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Reviewer’s Questionnaire for Evaluation of Submissions for EDL v3 Based on the Criteria for Selection of Essential Diagnostics for the EDL

Diagnostic test: Immunohistochemical test (IHC) for the evaluation of the over-expression of the Receptor tyrosine-protein kinase erbB-2 or human epidermal growth factor receptor 2 (HER2/neu).

Test purpose: To evaluate for HER2/neu protein over-expression in breast cancer tumor cells, to identify the subset of breast tumors that have been shown to benefit from HER2/neu targeted therapy with trastuzumab, or other biosimilar.

ID number: PreSubmission_ID63_FullSubmission_ID27

The selection process for essential diagnostics for the EDL will include consideration of a number of factors, including: 1. The public health and clinical need for the category of tests as determined for example,

by disease burden and whether the proposed category of IVDs can help to bridge any existing gap in access to diagnostics that has been identified.

Questions: 1. Does the disease addressed by the test cause:

☒ a high burden of morbidity (human suffering)

☒ mortality

☒ cost on the populations and societies where it occurs

2. How strong is the evidence provided to support this?

☐ weak

☒ strong Please complete the sub-questions below on evidence provided:

a. Disease prevalence data?

☒ yes

☐ no

b. Information on the disease impact on the quality of life of its sufferers?

☐ yes

☒ no

c. Information on the disease impact on the quality of life of the families of sufferers

and the communities in which they live? E.g. patients with high care needs, orphans,

spread of infection

☐ yes

☒ no

d. Impact assessments on health care resources and budgets?

☐ yes

☒ no

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Comment: There is generic cancer burden information in the pre-submission, but no breast cancer-specific data. It is worth pointing out that the breast cancer burden in low and middle-income countries occurs in predominantly pre-menopausal women in contrast to high-resource settings. Pre-menopausal women are typically still raising families and contributing to the workforce. These women, whilst they may not be working outside the home, are essential for the functioning of a family unit, and there is evidence published that a breast cancer diagnosis for most families in lower-resource settings pushes the family into poverty.

2. Is any information provided showing the degree of access to diagnostic testing for the

addressed disease in the primary care setting?

☒ yes

☐ no

Comment: The performance of immunohistochemistry requires highly skilled technicians to maintain the quality of the assay, and highly skilled pathologists to interpret the assay results. This assay is not designed to be used in the primary care setting and is best suited for regional or national laboratories.

Does the submitted test category help to increase access in any way? E.g. reduced skill

required, lower cost, improved performance vs alternative options

☒ yes

☐ no Comment: The WHO added HER2 targeted therapy with trastuzumab to the essential medicines list. To test for HER2 over-expression as only HER2 over-expressing (positive) patients will have a chance of benefiting from treatment, the current cheapest method is immunohistochemistry for HER2/neu. This treatment is a particularly important option in Estrogen Receptor negative patients, who have worse overall survival and progression-free survival. Utilization of FISH alone testing or a combination of the two is calculated to be more expensive both for cost benefit analyses, and at the individual test level than the “per-test” cost of IHC alone.

Note: Answers to the questions above will have been assessed as part of the screening application and will have been deemed acceptable. Nevertheless, information provided on these matters in the full application may be commented upon in your assessment.

2. Availability of validated commercial diagnostic tests as indicated by sound and adequate data

on quality, safety, performance, and regulatory status.

Questions: 1. How many commercially available IVDs are included in the application for this category?

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a. Does the submission include a list?

☐ yes

☒ no

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Does the application consider IVDs of all technologies 1that are available for the analyte2 of interest?

☐ yes

☒ no

Comment: The application is for a specific test, the DAKO HercepTest, but the application should be for a product category (i.e. immunohistochemistry for evalaution of HER2/neu). Whilst this is an FDA-approved test, there are other HER2/neu IHC CE IVD and FDA-approved assays available from different vendors, from pre-dilute ready-to-go assays to lab-developed assays with approved concentrated antibody clones that require more laboratory technician expertise to validate, but that are significantly less expensive. These are not mentioned as other options, and should be included.

