeatability
assays are performed within quality control samples, a turbid plasma and a batch of
plasma supplemented with fibrin-fibrinogen degradation products (FDP) serum.
Following these analytical tests, reagents produced with the selected surfactants are
tested against actual patients’ plasmas for a comparison of reagents methods.
Results of Phase 2 show that:
RESULTS OF PHASE 2: DETAILED ANALYTICAL PERFORMANCE
COMPARED TO REFERENCE SOLUTION
2 REACTIVITY SPECIFICITY PRECISION
BRIJ L9 ≈ Weak under
estimation ≈
CRODURET 40 + Weak over
estimation ≈
TWEEN 20 - Under estimation ≈
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 52
Table 25. Surfactants selected for further investigation in Phase 2. Analytical performances:
≈ similar, + increased, - decreased compared to that of reference solution
In addition, the results of the reagents comparison of methods are synthesised
in the table below:
FUNCTIONAL CRITERIA
❶
Slope
❷
R*
❸
Median of
absolute deviations
❹
Median of absolute deviations of
plasmas between 0.3-1 µg/mL
BRIJ L9 ✓ ✓ ✓ ✓
CRODURET 40 ✓ ✓ x
TWEEEN 20 ✓ ✓ x
TERGITOL TMN6 ✓ ✓ x
TERGITOL TMN 10 ✓ ✓ ✓ x
Table 26. Results of reagent method analysis – functional criteria ✓ = compliance with requirements; = non-compliance with requirements
* Correlation coefficient
Results of the comparison of methods have confirmed Brij L9 as the most
promising potential alternative to IGEPAL® CA-630.
Phase 3 – Validation of the selected surfactant in the substitution
of IGEPAL® CA-630
Phase 3 aims at consolidating the reliability of Brij L9 as an alternative to IGEPAL®
CA-630 under Use-2. Batch-to-batch variability has therefore been tested.
To do it, a total of three different batches of Brij L9 are tested. With each batch of
BrijL9, a reactive buffer has been produced at a larger scale than under Phase 2. Pre-
calibration has been performed for each reagent; reactivity, compliance with
reference solution and specificity of the dosage are tested for each reagent.
Results of Phase 3 have confirmed analytical and clinical performances of Brij L9:
- No difference in terms of reactivity have been identified between reagents
produced with Brij L9 and reagents produced with IGEPAL® CA-630
- Compliance with controls sample and specificity are similar to that of reagents
produced with IGEPAL® CA-630
- Methods comparison results did not show any difference of dosage with
patients’ real plasmas.
Phase 4 - Industrial validation of the substitution
Once validated at R&D scale, an alternative has to follow Stago’s industrial
validation procedure.
Tests are currently on-going, for which results will be obtained in September but
the following elements can be brought forward to date:
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 53
- The industrial validation of the alternative will require to validate results
obtained with both the substituted solution and the final product at
industrial scale, upon several batches;
- The products being in liquid form, long-term tests will have to be
performed prior to their validation;
- Complementary regulatory requirements (national product registration)
may be needed in case of the substitution of IGEPAL® CA-630.
The exact foreseen chronology of substitution will be discussed in the chapter
substitution timeline.
Phase 5 – Multicentric clinical tests
Given the criticality of the products of Use-2 as a diagnostic support, multicentric
clinical tests will be required to validate the results obtained with the substituted
product. Such a large-scale study will require an extensive period of time (5 years) as
well as a very significant level of financial and human resources.
4.2. Resources
Stago substitution initiative for Use-2 involved a significant number of
contributors, as listed below:
CONTRI
BUTOR(*) TRAINING FUNCTION INVOLVEMENT
1 PhD Head of R&D
department
- Project manager
- Scientific & technical elements
- Expertise in colloids physico-chemistry
and surfactants solutions
2 Engineer Study manager
R&D expert
- Expertise in formulation and
implementation in immunologic
diagnostic reagents
3 Engineer R&D manager - Coordination of workload for substitution
studies
4 Engineer R&D study manager - Coordination of substitution studies
5 PhD Study manager
R&D expert
- Expertise in the formulation and
implementation in immunologic
diagnostic reagents
- Company strategy
6 Engineer R&D director - Company strategy
7 Technician R&D technician - Technical elements: testing and analysis
of results
8 Technician R&D technician - Technical elements: testing and analysis
of results
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 54
9 Technician R&D study manager - Technical elements: testing and analysis
of results
Table 27. Contributors involved in Stago’s substitution initiative for Use-2. (*) Names anonymised, for privacy matters
4.3. Assessment of shortlisted alternatives
4.3.1. Alternative 1: Brij L9
4.3.1.1. Substance ID and properties
Brij L9 is supplied by Croda Health Care.
4.3.1.2. Technical feasibility of Alternative 1
The technical feasibility of Alternative 1 is being investigated, as described in the
previous section.
4.3.1.3. Economic feasibility and economic impacts of Alternative 1
Alternative 1 is considered as economically feasible as 4-tert-OPnEO but leads to
a clear increase of the cost.
