Introduction:

The goal of conducting a reimbursement policy is to allocate limited financial resources while maintaining the widest possible access to medicinal products characterised by proven efficacy and safety. [1] Reimbursement decisions are a part of the decision-making process specified in applicable legal provisions. In the Polish reimbursement system, the key stakeholders involved in shaping the above-mentioned policy are the Agency for Health Technology Assessment and Tariff System (AHTAPol, pol. AOTMiT) (as part of its structures, the President of the Agency and the Transparency Council – supporting the President in the assessment process), as well as the Minister of Health (MoH). Their competences have been characterised in the Act on reimbursement of medicines, foodstuffs intended for particular nutritional uses and medical devices ( “Reimbursement Act”) [2] and the Act on healthcare services financed from public funds [3].

For several years, changing trends in the assessment of health technologies by regulators (European Medicines Agency (EMA), Food and Drug Administration (FDA)) could be observed, in particular in therapies applying for early access. In such cases, more and more often, decisions about the granting of marketing authorisation are made based on surrogate endpoints (surrogates) and/or lower-quality evidence (e.g. single-arm studies). HTA agencies adopt various policies regarding the use of surrogates in health technology assessment. [4]

This analysis takes into account the practice of the AHTAPol in the assessment of technologies applying for reimbursement in oncological indications, with particular reference to the reasons for negative decisions being issued. Furthermore, announcements of the MoH were analysed to show the relationship between positions presented by bodies of the AHTAPol and the listing of substances on the list of reimbursed medicines.

Methods:

The analysis included orders directed to the AHTAPol's assessment in the years 2009-2018. The analysis includes decisions issued by the Transparency Council/Consultative Council (since January 2007 the Consultative Council, in February 2012 replaced by the Transparency Council) and the President of the AHTAPol for oncological drugs. For the identified orders, announcements of the MoH on reimbursed medicines, foodstuffs intended for particular nutritional uses and medical devices published between 01.2012 and 09.2018 have been reviewed.

Decisions on orders directed to the AHTAPol

The orders were identified using the Public Information Bulletin (BIP) of the AHTAPol [5] filtered for the above-mentioned period of time. The orders made out to the AHTAPol under Article 35.1 of the Reimbursement Act, concerning the reimbursement of new health technologies (for directed to the Agency after January 2012) and orders regarding the preparation of the recommendation of the Agency’s President pursuant to Article 31 of the Act on health care services financed from public funds (for orders assessed by the Agency before the Reimbursement act came into force) in oncological indications. Article 35.1 of the Reimbursement Act includes the mode of the AHTAPol‘s assessment regarding medicines, foodstuffs intended for particular nutritional uses and medical devices for which there is no reimbursed equivalent in a given indication. The analysis did not include supportive therapies and radiopharmaceuticals.

Qualification of the order was carried out on the basis of tabs dedicated to individual orders, taking into account in particular the "indication" area. The identified orders were aggregated in two areas of indications (haematological and other oncological indications [solid tumours]) and divided into 25 groups of indications selected with regard to the tumour’s location.

The publication constitutes an analysis of orders regarding the reimbursement coverage. The following categories were distinguished in the analysis: A – general list, B – drug programme, C – chemotherapy catalogue.

On the basis of issued Council positions (CP) and recommendations of the President (PR), orders were qualified to the following groups:

• positive: the position (pCP)/recommendation (pPR) is positive and was expressed directly in a decision of the authority in the entire scope of the reimbursement application,
• negative: the position (nCP)/recommendation (nPR) is negative and was expressed directly in a decision of the authority in the entire scope of the reimbursement application,
• conditional: the position (cCP)/recommendation (cPR) is positive or partially positive, provided that a certain condition is met.

Based on the justification presented in the CP and the PR, reasons for issuing negative decisions were classified to at least one of 9 groups:

1. OS – lack of results or no statistically significant improvement in overall survival (OS) has been proven, little benefit was demonstrated,
2. QoL – lack of results or no statistically significant improvement in quality of life (QoL) has been proven,
3. Efficacy – the results (not referring directly to OS or QoL) included in the clinical analysis were subject to high uncertainty,
4. Safety profile – the therapy’s uncertain or unfavourable safety profile,
5. Cost-effectiveness – lack of demonstrated cost-effectiveness of the therapy,
6. Economic analysis – incorrectly conducted economic analysis or economic analysis associated with high uncertainty,
7. Population – the evidence did not match the population indicated in the reimbursement application,
8. Methodology – the studies included in the analysis were characterised by poor quality or the wrong methodology of clinical analysis was used,
9. Other.