The other FDA-approved HER2/neu IHC test kit is from Ventana (PATHWAY), and there is a CE IVD approved system (Leica’s ORACLE).

Whilst the published data is excellent for the performance of the HercepTest, there is also data available comparing robustness and accuracy of the assay compared with other commercially available assays (both FDA-approved and not), that suggests that it is not the best and most robust assay to use (see NordiQC data over the last 10 years, published by Nordic laboratories of Copenhagen, and comparing the use of the most popular ER, PR and HER2 assays in over 300 laboratories,; http://nordiclabs.com/Default.aspx and http://www.nordiqc.org/downloads/assessments/)

The application does mention in situ hybridization (ISH) testing for HER2 but does not take into consideration the added cost of combining this assay with IHC, or alternatively considering just a HER2 FISH assay. This ISH assay is the test required to clarify the 15-20% of patients tested for HER2 by IHC that produces an equivocal HER2 IHC result. It can also be used instead of HER2 IHC. ISH testing is roughly two to five times more expensive than IHC per assay, but, for a long time has been considered a gold standard, as response to HER2 targeted therapy in early trials correlated better with FISH results than IHC results, as the quality control for the HER2 IHC assays has always been very challenging, especially at the advent of HER2 targeted therapy. ISH testing in breast cancer, as reflex testing for equivocal HER2 results by IHC, can only be ignored as a HER2 IVD if the algorithm being promoted is intent to treat only HER2 positive (3+) patients by an IHC assay, and not further investigate those with equivocal results with ISH. This would not be following international ASCO/CAP HER2 testing guidelines, but has been studied in cost-benefit publications, and would identify the majority of women with unequivocal HER2 positive breast cancers most cost efficiently according to published data.

2. Which national regulatory bodies have approved these tests for market access e.g. CE IVD,

US FDA, SFDA, WHO-PQ, others?

Comment: US FDA has approved two HER2/neu IHC tests, Dako’s HerceptTest and Ventana’s PATHWAY assay. Leica has a CE IVD approved system (ORACLE). The FDA-approved ISH assays quantify HER2 gene copy number; two via FISH assays (PathVysion HER2 DNA probe kit [Abbott Laboratories, Abbott Park, IL, USA] and HER2 IQFISH pharmDx kit [Dako Denmark A/S]), one by chromogenic in situ hybridization (CISH) assay (HER2 CISH pharmDx kit [Dako

1 Technologies: It may be that, within the IVD category, there are tests that use different technologies to measure or detect the same analyte e.g. an RDT or and EIA for HIV antibody 2 Analyte: Marker that the IVDs in the category measures or detects

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Denmark A/S]), and one by dual in situ hybridization assay (INFORM HER2 Dual ISH DNA probe cocktail [Ventana Medical Systems, Inc.]). All are FDA-approved for use as a companion diagnostic to assess suitability for initiation of trastuzumab treatment. HercepTest is the only companion diagnostic approved for use in treatment with trastuzumab, pertuzumab, and ado-trastuzumab.

3. Have package inserts been provided showing studies demonstrating quality, safety, and

performance of regulatory approved IVDs in this category?

Quality: ☒ yes ☐ no

Safety: ☐ yes ☒ no

Performance: ☒ yes ☐ no Comment: The safety sheet submitted is actually for the Gastric Cancer HER2 assay, not the breast cancer assay.

a. If so, what is your assessment of the strength of the study data described in the

package inserts?