4.3.1.4. Availability of Alternative 1
Alternative 1 is commercially available.
4.3.1.5. Hazard and risk of Alternative 1
Classification of product is synthesised as follows:
REGULATION BRIJ L9
Classification according to Regulation (EC) No 1272/2008
- Eye damage (Category 1)
Labelling according Regulation (EC) No 1272/2008
Signal word Danger:
- Hazard statement(s)
- H318 Causes serious eye damage.
Table 28. Hazards identification for Brij L9
The alternative is less toxic for the environmental compartments and based on the
available data no endocrine disrupter properties are expected.
4.3.1.6. Conclusions on Alternative 1
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 55
4.4. Substitution timeline
The substitution timeline, outlined on the basis of the general description
provided in the previous sections is the following:
Table 29.General substitution timeline for Use-2
20
17
20
18
201
9
20
20
20
21
20
22
20
23
20
24
20
25
20
26
20
27
20
28
20
29
20
30
20
31
20
32
20
33
R&D works ● ● ● Tests at reduced production scale ● ● ● ●
Tests at commercial scale ● ● ● ● ● ● ●
Multicentric clinical tests ● ● ● ● ●
Notification, agreement and deployment ● ●
Of all potential alternatives identified and tested, Alternative 1 is the most
likely to substitute Igepal CA-630 in the context of Use-2.
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 56
4.5. The most likely “non-use” scenario
In the context of Use-2, the relocation or sub-contracting of the production of
STA® - Liatest® D-Di assays outside the European Union cannot be considered, as their
production:
- Has a strong human factor and requires an extremely high level of know-how;
- Follows a complex process for the qualification of raw materials
(compatibility between latex couples);
- Bears issues in the sourcing of antibodies;
- Follows a very stringent batch qualification process (Ring 2 criteria) that
requires an extremely low batch-to-batch variability and for which any
deviation implies the destruction of batches.
A downgrade of product performances, that may arise from a non-optimal
substitution, cannot be considered either, given the extremely high level of
requirement in terms of reliability of diagnostics provided to end-users.
In this context, the most likely “non-use” scenario is a permanent cease of
production of STA® - Liatest® D-Di assays. Strong impacts are foreseen in this scenario,
notably:
- Direct impacts – loss of revenues and profits, loss of employment
- Indirect impacts – impacts on patients’ health and national healthcare
systems
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 57
5. IMPACTS OF GRANTING AN AUTHORISATION
Significant efforts have been made by Stago towards the management of
environmental risks associated to the use of 4-tert-OPnEO. In this context, a collection
policy of all effluents containing 4-tert-OPnEO in concentrations above 0.1% has been
implemented at the site of Franconville and is going to be implemented in Taverny’
site in 2018.
In these conditions, any further reduction in emission can only be envisaged as a
cessation of use of the substance; as demonstrated in section 4.5, such a situation
corresponds to the “non-use” scenario for Use-2: a permanent cessation of the
production of STA® - Liatest® D-Di assays and consequently a cessation of use of 4-
tert-OPnEO.
As an uncertainty analysis, a cost-effectiveness ratio will therefore be laid out as:
𝐸𝑐𝑜𝑛𝑜𝑚𝑖𝑐 𝑐𝑜𝑠𝑡𝑠 𝑜𝑓 𝑡ℎ𝑒 "𝑛𝑜𝑛 − 𝑢𝑠𝑒" 𝑠𝑐𝑒𝑛𝑎𝑟𝑖𝑜 𝑓𝑜𝑟 𝑜𝑛𝑒 𝑦𝑒𝑎𝑟 (€)
𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝑠𝑢𝑏𝑠𝑡𝑎𝑛𝑐𝑒 𝑟𝑒𝑙𝑒𝑎𝑠𝑒𝑠 (𝑘𝑔)
An additional perspective will be provided in the form of a discussion regarding
cost assessment of environmental impacts in the context of the present AfA.
5.1. Economic impacts
The cease of production and commercialisation of STA® - Liatest® D-Di assays
would entail both direct impacts (loss of revenues and profits directly related to those
products) as well as indirect impacts (loss of revenues and profits related to markets
that would be lost to Stago in case of unavailability of STA® - Liatest® D-Di assays in
Stago’s portfolio).
Collection and disposal of production wastewaters containing 4-tert-OPnEO is
being contemplated by the sunset date of the substance.
In these conditions, the only realistic assumption for the assessment of costs
per reduced emission is the “non-use” scenario, as all other emission
avoidance initiatives have already been performed.
