SOCIO-ECONOMIC ANALYSIS

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Public Version

Legal name of Applicant(s): Abbott Diagnostics GmbH

Submitted by: Abbott Diagnostics GmbH

Substance: 4-(1,1,3,3-tetramethylbutyl)phenol, ethoxylated

Use title: Professional use as a surfactant, in Wash Buffer components used in conjunction with Fluorescence In Situ Hybridisation (FISH) test kits and/or their Laboratory Developed Test (LDT) equivalents, in clinical diagnostic use for medical analysis of human tissue and blood samples to identify characteristic genetic abnormalities related to specific disease conditions.

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List of tables

Table 2-1: Annex XIV substance details ... 10

Table 2-2: FDA-approved Companion Diagnostics by the Applicant ... 15

Table 2-3: EEA sales of the Applicant’s FISH products in 2017 ... 21

Table 2-4: 4-tert-OPnEO EU consumption by the Applicant until Sunset Date (in kg per year) ... 23

Table 2-5: Incidence, mortality and 5-year prevalence of different types of cancer in Europe in 2018 ... 25

Table 2-6: Range of environmental concentrations (calculated) ... 27

Table 2-7: Duration of individual R&D phases ... 30

Table 2-8: Potential Non-use Scenario assessment ... 31

Table 3-1: EU consumption of tert-OPnEO by the Applicant’s customers after Sunset Date (in kg 4-tert-OPnEO per year) ... 40

Table 3-2: FDA-approved Companion Diagnostics by the Applicant ... 43

Table 3-3: Comparison of Hazard Classification of 4-tert-OPnEO and 4-tert-OP ... 45

Table 3-4: EU revenue and profit from FISH products (in € million) ... 47

Table 3-5: Applicant’s employees relevant to manufacturing and sales of FISH assays ... 50

Table 3-6: Calculation of duration of unemployment in Germany ... 52

Table 3-7: Calculation of scarring costs for the applicant’s employees (in €) ... 53

Table 3-8: Calculation of scarring costs for the applicant’s employees ... 54

Table 4-1: Summary of impacts from a refused authorisation ... 57

Table 4-2: Comparison of impacts during the review period ... 58

Table 4-3: Comparison of impacts per kg of 4-tert-OPnEO emissions prevented in the NUS for different net profit margins ... 60

List of figures

Figure 2-1: Timeline for substitution of 4-tert-OPnEO from wash buffer in Applicant’s FISH assays……….36

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LIST OF ABBREVIATIONS

4-tert-OPnEO 4-(1,1,3,3-tetramethylbutyl)phenol, ethoxylated

ALK Anaplastic lymphoma kinase

ALL Acute Lymphocytic Leukaemia

AoA Analysis of Alternatives

ASCO American Society of Clinical Oncology

CDx Companion Diagnostics

CGH Comparative Genomic Hybridisation

CISH Chromogenic in situ hybridisation

CLL Chronic Lymphocytic Leukaemia

CLP Classification, Labelling and Packaging

CML Chronic Myeloid Leukaemia

CMO Contract Manufacturing Organisation

CRO Contract Research Organisation

DAPI 4′,6-diamidino-2-phenylindole

ECHA European Chemicals Agency

ERR Exposure-Response Relationship

FDA Food and Drug Administration

FISH Fluorescence In Situ Hybridisation

FTE Full Time Employees

HER2 Human Epidermal Growth Factor Receptor 2

IDH2 Isocitrate Dehydrogenase (NADP(+)) 2, Mitochondrial)

IHC Immunohistochemistry

ISH In Situ Hybridisation

IUO Investigational Use Only

IVD In Vitro Diagnostic Device

IVDD In-Vitro Diagnostics Directive

IVDR In-Vitro Diagnostics Regulation

LAD Latest Application Date

MDS Myelodysplastic syndrome

MLL Mixed-Lineage Leukaemia

NGS Next Generation Sequencing

NUS Non-Use Scenario

OECD Organization for Economic Cooperation and Development

PCR Polymerase Chain Reaction

PNEC Predicted No Effect Concentration

qPCR Quantitative Polymerase Chain Reaction

SEA Socioeconomic Analysis

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REACH Registration, Evaluation, Authorisation and Restriction of Chemicals

SD Sunset Date

STP Sewage Treatment Plant

SVHC Substance of Very High Concern

UVCB Chemical Substances of Unknown or Variable Composition, Complex Reaction Products and Biological Materials

WHO World Health Organization

WTP Willingness to Pay

WWTP Wastewater Treatment Plant

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Executive summary of Socio-economic Analysis

1.1 Background

4-(1,1,3,3-tetramethylbutyl)phenol, ethoxylated, covering well-defined substances and UVCB substances, polymers and homologues (“4-tert-OPnEO” or “the substance”) was included in Annex XIV of EU Regulation 1907/2006 (REACH), also known as the Authorisation List, because it was identified as meeting the criteria of Article 57(f) of REACH, through their degradation to 4-(1,1,3,3-Tetramethylbutyl)phenol, which is known to be an endocrine disruptor for the environment. 4-tert-OPnEO thus has probable serious effects on the environment, which give rise to an equivalent level of concern to those of other substances listed in points (a) to (e) of article 57 of REACH.

4-tert-OPnEO is contained as a detergent in reagents used to support Fluorescence In Situ Hybridisation (FISH) testing in approximately 400 of the Applicant assays, of which more than 100 ( ) are classified as in vitro diagnostic devices (IVDs). FISH kits are used by medical laboratories and clinics in the EU for diagnosing and determining the type of cancer. Some of the FISH products are Companion Diagnostics (CDx) to certain targeted therapies for various solid tumour cancer and leukaemia types. CDx are approved diagnostic tests that can be used by doctors to prescribe targeted treatment to cancer and leukaemia patients. Some FISH assays are the only approved CDx tests for certain drugs, e.g. for chronic lymphocytic leukaemia and non-small cell lung cancer.

The Applicant’s manufacturing plant is located outside the EU and all the FISH kits are imported in the EU through the Applicant’s distribution centre. The Applicant’s EU operations also include commercial offices in several EU countries.

1.2 Discussion on the length of the review period

The requested review period for the use of 4-tert-OPnEO in the Applicant’s FISH kits is 7 years. The Applicant has identified a potential alternative, but it will not be possible to substitute 4-tert-OPnEO in their FISH kits before the Sunset Date.

The potential alternative has been identified based on literature review, but the Applicant must run a series of validation tests on all their FISH assays before the alternative’s suitability can be verified and proceed to submitting the necessary regulatory approvals for all FISH products. 4-tert-OPnEO is an essential component of the FISH kits, so the Applicant must carefully test the new solution. After regulatory approval is received, the Applicant’s customers will have to run tests with the new FISH kits to calibrate them and associate them with their previous standards. As explained in the Analysis of Alternatives, the entire substitution process for all FISH assays is expected to take at least 7 years. In addition to this process, the review period coincides with the implementation of the new IVD Regulation (Regulation (EU) 2017/746) in May 2022. The Applicant is reviewing the updated requirements to determine whether additional testing, documentation and/or approvals will be required to place an IVD on the market in the EU. The change in the IVD classification for additional data generation, notified body review and approval is anticipated to require additional time during the design verification and regulatory submission phases. As the Notified Bodies’ resources are limited, and with all IVD manufacturers submitting products within the narrow implementation window, it is expected that the regulatory reviews for the resubmission will be extended. At this time, the uncertainty of the impact of the conversion from the IVD Directive to the IVD Regulation can only be speculated, but it is expected to add to the length and complexity of the substitution process.