Comment: Package insert for the HercepTest reports the concordance with the original Clinical Trial Assay used in the original Trastuzumab trials. Whilst the concordance data is relatively poor, it is well established in the literature that any IHC assay for HER2/neu is far from perfect, but it is currently recognized as the most cost-effective method of screening for HER2 overexpression and potential benefit from trastuzumab treatment. Older HER2 testing guidelines (2007) recommended at least 95% IHC result concordance with another method of assay (i.e. HER ISH), but this was dropped in the 2013 guidelines, after it was reported that only about 70% of laboratories can achieve this 95% concordance with other assays. The biggest commercial labs in the US only have 97% to 98% concordance with IHC and FISH results (PhenoPath published data; Allan Gown). Now it is considered an individual laboratory’s duty to ensure the quality of its testing with validation of their assay (easier if using a pre-dilute assay such as HercepTest or Ventana PATHWAY). A major part of this quality and performance bar to pass that is beyond the scope of this in vitro diagnostic, and yet essential for quality lab results, is for the lab to monitor its results with both internal quality assessment procedures and external quality proficiency assessment procedures, and lab accreditation, none of which may be in place in many low resource settings that would use this assay. Unfortunately, quality and performance of the HercepTest assay along with other HER2 assays is very much in the hands of the technicians performing the assay, with careful control of pre-analytic, and post-analytic variables too. This has not been emphasized in the application, but should be (see comments below).

4. Have any independently published studies been provided, showing IVDs’ performances

compared to a recognised gold standard? How strong are these studies?

☐ yes ☒ no

a. If no gold standard exists, what is your assessment of the characterisation of the

studies’ specimens?

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Comment: There are many publications comparing different HER2/neu antibody assays, including their concordance with FISH, and there is no one gold standard IHC assay or most accurate antibody that has been recommended by ASCO/CAP or any other body. A very useful large commercial laboratory quality control document is published by NordiQC annually, comparing the FDA approved and CE IVD approved assays and in-house validated systems in hundreds of its laboratories. Their data clearly show that the FDA-approved assays are the most reliable for assessing HER2 by IHC, with the Ventana assay performing best, and HercepTest second best. These annual publications can be used as evidence that the specific assay used matters, and that in general, laboratories should not use lab-developed assays unless they have a means to very robustly monitor their concordance with ISH results of their negative and positive results.

5. Where relevant, have studies to demonstrate ease of use by trained lay providers been

provided?

☐ yes ☒ no

What is your assessment of these studies? Comment: IHC assays cannot be performed by lay providers 6. Where relevant, have studies been provided to show the IVD’s robustness3 in variable

environmental conditions e.g. temperature and humidity?

☐ yes ☒ no

Comment: The product insert for the HercepTest has a section on trouble shooting assay issues and its robustness that include storage at 2-8C, and not to use beyond the expiry date, but the quality of the assays performance can only be determined by running appropriate negative and positive controls with every test run, and following quality assurance practices within the lab performing the assay. The ASCO/CAP guidelines for HER2 testing cover many of the issues around robustness of HER2 assay testing in general, but the full range of factors affecting HER2 IHC test accuracy has not been covered adequately in this application for recommending use of this IVD. Some of the issues not related to the actual assay itself are ischemic time of the tissue to be tested, sub-optimal epitope retrieval methods, inaccurate scoring of results including artifacts like crush and edge artifact, and poor use of positive controls (too highly amplified a positive and no equivocal, so that tumors may be underscored, missing amplified tumors). 3. Clinical effectiveness4 based on published peer reviewed data, safety and comparative cost-

effectiveness.

Questions:

1. Has the applicant provided strong peer reviewed clinical studies that demonstrate the

clinical utility 5and effectiveness of IVDs in this category?

3 Robustness: An IVD’s capacity to remain unaffected by small variations in method parameters, which

provides an indication of its reliability during normal usage 4 Clinical effectiveness: The degree to which a particular health care intervention does more good than harm. It is measured by the number of lives saved, or by improvements of objective parameters of a morbid condition 5 Clinical utility: The likelihood of improved outcomes from use of diagnostic tests in the IVD category

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clinical utility: ☒ yes ☐ no

effectiveness: ☒ yes ☐ no

Comment: The evidence for use of this IVD is well-established and the HercepTest is

essentially one of two gold-standards for HER2 testing, but I would include the other FDA-

approved assay in the WHO’s recommendation (Ventana PATHWAY).

