Introduction

In accordance with the Constitution of the Republic of Poland, all citizens are granted access to the healthcare system. Under the reimbursement system, patients have access to drugs included in the official Reimbursement List, which is updated every 2 months. On the one hand, the Reimbursement List guarantees availability of the drugs which have been included in it, but on the other hand, it limits access to those which cannot be found there and whose total cost must be covered by the patient, which in the case of novel drugs is most often beyond the financial capacity of an individual.

The reimbursement process is highly proceduralised. Decisions concerning the financing and pricing of a given drug (especially a novel one whose active substance has not been reimbursed yet) are made on the basis of the best clinical trial data available and the assessment of clinical efficacy. The entire decision-making process should not exceed 180 days [[1]]. However, in practice this frequently takes much longer. The negotiation process consists of multiple stages and expectations of each party involved are divergent, which only extends the time of whole process. Additionally, in the case of technologies used in drug programmes (i.e. those made available in hospitals to restricted groups of patients in a strictly defined indication) the access is further delayed due to the need to specify the conditions which must be fulfilled by hospitals and conclude contracts with particular sites.

From the perspective of an individual patient and taking into account current medical knowledge, saving a person’s health and life requires by achieving a therapeutic effect through the use of a specific drug at a given moment. In consequence, if the drug was not included in the current list of guaranteed benefits, its use was not possible. In addition, the time which passed until a positive reimbursement decision was made generally constituted a barrier preventing the patient from receiving treatment due to the rapid disease progression, which consequently led to permanent worsening of their condition or death. Therefore, a procedure was introduced to secure the state’s obligation towards patients in need of non-standard treatment [[2]]. The Act Amending the Act on Healthcare Services Financed from Public Funds which introduced the so-called emergency access to drug technologies entered into effect on 23 July 2017. This procedure authorizes the Minister of Health to issue an individual consent to cover the cost of a drug which is not reimbursed in a given indication, if it is necessary to save the patient’s life or health and provided that all available medical technologies (including medicines) financed from public funds have already been exhausted [[3]]. The emergency access to drug technologies can be considered a provisional procedure ensuring access to effective treatment while the reimbursement application is being prepared and undergoes subsequent formal assessment by the Agency for Health Technology Assessment in Poland (AHTAPol), and until the required procedures necessary for the drug to be entered in the Reimbursement List are completed.

The emergency access to drug technologies procedure

Pursuant to the amendment to the Act (Article 47e(1)) applications submitted under the emergency access to drug technologies programme can only be filed by healthcare providers offering medical treatment in a hospital setting. The applicant is obliged to request a competent provincial or national consultant’s opinion on the justifiability of the use of a given therapy in a patient with a particular disease. The consent ought to be issued within no longer than 14 days from the date of receipt of a complete application [3]. However, the Act (Article 47e(4)) provides for the extension of this period if prior opinion of AHTAPol is deemed necessary i.e.

·         in the event when the cost of the requested therapy per quarter or 3 treatment cycles exceeds a quarter of the Gross Domestic Product per capita (currently the limit is PLN 11,663 [[4]]) and the application is the first one concerning a given indication, or

·         when the cost of requested therapy per quarter or 3 treatment cycles does not exceed a quarter of the Gross Domestic Product per capita and the application for financing the drug from public funds under the emergency access to drug technologies programme is not the first one concerning this indication and the aforementioned opinion has not been issued so far [3].

In accordance with the amendment (Article 47f(3)) AHTAPol draws up such an opinion within 30 days of the date of receipt of the Minister of Health’s order. The opinion may also specify the maximum cost of the drug subject to the assessment, beyond which it is not justified to fund the medicine from public funds [3].

The consent for the use of medicines under the emergency access to drug technologies programme is issued by the Minister of Health for a period no longer than 3 months or 3 treatment cycles. The therapy can be further continued provided that a specialist in a given medical field confirms its efficacy in the patient [3]. However, the Act on Healthcare Services Financed from Public Funds (Article 47d) specifies neither the verification criteria nor the time limit for performing such an assessment. Consequently, this can lead to therapy discontinuation or suspension.