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1.3 Balance of benefits and costs

If authorisation is refused, it will prevent total emissions of less than 100 kg ( kg) 4-tert-OPnEO over the whole 7-year review period. These emissions are spread over the Applicant’s 100-1,000 (over ) of customers in several EU countries. As there is no manufacturing of FISH kits within the EU, any non-EU emissions will not be affected by a refused authorisation. The environmental concentrations relevant to these emissions, as calculated in the CSR, are very low, in the ng/l range. Furthermore, it is possible for the Applicant’s low-volume usage customers to batch their tests to reduce the quantities of 4-tert-OPnEO used and it is believed that this is practised by larger customers, who run a higher volume of tests.

The Applicant’s FISH IVD kits are routinely used in oncology to detect, classify and monitor the progress of cancer in patients. It is a versatile and well-established method and many doctors ask for FISH test results before they decide to prescribe a treatment to their patients. Customers using FISH products will have to either develop or utilise different techniques (and install different equipment) to continue offering this service. This is a process that requires time and can be costly for the customers as they will need to purchase new equipment and perform new regulatory submissions. Furthermore, one of the main advantages of FISH is the method’s versatility, so it is easier to train laboratory technicians in FISH to cover a larger number of assays and cancers. Noteworthy, the Applicant is providing the only approved CDx for personalised treatment of chronic lymphocytic leukaemia and non-small lung cancer, while also developing new CDx that will be unique

. CDx allows doctors to determine the suitability of these drugs for cancer patients and to prescribe appropriate targeted treatment. If FISH were not available, many cancer patients could have less effective treatment and increased negative health outcomes. Therefore, lack of FISH testing could lead to more misdiagnoses and incorrect treatment prescriptions, if no equivalent tests are available.

If an authorisation is not granted, during the requested 7-year review period, the Applicant is expected to lose €20-200 million (€ million) in sales of FISH products in the EU. The lost profits during the review period will be approximately €1-10 million (€ million) in end of 2021 prices, using a default 4% discount factor. Comparing the known economic impacts to the emitted quantities of 4-tert-OPnEO shows that a refused authorisation would have an annual cost of approximately €135,000 per emitted kg of prevented 4-tert-OPnEO emissions.

In case of a refused authorisation, it is expected that 5-50 ( ) employees will lose their job in the Applicant’s manufacturing plant outside of the EU and approximately 10-100 ( ) employees in EU facilities. Of those, 5-50 ( ) currently work in the distribution centre in Wiesbaden, Germany and the remaining in commercial offices in other EU countries.

Overall, the impacts from a refused authorisation are expected to be severe for all affected stakeholders; including the Applicant, the users of FISH tests in the EU and the patients relying on these tests for diagnosis and therapy. On the other hand, if authorisation is granted, emissions to the environment would continue to be very low as the FISH kits would be used by hundreds of individual customers spread across the EU.

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Aims and scope of the SEA

2.1 Aims and scope of the SEA

2.1.1 Regulatory background for 4-tert-OPnEO

4-(1,1,3,3-tetramethylbutyl)phenol, ethoxylated, covering well-defined substances and UVCB substances, polymers and homologues (henceforth “4-tert-OPnEO” or “the substance”) was included in Annex XIV of EU Regulation 1907/2006 (REACH), because it was identified as meeting the criteria of Article 57(f) of REACH, through its degradation to 4-(1,1,3,3-Tetramethylbutyl)phenol, which is known to be an endocrine disruptor for the environment. 4-tert-OPnEO thus has probable serious effects on the environment, which give rise to an equivalent level of concern to those of other substances listed in points (a) to (e) of article 57 of REACH.

4-tert-OPnEO was included in the 5th_{ECHA recommendation of substances for inclusion in the}

Authorisation List, on 6 February 2014[1]. The substance was included in the Authorisation List on 4 July 2017 [2]. The Latest Application Date (LAD) for 4-tert-OPnEO is 4 July 2019, 24 months after inclusion in the Authorisation List. The Sunset Date (SD), beyond which no use without an Authorisation is allowed, is on 4 January 2021, 18 months after the LAD.

Table 2-1 shows the Annex XIV entry for the substance.

Table 2-1: Annex XIV substance details Entry

No Substance Intrinsic properties

Latest Application Date Sunset Date 42 4-(1,1,3,3-Tetramethylbutyl) phenol, ethoxylated (covering well-defined substances and UVCB substances, polymers and homologues

Endocrine disrupting properties (Article 57(f) - environment)

4 July 2019 4 January 2021

Source: Annex XIV, Official Journal of the EU [2]

2.1.2 SEA requirements and aims

4-Tert-OPnEO is used by the Abbott Molecular Division in 1-10 general reagents used to support FISH testing in 10-100 ( ) FISH probe kits, covering approximately 400 assays, of which more than 100 ( ) are classified as IVDs. FISH kits are used for diagnosing cancer, determining the type of cancer of a patient, and for prescribing Companion Diagnostics (CDx) therapies. The products enter the EU market through the Applicant’s distribution centre in Wiesbaden and are used by professionals in laboratories, hospitals, academic centres and cancer care facilities that test and treat cancer patients. The use is carried out by the Applicant’s customers. This is an upstream application with the intention to cover all EU downstream users. The application for authorisation (AfA) is submitted by the EU distribution centre legal entity, Abbott Diagnostics GmbH (“the Applicant”), which is the importer of the substance in the EU.

The substance is used as a surfactant in the wash buffers of FISH assay kits, to wash unbound DNA and other unbound biological components originating from the specimen, including proteins. It also removes critical non-specific signals to ensure the precision, accuracy and specificity of the test. The use of sufficiently high concentration of an effective surfactant is considered essential to the correct functioning of the post hybridisation process and the generation of accurate results. The substance has

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The endocrine disruptive effects of the substance’s breakdown products do not have an identified threshold. As it is not possible to show that risks from use of 4-tert-OPnEO are adequately controlled, this AfA will follow the socio-economic route. The purpose of the Socioeconomic analysis (SEA) report is to show that the benefits of continued use of the substance in the wash buffer for FISH assays far outweigh the risks, according to articles 60(3) and 60(4) of REACH, during the requested review period of 7 years, and that a refused Authorisation is not a cost-effective option to prevent emissions of 4-tert-OPnEO when all impacts are considered.

2.1.3 Temporal and geographical boundaries (scope of the SEA)

Temporal boundaries

The SEA will examine the impacts of the decision on authorisation from the Sunset Date to the end of the review period, after which 4-tert-OPnEO will be substituted in all FISH products.

The Applicant is looking for alternatives for 4-tert-OPnEO in the use within all the FISH assay kits. Some potential alternatives, including Polysorbate 20, have been identified, but the requirements for thorough testing to receive regulatory authorisation of the new products will not allow for full substitution of 4-tert-OPnEO by the Sunset Date. The efforts for identifying alternatives are described in more detail in the Analysis of Alternatives (AoA).