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 58
5.1.1. Direct loss of revenues and profits
5.1.1.1. Loss of profits
Average D-Di assays profits for the years 2015, 2016 and 2017 are the following:
PRODUCT REVENUES
D-DI TEST® [100,000-1,000,000](#1b)
STA®- LIATEST D-DI [10,000,000-
100,000,000] (#1c
STA®- LIATEST D-DI PLUS [10,000,000-
100,000,000](#1d)
ASSERACHROM D-DI [100,000-1,000,000](#1e)
STA®- LIATEST D-DI [10,000,000-
100,000,000](#1f)
STA®- LIATEST CONTROL N+P [10,000,000-
100,000,000](#1g)
STA®- D-DI CONTROL [1,000,000-
10,000,000](#1h)
STA®- CUVETTES [1,000,000-
10,000,000](#1i)
TOTAL [50,000,000-
500,000,000](#1j)
Table 30. Profits associated with D-Dimer assays per year
A total of [50,000,000-500,000,000] (#1j)} annual profits is related to the
commercialisation of products of Use-2. Considering the duration of impact for each
range of products as presented in the definition of the “non-use” scenario (12-year
post-sunset date review period), as well as an average 3% annual profits growth, the
total profits loss is the following:
Nominal value of profit loss [500,000,000-5,000,000,000](#1k)
Discounted value of profit loss [500,000,000-5,000,000,000](#1l)
Table 31. Total profits loss over the impact period for Use-2 (*): considering a 4% discount rate
With a loss of profits of over [500M-5B](#1l) over the 2021-2032 period,
the “non-use” scenario will generate critical impacts on the economic
activity of Stago and will jeopardise its very survival.
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 59
5.1.2. Loss of markets
D-Dimer assays are not only a major source of revenues for Stago, but they also
constitute key elements of Stago’s portfolio insofar as they are a prerequisite for
accessing calls for tenders.
Calls for tenders are regularly (periodicity of three to ten years depending on markets
maturity) issued by countries, that cover several diagnostic solutions. D-Dimer assays
are so-called routine tests. It is mandatory for any potential participant in the
tendering process to possess a D-Dimer dosage solution in its portfolio.
Exact figures are difficult to extract, but the loss of D-Dimer dosage kits would have a
significant knock-off effect on sales of other products of Stago’s portfolio. Several
markets would thereby be closed to Stago for a significant period of time.
A proper quantification of such a market loss can hardly be carried out. The
following elements, however, can be brought forward to characterise the knock-off
effect of the “non-use” scenario on sales of other products of Stago’s portfolio:
- Tenders are issued for a duration of three to ten years depending on
countries. Should a tender be closed to Stago due to missing critical
products in its portfolio, then said market would be lost for such a long
period of time, thereby jeopardising revenues for Stago over a medium
to long duration.
- Tenders represent the major share of Stago’s revenues; their loss will
jeopardise the very economical survival of the Company.
5.1.3. Discussion: net impact for the Society
Stago is the leader of the hemostasis diagnostic sector, both in terms of
performance (several of Stago products constitute gold standards in terms of
analytical performance) and in terms of market share (Stago represents 30% of the
global hemostasis market).
In these conditions, and within the current knowledge, it is difficult to predict how
would the sector adapt to Stago’s cease of marketing of products of Use-2 and what
the overall net impact for the Society of the “non-use” scenario would be. In addition,
Stago has no knowledge regarding whether or not competitors use 4-tert-OPnEO for
the production of their product and, if they do, whether or not they will be applying
for an Authorisation.
A significant knock-off effect will be generated by the cease of
commercialisation of products of Use-2, as access to several tenders would
be closed to Stago in such a case.
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 60
Products of Use-2 being linked to detection appliances, any competitor aiming at
replacing Stago for these products will not only have to offer reagent solutions but
also detection equipment.
It can however be noted that given [1] the large market share of Stago in the sector,
[2] the very high level of know-how required and [3] the extremely capitalist nature of
the production of IVD products, no competitor will be able to take over Stago’s place
in the market at a short to medium term. It is very unlikely that competitors will be
able to ramp up their production of alternative solutions on a short or even medium
term. As discussed in the following chapter, this could be problematical for the
patients’ health.
5.1.4. General conclusion on economic impacts
Test kits concerned by Use-2 are extremely strategic for Stago, as [1] they
represent a significant share of the company’s revenues and [2] they are a
prerequisite to participate in call for tenders for other products.
5.2. Social impacts
Social impacts can be expected in the context of the “non-use” scenario, that fall
into two categories: loss of employment that would arise from the cease of production
and impacts on patients that may face a disruption in diagnostic due to the
unavailability of D-Dimer assays.
5.2.1. Impact on patients health
As discussed in section 2.4, D-Dimer assays are exclusion assays, that significantly
support the diagnostic of certain pathologies (deep vein thrombosis and pulmonary
embolism) without the need for more costly and resource intensive examination.
Given the high incidence of deep vein thrombosis/pulmonary embolism (3 to 6
million VTE suspicions per year in the U.S.) and the 30 percent mortality rate
associated with undiagnosed PE, the diagnostic process is crucial.
STA-Liatest D-di assay, as some other D-dimer assays used in clinical practice, have
a very high specificity (97.6%, 95% confidence interval: 91.7-99.7% for PE; 100%, 95%
confidence interval: 95.8-100% for DVT)64. These excellent performances allow a safe
64 Pernod G et al. Validation of STA-Liatest D-Di assay for exclusion of pulmonary embolism according to the latest Clinical and Laboratory Standard Institute/Food and Drug Administration
The net impact for the Society of Stago’s “non-use” scenario cannot be
estimated in a reliable way. It can however be stated that no competitor
will be able to supplant Stago for the products of Use-2 on a short to
medium term basis.
