HTA Core Model^® Online

Background

Given its high impact on the healthcare service, the management of breast cancer is a relevant issue for all European Union (EU) countries. The three tests assessed in this core health technology assessment (HTA)— uPA/PAI-1 (FEMTELLE®, American Diagnostica) based on immunostaining techniques and MammaPrint® (Agendia) and Oncotype DX® (Genomic Health), based on gene expression profiling—measure multiple markers within the tumour that may indicate how the tumour is likely to develop. The potential clinical utility of the tests lies in their ability to discriminate between patients who will benefit to a greater or lesser extent from a therapeutic intervention. The assessment of technologies of this type could be of interest to all the EU member states.

The uPA/PAI-1, MammaPrint and Oncotype DX tests are intended to predict the likelihood of breast cancer recurrence in women and to support the tailoring of treatment to the individual patient, which may reduce the number of women receiving chemotherapy and experiencing the associated side-effects. Specifically, the uPA/PAI-1 test is intended for women with newly diagnosed lymph node-negative breast cancer. MammaPrint is intended as a prognostic test for women with lymph node-negative and lymph node-positive breast cancer with a tumour size of 5 cm or less, or for women who are 61 years of age or less, with oestrogen receptor-positive or oestrogen receptor-negative, lymph node-negative breast cancer. The Oncotype DX assay is intended for use for women with newly diagnosed lymph node-negative or lymph node-positive, oestrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative invasive breast cancer.

Results

Safety of the technology (SAF)

The three tests under evaluation share general safety concerns about aspects of environmental safety and surgical pathology practice, such as sample contamination, delays in transfer of samples to the testing laboratory, incorrect labelling and other features that may affect the reliability of the result and thus patient safety. There is insufficient evidence, from the 12 included studies, of possible anxiety or other psychosocial harms caused to the patients by the tests.

Effectiveness of the technology (EFF)

Studies assessing the prognostic/predictive accuracy of the tests were excluded. The 15 poor quality observational studies included did not provide any comparative direct evidence on the effects of treatment with and without the use of the index test. They assessed issues such as quality of life, anxiety and patient satisfaction. There is a clear need for manufacturers to communicate at an early stage with the European Medicines Agency (EMA), the US Food and Drug Administration (FDA) and health technology assessment (HTA) bodies to obtain so-called “early scientific advice” when designing randomised controlled trials (RCTs).

Costs, economic evaluation of the technology (ECO)

If dominance of the prognostic tests for breast cancer recurrence (PTBCRs) were to be shown in prospective independent comparative studies, introduction of these tests might avoid unnecessary use of expensive chemotherapy with its associated adverse effects for women who would derive little or no benefit from it. The tests might reduce the mortality rate in high-risk women who would have benefitted from chemotherapy. However, the key effectiveness data needed to draw conclusions about cost-effectiveness ratios is missing. The generation of appropriate effectiveness data should make the estimation of such ratios possible in the future.

Ethical aspects of the technology (ETH)

Direct evidence of improved outcomes is lacking for all three tests, but studies of components of clinical utility might provide indirect evidence. There is encouraging indirect evidence for Oncotype DX, and plausibility for potential use of MammaPrint and, possibly, the uPA/PAI-1 test. It seems plausible that more women will benefit (i.e. avoid unnecessary chemotherapy), but there is the potential for significant harms among a small number of low or intermediate risk women (who might have benefitted from chemotherapy), possibly resulting in breast cancer recurrence or death. Currently, there are insufficient data to confidently estimate these risks and benefits. In addition, it is difficult to determine what proportion of women with moderate to high risk, based on conventional risk assessments, will have a “low enough” score to affect their decision about chemotherapy. The use of the tests raises the question of the extent to which patients are prepared to participate in informed decision making about their care.

Organisational aspects of the technology (ORG)

The introduction of PTBCRs into the clinical pathways of women with breast cancer is unlikely to have significant organisational impacts. However attention should be paid to costs, and to communication between provider units and patients.

Social aspects of the technology (SOC)

If PTBCRs are introduced, emotional and psychological support is likely to be useful, especially if results of these prognostic tests are not in accord with those of standard clinicopathological prognostic factors analysis. Feelings of distress and anxiety are frequently reported by patients undergoing prognostic tests and are related to the consequences of the tests on treatment decisions. It remains unclear whether and how these feelings affect the social areas of the patient. Overall knowledge about some aspects of PTBCRs, such as harms, is low.

Legal aspects of the technology (LEG)

Legislation/regulation on three aspects should be developed at the European level. (1) the absence of an ad hoc European directive on medical devices—in vitro predictive tests, (2) the absence of the FEMTELLE uPA/PAI-1 test, MammaPrint and Oncotype DX from the Eudamed register (European registry) and (3) the need to ensure equitable access to these tests.

Closing Remarks

The Core Model is not intended to provide a cookbook solution to all problems but to suggest a way in which information can be assembled and structured, and to facilitate local adaptation. The information is assembled around the nine domains, each with several result cards in which questions and possible answers are reported.

The reasons for having a standardised but flexible content and layout are rooted in the way HTA is carried out in the EU HTA institutions and in the philosophy of the first EUnetHTA Joint Action (JA1) production experiment.

HTA is a complex multidisciplinary activity addressing a very complex reality – that of healthcare. Uniformly standardised evidence-based methods of conducting assessments for each domain do not exist (Corio M, Paone S, Ferroni E, Meier H, Jefferson TO, Cerbo M.  – Systematic review of the methodological instruments used in Health Technology Assessment. Rome, July 2011.). There are sometimes variations across and within Member States in how things are done and which aspects of the evaluation are privileged. This is especially so for the “softer”, more context-dependent domains such as the ethical and social domains.

Currently there are only three applications of the HTA Core Model (medical and surgical interventions, diagnostic technologies, and screening technologies). In this work the HTA Core Model for diagnostic technologies was used to assess the clinical effectiveness of the three prognostic tests. However there are fundamental differences between diagnostic and prognostic tests. Because of these differences, a number of the HTA Core assessment element questions for diagnostic technologies are not suited to prognostic technologies. Prognostic/predictive accuracy was not assessed in this HTA Core Model.

This test would represents a useful lesson for methodological development in EUnetHTA Joint Action 2.