FISH IVD reagents and test kits are subject to a rigorous and lengthy change process. This is due to verification and regulatory approval processes that are required to ensure patient safety and guarantee accurate and reliable test results. Consequently, the introduction of any change requires a multitude of research and development and revalidation activities as well as global regulatory re-approval processes that can accumulate to timeframes of up to 12 years.

4-tert-OPnEO is used in the entire range of the Applicant’s FISH products. Therefore, there is a need for substitution in all products for approximately 400 assays that use the wash buffer. Each product will have to undergo thorough internal design verification and validation testing. Following that, the manufacturer of FISH products will have to prepare and submit applications for regulatory approval and marketing authorisation in the EU. Considering the significant number of affected products, the complexity and length of the required substitution and marketing authorisation processes and the need to allow for customer conversion by using up all remaining material with 4-tert-OPnEO, it will not be possible to substitute 4-tert-OPnEO before the Sunset Date. The Applicant thus has calculated that substitution of 4-tert-OPnEO from the FISH products will be achieved 7 years after the Sunset Date. Substitution requires considerable resources and time and it will take approximately 11 years to complete for all products. Work on identification of a suitable alternative started in 2014 and it is expected that 4-tert-OPnEO will be completely substituted by the end of 2027, as discussed in Section 4.3.2 of the AoA.

Geographical boundaries

The Applicant’s FISH assay kits are produced outside of the EU and are distributed to EU customers through the distribution centre in Wiesbaden. Only the EU use of the kits is of relevance to this AfA, but the decision will also affect non-EU stakeholders. The manufacturer of the kits, Abbott Molecular Division, is based in the US and all production of FISH kits takes place there. Any disruption in the EU supply of products caused by a refused authorisation will impact the non-EU manufacturing plant(s).

In case of a refused authorisation, there will also be impacts to supply within the EU, particularly to the Applicant’s customers, i.e. medical laboratories, hospitals, academic centres and cancer care facilities, and to patients. Without the access to the Applicant’s kits, these health care facilities will be unable to

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test patient samples for certain cancer types. Patients within the EU will be affected, as FISH testing is considered an essential tool by doctors in the correct diagnosing of cancer and particularly as Companion Diagnostics for personalised medicine [3]. Finally, EU employees of the Applicant, mostly in commercial and marketing operations will also be negatively affected if sales of FISH marketing in the EU stop.

According to ECHA’s guidance on preparation of socio-economic analysis for an AfA [4], the focus of the SEA should be on EU impacts, but non-EU impacts should be considered as well if they are considered significant. In this AfA, there will be impacts both in and outside the EU, so they will both be examined.

2.2 Definition of the “Applied-for Use” Scenario

2.2.1 The Applicant

Abbott is a US headquartered, global healthcare company that produces and supplies diagnostics products, medical devices, nutritionals and branded generic pharmaceuticals to over 150 countries. It employs app. 103,000 employees, and in 2018 had a combined sales value of $30.6 billion [5].

Abbott Molecular Division is the division of Abbott that manufactures and sells FISH assay kits. It is a market leader in the EU for these products. Its manufacturing site is based in Des Plaines, Illinois in the US and the FISH products are sold around the world through the commercial hub in Wiesbaden, Germany.

Abbott Diagnostics GmbH (the Applicant) is the main distribution centre for customers located within and outside the EU and provides products to distribution centres located outside the EU. It is located in Wiesbaden, Germany, and is the site applying for downstream use of 4-tert-OPnEO in FISH kits used by professionals. The Applicant produces and sells approximately 400 FISH assays in the EU, carried out using 10-100 ( ) different FISH probe kits. The products are distributed to hundreds of customers in the EU by the Applicant, who is applying on behalf of its EU customer base, professional end users of FISH assay test kits.

2.2.2 Importance of the Applicant’s FISH assays

Fluorescence In Situ Hybridisation

Fluorescence In Situ Hybridisation (FISH) is a cytogenetic technique, developed in the early 80s, which is used to detect and locate the presence or absence of specific DNA sequences on chromosomes (e.g. gene or chromosome copy number variations, rearrangements or translocations). It is used, for example, to diagnose and monitor genetic conditions associated with oncological disease.

It uses fluorescent DNA probes that bind onto specific parts of the chromosome. These probes are then detected with fluorescence microscopy, to find out where they have bound on the chromosome. This is particularly useful to researchers who wish to identify where a particular gene or DNA sequence falls within an individual’s chromosome or to identify chromosomal abnormalities and other genetic mutations.

A FISH assay is a well-established technique. It can be used to discover deletions or duplications in the DNA that cannot be seen under certain microscopes and to detect the amounts of a certain type of chromosome mutation that may be present.

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The FISH methodology involves a standardised procedure for each specific substance examined. An assay should not be confused with a product supplied by the Applicant. Each assay requires certain components (or reagents) for it to be carried out and many assays use the same components, albeit in different ways or concentrations. Therefore, a product may be used to run several assays for different types of cancer.

A typical FISH assay involves the following steps (see section 2.2.5 of the AoA for more details): • If necessary, any applicable assay-specific pre-treatment steps are performed.

• The specimen and FISH DNA are denatured at high temperature, so that the two sets of an individual’s complementary DNA strands separate.

• After denaturation, the single-stranded fluorophore-labelled DNA probe can anneal to the complementary target sequence within a specimen attached to a microscope slide (hybridisation).

• After hybridisation, the unbound probe is removed by a series of washes, after which the nuclei are counterstained with DAPI, a DNA-specific stain that fluoresces blue.

• Hybridisation of the probe on the specimen’s DNA is detected by fluorescence microscopy.

Applications of FISH assays

FISH is used for several diagnostic applications, but it is also widely used in research. The Applicant offers FISH products for two main types of analysis, namely genetics and oncology. In genetics, FISH assays are used to pinpoint the location of specific DNA sequences in a chromosome. FISH was among the techniques used in the mapping of the human genome and it is still used in mapping genomes of other organisms [6].

The main use of FISH in recent years has been in clinical diagnosis, particularly for cancer. If there are mutations on the target chromosome, the probe will detect them. If a deletion has occurred, the chromosome will not hybridise, while if there has been an amplification, it will hybridise in more than one location. FISH assays for oncology can detect DNA abnormalities in the patient’s specimen in locations that have been associated with a specific type of cancer.

The scope of FISH applications has broadened in recent years, with the discovery of numerous disease-related genes, such as HER2 amplification for breast cancer, ALK rearrangement for non-small cell lung cancer and BCR/ABL1 translocation for myeloid leukaemia. FISH is now considered as an important component in diagnosis of genetic diseases, haematological malignancies and solid tumours, and in personalised medicine [3].

Results from FISH testing can be used to support treatment decisions on patients with different types of cancer. It can be used to support decisions during every step of diagnosis:

• Identifying predisposition and risk of developing cancer, e.g. due to genetics or family history; • Diagnosing the type and subtype of cancer of the patient;

• Describing severity of the cancer and predicting the chances of survival;

• Choosing the appropriate therapy or treatment for the patient, based on the type and subtype of cancer;

• Monitoring the patient after therapy for the possibility of recurrence of cancer; • Re-evaluating the type and subtype of cancer in case of reappearance.