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 61
exclusion of VTE diagnosis when the D-dimer level below the predefined cut-off (0.5
µg/mL for STA-Liatest Ddi assay), in patients with low or moderate clinical probability.
Depending on studies, 20 to 60% of patients suspected of having VTE can be excluded
with a negative D-dimer assay, combined with the assessment of the clinical pre-test
probability.
A recent innovation in the PE diagnosis strategy is the application of an increased
D-dimer exclusion threshold for people older than 50, in order to improve the
specificity of the assay in this population. A threshold corresponding to “age x 10” (in
µg/L) allows to increase the number of people excluded with D-dimer assay and clinical
probability, without jeopardizing the safety of D-dimer testing65. The mean absolute
increase of people excluded based on D-dimer testing, as compared to conventional
threshold, is 10%66.
It is difficult to assess with precision the absolute amount of money saved by the
implementation of D-dimer testing in the diagnosis strategy of PE and DVT, as it
depends on VTE prevalence, local medical practices, costs of the different techniques
and study designs. A recent study shows that the implementation of D-dimer reduced
the average diagnostic test cost for a suspected PE patient by 38% and for a suspected
DVT patient by 24%.
Assuming the proportion of VTE suspected patients to be 30% PE and 70% DVT,
the weighted average reduction in the diagnostic test cost per suspected VTE patient
was 32%67
Furthermore, imaging technics are not devoid of risks. The diagnosis of PE by CT-
scan is associated with a 2% probability of false-positive diagnosis and its associated
guideline. Results of a multicenter management study, Blood Coagul Fibrinolysis 2017; 28(3): 254–260.
Aguilar C, Sartori M, D'Angelo A et al. Validation of the STA-Liatest DDi assay for exclusion of proximal deep vein thrombosis according to the latest Clinical and Laboratory Standards Institute/Food and Drug Administration guideline: results of a multicenter management study. Blood Coagul Fibrinolysis 2018; 29(6): 562-6. 65 Righini M, Van Es J, Den Exter PL et al. Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. JAMA 2014; 311(11): 1117-24. 66 Penaloza A, Roy PM, Kline J et al. Performance of age-adjusted D-dimer cut-off to rule out pulmonary embolism: Age adjusted D-dimer to rule out PE. J Thromb Haemost 2012; 10(7): 1291–6.
Douma RA, Tan M, Schutgens REG et al. Using an age-dependent D-dimer cut-off value increases the number of older patients in whom deep vein thrombosis can be safely excluded. Haematologica 2012; 97(10): 1507–13.
Righini M, Van Es J, Den Exter PL et al. Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. JAMA 2014; 311(11): 1117-24.
Sharp AL, Vinson DR, Alamshaw F et al. An Age-Adjusted D-dimer Threshold for Emergency Department Patients With Suspected Pulmonary Embolus: Accuracy and Clinical Implications. Ann Emerg Med 2016; 67(2): 249–57. 67 Verma K, Legnani C, Palareti G. Cost-minimization analysis of venous thromboembolism diagnosis: Comparison of standalone imaging with a strategy incorporating D-dimer for exclusion of venous thromboembolism. Res Pract Thromb Haemost 2017 Jul; 1(1): 57–61.
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 62
risk of unnecessary anticoagulation, the radiation exposure, the 1% risk of immediate
complication (such as allergy to contrast products) and the 15% probability of
developing contrast-induced nephropathy686970.
These side effects are also associated with lengthened hospitalization, increased
patients managing and increased costs.
D-dimer testing, while excluding VTE without the need of imaging technics, is thus
a major contributor to reduce hospital economic burden (imaging technics costs), to
reduce imaging technics side effects, and is highly beneficial for an optimized patient’s
flow in the emergency department.
Alternative testing methods for venous thromboembolism include:
Deep vein thrombosis
METHOD DESCRIPTION INVASIVE?
Duplex ultrasound Use of an ultrasound transducer to
characterise blood flow NO
Venography X-ray of the veins after a special dye is injected
into the bone marrow or veins YES
Magnetic resonance
imaging
MRI scanners use strong magnetic fields, radio
waves, and field gradients to generate images
of the organs in the body
NO
Table 32. Alternative methods for the diagnostic of deep vein thrombosis
Pulmonary embolism
METHOD DESCRIPTION INVASIVE ?
Ultrasound Use of an ultrasound transducer to
characterise blood flow NO
Computed Tomography
Scans X-ray scanning NO
68Courtney DM, Miller C, Smithline H, Klekowski N, Hogg M, Kline JA. Prospective
multicenter assessment of interobserver agreement for radiologist interpretation of
multidetector computerized tomographic angiography for pulmonary embolism. J
Thromb Haemost JTH. 2010;8(3):533–9.