Based on the justification presented in the CP and the PR, reasons for issuing conditional decisions were classified to at least one of the following 4 groups:

1. Price – regarding the condition of reducing the price per se or "reducing the cost of therapy to the level of cost-effectiveness",
2. RSS (risk-sharing agreements) – when the condition consists in the development of a risk-sharing instrument or when the RSS proposed by the MAH has not been accepted,
3. Change of stipulations – in particular when those changes concern stipulations of a drug programme (e.g. population reduction),
4. Other – e.g. in the case a decision limited in time and subject to conditions is issued, after the laps of which a reassessment will take place or in the case of which reimbursement will be granted under the condition of joining the existing drug programme.

Decisions taken by the Minister of Health

Only orders directed to the AHTAPol until the end of 2017 were the subject of the reimbursement availability analysis. The analysis did not include orders for which it was not possible to identify the cause and effect chain related to a positive/negative reimbursement decision being taken (in particular orders directed to the AHTAPol before 2012).

Information on reimbursement of individual substances was taken from the published announcement of the Minister of Health on reimbursed medicines, foodstuffs intended for particular nutritional uses and medical devices, which are published from January 2012 for medicines on the open list and from May 2012 for medicines in the B and C catalogue.

In order to estimate the time needed to obtain reimbursement for the technologies analysed herein, the date of the settlement understood as the date of the President's recommendations was taken into account. Average and the median waiting time for reimbursement coverage were taken into account.  Reimbursement success was defined as the date of the first inclusion of the substance in the announcement of the MoH in accordance with the indication as applied. Additionally, in the case of orders not concluded with reimbursement, further actions of the entity applying for reimbursement of the  technology, and the waiting time has been included for the entire analysed pathway (sequential approach).

Results:

Decisions on orders directed to the AHTAPol – Analysis of the Council's positions and the President's recommendations in the years 2009-2018

In the 2009-2018, 2090 orders were created on the AHTAPol websites, of which 23% (491) were orders regarding oncological indications. Of the oncology orders, 30% (152) concerned the coverage in accordance with the accepted inclusion criteria for analysis. Chart 1 Presents the distribution of orders sent to the AHTAPol broken down by individual years.

Chart 1. Distribution of orders for reimbursement coverage directed to the AHTAPol in individual years – breakdown by the reimbursement area as applied, (N)

In the analysed period, a steady increase in the number of orders for reimbursement directed to the AHTAPol assessment can be noted.

Of the analysed orders, 16% (25 out of 152) CP and 18% (27 out of 152) RP were positive. Conditional reimbursement was indicated in 38% cCP and cPR. 40% of positions and recommendations were negative (nCP and nPR). 5% of the orders  directed to the Agency for assessment did not result in a position/recommendation being issued due to withdrawal, cancellation or termination of the order. One of the orders included in this group is still being assessed by the AHTAPol at the time of analysis. [6] In the case of one order, no CP has been identified. [7]

The decisions of the two AHTAPol bodies were consistent in 76% (104 out of 144 cases).

Consistent decisions concerned 19 positive, 50 negative and 40 conditional positions/recommendations. The same decisions concerned 76% of orders in haematological indications and 75% of orders in oncological indications.

