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

Analysis of Alternatives – Socio-Economic Analysis

Use-2 Diagnostica Stago 2

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



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



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



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



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



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



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.



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.



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)



- 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.



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.



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



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.



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



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



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



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.



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.



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



- 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.



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



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


Diagnostica Stago Use-2 25

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



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



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



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.



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.



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.



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



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.



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:



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



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/



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



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



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



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



- 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



- 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.



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



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



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



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



- 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.



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.



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

http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32017R0746&from=EN



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



comparison with actual patients’ plasma

Mix of Tergitol TMN 10 and

Tergitol TMN 6 (70/30) DOW



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



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



- 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 ≈



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:



- 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



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



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.



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



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.



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.



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.



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.



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.



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.



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



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


ultraosonography, lung scan and helical

CT

36 2,447


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



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.



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



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



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)



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”



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€



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



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



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



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].



9. APPENDIXES

9.1. ISO 9001:2015 certificate



9.2. ISO 14001:2015 certificate

analysis of alternatives socio-economic analysis - …

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