69 Mitchell AM, Jones AE, Tumlin JA, Kline JA. Immediate complications of intravenous contrast for computed tomography imaging in the outpatient setting are rare. Acad Emerg Med Off J Soc Acad Emerg Med. 2011;18(9):1005–9. 70 Mitchell AM, Jones AE, Tumlin JA, Kline JA. Prospective study of the incidence of contrast-induced nephropathy among patients evaluated for pulmonary embolism by contrast-enhanced computed tomography. Acad Emerg Med Off J Soc Acad Emerg Med. 2012 Jun;19(6):618–25.
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 63
Lung Ventilation
Perfusion Scan
Lung scanner after injection of
radioactive albumin into a vein and
breathing in radioactive gas through a
mask
YES
Pulmonary Angiography Fluoroscopic procedure YES
Table 33. Alternative methods for the diagnostic of pulmonary embolism
Given the market share of Stago regarding D-dimer testing, the unavailability of
D-Dimer assays in the context of the “non-use” scenario will necessarily generate a
diagnostic discontinuity for patients, as no competitor will be able to provide
replacement solutions within appropriate delays. As an illustration, the sole
production of antibodies required for the production of D-dimer tests takes 18
months.
In addition to direct economic impacts for Stago, the “non-use” scenario will
indirectly impact national healthcare systems, as alternative diagnostic solutions are
both more expensive and/or invasive.
In what follows are compared the costs of tests for pulmonary embolism:
TEST GENEVA
(SWITZERLAND) UNITED STATES CANADA
D-Dimer 33 12 12
Ultrasound 90 69 36
Computed Tomography
Scans 600 135 138
Lung Ventilation
Perfusion Scan 301 683 69
Pulmonary Angiography 1,038 510 413
Table 34. Costs of tests for pulmonary embolism in Switzerland, the United States and Canada, in USD (2003)71
In addition, costs for treatment of pulmonary embolism are as follows:
GENEVA
(SWITZERLAND) UNITED STATES CANADA
5,910 20,040 2,534
71 Perrier et al., Cost-Effectiveness Analysis of Diagnostic Strategies for Suspected Pulmonary Embolism Including Helical Computed Tomography, American Journal of Respiratory and Critical Care Medicine, Vol. 167, No. 1 | Jan 01, 2003
Analysis of Alternatives – Socio-Economic Analysis
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Table 35. Treatment costs for pulmonary embolism in Switzerland, the United States and Canada, in USD (2003)72
D-Dimer dosage assays constitute cost efficient methods in comparison with
other tests for pulmonary embolism and deep vein thrombosis:
STRATEGY LIVES SAVED /
1,000 PATIENTS
COSTS PER ADDITIONAL
QALY SAVED ($)
Serial ultrasonography 4.3 15,475
Serial ultrasonography with D-Dimer 4.3 14,934
Clinical probability with serial
ultrasonography 4.4 14,339
Clinical probability with D-Dimer and
single ultrasonography 4.2 13,115
Table 36. Cost-effectiveness of various diagnostic strategies for deep vein thrombosis (2001)73
STRATEGY LIVES SAVED /
1,000 PATIENTS
COSTS PER ADDITIONAL
QALY SAVED ($)
Clinical probability with D-Dimer,
ultraosonography, lung scan and
angiography
38 2,467
Lung scan followed by angiography if
nondiagnostic 37 3,202
Clinical probability with D-Dimer,
ultraosonography, lung scan and helical
CT
36 2,447
Clinical probability with D-Dimer,
ultraosonography, helical CT and
angiography
35 2,700
Helical CT alone 28 3,439
Table 37. Cost-effectiveness of various diagnostic strategies for deep vein thrombosis (2001)74
72 Perrier et al., Cost-Effectiveness Analysis of Diagnostic Strategies for Suspected Pulmonary Embolism Including Helical Computed Tomography, American Journal of Respiratory and Critical Care Medicine, Vol. 167, No. 1 | Jan 01, 2003 73 Perrier, Cost-effective diagnosis of deep vein thrombosis and pulmonary embolism, Thrombosis and Haemostasis, 2001: 86/1 (July, State of the Art) pp.1-508 74 Perrier, Cost-effective diagnosis of deep vein thrombosis and pulmonary embolism, Thrombosis and Haemostasis, 2001: 86/1 (July, State of the Art) pp.1-508
Analysis of Alternatives – Socio-Economic Analysis
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Thromboembolic disease, which includes DVTs, PEs, and their associated medical
complications, affects more than 600,000 people in the United States each year and
generates approximately $10 billion in medical expenditures75,76,77.
5.3. Wider economic impact
As discussed in the previous sections, products of Use-2 are widely used on a
world scale by a vast array of medical specialties. In this context, wider economic
impacts can be expected for actors of the health chain. It will be shown in what follows
that, from a global point of view, negative impacts associated with the unavailability
of diagnostics will outweigh potential positive impacts related to the potential market
adaptation in favour of competitors.
5.3.1. Negative impacts
A major disruption of the associated medical sector
The medical sector relies, to various extends, on tests concerned by the present
application. Their unavailability on the market will generate a major disruption in their
functioning as replacements will have to be sourced, purchased, installed and
operators will have to be trained to their use.