At the same time, it is worth to emphasise the differences in the number of orders which formed the basis for overlapping between the President’s recommendations with positions of the Council. The overlapping rate for the most frequently considered indication (lung – 22 orders) was 73%. Results for indications in which individual orders were recorded should be treated with a high degree of uncertainty. (Chart 2)

Chart 2. Percentage of overlapping between the Council’s positions and the President’s recommendations in relation to individual indications, (%)

Negative decisions

Chart 3 presents the number of orders completed with individual types of positions/recommendations in particular years and the number of nCP/nPR , in which limitations in the scope of OS were indicated as one of the reasons. In the analysed period of time (2009-2018), almost 50% (72 out of 152) of orders directed to the AHTAPol ended with the issuance of a negative decision by at least one of the Agency’s bodies. Taking into account only the period after the entry into force of the Reimbursement Act (after 2012), this percentage is 45.5% ( 2012 – 10% (2 out of 20), 2013 – 47% (9 out of 19), 2014 – 30% (6 out of 20), 2015 – 63% (10 out of 16), 2016 – 70% (14 out of 20), 2017 – 79% (19 out of 24), and 29% (5 out of 17) in 2018).

Chart 3. Decisions of the AOTMiT bodies in 2009-2018, (N)

Among the identified negative positions/recommendations (respectively: 48/61, 46/61) the most frequent cause was failure to demonstrate cost-effectiveness of the technology. The above accounted for 79% of nCP and 75% of nPR.

In 52% nCP and 66% of nPR, the justification for the negative decision contained a reference to the poor quality of the studies or the wrong methodology of clinical analysis. The reasons listed included i.a. a small number of RCTs or their low quality, lack of long-term follow-up confirming the effectiveness of interventions [8] or the lack of direct comparisons of efficacy and "the scale of adverse effects" due to the small, diverse group of patients included in the trial [9]. In 34% of both the nCP/nPR, results in the field of efficacy raised doubts (e.g. no/insufficient evidence confirming the efficacy of intervention, limitation of outcomes for other endpoints than clinical relevant, limitations of clinical analysis). The reservations did not directly concern the measures of treatment benefit, including OS and QoL.

Limitations of OS results (lack of results/statistically insignificant results/no median achieved/slight benefit demonstrated) were pointed out in 31 (51%) of nCP and 40 (66%) of nPR. Cases in which, despite showing the superiority of the proposed technology in the scope of OS, its insufficient level was emphasised in 4 nCP and 6 nPR. Table S1 (Supplement) presents the arguments of the AHTAPol bodies referring to limitations of results in the scope of OS.

In the Agency's opinion, the QoL constitutes an important measure of clinical benefit, especially when assessing the efficacy of health technologies used in advanced stages of cancer, when obtaining a complete cure it usually not possible. Objections regarding the absence/limitation of QoL were raised in 17 (28%) of nCP and 25 (41%) of nPR. In the case of 14 nCP and 19 nPR, the objection of lack of results or lack of demonstrated statistically significant improvement in the scope of OS was correlated with a similar objection in the area of QoL.

The largest number of discrepancies in the justifications of negative positions/recommendations concerned the economic analysis (12 (20%) of nCP vs 36 (59%) of nPR, respectively) and evidence not corresponding in full to the population of patients specified in the reimbursement application (18 (30%) nCP vs 5 (8%) nPR).

Differences in the frequency of the most common reasons for nCP and nPR issued since the Reimbursement Act has been in force were analysed. In the last two years, an increased agreement between CP and PR have been observed. The analysis has shown the argument of lack of cost-effectiveness has been used less frequently last year. At the same time, it should be emphasised that the year 2018 is characterised by a small number of nCP and nPR in total. What is more only in 3 positions/recommendations, limitations of the OS analysis were identified as the cause of nCP/nPR. (Chart S1, Supplement)

The justifications included in negative positions/recommendations for oncological indications (solid tumours) and haematological indications were also compared. The biggest differences between the reasons for nCP/nPR can be observed in nPR referring to the safety profile of the therapy. This argumentation was indicated in 40% of nPR (32% of nCP) in oncological indications vs 71% of nPR (65% of nCP) in haematological indications.

Low quality of the studies included in the application or methodological errors were pointed out in 42% of nCP and 58% of nPR in oncological indications and 50% of nCP and 71% of nPR for haematological indications. It is noteworthy that the majority of haematological indications are rare (or ultra-rare) diseases, and thus drawing conclusions on the efficacy of drugs is often conducted on the basis of lower-quality studies (smaller sample, single-arm studies).