2. Are you satisfied that these studies are properly designed and sufficiently powered

statistically to support their conclusions?

☒ yes ☐ no

3. Has the applicant provided cost effectiveness, health economics or budget impact studies

demonstrating the value of IVDs in this category?

cost effectiveness: ☒ yes ☐ no

health economics: ☐ yes ☒ no

budget impact studies: ☐ yes ☒ no

How strong are these studies in terms of design and statistical power? (See Note above)

☐ weak

☐ strong

Comment: The application includes reference to a magnitude of benefit publication for use

of trastuzumab, and references the ASCO/CAP HER2 testing guidelines. There is a single

reference to a cost effectiveness assessment from 2006 in the UK, and a reference about

cost effectiveness of IHC versus FISH from a 2004 study, favouring IHC as a screening test.

There are additional references that could be included looking at the complex issue of the perfect algorithm for HER2 testing for cost savings (see recommendations at bottom of questionnaire). Using the strategy that I believe is being outlined here (all IHC testing, no FISH testing and Trastuzumab for those IHC 3+, studies) published data suggest the cost is around $50 000 for a QALY (quality adjusted life years gained) in Sweden. Back in 2008, the cost limit for a QALY being worth paying was set at approximately $71 000 (Mathias Lidgren, Nils Wilking, Bengt Jönsson & Clas Rehnberg (2008) Cost-effectiveness of HER2 testing and trastuzumab therapy for metastatic breast cancer, Acta Oncologica, 47:6, 1018-1028). The cost of the IHC assay in this Sweedish publication was approximately $200, the FISH testing $553, and one month supply of Trastuzumab approximately $2400. A similar number of $48 000 cost per QALY gained was obtained from the UK using different data (Hornberger J, Kerrigan M, Foutel V. Cost-effectiveness of trastuzumab (herceptin) for treatment of metastatic breast cancer. ESMO Poster 2002). An algorithm of treatment that includes HER2 FISH-only testing is documented as more expensive (in the order of $61 000 per QALY in Europe), but this algorithm should be considered for low and middle-income countries, given the significant concerns that poor quality IHC testing and reading in unaccredited laboratories may reduce the effectiveness of HER2 IHC as a sufficient screening test for HER2 overexpression.

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The cost effectiveness of HER2 testing method (IHC versus ISH or a combination),

specifically for use in a low or middle-income countries where quality of the test

performance may be very hard to monitor, and test volume may be significantly lower than

in high-resource settings, should be considered, along with estimates of QALY gained with

the testing method.

4. Has the applicant provided pricing information for commercially available IVDs in this

category? ☒ yes ☐ no

a. Is the pricing information given inclusive of instrument and service costs where

relevant? ☐ yes ☒ no

b. In your experience, based on the pricing information provided, how accessible are

IVDs in this category to LMIC settings?

accessible: ☐ yes ☐ no

not accessible: ☒ yes ☐ no

Please provide examples to support your conclusions.

Comment: This is a very difficult question to answer. The applicant lists the cost of IHC at $10

per assay, but this is the lowest I have seen it calculated at, anywhere in the world, and may not reflect the true total cost of the assay. Many labs cannot buy in bulk to take advantage of reduced prices or discounts for bulk purchase, because they cannot afford to have an antibody stock expire before it can be used as their test volume is not high enough, and they are not involved in government funded programs. In reality, when a laboratory performs only a handful of IHC assays a week, the cost of running the control tissue assays is significant, and the price-per-test will be a lot higher than $10.