The competitors’ capacity to produce and supply alternative tests is
unknown
Given [1] the biological and sensitive character of in vitro diagnostics products and
[2] the large market share of Stago in hemostasis, it appears unlikely that competitors
will be able to provide alternative solutions in sufficient quantities on a short to
medium term.
75 Beckman et al., Venous thromboembolism: a public health concern. Am J Prev Med. 2010;38(4 Suppl):S495–S501. 76 Mozaffarian et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131(4):e29–e322 77 Grosse, Incidence-based cost estimates require population-based incidence data. A critique of Mahan et al. Thromb Haemost. 2012;107(1):192–193; author reply 194-195.
Millions of diagnostics are performed each year with products of Use-2.
Given their very high medical added value, significant impacts are foreseen
in case they cannot be marketed by Stago. Give the scale of number of
patients concerned, and the diversity of actors concerned (hospitals,
laboratories, …) a significant diagnostic disruption is expected in the
context of the “non-use” scenario.
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 66
Products of Use-2 are specifically designed to be used with Stago’s
automated analysers
D-Dimer assays are to be specifically used on Stago’s automated analysers.
Competing products cannot be directly used on these equipments. As a consequence,
hospitals and laboratories that are equipped with Stago’s equipment will not only have
to source alternative testing solutions but also to purchase and calibrate new
automated analysers as well as to train personnel to their use. Major economic
impacts will therefore be generated by the unavailability of D-Dimer assays to
hospitals and laboratories.
5.3.2. Positive wider economic impacts
Stago’s “non-use” scenario will generate an opportunity for competitors. The
scale of these benefits cannot, however, be precisely assessed as:
- Medical diagnostics for pathologies addressed by products of Use-2 may
be supported via a vast array of tests and methods depending on medical
situations, practitioners’ judgement and equipment available within the
medical structure. It is therefore impossible to model the market
adaptation to Stago’s cease of supply of products of Use-2.
- Competitor’s manufacturing capacities are unknown. In addition, given
the sensitive nature of biological materials, production ramp-up is known
to require several years. It cannot therefore be anticipated whether or
not competitors will be able to supply solutions on a short-term basis
after Stago’s potential disruption of supply.
- It is not known whether or not competitors use 4-tert-OPnEO to
synthesise their products and if so, whether or not they will be granted
an Authorisation for their use.
Considering these elements, it appears realistic to consider that Stago’s “non-
use” scenario will benefit to competitors. The extent of those benefits cannot,
however, be modelled both in terms of identification of potential companies
affected, their location (within or outside the EU) and the share of revenues lost by
Stago that they will be able to recover.
5.4. Distributional impacts
5.4.1. Impact on employment
5.4.1.1. Number of jobs concerned
In order to place the assessment of the impacts on employment on realistic (and
under-estimated) assumptions, only actual working hours of Stago’s workers for the
production of products of Use-2 have been considered as potentially lost in the
context of the “non-use” scenario.
Following a precise account of hours worked per production process, it was
identified that an average total of 5,667 man-hours was affected to the production of
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 67
products of Use-2. Considering 1,600 man-hours per full-time equivalent, this
corresponds to 3.5 jobs.
It is reminded that this value can be considered as very conservative as it only
accounts for direct jobs and does not consider any indirect job loss that would be
generated in the context of the “non-use” scenario, notably in terms of other
productive functions (packaging, storage), logistics, sales and marketing.
5.4.1.2. Assessment via default value
SEAC’s note78 proposes a default welfare cost factor value of 2.7 for the
assessment of costs associated with unemployment.
Following this method, the social value of jobs lost in the context of the “non-use”
scenario for Use-2 can be estimated as follows:
Welfare cost factor 2.7
Gross wages of workers 32,000€
Number of jobs lost 3.5
Social value of jobs lost 306,018€
Table 38. Calculation of the social value of jobs lost via the default value methodology for Use-2
5.4.1.3. Detailed assessment
A complementary assessment is performed in what follows in view of providing a
more specific characterisation of the cost related to unemployment in the context of
Use-2. This assessment is largely based on the framework drafted by R. Dubourg79.
The following impact categories will be explored:
- Value of output/wages lost during the period of unemployment
- Impact of being made unemployed on future earnings and employment
possibilities (‘scarring’ effect)
- Cost of searching for a new job
- Recruitment costs
- Leisure time
For each impact categories, it was attempted to rely as much as possible on data
specific to the situation of Stago’ sites in France. Generic data, however, have had to
be used where specific data was unavailable.