In the analysed time period, a similar percentage of nCP/nPR may be observed in relation to orders in haematological and oncological indications (haematological indications – 38% vs oncological 41%, in both nCP and nPR). However, the difference between the number of orders directed to the AHTAPol for assessment in oncological indications as compared to the haematological indications (109 vs 42, i.e. more than double) should be emphasised. (Chart 4)

Chart 4. Reasons for negative positions of the Council and negative recommendations of the President in oncological indications and haematological indications, (%)

In the period included in the analysis, 74 orders directed to the AHTAPol resulted in a condition being imposed by at least one of the Agency’s bodies (58 cCP and 57 cPR). It should be emphasised that in the comparison to past years, 2018 is characterised by increased number of conditional decisions (59% CP and 53% PR vs 50% CP, 25% PR in 2017, 35% CP, 30% PR in 2016 and 31% CP, 44% PR in 2015). (Chart 3)

Among the oncological indications, 35 (32%) cCP and 37 (34%) cPR were reported, while there were 18 (42%) cCP and 15 (35%) cPR in haematological indications.

The conditions for reimbursement coverage were classified into four groups: price, RSS, change of stipulations and other. (Table 1)  

Table 1. Type of condition indicated in positions and recommendations

The most common type of condition was to propose an adequate risk sharing instrument in 69% of positions and 61% of recommendations. Conditional positions and recommendations often also indicate the need to reduce the price of the health technology, allowing for obtaining cost-effectiveness of treatment (59% of cCP and 47% of cPR). Changes to the stipulations of the drug programme were a condition for reimbursement coverage in 31% of cCP and 19% of cPR.

Decisions taken by the Minister of Health - an analysis of reimbursement announcements, 2012-2018

MoH decides to reimburse a product by listing it in the reimbursement announcement. Reimbursement announcements are published regularly, every two months, starting from 2012 (01. 2012 for the open list, 05.2012 for drug programmes and the chemotherapy catalogue). 122 orders were included in the analysis of reimbursement decisions.

Basic approach

Over half of the analysed orders (57%, 70 out of 122) ended with a positive reimbursement decision in line with the applied indication.

An overwhelming majority of orders concerned applications for funding under a drug programme (103 orders). 61 health technologies (59%) were granted positive reimbursement decision. Technologies included in the reimbursement announcement within the drug programme were listed on average 11 months (333 days) after the decision was issued by the AHTAPol. Due to the occurrence of outliers for individual orders, the median differed from the average and amounted to 213 days. It should be noticed that average time from a submission new order made by MoH to AHTAPol decision takes 89 days (85 days for drug programmes only).

Those orders which resulted in a positive decision, for which the waiting time for reimbursement  amounted up to 1000 days (2.7 years) are particularly noteworthy. Among the analysed orders, the longest reported waiting time was the 1,254-day period for temsirolimus used under a drug programme in treatment of advanced renal cell carcinoma in the group of patients with an unfavourable prognosis (Table 2).

Table 2. Orders for drug technologies characterised by the longest waiting times for reimbursement from among technologies included in reimbursement announcements

From among oncological indications, 58% (49 out of 84) orders were granted positive reimbursement decision; for haematological indications the percentage was 55% (21 out of 38). Significant differences were found between waiting times for reimbursement with respect to haematological indications (mean: 194, median: 115 days) vs oncological indications (mean: 348, median: 222 days). Average waiting time for technologies financed within the drug programme was 237 and 366 days respectively for haematological and oncological indications.

Out of 22 pCP, 91% of orders translated into a reimbursement success (83% of orders resulting in a pPR, 19/23). In the case of 42% positions and 36% of recommendations orders which ended with a negative decision, the MoH decided to include the technology in the reimbursement announcement. (Chart 5)

Chart 5. Reimbursement coverage according to types of positions/recommendations, (%)

Sequential approach

Actions taken by entities applying for reimbursement are often sequential. Failure to obtain reimbursement success may result in resubmission of the reimbursement application for the same substance for a population similar to the original population. (identified sequence orders - Table 3)

Table 3. Waiting time for reimbursement – the sequential approach

The analysis of the waiting time for reimbursement in that approach, allows to interpret results for 5 technologies in a different way (all applied for reimbursement under the B-catalogue). The sequential approach affects the 73-day prolongation of the average waiting time (333 vs 406) and the 54-day change in the median waiting time (213 vs 267) in drug programme category.