In the low resource settings I have visited (South East Asia: Vietnam, Cambodia, Myanmar, and

Africa (Zimbabwe and Rwanda), the cost to patients who have to pay for the assay with minimum profit for the testing lab has been remarkably consistent and is always around $30.00 per assay. This covers the reagent use, equipment cost and professional time to report the assay results. In high resource settings the cost of IHC is >$200.00 per assay.

The cost of additional equipment is listed at $2000, but I’m not sure what this refers to. Is this

the autostainer equipment cost? Additional reagents/equipment are needed for IHC and may or may not be included in this price. Annual maintenance contracts must also be included and professional costs. These are difficult to provide as costs vary around the world, but some attempt to quantify them is needed and an overall cost per assay should be included (not just $10.00 and $2000).

5. In your experience, do you consider the cost of tests in this category (cost per test includes

reagents, any amortised instrument capital expenditure and service contracts) to justify the

clinical benefits. Please provide examples to support your conclusions.

☒ yes ☐ no Examples

Given the QALY cost of therapy with trastuzumab, or a biosimilar is currently in the range of $45

- 50 000 in high-resource settings, the cost of this IHC assay as a companion diagnostic is very small ($30 - $200), but if a patient is paying for the assay themselves, the cost per assay is high, and is frequently a barrier to testing. Assuming that the therapy is available, the cost of the assay is not significant.

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There is no cheaper alternative assay available currently, and it is a reliable method if testing is performed in an accredited laboratory environment with attention paid to quality control.

As noted above and below, cost effectiveness of the testing algorithm should be calculated for any country considering introducing HER2 testing and therapy. The cost of the QALY is high, even for wealthy countries. 4. Appropriateness of the IVD category for use at specified levels of the laboratory or health

care system.

Answer questions 1 and 2 for each IVD technology in the category. A table may help with reaching your recommendation, the characteristics of each IVD represented by one row of the table 1.

a. What specimen type is required?

Comment: Breast Cancer tissue in the form of FFPE (formalin-fixed paraffin

embedded blocks)

b. What skill level and training is required for specimen collection? E.g. Phlebotomist

Comment: Advanced skills – the tissue is procured by a doctor, typically a surgeon in

low-resource settings and the specimen must be handled appropriately to avoid

false-negative results with IHC testing (rapid placement into formalin and good

quality grossing procedures followed).

c. Do specimens need to be processed in any way prior to analysis? E.g. centrifugation,

microscope slide staining, etc. ☒ yes ☐ no

i. If so, for how long and at what temperature is the specimen stable before

being processed (00:00:00 hours, min, seconds format)

ii. At what temperature is the processed specimen stored before testing

(please specify if Celsius or Fahrenheit)

Comment: Pre-analytic issues: The tissue must be fixed in 10% formalin, processed and made into a paraffin block, with tissue sections cut and placed on a microscope slide requiring highly skilled technicians. Tissue fixation times must be monitored (6-72 hours), and cold-ischemic time should be <1hr to reduce the risk of false-negative IHC results.

d. How long does it take to get a result? E.g. can a result be obtained during a

consultation i.e. < 10 minutes, or while the patient is at the facility i.e. 2 – 3 hours or

specimens are tested in a batch using the IVD i.e. days?

Comment: An IHC run typically takes 2 - 3 hours, but the pre-analytic step takes a minimum of 12 hours, and result must also be read by a skilled pathologist. This is always too long for same-day results, but can be obtained within 24 hours.

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e. Where relevant to the IVD has ease of and effective use by trained lay providers

been demonstrated?

☐ yes ☒ no

f. What equipment, if any, is required to perform this type of test?

Comment: All IHC can be performed manually (with potential for quality assurance

issues) or using an autostainer (automated process). For the HerceptTest, the

reagents are pre-diluted and an autostainer is required. Other requirements are

standard lab equipment (e.g. heat bath) for handling anatomic pathology specimens

and performing IHC on FFPE tissue, appropriate positive and negative control tissue,

and on-slide negative, equivocal and positive control tissue.

g. Do instruments need to be calibrated, maintained, or serviced on a regular basis?