78 ECHA, SEAC/32/2016/04 - 32nd meeting of the committee for socio-economic analysis, 6-15 September 2016, Helsinki, Finland 79 R. Dubourg, Valuing the social costs of job losses in applications for autorisation, The Economics Interface Limited, September 2016
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 68
Value of output/wages lost during the period of unemployment
The value of output (wages) lost during the period of unemployment was
calculated using the gross wages of workers concerned and the average duration of
unemployment in France (388 days80):
Gross wages of workers 32,000€
Average duration of unemployment in France 388 days
Nominal value of lost output due to the initial unemployment spell 34,016€
Discounted value of lost output due to the initial unemployment spell 29,011€
Table 39. Calculation of the value of output/wages lost during the period of unemployment for one job, Use-2
Impact of being made unemployed on future earnings and employment
possibilities (‘scarring’ effect)
Scarring effect reflects the tendency to obtain a job with lower wages when
unemployed compared to when employed. A scarring effect value of 20% is proposed
by Dubourg and will be used in the present assessment.
Scarring effect (average reduction in output following reemployment) 20%
Duration of scarring effect 5 years
Nominal value of lost output due to scarring 32,000€
Discounted value of lost output due to scarring 22,517€
Table 40. Calculation of the value of Discounted value of lost output due to scarring for one job, Use-2
Cost of searching for a new job
The value for unemployed persons of time spent searching for a new job can be
roughly estimated via data proposed by Dubourg (it is considered an average of 2.5
hours spent per week searching for a job) and hourly wages derived from the expected
“scarred” gross wages. Please note that the figure of time spent searching for a new
job is a rough estimate whose main purpose is to provide an order of magnitude of
this cost item.
Weekly time spend looking for a new job 2.5 hours
Hourly wages (*) 15.6€
Duration of unemployment 388 days
80 Pôle Emploi, La durée du chômage se stabilise au 2e trimestre 2018(Statistiques et indicateurs n°18,034)
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 69
Nominal value of time lost searching for a new job 2,156€
Discounted value of time lost searching for a new job 1,839€
Table 41. Calculation of the value of output/wages lost during the period of unemployment for one job, Use-2
(*) Considering 35 hours per week and 5 weeks of vacation per year
Recruitment costs
The assessment of recruitment costs (cost of hiring employees) is carried out
considering a global of 30% of expected annual gross wages for the unemployed
person. Please note that, as per the previous impact category, the figure for
recruitment cost is a rough estimate whose main purpose is to provide an order of
magnitude of this cost item.
Recruitment costs (percentage of expected annual gross wages) 30%
Gross ('scarred') wages 25,600 €
Total recruitment costs 7,680 €
Table 42. Calculation of the recruitment costs for one job, Use-2
Leisure time
The assessment of leisure time aims at characterising the value of time freed from
work due to unemployment. As per Dubourg, a reservation wage81 of 80% of expected
post-tax wages is considered.
Reservation wages (of expected post-tax wage) 80%
Expected 'scarred' gross wages 25,600€
Average personal tax on wages 30%
Average duration of unemployment (days) 388
Nominal value of benefits from leisure time 15,239 €
Discounted value of benefits from leisure time 12,997 €
Table 43. Calculation of the value of benefits from leisure time related to unemployment for one job, Use-2
Total cost of unemployment
Individual costs of unemployment are detailed in what follows:
81 From Dubourg: “The reservation wage is the point at which the individual is just indifferent between working and not working”
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 70
Global costs Costs on yearly
basis
Lost output 29 011€ 27 354 €
Job search 1 839€ 1 734 €
Recruitment costs 6 070 € 6 070 €
Scarring 22 517 € 4 863 €
Leisure time -12 997 € -12 254 €
Total 46 440 € 27 766 €
Table 44. Individual costs of unemployment, discounted
Considering the number of jobs lost foreseen in the context of the “non-use”
scenario for Use-2 (3.5 jobs), the total cost of unemployment amounts to 164,910€
and 89,640€ on yearly basis.
5.4.1.4. Comparison of assessment via default value and detailed
assessment
Assessment via default value 306,018 €
Detailed assessment 164,486 €
Detailed assessment on yearly basis 98,345 €
Table 45. Comparison of the characterisation of costs of unemployment using the default value and the detail assessment methodologies
In a conservatory approach, the detailed assessment value will be used in the
calculation of the monetised impacts of the “non-use” scenario.
5.5. Conclusion of the socio-economic analysis
5.5.1. Synthesis of the impacts of the “non-use” scenario
Main foreseeable quantitative impacts of the “non-use” scenario are synthesised
in what follows:
CATEGORY MONETISED IMPACT MONETISED IMPACT
ON YEARLY BASIS
Loss of profits [500,000,000-
5,000,000,000](#1l)
10,000,000-
100,0000,000] (#1l*)
Impact on employment € 164,486 98,345€
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 71
Total [500,000,000-
5,000,000,000](#1m)}
10,000,000-
100,0000,000]
(#1m*)}
Table 46. Synthesis of monetised impacts of the “non-use” scenario, Use-2
To these monetised impacts can be added complementary impacts of major
importance that can only be described in a qualitative manner:
CATEGORY IMPACT
Loss of markets A significant knock-off effect can be expected with the
unavailability of products of Use- 2 in Stago’s portfolio
Medical impacts
A significant disruption and reorganisation of medical
analysis activities on a worldwide scale would be generated
in case of Stago’s inability to supply products of Use-2
Table 47. Synthesis of qualitative impacts of the “non-use” scenario, Use-2
5.5.1. Complementary element: cost-effectiveness ratio
As detailed in the methodological section, the cost-effectiveness ratio constitutes
complementary characterisation metric of the socio-economic analysis.