In order to illustrate the waiting times for reimbursement, the mean time and median waiting time were calculated in relation to: individual parts of the guaranteed benefits package, oncological and haematological indications, basic and sequential approach. It was assumed that the positions/recommendations were issued on January 1 and subsequent days were counted from that moment. (Chart 6)

Chart 6. Waiting time for reimbursement coverage: 1. basic approach and sequential approach; 2. the part of the guaranteed benefits package subject to the application 3. oncological and haematological indications

Discussion

Analyses of Positions of the Transparency Council and Recommendations of the President of the AHTAPol in the context of reimbursement decisions have already been the subject of numerous papers, however it should be emphasised that the available publications concerned specific therapeutic areas (orphan drugs, add-on therapies) or included a short time horizon [28-30]. Analyses concerning a longer period of time take up the subject of the AHTAPol’s organisation and work in general. [31] This report constitutes an analysis of not only the practice of making decisions by the Agency, but also the further stages of the process of applying for financing of oncology drug technologies, until obtaining reimbursement coverage.

The analysis conducted by authors hereof has indicated that orders directed to the AHTAPol (meeting inclusion criteria of the analysis) resulted in a decision corresponding to the intention of the application in 16% of CP and 18% of PR, respectively.

In comparison to the period before the entry into force of the Reimbursement Act, the analysis showed an increased frequency of issuing negative positions/recommendations in relation to orders concerning reimbursement coverage. It should be noted that in the first years of the Agency's work, therapies with an established position or a breakthrough in the treatment of a given disease were assessed. Demonstrating added value of new health technologies as compared to options which are already being reimbursed is becoming increasingly difficult. In the case of disease entities characterised by a high, 5-year survival, the course clinical trials aimed at demonstrating improved OS continues to become longer. At the stage of applying for the financing of medicines from public funds, data on efficacy are often available as surrogate endpoints.

Limitations of clinical analyses resulting from the availability of results in clinically significant endpoints constitute a frequent cause of negative decisions by the AHTAPol bodies (OS: 31 (51%) nCP and 40 (66%) nPR; QoL: 17 (28%) nCP and 25 (41%) nPR).

The reservations of the AHTAPol’s bodies in terms of OS in particular relate to situations where no improvement in OS has been demonstrated, when the improvement is statistically insignificant, or when the number of reported events did not allow for determining the median OS. Lack of data in this area is one of the reasons for the nCP concerning pre-operative breast cancer treatment with pertuzumab and trastuzumab. [32] In the case of the health technology in question, the primary endpoint presented in the studies constituting the basis for drawing conclusions on the technology’s efficacy was the pathological complete response(pCR). The President's recommendation includes references to Cortazar 2014 [33] and Broglio 2016 [34] indicating the relationship between pCR and OS results in the aggressive tumour subtypes. Nevertheless, when referring to the aforementioned publications and justifying the negative decision, the President points out that "the association of pCR with the clinical outcome as well as EFS and OS should be proven both at the level of individual patients and the entire study population, which was not presented as part of the applicant’s clinical analysis.” It should be noted that in the recommendation, the President does not refer to the EMA guidelines, according to which pCR constitutes a reliable indicator of the efficacy of add-on therapies for the adopted neoadjuvant regimen, used in patients with early stages of highly malignant breast cancer. It is being indicated that pCR constitutes a prognostic factor in patients with aggressive subtypes of breast cancer (such as HER2+ and triple-negative). [35] It should be noticed that NICE (National Institute for Health and Care Excellence) recommended this technology under condition of RSS implementation. NICE concluded that the clinical trial evidence for pertuzumab in the neoadjuvant setting was limited, but in the absence of stronger evidence, results from two trials (phase 2, TRYPHAENA, NeoSphere, where basic included endpoint was pCR) were taking into account. [36-38] Despite the initial negative evaluation (assessment in 2016), after – 2^nd resubmission, Scottish Medicine Consortium (SMC) in 2019 accepted technology for use within NHS Scotland. [39]  Canadian Agency for Drugs and Technologies in Health (CADTH) does not recommend this technology because lack of efficacy evidence. [40]

