Adoption of trastuzumab for breast cancer in four emerging countries in the use of health technology assessment: a case study

The case study approach is a research design that allows explaining the process of and reasons behind health policy development, such as those relating to HTA [14,15]. Since the goal of this paper was to capture a variety of HTA systems among the regions of interest, a multicountry collective case study was designed.

In order to collect data in the countries selected, a survey of key informants involved in the HTA for trastuzumab in their respective countries was designed. A review of relevant HTA literature was conducted to identify good HTA practices, concepts to be used, previous HTA surveys and key informants. The questionnaire was developed in an iterative process, and pilot tested with HTA experts from different countries and organizations (e.g., for format, structure, formulation of questions and answer options). The questionnaire was based on key principles for HTA [16–18], with 39 questions divided into four themes, as follows: (1) structure of HTA programs; (2) methods of HTA; (3) processes for conduct of HTA; and (4) use of HTAs in decision-making, implementation and monitoring. The instrument (full questionnaire available upon request) included both dichotomous and multiple choice questions, as well as a number of open questions to allow for clarification and explanation of responses (see summary table of questionnaire in Supplementary Table 1).

Key informants involved in the assessment of trastuzumab from the selected countries were invited to complete the survey via email in July 2014, and followed up by email and telephone until survey completion (January 2015). We contacted 32 organizations or people related with HTA in different countries, with only four countries responding and accepting to participate. The data gathered from survey responses were examined following a content analysis approach. A conceptual framework aiming to connect the typical steps of an HTA process (topic selection, scoping, assessment, appraisal, decision-making, dissemination, implementation and monitoring of impact) with the key principles for HTA (e.g., transparency, inclusiveness, relevance) [16,17] was employed. Once the survey responses were compiled and analyzed, results were contrasted with available assessment/appraisal reports on the different websites [19–22], a previous output of the ADVANCE HTA project [23], as well as clarifications provided by the country experts involved in the respective HTA processes.

The findings of the trastuzumab case study are described according to the typical steps of an HTA process. It is important to highlight that the HTA of trastuzumab was conducted at the national level in Poland (Agency for Health Technology Assessment and Tariff System [AOTMiT]), Colombia (Institute for Health Technology Assessment [IETS]) and Brazil (National Committee for Technology Incorporation [CONITEC]), whereas the process occurred at the hospital level in Albania (Tirana University Hospital Centre [QSUT] Nene Tereza). Although the steps followed in the latter case were less well defined, parallelisms have been drawn for analysis purposes. Table 1 shows the main bodies that constitute the HTA systems described.

Overall, this case study of the adoption of trastuzumab in four emerging countries shows that the selected technology was evaluated following well-structured HTA processes, comprising steps previously defined and somewhat consistent across settings. Moreover, these processes were generally supported by legislation. With these HTAs, researchers and policymakers attempted to respond to population health needs, taking account of economic and social impact [24]. This case study sets the example for how emerging countries can successfully implement HTA and inform complex decisions on interventions such as those relating to cancer treatments. Although final decisions were favorable in all study countries, restrictions/recommendations on treatment access and process steps followed are the elements providing an avenue for discussion in this study.

Clear recommendations on good HTA practices exist [13,16,25], although little is known about its actual implementation [25]. Some authors [25,26] have already revealed the general adherence to good practice in the Brazilian and Polish systems, but there is no information with regards to Albania and Colombia. Discrepancies were found in the case studied in Albania, although this can be explained because HTA was conducted at hospital level. Hospital-level or mini-HTA has been advocated as a better solution to translate evidence into practice due to its integration into the local context. Although mini-HTAs (by definition) are less systematic and thorough than standard HTAs, they are usually more context-specific, relevant and timely than their counterparts conducted at regional or national levels [12].

Diverse levels of stakeholders’ participation in the HTAs of trastuzumab were observed, both in terms of who is involved, and when and to which extent. For instance, in some cases topic selection was determined as a result of a manufacturers’ request to have their technologies included in benefit packages or from clinicians’ interest. In this regard, the literature on good practices recommends the participation of different actors throughout the HTA process, and its explicit recognition as an element to promote the legitimacy of decisions [16]. In their analysis of 30 countries, however, Stephens et al. [25] showed that stakeholders were involved in the assessment and appraisal stages in just 50 and 65% of surveyed countries, respectively.