☒ yes ☐ no

h. How robust is the IVD?

Comment: Provided the test kit has been transported and stored according to

instructions (at 2-8C), and all instructions for use are adhered to rigidly, the IVD is

robust.

The robustness of the assay has not been fully documented. Data comparing this IVD

with other similar HER2 IHC assays when directly compared staining the same

samples in a commercial lab setting could be provided (NordiQC data, see below),

along with the pre- and post-analytic variables that must be controlled to produce

an accurate result.

i. What is the impact of an unreliable power supply, or can the IVD operate without a

power supply?

Comment: The test cannot be performed without a power supply.

What is the minimal skill level and training required for personnel to perform this

test?

☐ Unskilled

☐ Skilled

☒ Highly trained

2. Considering a 4-tier laboratory system, with the following levels:

i. Primary care

ii. District hospitals/laboratories

iii. Regional hospitals/laboratories

iv. National hospitals/Reference laboratories

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In your judgement, which level would be best suited to handle the required complexity of the relevant IVD?? Please include your answer in the table based on the likely availability of the following at district, regional and national laboratory level:

a. Infrastructure requirements e.g. instrument size and complexity, biosafety

requirements

b. Specimen types

c. Testing volumes expected (sample throughput required)

d. Complexity of specimen handling e.g. biosafety level required, centrifugation or

complex protocols requiring highly skilled laboratory technicians

e. Availability of infrastructure for transporting specimens

f. Result turn-around times required

g. Reagent shipping, storage and operating conditions required

h. Where relevant, instrument operating conditions required

i. Required qualifications, training and skill levels needed for test performance and

result interpretation e.g. non-laboratory personnel for a simple rapid test, trained

laboratory technician to perform routine testing, medically trained personnel for

result interpretation, Ph.D. level scientist required for highly complex and variable

methodologies

j. Quality management requirements based on complexity of facilities & support

required to perform the test

Comment: I would recommend this assay is for use primarily in national hospitals/reference laboratories that are accredited and can adhere to internal and external quality control procedures. It could be used by regional hospitals/laboratories, provided those hospitals can demonstrate their quality control procedures and what they are doing to ensure accuracy of the results they report out, but testing in laboratory settings with low volume IHC should be discouraged, given the semi-quantitative skilled nature of the scoring algorithm, and large variety of pre-analytic and post-analytic factors that can influence the test result. Proposed answer table:

Primary care District hospitals/lab

Regional hospitals/lab

National hospitals/ Reference lab

Infrastructure requirements No No Possibly – if have access to tissue processing facilities

yes

Specimen types No Yes Yes Yes

Testing volumes expected None None Yes: at least 5 tests/week

Yes: Much greater than 5 tests/week

Complexity of specimen handling Not available Not available Possibly Available if technical staff are trained to perform IHC

Yes. Technical staff should be trained to perform IHC

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Infrastructure for transporting specimens

Rarely available in quality and timely manner

Rarely available in quality and timely manner

Likely available Poor tissue handling is always an issue in LMICs

Likely available Poor tissue handling is always an issue in LMICs

Result turn-around times required

- - 24 hours minimum from tissue procurement

24 hours minimum from tissue receipt

Reagent shipping, storage and operating conditions required

- - Yes, a lab should be able to order and store reagents appropriately. May not have technical expertise to run assay

Yes, a lab should be able to order and store reagents appropriately, and have technical expertise to run assay

Instrument operating conditions required

Not available Not available Equipment maintenance is essential, and contracts may not be available

Equipment maintenance is essential, and contracts should be in place

Required qualifications, training and skill levels

Not available Not available Possibly available

Available and required

Quality management requirements

Not available Not available Required for accuracy of assay

Required for accuracy of assay

5. What is your recommendation to SAGE IVD? Please summarise the key points you considered

in reaching your conclusion.