The issued nCP/nPR also pointed out the lack of reached median OS/lack of a statistically significant difference in terms of the median OS, and thus the difficulty in demonstrating the impact of the proposed technology on the survival of patients. Available results for the median progression-free survival (PFS) in the absence of available results for the median OS were considered insufficient, i.a. palbociclib with fulvestrant (PAL+FUL) [41] and palbociclib with letrozole (PAL+LET) [42] combination therapies in breast cancer. In the aforementioned cases, the uncertainty of extrapolating PFS results to future OS results is underlined.  It is worth noting that the technology in question concerns the use of substances in the indication of breast cancer in naive patients. It should be pointed out that in line with EUnetHTA‘s recommendations, PFS as the endpoint in clinical trials in oncological indications has different values depending on the disease stage. In adjuvant indications, in first lines of treatment of chronic disease entities, PFS is an acceptable endpoint, while in the metastatic stage of the disease, in the last lines of treatment, it is recommended to support the application with data in terms of OS and/or QoL. [43] SMC accepted combination treatment of PAL+FUL (in woman who are received prior endocrine therapy) and palbociclib with an aromatase inhibitor for restricted use (December 2017). [44] In the same indication, PAL+FUL receive recommendation under condition (cost-effectiveness improvement) in May 2019. [45]  Technology is under evaluation of NICE (expected date of publication: December 2019). [46]

The marketing authorisation requirements for the selection of endpoints in clinical trials have been evolving for decades – from ORR (overall response rate) (1970s), throughout OS, QOL or endpoints related to tumour evaluation (1980s), to PFS and surrogate endpoints (such as minimal residual disease [MRD], pCR). [47] Those e.g. of specific endpoints were underlined in the EMA guidelines [48, 49], which determine when pCR can constitute a basis for a marketing authorisation decision (add-on medicines for the adopted neoadjuvant regimen, used in patients with a high grade of malignancy of early-stage breast cancer, with simultaneous collecting of data on EFS/DFS (event/disease-free survival) or OS). [48, 50] Differences in terms of MRD response rates may be used as an intermediate endpoint for licensure in randomised well controlled studies designed to show superiority in terms of PFS in CLL (chronic lymphocytic leukaemia). [48]  What is more, MRD is a subject of discussion in multiple myeloma (MM), where early approval of a medicine based on MRD as an intermediate endpoint may be considered due to medical need provided that confirmatory comprehensive data on PFS and OS from the same trial are submitted at a later stage. [49]

Objections resulting from the lack of presented results in terms of OS should be compared with the position of the Committee for Medicinal Products for Human Use (CHMP) Scientific Advisory Group for Oncology, which considers PFS to be an less significant endpoint than OS, however still constituting a clinically relevant endpoint. [51] If PFS is considered a clinically relevant endpoint for the assessed treatment line, it is necessary to exclude the risk of reduction of the expected OS. If that is not possible, PFS for the next line of treatment (PFS2) should be adopted as an alternative endpoint. [51]

The discussion on the importance of PFS as a clinically significant endpoint is particularly important in relation to chronic disease entities, characterised by relatively long survival (e.g. 5-year survival: CLL – 85%, breast cancer – 90%, lymphoma – 86%) [52, 53]. Demonstrating improvement in terms of OS is associated with the need to conduct long-term follow-up. In the case of diseases occurring rarely or in narrow subpopulations, difficulties in demonstrating an advantage in terms of OS may result from limited possibilities of enrolling a sufficiently large group of patients (e.g. patients with del17p and/or mTP53 [54]). Furthermore, OS results may be impaired as patients move from the control to the intervention arm (technologies with high efficacy, or when the control arm is PLB). [55] The lack of reached median OS may, however, indicate high efficacy in terms of the OS of patients using the health technology in question.

According to results of the analysis, in 52% of negative positions and 66% of negative recommendations, the justification mentioned the poor quality of the studies or the wrong methodology of clinical analysis. The CP and PR also indicate the uncertainty of drawing conclusions on the efficacy of the intervention in question on the basis of single-arm studies. The approach presented by the AHTAPol differs from that of regulatory agencies, which in recent years, in justified cases (as defined by the guidelines), more and more often decide to grant marketing authorisation to drug technologies based on lower quality studies.