Correct and timely identification of cancer and of the responder / non-responder groups can be crucial for determining suitability for prescription of approved therapies or enrolment in clinical trials, where

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no approved therapy exists. This can increase the patient’s chances for therapy, successful treatment and survival.

FISH detection with fluorescence microscopy is a qualitative technique, giving only a yes / no result. It is used to detect the presence or absence of a signal, but not, for example, the intensity of the observed signal against a standard curve. The researcher counts the number of FISH signals of each colour present in each cell.

FISH can be used for the diagnosis of different types of cancer. The products offered by the Applicant fall under the following categories, all of which use 4-tert-OPnEO:

• Haematological cancer: leukaemia (Acute Lymphocytic Leukaemia - ALL, Mixed-Lineage Leukaemia - MLL, Chronic Myeloid Leukaemia - CML, Chronic Lymphocytic Leukaemia - CLL), multiple myeloma, myelodysplastic syndrome (MDS), non-Hodgkin’s lymphoma and sex-mismatched bone marrow transplantation.

• Solid tumour: bladder cancer, breast cancer, gliomas, lung cancer, melanoma, prostate cancer, sarcomas, etc.

The Applicant also offers FISH kits and probes for identification and characterisation of chromosome anomalies in pre-implantation, prenatal and postnatal genetics testing and research. The kits and probes can be used to detect such abnormalities that can cause genetic diseases and advise medical professionals on clinical decisions, thus improving the quality of life of the patient.

Some of the FISH assays offered by the Applicant are unique in their function and utility and are the only available such test to assist the doctors in diagnosing some types of cancer. The Applicant is offering the only FDA approved urine-based molecular test for bladder cancer. This test is intended for use in conjunction with current standard diagnostic procedures to aid in the diagnosis of bladder carcinoma in patients with haematuria and subsequent monitoring for tumour recurrence in patients previously diagnosed with bladder cancer. The test has also been CE marked and is available in the EU to aid in the diagnosis of bladder cancer and subsequent monitoring of tumour recurrence.

The FDA approved FISH in 2001 for use in conjunction with cystoscopy to monitor for recurrence among those with previously diagnosed bladder cancer. Since then, several studies have confirmed the usefulness of including FISH analysis when monitoring for recurrence. Low-grade bladder cancers rarely demonstrate changes that can be detected by FISH analysis. Thus, a clinical benefit of FISH is its ability to identify the more aggressive bladder cancers earlier. Identifying the tumour type that may eventually become life-limiting allows the patient and health care providers to initiate a treatment plan that includes scheduled surveillance and pro-active or appropriate treatment [7].

FISH and companion diagnostics for personalised medicine

Cancer patients do not respond in the same way to any specific treatment. Their individual responses can often depend on various characteristics in each patient’s genes. So, identification of an appropriate treatment for each patient is a delicate exercise. As cancer is generally caused by changes (mutations) in a person’s genes (oncogenes), there is an increasing need for testing gene variants by doctors examining patients for cancer. For example, in certain types of cancer, e.g. breast cancer, there are certain types of drugs that are known to work only for women with particular genetic variations [8].

Personalised medicine is a relatively novel approach to healthcare, moving away from traditional ‘one size fits all’ approach. It has the potential to tailor therapy with the best response and highest safety margin to ensure better patient care [9]. Medical decisions are tailored to the individual patient, based

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on their susceptibility to disease or response to a particular treatment. A key component of personalised medicine includes testing of a patient’s genetic information to help identify targeted treatment options. CDx are laboratory tests, developed in parallel with particular drugs to help doctors decide which treatments to offer to patients. The companion diagnostic is thus essential to the safe and effective use of the drug [10]. The tests are used to select which patients should be treated with that particular drug. Without the CDx, it is not possible to prescribe the particular drug. All of the Applicant’s CDx assays have results linking to drug outcome.

Multiple companion diagnostic tests can be developed for a drug, but there are still some drugs for which only a single CDx exists. In the EU, the use of CDx to measure predictive biomarkers is recognised as a well-established method to select the right treatment for patients. The EU requires that a validated test is on the market for the personalised drugs and the drug registration points to the diagnostic test. Currently, most of the CDx only require self-declaration before entering the market, but this will change when the In-Vitro Diagnostics Regulation (IVDR) comes into force in 2022 [11].

As of October 2018, the FDA in the US had approved 35 CDx tests by several companies, including five of the Applicant’s. All the tests shown in Table 2-2 are (self-declared) CE marked and are marketed in the EU mentioning the therapies they can be used as CDx for.

Table 2-2: FDA-approved Companion Diagnostics by the Applicant

Name Trade Name (generic) Target disease Comments

Abbott RealTime IDH1 Tibsovo (ivosidenib) Acute myeloid leukaemia Not FISH - No CDx from a different company available

Abbott RealTime IDH2 Idhifa (enasidenib) Acute myeloid leukaemia

Vysis CLL FISH Probe kit Venclexta (venetoclax) B-cell chronic lymphocytic leukaemia

No CDx from a different company available

PathVysion HER-2 DNA

Probe kit Herceptin (trastuzumab) Breast cancer Several CDx available Vysis ALK Break Apart

FISH Probe kit Xalkori (crizotinib) Non-small cell lung cancer

The only approved FISH method – Several other CDx available

Source: FDA (2018), List of cleared or approved Companion Diagnostic Devices (In Vitro and Image tools). Available online at: https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm, accessed on 4 November 2018

As can be seen in Table 2-2, for B-cell chronic lymphocytic leukaemia, the Applicant is the only manufacturer offering CDx for predictive markers. For non-small cell lung cancer, the Applicant is the only manufacturer offering FISH CDx.

The Applicant is also developing three new CDx products, for other cancer types (

), for which they will be the only option when they become commercial. The former is expected to be available before the Sunset Date and will be the only CDx for that therapy. These products are expected to be launched in the EU in 2019 and 2020. They are proprietary at the moment. Furthermore, clinical studies with existing products (e.g. Vysis ALK) are currently underway to expand the products’ scope by adding more drugs.

According to data presented in the 2017 ASCO Quality Care Symposium, patients who were tested for ALK biomarkers before initiating first-line treatment for non-small cell lung cancer were more likely to receive appropriate targeted therapy than if they were tested after the first-line treatment was initiated. Specifically, for patients with a positive test result available prior to initiation of first line treatment, 94% of ALK+ patients received the appropriate targeted therapy [12].

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Advantages of FISH method

FISH was developed in the late 1980s as a technique that could detect trisomies and translocations in metaphase spreads and interphase nuclei. Its high sensitivity and specificity make it a powerful technique with numerous applications, including gene mapping and oncology [13]. It is a technique that can provide rapid turnover with high efficiency of hybridisation and detection.

