Pre-reimbursement: early assessment for coverage decisions

As mentioned, Austria is one of the countries where new anti-cancer treatments are adopted faster and are available earlier after approval by the European Medicines Agency (EMA) compared to many other European countries [8, 9]. Therefore, the LBI-HTA was asked by regional hospital providers and the Austrian Ministry of Health (MoH) to establish an early awareness and alert system specifically focusing on cancer drugs. The so-called Horizon Scanning in Oncology (HSO) program was developed and tested between 2007 and 2008 in cooperation with horizon scanning experts from the EuroScan International Network (International Information Network on new or emerging, appropriate use and re-assessment needed Health Technologies). In October 2009, the program was routinely introduced. Since then, 83 LBI-HTA assessments and three updates have been conducted and published on the LBI-HTA website (http://​eprints.​hta.​lbg.​ac.​at/​view/​types/​dsd-hso.​html). Two to three new therapies are assessed quarterly, resulting in at least eight early assessments annually. The aim of the HSO program is to identify new anti-cancer drugs or already approved drugs with licensing extensions that have a potentially relevant therapeutic and/or financial impact on the Austrian health care system. Thus, it shall not only contribute to a rational and evidence-based decision-making process, but also facilitate estimations of the impact on the health budget [8].

Across those countries that have implemented HSS, like the UK, Canada and Sweden, the inherent process basically includes the same steps (Fig. 1a; [6]). However, individual adaptations to respective contexts and needs, such as the time horizon of the HSS—which can vary from an early stage (phase I) to later stages (phase III) of drug development—have to be applied. In the HSO program of the LBI-HTA, a maximum time horizon of 3 months after marketing authorisation by the EMA, which mostly includes phase III trials, was chosen. As a first step, potential customers have to be determined prior to an HSS establishment. Thus, the LBI-HSO program was commissioned by the Austrian inpatient sector and should inform representatives of the Ministry of Health (MoH), medical directors, heads of hospital pharmacies and members of regional pharmaceutical committees [8].

The first step in the Austrian HSO process (Fig. 1b) is to identify only originator cancer drugs and indication extensions in development by regularly scanning nine sources (e.g., Medscape, websites of regulatory bodies) and periodically scanning four additional sources (e.g., conference abstracts). As a next step, drugs of the horizon scanning list that meet the inclusion criteria, which currently consists of over 400 cancer drugs in the development pipeline, are filtered out quarterly. Two blinded researchers make a first selection through a priori set filter criteria (about ten to fourteen), which mainly include the availability of positive phase III or phase II (orphan drugs) results and the maximum period of 3 months after EMA approval. Available information on the drug, indication, incidence, regulatory status and trial results are collected and sent quarterly to a group of eight experts made up of oncologists and hospital pharmacists. On the basis of five criteria, such as the potential for a significant health benefit to the patient group, the expert panel is asked to prioritise the drugs by choosing one of the following three categories—“highly relevant”, “relevant” and “not relevant”—to identify oncology drugs with a potential health and/or budget impact (Table 1). Based on the cross-sectional score of all experts, those drugs considered as highly relevant are selected for an assessment [8]. Results of the prioritisation are available on the LBI-HTA website (http://​eprints.​hta.​lbg.​ac.​at/​view/​types/​dsd-hso.​html).

Since 2015, the structure of HSO assessments has been based on the HTA Core Model® for Rapid Relative Effectiveness Assessment of Pharmaceuticals developed by the European network for HTA (EUnetHTA) [14]. The HTA Core Model® organises relevant information according to pre-defined generic research questions and clusters them into the following five domains: description of the technology, health problem and current use, clinical effectiveness and safety. In addition to the HTA Core Model®, chapters regarding the systematic literature search, clinical effectiveness and safety of further studies, ongoing trials, costs (ex-factory prices) and a comprehensive commentary section are implemented [8]. As a first step in conducting an HSO assessment, the research question has to be defined and a systematic literature search has to be performed in relevant databases like PubMed and Embase. The reports are written in English so that they may also be used in other European health care systems and to reduce redundancies in European HTA [15].