The criteria for rejection of drug reimbursement under the emergency access to drug technologies programme are set out in the Act (Article 47f(7)). The Minister of Health is obliged to reject the request for financing the medicine under the emergency access to drug technologies programme if:

·         a negative opinion is issued by AHTAPol;

·         a positive opinion is issued by AHTAPol, but the pharmaceutical company which owns the product financed under the emergency access to drug technologies programme is requested to participate in the reimbursement procedure regarding the inclusion of the drug in the Reimbursement List (i.e. to submit a reimbursement application and a health technology assessment [HTA] report as part of the standard reimbursement process); the company is given 90 days to comply with the request and if the application is not filed or a negative opinion is issued by AHTAPol, the drug cannot continue to be financed under the emergency access to drug technologies programme;

·         a negative reimbursement decision is issued for a given active substance in the specific indication in the course of the standard reimbursement procedure [3].

The provisions of the Act may lead to a situation in which a negative opinion is issued by AHTAPol under the standard reimbursement process due to the lack or poor quality of clinical trial data and so the request for financing the product from public funds in a given indication under the emergency access to drug technologies programme is rejected by the Minister of Health, while new clinical evidence emerges which confirms the drug’s efficacy. Moreover, both the prior negative opinion issued by AHTAPol and the rejection of the reimbursement application by the Minister of Health may not necessarily be based on the lack of clinical efficacy of the drug but on the conviction that its cost (often lowered by the confidential risk sharing agreement proposed by the company) is too high for the public payer to reimburse the therapy in a broad indication [1,[5]]. In addition, the time for the submission of the reimbursement application after the receipt of a positive AHTAPol opinion is relatively short (90 days) and as such it may in many cases prove insufficient for the collection of data and drawing up relevant analyses (i.e. the complete HTA report), what can even take up to 6 months.

Pursuant to the provisions of the Act (Article 47i(1)) the cost of the drug is covered by the National Health Fund (NHF) up to the amount specified in the receipt or invoice documenting the purchase of the medicine by the hospital (not exceeding the price given in the administrative decision regarding the consent for financing the drug under the emergency access to drug technologies programme) [3]. Nevertheless, the Act does not indicate specific sources of such financing. As a result, the cost of the drug is settled under the contract for healthcare services provided in a hospital setting, i.e. the financing takes the form of a lump sum payment by the basic hospital healthcare provision system. In consequence, the purchase of medicines under the emergency access to drug technologies programme comes at the expense of other medical procedures [2]. The obligation of the hospital to cover the cost from its own funds may make it difficult for patients to find a site willing to conduct such treatment.

The emergency access to drug technologies programme is not the first initiative of this kind in Poland. There had been other procedures in operation under which medicines could be financed as the so-called “non-standard pharmacotherapy” or “non-standard chemotherapy”. Their use was gradually limited and finally discontinued due to the changes introduced by the Act on Reimbursement of 12 May 2011, currently in force [2].

Applications for the emergency access to drug technologies

Until the end of March 2019 the Ministry of Health ordered 107 opinions of the Agency for Health Technology Assessment on the justifiability of financing drugs under the emergency access to drug technologies programme, out of which 4 orders were cancelled and 8 are still being drafted. Out of the 95 opinions already issued by AHTAPol for various indications, 71 (75%) are positive. The opinions concern 53 different active substances. A summary of the number of positive and negative opinions by the type of the disease (malignancies, genetic diseases, others — e.g. inflammatory and autoimmune) is presented in the following table.

Table 1. A summary of the number of positive and negative opinions by the type of the disease (malignancy, genetic disorder, others)

*95 different indications for 53 molecules.

The greatest number of opinions was issued for active substances used in the treatment of malignancies (70), while the molecules most often assessed by AHTAPol were nivolumab (11 opinions regarding its use in the treatment of malignancies, including 10 positive ones) and rituximab (7 opinions regarding its use in the treatment of other diseases, e.g. inflammatory or autoimmune ones, all of them positive). Apart from that, 3 opinions were issued for adalimumab (3 positive ones regarding the treatment of inflammatory/autoimmune diseases), daratumumab (1 positive opinion and 2 negative ones regarding the treatment of malignancies), eltrombopag (3 positive opinions regarding the treatment of inflammatory/autoimmune diseases), ibrutinib (2 positive opinion and 1 negative one regarding the treatment of malignancies), pembrolizumab (2 positive opinions and 1 negative one regarding the treatment of malignancies) and regorafenib (3 negative opinions regarding the treatment of malignancies).