One of the biggest advantages of the FISH method is its versatility. There is no single FISH technique, but a number of variations, each suitable for detecting different chromosomal aberrations / abnormalities. Some aberrations / abnormalities in specific chromosome regions have been associated with certain types of cancer, haematological conditions and other genetic effects (e.g. developmental conditions). Therefore, accurate and specific detection of the aberrations allows for better identification of a patient’s condition. FISH methods can target the specific genes or chromosome regions with the same equipment, just by using different probes for each one. This versatility is very important for laboratory personnel, because they can specialise on a single method that can produce comparable, reproducible results, instead of having to operate multiple techniques, often on the same patient sample.

FISH can also identify several regions of a gene simultaneously by using fluorescent DNA probes with different colours that bind on different chromosome regions. It can colour the whole chromosome complement in a single hybridisation, through labelling each chromosome with a different combination of fluorophores. The main application for this technique is in the characterisation of unbalanced translocations, complex chromosomal rearrangements and marker chromosomes in solid tumours [14].

The Applicant’s FISH assay kits include direct-labelled probes, which can produce high intensity signals, making it easier for the user of the kit to identify and count them. Furthermore, their assays provide for lower background noise, making the detection of signals easier. This is very important for the accuracy of the test as the method is qualitative (signal present / absent). Because of this, the detection of the signal is critical for the process, and the Applicant’s assays can provide for better, easier detection and thus a clearer result for use by doctors.

FISH State of the Art review by the Applicant

A systematic review of scientific literature conducted by the Applicant showed that the scientific community still considers FISH as a state-of-the-art method. The review was carried out as per the requirements to comply with the provisions of the IVDD. A State-of-the-Art review is required every three years after the first time that the products receive marketing authorisation.

The Applicant performed literature searches on papers referencing FISH or variants, within three subject areas:

• Search A: 79 articles on Clinical utility of FISH

• Search B: 109 articles on FISH comparison articles (against competing technologies) • Search C: 249 articles on FISH diagnose and detect

The search results from all three searches were manually reviewed to determine relevance to the state-of-the-Art assessment. All results have been documented in an Electronic Lab Notebook.

A 2017 review article critically evaluated the use of FISH in clinical oncology and concluded that [15]: “In comparing a regular application of clinical diagnosis, the FISH is much more accurate and straightforward, as well as reliable, than the other molecular profiling techniques, e.g. array-based comparative genomic hybridisation, single nucleotide polymorphism (SNP), etc.”.

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The review article did not conduct a meta-analysis of FISH with other conventional techniques.

FISH techniques can also study chromosomal aberrations in non-dividing cells, which allows for chromosomal mapping of commonly deleted or amplified regions, providing a starting point for one or more genes involved in growth control in certain tumour types. Amplification of oncogenes is an important factor in carcinogenesis and is often correlated to poor prognosis. Therefore, identification and characterisation of genes subject to amplification can provide valuable tools for evaluation or prognosis of human cancer [13].

Overall, the state-of-the-art review carried out by the Applicant concludes that:

FISH technology, including specific instances where [the Applicant’s] FISH products were used, continues to offer significant advantages in the direct visualisation of chromosomal rearrangements, copy number variation, mosaicism and tissue heterogeneity not possible with other methods.

Nevertheless, many of the published studies that were reviewed comment that no single assay methodology is considered superior to all others as a truly superior method for any or all clinical conditions. The authors’ clinical practice recommendations often pointed to the use of multiple assay methods in combination as the optimal way to ensure the best possible management outcomes.

Other technologies and future developments

FISH is an established technique which has been continuously improving and implementing new advances to broaden its scope and increase its sensitivity. COBRA-FISH, M-FISH, and SKY are some of the most advanced FISH-based approaches allowing for simultaneous staining of each of the 24 human chromosomes with a different colour [16].

Comparative Genomic Hybridisation

Comparative Genomic Hybridisation (CGH) is another development of the FISH technique, which allows for analysing chromosomal imbalances and for examining possible correlations between findings and tumour phenotypes. It can be used as a discovery tool, because it does not require prior knowledge of the chromosomal imbalance involved. This has made it quite effective in the analysis of haematological malignancies, such as chronic lymphocytic leukaemia and non-Hodgkin lymphoma [17]. Furthermore, it is a technique that can be easily automated for high-throughput applications.

The major advantage of CGH over standard FISH techniques is that only the DNA from the tumour cells is needed for analysis, avoiding the difficulties of obtaining metaphase chromosomes with good morphology and resolution for the analysis. Although chromosomal CGH has increased the potential for identifying new chromosomal abnormalities, this technique is time consuming and does not significantly improve resolution (> 3 Mb) compared with routine G-banding chromosome analysis.

In an attempt to overcome some of the limitations associated with traditional CGH, investigators have developed a newer method that combines the principles of CGH with the use of microarrays [18]. The primary advantage of array-CGH (aCGH) is the ability to simultaneously detect aneuploidies, deletions, duplications, and/or amplifications of any locus represented on an array. In fact, one assay using this technique could be equivalent to thousands of FISH experiments, with the attendant savings in labour and expense. In addition, aCGH has proven to be a powerful tool for the detection of submicroscopic chromosomal abnormalities in individuals with idiopathic mental retardation and various birth defects.

However, CGH is not validated for wide diagnostic use. It is mainly used for research and, to the Applicant’s knowledge, has not been used in therapeutic applications. So, it is unlikely that CGH assays will be available as an alternative to the Applicant’s FISH assays.

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Immunohistochemistry

Immunohistochemistry (IHC) is the utilisation of monoclonal and polyclonal antibodies for the detection of specific antigens in tissue sections. IHC is an important application of monoclonal as well as polyclonal antibodies to determine the tissue distribution of an antigen of interest in health and disease. It is widely used for diagnosis of cancers because specific tumour antigens are expressed de novo or up-regulated in certain cancers. IHC requires the availability of biopsies; these are processed into sections with a microtome and then the sections are incubated with an appropriate antibody. IHC has a wide range of applications, including prediction of response to therapy in carcinoma of breast and prostate, confirmation of infectious agents (e.g. cytomegalovirus, hepatitis B, etc.), in genetics and brain trauma [19].

In breast cancer diagnosis, a number of papers illustrate that IHC technology can provide roughly similar results to FISH for detection of HER-2 gene amplification and ALK gene rearrangement, but that FISH remains preferable for these markers to many clinical diagnostic labs (for the reasons noted above) [20, 21, 22, 23]. IHC performance can vary between vendors due to the different performance characteristics of the primary antibody reagents utilised, and IHC is open to subjectivity of interpretation which may lead to an unacceptably high rate of equivocal results. Furthermore, competitive IHC assays acknowledge the limitations of IHC and that precautions in the lab must be used to reduce false positive and false negative results. Guidelines for lung and breast cancer call out use of IHC and FISH as an algorithm, where FISH is often used to confirm IHC results. Thus, having one test and not the other would not enable compliance with medical practice guidelines.

Moreover, for IHC assay development, each new unique analyte requires the laborious generation of a correspondingly unique and specific antibody reagent before an IHC assay can be developed; whereas FISH assay development only requires knowledge of the target chromosomal DNA sequence(s), which are now generally available from genomic sequencing databases.

Polymerase Chain Reaction

Polymerase chain reaction (PCR) is a technique that creates unlimited copies of DNA from a single strand using polymerase enzymes, primers (small DNA sequences that determine the DNA to be amplified) and multiple thermal cycles [24].