• An IHC method of HER2 testing should be included on the list given the overall survival

benefits documented with Trastuzumab (or biosimilar) therapy in HER2-positive early and

advanced breast cancer, particularly in ER-negative breast tumors.

• Use of IHC alone as a method of testing has been compared for cost-benefit and QALYs with

the current ASCO/CAP recommended algorithm of using HER2 ISH assays to decide the HER2

status of HER2 IHC equivocals. Whilst a number of women who are HER2 positive only by ISH

and not by HER2 IHC would be denied HER2-directed therapy by this method, the QALYs are

very similar, and those women tend to have lower levels of HER2 overexpression, that are

currently believed to respond less well to HER2 targeted therapies anyway. The peak of

tumor response to HER2 targeted therapy is actually in the mid-range of HER2 expression by

mRNA assays (not the high or low ends).

• The Dako HercepTest is currently a gold standard and FDA-approved assay, and it is a ready-

to-go assay as it includes use of pre-dilute reagents, all of which are provided, and thus is the

perfect candidate for this.

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• I would recommend this be changed to a general product application and avoid endorsing a

particular assay, and at least including the other FDA-approved assay, the Ventana

PATHWAY assay in the data presented, as this assay performs better in comparison Quality

Assurance assays, and is actually more widely used in labs across Europe and the US. Listing

both assays would be both equitable and give more choice to low and middle-income

country laboratories, including considering any cost differences.

The Dako HercepTest assay is a perfectly adequate assay with the caveats outlined below

a. Because the assay is FDA-approved, it is more expensive, making it a very expensive

choice compared with non-FDA-approved HER2 IHC assays

b. Because in comparison data (e.g. from NordiQC), the assay has not performed as

robustly as the other FDA-approved assay (Ventana PATHWAY), the majority of labs

using ready-to-go assays, do not consider this the assay of choice for HER2 IHC

6. Please list the items that require further clarification from the originator of this submission.

1. Inadequate Quality Assurance/Quality Control data provided that is important to emphasize,

specifically with this higher-priced IVD, compared with other assays

Does the assay kit include control slides (1+, 2+ and 3+) to run with tests? Many labs use a

control that is inadequate (too high a positive) and do not include an equivocal in their

control tissue. Please make this very clear.

Recommended methods of quality assurance by ASCO/CAP are to use in an accredited

laboratory setting, with documented adherence to proficiency testing guidelines (taking part

in internal and external quality assurance for HER2 IHC). This is an important part of the QC

for this IVD and should be included, not just in the publications included in the application,

but as part of the details of the written application

ASCO/CAP used to recommend 95% concordance with ISH data, but this is challenging for

laboratories to achieve and is no longer recommended as QC, so comparison with ISH for

quality control is no longer required.

What other advantages does this assay have over other HER2 IHC assays, both ready-to-go

and laboratory-developed?

2. Please include quality assurance data comparing the different HER2 assays in real-time use

across hundreds of different laboratories (NordiQC data from the last five years can be used

obtaining testing results from >300 different labs – report the QA data for the HercepTest

assay compared with Ventana PATHWAY (4B5 clone), and Lecia’s approved assay Oracle

(CB11 clone), plus concentrated antibodies for lab-developed assays (e.g. A0485, SP3, 4B5

and CB11). The NordiQC data is widely used as a benchmark and quoted by the large

commercial labs performing HER2 IHC.

http://www.nordiqc.org/downloads/assessments/

The author of the submission may be able to find other contemporary examples.

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3. Include Quality Assurance/Quality Control data that is important to emphasize when

recommending use of any IHC IVD in the written part of the application.

Include that the documented recommended methods of quality assurance by ASCO/CAP are:

I. To control pre-analytic, analytic and post-analytic variables including tissue cold

ischemic time, fixation time.