To facilitate further European collaboration and to continuously refine scientific methods, additional research tools have been incorporated into the HSO reports in recent years. Therefore, the internal and external validity of clinical trials are assessed by applying tools based on EUnetHTA guidelines. These methods assess the methodological quality of evidence by evaluating the risk of bias (RoB) at study level (internal validity) and the applicability of study results, specifically the extent to which the results can be generalised to clinical practice (external validity) [16, 17]. Moreover, the Magnitude of Clinical Benefit Scale (MCBS) developed by the European Society of Medical Oncology (ESMO) was introduced to systematically and transparently evaluate the magnitude of meaningful clinical benefit (MCB) that can be expected from a new cancer drug [5, 18, 19]. The scale can only be applied to solid tumour drugs and ranges from zero to five, whereby scores of four and five indicate MCB. The evaluation of the clinical benefit is based on a dual rule taking both the observed relative benefit (hazard ratio) and the absolute benefit (median) into account. HSO assessments are internally and externally reviewed to guarantee quality assurance.

To ensure a transparent HSS system, final HSO reports are published on the LBI-HTA website (http://​eprints.​hta.​lbg.​ac.​at/​view/​types/​dsd-hso.​html), as well as sent out via a mailing list including health stakeholders from different areas including oncologists, hospital pharmacists, medical directors, representatives of the MoH and health insurance providers [8]. Additionally, an HSS has to monitor upcoming evidence of already approved therapies and conduct assessment updates. Between 2009 and 2016, 63 novel cancer indications were under evaluation within the HSO program of the LBI-HTA and three assessments were updated later on; 60 of those were consequently approved by the EMA.

As one of the first European countries, Austria began introducing a systematic evaluation of new hospital interventions submitted for reimbursement in 2008. The Federal Health Commission (FHC) of the Austrian MoH maintains a benefit catalogue of medical interventions that are provided in the inpatient sector. As mentioned in the introduction, the hospital benefit catalogue includes a list of MELs for which costs are reimbursed in addition to the DRG flat rates [11, 12]. Every year, suggestions for new interventions are submitted electronically by individual hospitals or by regional hospital cooperatives to the FHC at the MoH. These topics are compiled (in a long list) and subsequently prioritised by the MoH according to criteria such as the same suggestions by multiple hospitals or high-volume/high-cost suggestions. Finally, a (short) list of new interventions is prepared and the LBI-HTA is commissioned to conduct assessments. These topics are single-technology assessments (STA; one device/intervention for one indication) or multiple-technology assessments (MTA; one device/intervention for several indications or several interventions for one indication). The evidence syntheses have to be conducted within 3–5 months [12]. These assessments serve as evidence-based decision-support documents that include a recommendation to the FHC [11, 12]. These systematic evaluations follow generic steps that are represented in Fig. 2a. The introduction of this process was accompanied by the implementation of a new decisional option, the “XN code”. In contrast to preceding years when the sole options were to include/exclude interventions in the benefit catalogue and were not based upon evidence, XN interventions can be included temporarily (3–5 years) and will be re-evaluated [20]. Within the period of 2008–2018, 96 MELs (74 new systematic reviews and 22 updates) were carried out by the LBI-HTA (http://​eprints.​hta.​lbg.​ac.​at/​view/​types/​dsd.​html).

After initial compilation and prioritisation by the MoH, potentially relevant topics are provisionally communicated to the LBI-HTA for scoping. This process includes the scanning of different sources, like the HTA and Planned and Ongoing Projects (POP) Databases, Deximed, UpToDate, S3 guidelines (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF), other evidence-based guidelines and Open Knowledge Maps [15]. These consist of information from other evidence-based advisory boards (e.g., The National Institute for Health and Care Excellence, NICE; or the Canadian Agency for Drugs and Technologies in Health, CADTH). High-quality systematic reviews or assessments of other institutions and information on the regulatory and implementation status of the technology can thereby be identified. Accordingly, there is a second prioritisation by the MoH in cooperation with the LBI-HTA when the decisions on the final topics for the ensuing assessments are made (Fig. 2b).