There are some cases in which PCR can be used for diagnosis, such as in the diagnosis of pulmonary tuberculosis, to replace the standard sputum smear microscopy method. PCR diagnostics can be used in multiplex assays - the amplification of multiple targets in a single PCR experiment by simply using multiple primer pairs. This can be useful in diagnosing infectious agents where symptoms are not easily characterised.

Real time PCR (qPCR) is a technique with potential in diagnostics. It works by using fluorescently-labelled oligonucleotide probes and monitoring the fluorescence after each cycle - the intensity of the signal reflects the amount of DNA amplified and the number of cycles at which the fluorescence is first detected is used to calculate the initial number of DNA molecules in the sample, once the system has been calibrated. It can be used to detect invasive fungal diseases, but has also potential to detect RNA viruses, such as HIV and Hepatitis C.

However, the technique has several limitations. The qPCR technique requires a sample of very good quality and, therefore, has increased requirements for sample preparation and relevant equipment. Most qPCR techniques are carried out by automated systems, but there are still requirements for significant human involvement in their standardisation and quality control.

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Next Generation DNA Sequencing

Next Generation DNA Sequencing (NGS) is a series of techniques that can rapidly sequence an individual’s DNA and could potentially replace FISH. However, this technique is not yet standardised. NGS has a significantly higher cost than FISH, in equipment and in running costs. Specific reagents (primers and dNTPs), flow cells/cartridges, large capital equipment and intensive computational software may pose as a barrier for entry for most clinical labs [25]. Some labs may also use multiple sequencing instruments in parallel to cross-reference results for confirmation.

NGS also requires highly trained specialised lab technicians and biostatisticians. Finally, it cannot be modified easily to detect new or different genetic alterations.

Discussion

None of the techniques discussed above, however (ICH, NGS, qPCR), offer the versatility of FISH, despite providing advantages in specific cases, such as, e.g. the diagnosis and monitoring of breast cancer. FISH is a standardised methodology, which can be used for a multitude of different tests [26].

Overall, the best current judgment based on the literature reviewed by this Applicant is that FISH remains an essential technique within the medical decision-making repertoire for clinical diagnostic laboratories. For example, FISH remains unparalleled in its ability to directly visualise tissue heterogeneity to distinguish cancerous cells from normal ones within solid tumour specimens. Furthermore, not all analytes currently well served by FISH have well-validated alternatives (whether by IHC, PCR, sequencing or any other techniques) that can be quickly implemented and then deliver high quality results. FISH is a highly versatile technique and is not easily substituted with a single alternative diagnostic method. Furthermore, the Applicant cannot state if alternative techniques are using 4-tert-OPnEO in the preparation of specimens, some literature refers to the use of 4-tert-OPnEO in the methodologies.

It is also common practice for labs to run the tests using multiple techniques, to have verification of the result from several sources, so FISH results may be required to verify the results of a different technique and vice versa.

FISH kits

The Applicant is supplying their customers with FISH assay kits, which contain all the necessary components to carry out the required analyses. These kits are modular products, which contain several separate components. Some of these components are specific to a particular assay, while others can be used in more than one.

The main components of a FISH assay are:

• A set of fluorescent DNA probes, which bind on the desired section of the chromosome and can be detected by microscope. The number and position of the probes in the treated specimen can indicate if abnormalities are present in the patient’s chromosomes and whether this is an indication of cancer or not.

• Wash buffer contains 4-tert-OPnEO. The solution is used to repeatedly wash the slides with the hybridised DNA specimen to remove the unbound probe before examination.

• Other reagents and chemicals, which do not contain 4-tert-OPnEO, are used to facilitate the hybridisation and the other reactions in the assay.

4-tert-OPnEO is only present as a surfactant in the wash buffer, which is used for washing the unbound DNA and other unbound biological components that originated from the specimen (including proteins).

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That way, non-specific signals are removed from the specimen and the test’s precision, accuracy and specificity are increased.

The wash buffer performs the same post-hybridisation functions in all FISH assays of the Applicant. Without the buffer, the visual inspection of the hybridised specimen with fluorescence microscopy would have a high amount of noise and would not produce reliable results.

FISH instruments

The Applicant manufactures and supplies automated FISH testing platforms to make processing of slides more streamlined and to fully automate FISH testing. These instruments can work with predefined protocols for different staining and specimen pre-treatment procedures. They are designed to be used with all FISH assays supplied by the Applicant and are specific to the Applicant’s products.

BioView is an instrument series used for automated FISH analysis for tissue and haematology FISH tests. The instruments have applications on several FISH assays, including bladder, breast and cervical cancer, as well as haematology tumours such as leukaemia, multiple myeloma and bone marrow transplantation.

FISH assays tend to involve a lot of manual handling of the slides with the samples. The Applicant provides instruments that automate and standardise this process, reducing manual intervention and potential for errors. Such instruments are Thermobrite, which allows for processing the slides with samples for hybridisation and VP2000, which allows for pre-treatment and staining of specimens.

These instruments may be supplied to customers using FISH as part of the contract or independently. They are not necessary for using the FISH assay kits, but they can increase the cadence of tests and reduce the possibility of errors by automating some of the steps in the FISH test process.

Regulatory requirements

FISH IVD kits have to pass a conformity assessment in the EU, to prove that their use is safe and that the assays perform as intended. Once the conformity assessment is passed, the supplier can self-certify the kits for CE-marking. The product will have to be labelled according to its intended use. If the kit can be used as a Companion Diagnostic kit, the label should provide information about that along with the overall indications for use.

Before a FISH assay is considered as a suitable CDx for a personalised treatment, the manufacturer must provide evidence from clinical trials that show correlation between the assessed biomarkers and the efficacy of the personalised treatment. This information is included in the FISH kit’s label, so that interested professionals will be aware of its indications.

FISH assays that are not considered IVD cannot be CE-marked by the supplier. It is the responsibility of the laboratory purchasing the assays to set up the test and validate the assay themselves.

FISH marketing constraints

FISH assay kits are mainly sold through contracts, which generally involve analytical services and do not refer to individual FISH kits or assays. Customers tend to purchase portfolios of FISH assays from a single supplier (in this case the Applicant) instead of purchasing individual kits from multiple suppliers. This reduces complexity, as the customer only has to train their personnel on one methodology instead of multiple. It also reduces the possibility of error, due to the personnel’s specialisation on one type of assays. Another reason is that some of the FISH assays may be run in arrays / panels. Labs run multiple tests on a single patient to cover different possibilities and get a

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comprehensive result. Such tests have higher specificity when they are run using kits from the same supplier, as the methodology is the same and the results are easier to correlate.

Tenders are usually for contracts of a duration of , however, for smaller tenders, shorter ( ) durations are observed. Once the contract is nearing an end the buyer will look to re-tender or to renew the contract with the existing supplier for smaller tenders.

2.2.3 Relevant stakeholders

Applicant plants using 4-tert-OPnEO

Manufacturing sites and employees

FISH assays are manufactured in a single plant outside of the EU. The plant is owned by Abbott Molecular and it is located in Des Plaines, in USA. There are 100-200 ( ) employees working in manufacturing operations at the Des Plaines site, of which 10-100 ( ) are involved with manufacturing of FISH assay kits, either partly or fully. Some of the employees split their time between FISH and manufacturing of other products.