Both the EMA and the FDA define criteria which must be met for single-arm studies to constitute a basis for granting marketing authorisation. In line with the EMA guidelines, ORR in single-arm studies can constitute a primary endpoint used as a basis to apply for marketing authorisation in the accelerated assessment procedure. ORR should be reported in accordance with current international criteria (e.g. RECIST). [56, 57] The latest FDA guidelines indicate the possibility of using the ORR and DOR (duration of response) results from single-arm studies for the purpose of applying for marketing authorisation under the accelerated approval procedure (in disease entities for which alternative treatment methods are not available and at the same time it is possible to demonstrate significant tumour regression) in relation to the applied treatment. Furthermore, response rates can be used as part of a traditional pathway to obtaining marketing authorisation in acute leukaemia, where response rates translate into a reduction in the number of transfusions performed, the occurrence of an infection, and an increase in the likelihood of survival of patients. [58] It is emphasised that in the case of slowly-progressing disease entities and the availability of PFS emergency treatment in metastatic stages of cancer and DFS in the adjuvant treatment are important indicators of efficacy (consensus of French clinical experts). [59]

The authors of Kleijnen 2016 evaluated national (England, France, Germany, the Netherlands, Poland, Scotland) guidelines on the use of endpoints during the assessment of the legitimacy of financing drug technologies in oncological indications in 2011-2013. [4] Authors noted that the results in the scope of OS translated into issued recommendations in 94% of the Agency’s positions/recommendations. The impact of OS results was rated as positive in 48% or neutral in 35%. PFS data affected 56% of recommendations. In terms of individual countries, the results varied considerably (0% in Germany, 85% in Scotland). The impact of PFS data was mainly positive (in 35% of cases). According to the authors, the impact of data with regard to QoL seems to be limited due to a small percentage of studies reporting it. The impact of QoL was defined as neutral (in 19%) or positive (in 16%). [4]

The author's earlier publication (Kleijnen 2015 [60]) indicates examples of different agencies' approaches to using PFS results for pazopanib (advanced/metastatic renal cell carcinoma). Some of them considered PFS to be a significant endpoint from the patient's perspective, while others were of the opinion that the PFS score is only relevant in the absence of OS data and when the result is supported by improved QoL. [60] Also in the case of the AHTAPol’s appraisal, the lack of improvement in terms of OS and QoL was mentioned in the justification of nCR/nPR. [61]

The analysis has demonstrated that the most common reason for nCP/nPR was failure to prove cost-effectiveness. It should be noted that new technologies, especially those used in rare indications, often exceed the cost-effectiveness threshold adopted in Poland. Reservations regarding the failure to demonstrate cost-effectiveness were presented as the argument for issuing a negative decision most frequently (79% of nCP and 75% of nPR). At the same time, the need to lower the price by the applicant in order to achieve cost-effectiveness was discussed in 59% of cCP and 47% of cPR. In the case of conditional decisions (69% of cCP and 61% of conditional recommendations cPR), the issue of the need to supplement the reimbursement application by implementing a RSS or to introduce a more in-depth RSS which has already been proposed.

A positive decision of the AHTAPol bodies is not tantamount to a positive reimbursement decision of the MoH. From among the orders which resulted in a positive opinion of the Agency body, 83% of pCP and 91% pPR translated into reimbursement success. At the same time, 36% of nCP and 42% of nPR  also resulted in reimbursement success.

When analysing the results in terms of reimbursement success, it is worth to consider Borowiack 2018, where attention was paid to the specificity of reimbursement decisions regarding therapies added in oncological indications (breast cancer and cancers of the genitourinary system). The authors showed significant differences between the percentage of positive recommendations in Poland and elsewhere in the world (Poland – 20%, in total outside Poland – 59%). [29] The comparison of the results of Borowiack with this analysis (20% vs 57%) should be interpreted with caution, due to the different range of analysed therapies (only add-on therapies in oncological indications).