To define it on the same time scale, this ratio will be done on an annual basis
corresponding to 2022 regarding this present case.
Taking into account that the consumption of 4-tert-OPnEO by Stago will remain
on average in the same levels of the year 2017 and also that Stago had put in place a
plan to not have releases into the sewers of substances that can lead to water
pollution, the ratio is calculated on the basis of the releases measured in 2017 and
mentioned in the Chemical Safety Report.
Release avoid C/E ratio = 10,000,000−100,0000,000] (#1𝑚∗)}
0.0043 (𝑘𝑔)
= [1,000,000,000 − 100,000,000,000](#1s)}
In the context of Stago’s industrial situation, releases of 4-tert-OPnEO are reduced
to the maximum as all potential releases of the substance are collected and the only
remaining release sources are residues in washed glassware. In these conditions, a
release cost-effectiveness ratio would tend toward infinite, making a strong case for
the benefits of continued use outweighing the risk.
5.6. Uncertainty analysis for both the “applied for use” and
the “non-use” scenario
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 72
5.7. Consumption cost-effectiveness ratio
A complementary perspective can be provided with consumption cost-
effectiveness, as follows:
𝐶𝑜𝑛𝑠𝑢𝑚𝑝𝑡𝑖𝑜𝑛 𝐶 𝐸⁄ 𝑟𝑎𝑡𝑖𝑜 = 10,000,000 − 100,0000,000] (#1𝑚 ∗)}
8.2(𝑘𝑔)
= [10,000,000 − 100,000,000](#1s ∗)}
5.8. General conclusion on the impacts of granting an
authorisation
Even though no direct conclusion can be drawn on the basis of threshold values
for consumption cost-effectiveness ratio, it provides a complementary argument in
favour of the conclusion that benefits of continued use widely outweigh the risk.
We can see avoiding releases of less than on gram of 4-tert-OPnEO involves a
unacceptable and disproportionate cost for Stago business
A synthesis of the monetised impacts of the “non-use” scenario is provided below:
MONETISED IMPACTS
Economic impacts Loss of profits [500M-5B](#1l)
Social impacts Loss of employment € 164k
Total monetised impacts of the “non-use” scenario [500M-5B](#1m)}
Table 48. Synthesis of the monetised impacts of the “non-use” scenario
As a complement, other impacts of the “non-use” scenario are synthesised in the
table below:
Table 49. Other impacts of non-use scenario
IMPACTS
ORDER OF
MAGNITUDE
Economic
impacts Loss of markets
A significant knock-off effect can be expected with the
unavailability of products of Use- 2 in Stago’s portfolio
Millions to tens
of millions of
Euros
Human
health
impact
Impacts on human health From a global point of view, the “non-use” does not
involve an overall reduction of risks for workers. -
Wider
impacts
Impact on the society
health system
The “non-use” scenario will generate strong impacts on
the health system of European and non-European
countries
Millions of
patients
impacted
Analysis of Alternatives – Socio-Economic Analysis
Diagnostica Stago Use-2 73
6. CONCLUSION
6.1. Comparison of the benefits and risks
No benefits/risks assessment can be performed for this substance. Nevertheless, the
different documents show that:
✓ the level of exposure is extremely low compare to
➢ the benefits for Stago company ([500M-5B1m)})
➢ the global society health system (millions of patients impacted
worldwide)
6.2. AoA-SEA in a nutshell
Analysis of Alternatives – Socio-Economic Analysis
Use-2 Diagnostica Stago 74
6.3. Information for the length of the review period
Given the arguments put forward, and in order to develop, implement and validate
alternatives for Use-2, Stago applies for a twelve-year review period.
6.4. Substitution effort taken by the Applicants if an
authorisation is granted
If an authorisation is granted, Stago will pursue the substitution process described
in section 4.1.
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8. ANNEX – JUSTIFICATIONS FOR
CONFIDENTIALITY CLAIMS
Confidential business information was blanked out in the public version in order
to preserve the confidentiality of strategic data of the present AfA.
The following table provides a justification for confidentiality of the blanked-out data
of this document.
BLANKED OUT
ITEM REFERENCE
PAGE
NUMBER JUSTIFICATION FOR CONFIDENTIALITY
#1 8, 58,59, 71,
72, 73
Strategic data: the blanking of these data is made
necessary by the blanking of data concerning the
profits of the Applicants.
#2 30 Strategic data: the blanked-out data concern
innovation and cannot be publicly disclosed.
Table 50. Justifications for confidentiality claims
Please note that, wherever possible, and in order not to affect the understanding
of the application, an effort was made to provide range of values for key confidential
data. These data ranges are presented in square brackets, e.g. [10-100].
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9. APPENDIXES
9.1. ISO 9001:2015 certificate
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9.2. ISO 14001:2015 certificate
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