FISH assay kits are distributed to EU customers via the Applicant’s distribution centre in Wiesbaden, Germany. This is the central commercial hub of the Applicant for all non-US customers. Apart from FISH assays, other products from the Applicant are distributed to the EU via the distribution centre. It is estimated that 5-50 ( ) employees in Wiesbaden and 5-50 ( ) in the rest of the EU are carrying commercial and other support work related to FISH assays for EU customers. Overall, more than 100 employees worldwide work in the various operations relevant to FISH assays and the instruments.

The number of employees is not expected to change in the future. There will be the usual churn of new employees moving in to replace those who have left, but the total number will remain stable.

4-tert-OPnEO use

4-tert-OPnEO is used in 1-10 reagents used to support approximately 400 different FISH assays in 10-100 ( ) IVD FISH probe kits. The kits are used for diagnosing, determining appropriate therapy or monitoring disease progression in cancer patients. The substance is present in a solution which is used in wash buffer components. It is supplied to customers either in pre-filled vials or as wash buffer solutions, in larger vessels. The Applicant is not carrying out any tasks involving 4-tert-OPnEO in the EU, other than its import and distribution to customers.

Sales value and market share

In 2017, the Applicant’s global sales value for oncology FISH products was approximately €10-100 million (€ million). Approximately 0-25 ( %), i.e. €1-20 million (€ million) of those sales are in the EU region. FISH genetics products sales are approximately % of the oncology sales, so the estimated EU sales in 2017 were 1-20 million (€ million). Table 2-3 shows the global and EU sales for the Applicant’s genetics and oncology product lines.

Table 2-3: EEA sales of the Applicant’s FISH products in 2017

Product family Global sales (€ million) EU Sales (€ million)

Genetics 10-100 ( ) 1-20 ( )

Oncology 10-100 ( ) 1-20 ( )

Total 20-200 ( ) 2-40 ( )

Note: Sales values were converted from US $ using a 0.820 €/$ conversion factor as the average exchange rate for 2017. J J f f f f d d d d d d d d d d d d d

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The Applicant’s sales have been fluctuating in recent years, but the Applicant maintains a significant market share. According to a market research study carried out in 2015, the global market for In Situ Hybridisation (including FISH and other techniques) was $554.4 million in 2014 and was expected to reach $681 million in 2019, with the European market expected to grow by 4.3% during that period. According to the Applicant’s own assessment, demand for their oncology products is expected to increase by 1-10% ( %). This is in part driven by the increase in demand for testing associated with personalised medicine in oncology (Companion Diagnostics). However, as a more conservative approach, and considering the irregularity in the trend of the Applicant’s sales in recent years, as evidenced by the consumed quantities of 4-tert-OPnEO shown in Table 2-4 below, it was decided to assume that sales volume and revenue will be stable and equal to the 2017 values.

According to a report on diagnostic biomarker trends, biomarker testing has increased tenfold between 2000 and 2016 and the trend is expected to continue [27]. FISH and ISH (in situ hybridisation) testing continues to be a necessary component for biomarker and cancer testing until now and for the foreseeable future [28].

The figures from the market report include all hybridisation techniques, both DNA or RNA and fluorescence (FISH) or chromogenic (CISH). DNA FISH accounted for the largest segment of the market, approximately 55.7% in 2014. The global market value of FISH is thus calculated at approximately $309 million in 2014.

The report names the Applicant among the five major companies operating in the global FISH market, along with F. Hoffmann-La Roche Ltd (Switzerland), Affymetrix, Inc. (U.S.), ThermoFisher Scientific, Inc. (U.S.), and Agilent Technologies, Inc. (U.S.). The Applicant is the largest supplier of FISH assay kits in the EU, holding a market share of approximately 20-50% ( %) of the oncology market in the EU, according to internal validations. The market share of individual products ranges from %, depending on the product. Individual country market shares range from %.

The market research report classified the end users of ISH assays into hospitals, pharma & biotech companies, research labs and Contract Research Organisations (CROs), with the hospital segment accounting for approximately half of the global sales.

The values presented above do not consider any sales of drugs that are connected to the CDx assays. This information is not available to the Applicant, because it is proprietary to the manufacturers of these drugs. It is estimated by the Applicant, though, that the annual cost of targeted treatment can be higher than $100,000 per patient [54].

Ancillary operations affected by use of 4-tert-OPnEO

Instrument platform manufacturing

The Applicant’s FISH assay kits can be used manually, with little to no automation. The Applicant, however, offers instruments that can help automate parts of the process, leading to better reproducible results and to better management of laboratory time. By automating a step of the process, lab workers can work on other assays or carry out other tasks, thus increasing productivity in the laboratory.

Reagents and process solutions formulation

The wash buffers containing 4-tert-OPnEO are only one component of the FISH assay kits supplied by the Applicant. The FISH kits consist of several reagents and other system solutions that are used in the analysis of the patient specimens.

These components are manufactured in the Applicant’s US facilities and, even though they do not

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assay kits need all components to be used properly to produce reliable and reproducible results. Therefore, it is not possible to remove any one of the components from the kit. So, if the wash buffer containing 4-tert-OPnEO cannot be used, the FISH assay cannot be used either.

Commercial offices

The Applicant’s sales to the EU are supported by commercial offices based in the EU. The commercial employees are carrying out work related to marketing and selling the Applicant’s products in the EU. There are 5-50 ( ) employees working in the distribution centre in Wiesbaden, for various support operations, and 5-50 ( ) in other locations, mainly for commercial activities. These numbers are not expected to change in the future.

Upstream supply chain

4-tert-OPnEO suppliers

The Applicant does not use 4-tert-OPnEO in manufacturing in the EU. All manufacturing of FISH IVD kits is carried out in a non-EU facility of the Applicant. The 4-tert-OPnEO used in these operations is imported directly from a non-EU manufacturer, which manufactures the solution in house.

4-tert-OPnEO is used by the Applicant’s EU customers, when they are running FISH tests. EU usage of 4-tert-OPnEO by the Applicant’s customers is approximately 0-25 % ( %) of global sales for the Applicant. This was determined from the EU sales share of oncology FISH products compared to global oncology sales. Table 2-4 shows the global and EU usage of 4-tert-OPnEO in the Applicant’s FISH kits since 2015. From 2019 onwards, steady sales were assumed as a conservative approach. The annual sales are assumed to be the average of the three most recent years (2016 – 2018).

Table 2-4: 4-tert-OPnEO EU consumption by the Applicant until Sunset Date (in kg per year)

Year _{Worldwide usage} _{EU usage}

2015 2016 2017 2018 2019-2027 Total (2021-2027) 100-1,000 ( ) 10-100 ( )

Note: 4-tert-OPnEO consumption after 2017 is assumed stable and equal to the average quantities for 2016 to 2018.

The quantities of tert-OPnEO relevant to this AfA are small, as shown in Table 2-4. The price of 4-tert-OPnEO is $ per litre of 4-tert-OPnEO. So, in case of a refused Authorisation, the consequences to the supplier will be low (approximately $1,000-10,000 - $ per year), compared to the Applicant’s and the supplier’s overall revenue.