What is more, the Ministry of Health has also issued calls for the submission of reimbursement applications for a total of 9 molecules assessed under the emergency access to drug technologies programme [[6],[7]]. Other active substances which received positive opinions of AHTAPol with regard to their financing under the emergency access to drug technologies programme, at the moment of issuing the said opinions were being assessed by AHTAPol in accordance with the standard reimbursement procedure, had already received a positive AHTAPol opinion in a given indication in accordance with the standard reimbursement procedure or the requested indications were off-label ones which precludes the submission of the reimbursement application by the marketing authorisation holder.

At the moment reimbursement applications in the requested indications have been filed for only 3 out of the 9 aforementioned molecules. The first active substance for which the entire process beginning with the AHTAPol’s opinion on financing under the emergency access to drug technologies programme and completed with the recommendation for its use under the standard reimbursement procedure is vandetanib for which the opinion of the President of AHTAPol was issued on 9 October 2018.

Case study: vandetanib

According to the Summary of Product Characteristics vandetanib (Caprelsa^®) is indicated for the treatment of aggressive and symptomatic medullary thyroid cancer (MTC) in patients with unresectable locally advanced or metastatic disease. It is indicated in adults, children and adolescents aged 5 years and older [[8]]. The efficacy of vandetanib in the target population was demonstrated in the ZETA clinical trial [[9]]. It was an international, multicentre, randomized, double-blind, parallel-group phase III study in 331 patients (221 in the vandetanib arm and 100 in the placebo arm). The study population included adult patients with unresectable locally advanced or metastatic medullary thyroid cancer. The patients received the drug until disease progression, however those who discontinued treatment for that reason were able to enter the open label period. The primary endpoint of the trial was progression-free survival (PFS). The median follow-up period was 24 months [9].

The results of intention-to-treat (ITT) population analysis conducted by independent experts for the median follow-up period of 24 months showed statistically significant improvement of progression-free survival in patients receiving vandetanib compared to the placebo group. The hazard ratio (HR) for this comparison indicated a 54% reduction in disease progression risk or death in the vandetanib group, compared to placebo (HR=0.46 [95% CI: 0.31; 0.69], p<0.001). The predicted median PFS in the vandetanib arm was 30.5 months (based on Weibull distribution model, as less than a half of patients in this study arm experienced disease progression), whereas median PFS in the placebo group was achieved and equalled to 19.3 months. The analysis not including patients receiving vandetanib in the open-label period (a total of 51 individuals) also demonstrated statistically significant reduction of disease progression risk in the vandetanib-treated group, compared to the placebo arm (by 73%, HR=0.27 [95% CI: 0.18; 0.41], p<0.001) [9].

Vandetanib showed statistically significant superiority over placebo in terms of secondary endpoints such as objective response to treatment (45% vs. 13%, OR=5.48 [95%CI: 2.99; 10.79], p<0.001), disease control (87% vs. 71%, OR=2.64 [95%CI: 1.48; 4.69], p=0.001) or biochemical response to treatment (calcitonin: 69% vs. 3%, OR=72.9 [95%CI: 26.2; 303.2], p<0.001; CEA: 52% vs. 2%, OR=52.0 [95%CI: 16.0; 320.3], p<0.001] [9]. 

Moreover, the ZETA study demonstrated good tolerability of vandetanib with a majority of adverse effects being controlled with standard clinical practice or dose reduction, which allowed patients to continue their therapy [9].

Positive AHTAPol opinion on vandetanib therapy under the emergency access to drug technologies programme

The first application for financing vandetanib therapy under the emergency access to drug technologies programme, which was submitted prior to the formal reimbursement process initiation, regarded the indication: medullary thyroid cancer in patients with RET mutation and hepatic metastases, which was narrower than that included in the label. Due to the fact that the cost of requested treatment per quarter exceeds a fourth of the average Gross Domestic Product per capita, the opinion of AHTAPol was required for the decision on financing the drug under this procedure to be issued. In December 2017 both the Transparency Council and the AHTAPol President issued a positive opinion with regard to financing vandetanib under the emergency access to drug technologies programme [[10],[11]]. It has been emphasized in both opinions that there is no publicly financed therapy for the treatment of patients with medullary thyroid cancer in patients with RET mutation and hepatic metastases, which was the indication requested in the application. Therefore, this indicates the presence of an unmet medical need in this area. Cabozatinib could be considered an alternative medical technology as it is a tyrosine kinase inhibitor (TKI) just like vandetanib. However, the application for reimbursement of this drug received a negative opinion of AHTAPol, which precludes it from being prescribed also under the emergency access to drug technologies programme [[12]]. Vandetanib and cabozatinib are the only approved therapeutic options which are included for instance in the European (European Thyroid Association, European Society for Medical Oncology, British Thyroid Association), American (National Comprehensive Cancer Network) or Polish (Polskie Towarzystwo Endokrynologiczne, Polskie Towarzystwo Onkologii Klinicznej) clinical recommendations for the treatment of medullary thyroid cancer and are acknowledged as the treatment of choice in this patient population. It ought to be noted that standard chemotherapy is characterised by low efficacy and should not be considered an effective option in the discussed indication [[13],[14],[15],[16],[17]].