Achieving reimbursement success is usually postponed in time. In an analysis of reimbursement announcements of the MoH following the entry into force of the Reimbursement Act (01.2012-09.2018) for area B, which is the most representative group, the mean waiting time for basic reimbursement amounted to 333 days. 4 technologies were identified, for which the waiting time for reimbursement exceeded 1,000 days (2.7 years). The analysis, taking into account the sequential approach, showed an increase in mean and median waiting times (mean: 333 vs 406 days; median: 213 vs 267 days).

An analysis of orders broken down by haematological and oncological indications indicates a similar percentage of technologies achieving reimbursement success (55% vs 58%, respectively). However, the waiting time for reimbursement coverage was significantly different (in drug programme area: oncological: average: 366 days [median 249]; haematological [median 186 days]). The sequential approach resulted in a prolongation of the average waiting time for reimbursement.

43 technologies still awaiting being entered to the reimbursement announcement of the MoH have been identified (as at 09.2018). Both technologies which applied for reimbursement only once and those which, after the failure of the first order, reapplied for a reimbursement in the same/similar population were taken into account. Assuming an entry into the reimbursement announcement would have been in September 2018, the average waiting time for these technologies lasted  991 days (32.5 months; median - 780 days (25.6 months). From among the analysed group, the longest identified waiting time was recorded for nilotinib, seeking reimbursement for the treatment of adult patients with newly diagnosed chronic myelogenous leukaemia (CML) in the chronic phase with the presence of the Philadelphia chromosome and dasatinib in the indication of newly diagnosed CML. For these orders, assessed in October 2012, the waiting period is 2,182 days (71.7 months).

As part of the analysis, 4 technologies were identified which, despite re-assessment (e.g. after narrowing down the population in the subsequent application), did not receive reimbursement. Table S2 presents their characteristics and the potential waiting time for reimbursement coverage in the case the technology is included in the September reimbursement announcement.

This report covers a broad time range for both MoH's orders and reimbursement announcements of the MoH. Limitation of this paper is restriction only to oncological and haematological indications. On the other hand it should be noticed, that the report includes all of the orders found on the AHTAPol websites regarding considered indications. [5,62] An analysis of AHTAPol's practice was possible thanks to the principle of public access to information. However, when analysing AHTAPol documents, a number of restrictions have been identified. Firstly, there were cases in which the complete documentation was not available (no CP) [7]). The limitations of the analysis are also affected by cases of "censoring" significant parts of documents, limiting the possibility of exact verification of the indication or reimbursement area. In the case of older orders, the authors encountered difficulties in identifying the Agency’s decisions found in the Archive of Recommendations and Positions in relation to relevant orders presented on the Public Information Bulletin page.

In the reimbursement part, the limitations result mostly from the possibility of conducting a reliable analysis of reimbursed health technologies only after 2011, i.e. after the entry into force of the Reimbursement Act. Lists of reimbursed medicines are published on the MoH website with frequency provided for in the Act. However, it should be noted that there is no publicly available information on orders for which a negative reimbursement decision has been issued or for which the reimbursement process is still ongoing (negotiation in progress – unknown reimbursement status), for which the process was suspended and for which negotiations have been terminated. The above limitations make it difficult to interpret the results unambiguously. It should be noted, there are some commercial databases available in Poland that monitor the current practice of obtaining assessment and reimbursement, although they are not publicly available.

Conclusions:

The report currently constitutes the widest study on the AHTAPol’s practice as well as the reimbursement practice in Poland in oncological indications. The document indicates the reasons for nCP/nPR. Differences in the approach to the need to present results of clinically significant endpoints between regulatory agencies and the AHTAPol have been highlighted. It was pointed out that the frequent reason for nCP/nPR were limitations to clinically significant endpoints (OS and QoL). It has been demonstrated that decision to include a health technology in the reimbursement announcement is significantly delayed in relation to the recommendation made by the AHTAPol's President, especially in “drug programme” area. 

Supplementary materials

Chart S1. Differences in the justification for negative positions of the Council and negative recommendations of the President (2012-2018): A) efficacy, B) OS, C) QoL, D) safety profile, E) cost-effectiveness, (%)

Table S1. Justification of objections with regard to OS in negative positions of the Council and negative recommendations of the President of AHTAPol

Table S2. Waiting time for reimbursement coverage in the case the technology is included in the 09.2018 reimbursement announcement