Other raw material suppliers

Manufacturing of the FISH kits requires sourcing of other raw materials that will end up in the formulations. These raw materials can include:

• Chemicals used in the formulations that are components of the FISH products; • Cell lines and other biological material;

• Fluorescent probes, which hybridise with the patient’s DNA to produce the fluorescence signal to be detected by the user;

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• Vials, caps and other containers of FISH components; • Packaging material, including boxes and labels.

The Applicant has 10-50 ( ) suppliers, 1-10 of which are based in the EU and the rest in non-EU locations. The total value of raw materials procured from all the Applicant’s suppliers in 2017 for the Applicant’s operations was approximately $0-1 million ($ million).

Downstream supply chain

Direct customers in healthcare

The Applicant’s customers are healthcare professionals that need to carry out patient specimen analyses daily. The customers all belong to the mainstream healthcare industry, which care for and treat cancer patients. In general, they fall into the following groups:

• Laboratory personnel (medical technologists) and laboratory management that will perform the FISH testing requested by medical professionals

• Qualified Healthcare Professionals (including pathologists, such as when it is required to pre-certify that the specimen is cancerous tissue prior to FISH testing) that will perform the interpretation of FISH results for each specimen

• Clinicians (physicians, medical doctors) who will request the tests from their local or regional laboratory, provide the required specimens to the laboratory, and use the results of the FISH tests performed (in conjunction with other available clinical information) to make patient management and associated therapy decisions for their patients, in consultation with the Qualified Healthcare Professionals providing the interpreted FISH results

The clinical interpretation of any FISH test results should be evaluated within the context of the patient’s medical history and other diagnostic laboratory test results. FISH CE-marked IVD assays sold by the Applicant are intended to be used in combination with additional biomarkers, patient demographics, history, tissue morphology, and other clinical information. Non-IVD FISH assays (and/or components thereof) sold by the Applicant must be validated for their intended use by the end user laboratory prior to use of the Lab Developed test (LDT) assay in clinical diagnostic testing for the purpose of making patient management and associated therapy decisions.

The Applicant serves hundreds (more than ) of customers in the EU. Sites of use for the Applicant’s FISH products include the following:

• Reference diagnostic laboratories that perform FISH testing when requested by medical professionals (hospital-associated and/or private physicians),

• Private diagnostic laboratories that perform FISH testing when requested by in-house and/or unaffiliated medical professionals (hospital-associated and/or private physicians),

• Hospital-based and academic institution-based diagnostic laboratories that perform FISH testing when requested by medical professionals (hospital-associated and/or unaffiliated private physicians); usually these laboratories are associated with medium to large hospitals.

Patients

The Applicant’s oncology FISH assays are not used independently, but rather they are requested to support data from other tests and examinations on the patient. Doctors normally ask for additional FISH information before they make any treatment decision on the patient as the FISH assays can help identify the type and sub-type of cancer a patient has. This is particularly the case for Companion Diagnostics which are associated exclusively to a specific drug. This type of information plays a significant role in

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treatment. FISH assays are also used for monitoring the progress of tumours of patients and can also be used to identify possible reappearance of cancer that was cured in the past. The Applicant’s FISH assays can be used for different types of cancer, both haematology malignancies (leukaemia, etc.) and solid tumours (e.g. lung, breast).

Genetics FISH assays are used in identifying and monitoring genetic abnormalities in embryos and on new-borns, helping to identify genetic diseases, thus allowing for timely and appropriate treatment to improve quality of life.

Table 2-5 shows information on cancer patients in Europe for selected types of cancer, which are also targeted by the Applicant’s FISH assays.

Table 2-5: Incidence, mortality and 5-year prevalence of different types of cancer in Europe in 2018

Cancer type

Incidence (per 100,000 inhabitants)

Mortality (per 100,000 inhabitants)

5-year prevalence (per 100,000 inhabitants)

Men Women Men Women Men Women

Leukaemia 9.0 6.0 4.6 2.8 41.1 29.6 Non-Hodgkin lymphoma 9.8 6.6 3.4 2.0 50.4 41.0 Multiple myeloma 3.6 2.3 2.0 1.3 18.1 14.4 Bladder 20.2 4.3 5.6 1.2 139.5 33.8 Prostate 62.1 - 11.3 - 431.5 - Breast - 74.4 - 14.9 - 534.7 Lung 44.3 18.3 36.8 13.0 86.3 48.7 Skin melanoma 11.5 11.3 2.2 1.3 67.4 65.5 Brain 6.6 4.7 4.9 3.2 25.9 23.2 Source: Globocan, available online at: http://gco.iarc.fr/today/online-analysis-table

Using Age-standardised rates (ASR)

Incidence refers to the number of new cases of a type of cancer arising in a year. Mortality is the number of deaths from that type of cancer in the same year. Finally, prevalence is the number of persons who have been diagnosed with a type of cancer and are still alive at the end of a given period. A 5-year prevalence rate is a good indication of a cure, since the death rates of such patients are usually comparable to those of the general population (with the possible exception of breast cancer) [29].

The Applicant’s FISH products are important to all patients indicated by the incidence rate and by the 5-year prevalence rate. New cases (incidence) can be diagnosed more accurately and faster with the help of the FISH assays. In the EU-28, the new cases of cancer in 2018 were estimated to be 4.2 million. FISH products are also important for all those living with cancer, both during therapy and after they are cured, to monitor their progress. The population of those living with cancer 5 years after the first diagnosis in the EU was estimated at approximately 12.1 million in 2018 [30].

More than 90% of women diagnosed with breast cancer at the earliest stage survive their disease for at least 5 years compared to around 15% for women diagnosed with the most advanced stage of disease [21]. More than 80% of lung cancer patients will survive for at least a year if diagnosed at the earliest stage compared to around 15% for people diagnosed with the most advanced stage of disease [31]. Missed or delayed diagnoses often results in higher downstream costs for treating a disease that has advanced more progressively.

SOCIO-ECONOMIC ANALYSIS

Public Version

Table of Contents

List of tables

List of figures

LIST OF ABBREVIATIONS

Executive summary of Socio-economic Analysis

1.1

Background

1.2

Discussion on the length of the review period

1.3

Balance of benefits and costs

Aims and scope of the SEA

2.1

Aims and scope of the SEA

2.1.1 Regulatory background for 4-tert-OPnEO

2.1.2 SEA requirements and aims

2.1.3 Temporal and geographical boundaries (scope of the SEA)

Temporal boundaries

Geographical boundaries

2.2

Definition of the “Applied-for Use” Scenario

2.2.1 The Applicant

2.2.2 Importance of the Applicant’s FISH assays

Fluorescence In Situ Hybridisation

Applications of FISH assays

FISH and companion diagnostics for personalised medicine

Advantages of FISH method

Other technologies and future developments

FISH kits

FISH instruments

Regulatory requirements

FISH marketing constraints

2.2.3 Relevant stakeholders

Applicant plants using 4-tert-OPnEO

Ancillary operations affected by use of 4-tert-OPnEO

Upstream supply chain

Downstream supply chain