After the final selection of the topics, the exact research question is defined by clarifying the target Population, the investigated Intervention, the Comparator intervention(s) and patient-relevant Outcomes (PICO). A systematic literature search is then conducted in the following databases: Medline via Ovid (including PubMed), Embase, The Cochrane Library, and the Centre for Reviews and Dissemination (CRD). Furthermore, to identify ongoing and unpublished studies, a search in three clinical trial registries (ClinicalTrials.gov, WHO-ICTRP, EU Clinical Trials) is carried out. As a final step of the systematic literature search, a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram has to be prepared and implemented in the assessment [13, 21].

Subsequently, the quality of the studies is rated by an RoB assessment. Based on the study design, different methodological tools can be considered for the RoB assessment (e. g., Cochrane RoB checklist, ROBINS-I, AMSTAR, IHE 20-Criteria Checklist). The external validity is additionally evaluated, i. e., the extent to which the results can be generalised to the population in clinical practice. In a next step, efficacy and safety data of the included studies are extracted by one author and reviewed by another independent author [16, 22]. Since 2016, the structure of MEL assessments has been based on the HTA Core Model® (Application for Rapid Relative Effectiveness Assessment), which was developed within EUnetHTA (www.​eunethta.​eu, see Horizon Scanning in Oncology program—process and method) [23].

Accordingly, a critical appraisal based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework is conducted to evaluate whether the overall strength of evidence supports the conclusions [24]. Therefore, the extracted outcomes have to be categorised, according to patient relevance, as either decisive for the final decision (critical), clinically important (important) or not clinically important (not important). To estimate the effect for each outcome, data on selected outcome categories are synthesised across studies by two independent researchers in a summary of findings table [24]. To rank the overall strength of evidence across all outcomes, GRADE applies four categories, whereby the lowest quality of any critical outcome is decisive (Table 2). The main focus is on the predefined outcomes of the PICO question and the outcomes defined as critical during the GRADE process. On these grounds, conclusions are derived and recommendations are given on whether the new hospital intervention should be included in the MEL list and thus reimbursed.

The recommendation can include one of the four following categories: “yes”, “yes—with restrictions”, “no—preliminary” and “no” (Table 3). The categories “yes” and “no” shall recommend or not recommend the inclusion into the hospital benefit catalogue, respectively. Moreover, a “recommendation with limitations” includes a statement on advised restrictions (e. g., use in specialised centres). Regarding the third category of “preliminary rejection”, the recommendation is accompanied by a description of gaps in clinical evidence (e. g., lack of long-term follow-up data or controlled studies, unreliable clinical endpoints). LBI-HTA recommendations given in the MEL assessments are taken into consideration by the FHC. However, the final decision of the FHC can be either the inclusion into the hospital benefit catalogue with or without any restrictions or the exclusion from reimbursement [12]. After amendments to the hospital benefit catalogue have been published, early assessments are published via the LBI-HTA website (http://​eprints.​hta.​lbg.​ac.​at/​view/​types/​dsd.​html) and a mailing list addressing health care stakeholders.

Between 2008 and 2017, 69 assessments for hospital interventions (often, but not always medical devices) that can be followed-up to a political decision were conducted within the MEL program of the LBI-HTA. Twenty-five (36.2%) of those were included into the hospital benefit catalogue, whereby only five (7.2%) were included without any restrictions. On the other hand, 44 (63.8%) were not eligible for inclusion into the catalogue. Regarding the MEL recommendations, 54 (78.3%) interventions were initially not recommended to be included, of which 50 (72.5%) were preliminarily not recommended due to gaps in clinical evidence. Fifteen (21.7%) of the interventions were recommended with restrictions for inclusion into the benefit catalogue and none were recommended without any restrictions (Table 3).