One of the key principles of the HTA process is to have its transparency guaranteed, understood as the environment in which information relative to policies is provided to the public in a clear, accessible and timely fashion [27]. Such a principle should be present throughout the HTA process of all technologies evaluated. It is therefore necessary to disclose the criteria taken into account in the identification and initial selection of technologies, as well as the potential conflicts of interest of the researchers and stakeholders who participate in it [16]. Along with this information, the origin and use of the data assessed should be specified. Recommendations and guidelines have been published to support improvements in this area [28–30]. The results of this case study indicate some weaknesses in terms of transparency that the various agencies involved should address, particularly in some points regarding the information provided in their reports and across the HTA process (especially at the appraisal and decision-making levels). In general, aspects related to transparency constitute one of the main weaknesses around HTA processes, and a series of recommendations have been issued by authoritative agencies in this field [30,31].

Regarding the evidence considered in the assessment, it is noteworthy that only Brazil reported using systematic reviews, while the other countries employed data from randomized controlled trials. Systematic reviews (with or without meta-analysis) are regarded as the highest level of evidence for efficacy/effectiveness of an intervention [32], constituting an essential component of HTAs. On the other hand, selected clinical end points were clinically similar across study cases and meaningful (overall survival, progression-free survival). However, only two countries (Poland and Colombia) took account of quality of life, an outcome usually less commonly employed in oncology. Although the selection of end points depends on the type of malignancy and its stage, it is central that HTA agencies make efforts to consider the outcomes that are the most relevant to patients [33]. Engaging in early dialogue with manufacturers about the choice of meaningful end points for RCTs is a practice that could also be explored by emerging settings [34].

On the other hand, limitations in the economic evaluation methods used were found. HTA requires robust and explicit methods that are capable of synthetizing evidence of both benefits and costs in a summary measure for decision makers to compare with competing interventions. As a result, cost-utility analysis has become the most favored type of study [35]. However, cost–effectiveness analysis (with cost per life year gained as outcome) is widely employed in the HTA of cancer drugs, since increasing survival remains as the chief objective of treatment [36]. An interesting fact is that budget impact analysis alone was employed in the cases of Albania and Brazil. As countries progress in the implementation of HTA, a shift toward including also value for money in decision-making rather than simply separate indicators of effectiveness and cost will bring notable benefits. In particular, budget impact is not generally considered as a rational criterion for decision-making on its own, which may affect the legitimacy of decisions in cases where the technology in question is rejected [37]. Moreover, the use of economic evaluation as a tool for price negotiation may help resource limited settings to increase access to high-cost technologies, such as cancer drugs [12,36]. Findings from this study show that price negotiation has become a common practice in Brazil and Poland.

Nonetheless, the most marked observation to emerge from the analysis is the fact that trastuzumab was recommended across all countries, when there is some evidence pointing to its cost–ineffectiveness and unaffordability in low- and middle-income countries [12]. The reason for this apparently contradictory result is not completely clear, but it may be due to lower trastuzumab prices being offered by industry to governments, or to a higher weight placed on other values by stakeholders. Furthermore, it is also interesting to note that fewer restrictions on the use of trastuzumab were made in Albania. This phenomenon has been observed by other authors, and can be explained in part by the type of HTA performed (with or without economic evaluation) and the relative price of the drug assessed [38].

Except for Albania, reports were disseminated and publicized to some extent or another and made available on the agencies’ websites, thereby complying with good practice recommendations on this matter [16]. Colombia and Brazil are two cases in point, where the HTA report was disseminated with and/or used to inform CPGs for the early detection, integrated treatment, follow-up and rehabilitation for breast cancer. This use of CPGs contributes to diffusion of evidence among professionals [39].

The main limitation of this study lies on the fact that not all agencies publish and disseminate their reports and, therefore, some information could not be compared. Researchers have also failed to ensure that the questionnaire sent to agencies was always completed by the most knowledgeable person in the matter. Despite this, the authors were particularly careful in the process of review and triangulation of data, using different sources such as country experts and – when available – the pertinent HTA reports.

This paper shows the whole process of HTA of a high-cost cancer drug in settings not previously deeply studied. Although similar case studies have been conducted in countries with long-established HTA systems [40–42], this paper offers an exhaustive account of policy development rather than an analysis of external influences on decision-making. This work covers an area in which information may not always be available in the public domain or published, especially as it pertains to emerging countries. In this regard, future studies on different technologies and countries are therefore suggested in order to provide a better understanding of how difficult coverage decisions are made across settings.

The authors gratefully acknowledge all key informants and survey respondents who have voluntarily collaborated in the development of this study. They also thank the organizations that participated in this study and Work Package 6 partners.

This work is part of ADVANCE-HTA, a broader, multipartner and multidisciplinary research project (www.advance-hta.eu), funded by the European Commission's Research Framework Programme (FP7). It comprises several complementary streams of research that aim to advance and strengthen the methodological tools and practices relating to the application and implementation of HTA. This paper comes from the Work Package 6, Strengthening and Implementing HTA in Emerging Settings. The design, interpretation and presentation of results are independent from the funding organization. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.