II. To use negative and positive controls with every test run and include positive and

negative controls on the test slide, and report out positive internal control staining on

test tissue as quality assurance

III. To use only an approved antibody clone/assay and avoid lab-developed assays if robust

validation is not available (comparison with ISH results)

4. A generic $10 per assay and $2000 for the autostainer was listed as the assay costs. This is

inadequate information and does not accurately reflect the cost that a laboratory charges,

or patient typically pays in low and middle-income countries (the cheapest I have ever seen

it and what seems to be a minimum is at least $30.00, and it costs hundreds of dollars in

Europe and the USA).

I understood where this number came from as I read the application for a panel of IHC to

diagnose solid tumors, it is reported as the cheapest possible cost per slide of an antibody

test, using a concentrated antibody and generic reagents for testing in a publication of how

to set up a 10 antibody IHC panel in low resource settings in the most cost-efficient way. In

general, the issues of quality control for ER, PR and HER2 testing are so challenging and so

important that it is hard to endorse use of antibodies that must be diluted, and also to

endorse manual staining for ER, PR and HER2. It is not a realistic price for HER2 IHC and it

doesn’t take account of quality assurance testing and validation testing required with each

batch of antibodies bought, which is extremely important for laboratory-developed IHC

assays in general.

(http://mjpath.org.my/2018/v40n2/immunohistochemistry-bench.pdf)

A table comparing the typical total reagent/kit costs in different regions of the world

(Europe, USA, South America, Africa and South East Asia) would be the most valuable piece

of information to put together and that is lacking in this application. Dako should be able to

provide this information for it’s ready-to-assays and reagents for lab-developed and

validated use. Kit cost does vary according to region sold and country sold in, and whether

bought in bulk or not, but price for a 50-test kit would at least allow comparisons. At least

the two FDA-approved assays in use should be included in this table (Dako HercepTest,

Ventana Pathway) as they are very comparable, and also include lab-developed assays from

concentrated antibodies (SP3, A0485, 4B5), although these will be harder to calculate total

cost of the assay, as all the reagents will need to be included (e.g. the secondaries and other

reagents will not be included in the costs of these antibody concentrates – so they can

appear significantly less expensive as assays to perform).

To justify recommending this assay, since costs are obviously higher for the FDA-approved

assay, the table could also state the advantages of this higher cost kit (e.g. control slides are

included, all reagents for the test are included, the antibody comes pre-diluted to reduce

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errors in lab technician reagent handling, and does not need 30 or 60 sample validation

before it can be used in a laboratory).

5. Given the very high cost of the therapeutic associated with this diagnostic assay, to truly

demonstrate how to calculate if this IVD and therapeutic is cost-effective for a country, a

reference on how a country can calculate its limit for cost effective QALY based on its GDP

would significantly help, and how it can use costs of diagnostics and therapeutics to decide if

therapy is cost-effective (e.g. Leung W, Kvizhinadze G, Nair N, Blakely T (2016) Adjuvant

Trastuzumab in HER2-Positive Early Breast Cancer by Age and Hormone Receptor Status: A

Cost-Utility Analysis. PLoS Med 13(8): e1002067).

https://doi.org/10.1371/journal.pmed.1002067)

The above reference uses New Zealand data and an arbitrary threshold of $30 000 for cost

effectiveness based on the country’s GDP. In this scenario, only HER2 therapy in ER negative

patients is cost-effective. In the UK and Sweden, the QALY threshold for the national health

service is around $50 000 to $70 000, making therapy for both ER negative and ER positive

worthwhile, the QALY threshold for private insurers in the US is significantly higher and not

applicable. Current QALY cost of HER2 therapy is around $45 000 to 50 000. Use of

biosimilars will bring this cost down, but countries need a method of calculating their costs

and cost limits, that would be helpful to include in this application, since as an initial

introduction, treating only ER negative HER2 positive patients with HER2 targeted therapy is

pragmatic and more cost-effective than treating all HER2 positive patients.