The main arguments evoked in support of the positive opinion on financing vandetanib under the emergency access to drug technologies programme were the drug’s efficacy demonstrated in clinical trials, the opinion of clinical experts and scientific associations as well as a relatively small size of the target population [10,11].

The call of the Minister of Health and the submission of a reimbursement application

In accordance with the amendment to the Act on Healthcare Services Financed from Public Funds, after a positive opinion was given by AHTAPol on the financing of vandetanib under the emergency access to drug technologies programme, the Minister of Health issued a call to the pharmaceutical company being the drug’s marketing authorisation holder for the submission of a reimbursement application.

The complete document was filed within the time limit defined in the Act and the attached HTA report was verified by AHTAPol analytics under the standard procedure. In this case the indication applied for was consistent with that in the label (with adults included), however, the programme was restricted to patients who were RET-positive [[18]]. Also, in this case vandetanib was granted a positive opinion both of the Transparency Council and of AHTAPol’s President under the condition that the medicine’s price is reduced and the risk sharing scheme (RSS) extended [[19],[20]]. In line with AHTAPol’s stance, the condition consisting in the presence of the RET mutation should be removed from the programme’s inclusion criteria, which is further supported by the recommendations of scientific associations and experts’ opinions. This confirms the validity of financing the drug in the indication proposed in the reimbursement application by the marketing authorisation holder.  

Vandetanib therapy under the emergency access to drug technologies programme

Even though the positive recommendation of the President of AHTAPol in a standard reimbursement process was issued on 1 October 2018, the Minister of Health has not yet decided to place this medicine on the Reimbursement List. The treatment is financed from public funds only under the emergency access to drug technologies programme.

Information obtained from 6 sites in Poland which administer vandetanib therapy under the emergency access to drug technologies programme (unpublished data) says that 24 applications for initiation of vandetanib therapy have been filed with the Ministry of Health by March 2019 (unpublished data). In addition, applications regarding treatment continuation have also been submitted for 13 of the aforementioned patients.

It is reported that preliminary real-world data indicate that the use of vandetanib resulted in partial response or stable disease, according to the RECIST 1.1 criteria, in 83% of patients (10/12 patients assessed). In 56% (9/16) of patients a biochemical response defined as at least 50% calcitonin level reduction from baseline in the last available measurement was observed. The most frequently reported adverse events were diarrhoea (6 patients) and skin lesions (6 patients). The adverse events were mild and transient in nature, which is indicative of good treatment tolerability.

Considering the aforementioned numbers and the fact that an application for continuation of financing the drug under the emergency access to drug technologies programme must include a confirmation of treatment effectiveness issued by a specialist physician, it should be acknowledged that continuation of therapy within the RDTL procedure can be considered as a potential determinant of treatment benefit.

Conclusion

Emergency access to drug technologies programme is a procedure designed to provide treatment financing to patients in whom all available therapeutic options available under the guaranteed services system, including reimbursed drugs, have been exhausted. The introduction of such a possibility seems justified, especially considering the fact that drugs which can be used under this programme are included in clinical recommendations for a given case as first-line treatment but not yet reimbursed in Poland. Nevertheless, this mechanism is significantly limited and ought to be regarded as a provisional measure used when needed, and not as an alternative reimbursement strategy. The main issue here is the lack of a separate budget for financing medicines under this procedure, which necessitates covering the cost of drugs from the hospital funds at the expense of other procedures. This limits the scope of action for institutions which would be willing to undertake administration of such a therapy, but do not have funds allocated especially for this purpose. Consequently, this leads to the limitation or, particularly in the smaller sites, to the interruption of financing a given patient’s therapy already at the beginning of the procedure, or actually even before its formal initiation. Therefore, financing of such a therapy from a separate budget should perhaps be considered in order for its costs not to become a direct burden to the hospital. Other issues are associated with formalities that need to be dealt with when applying for the therapy financing under the emergency access to drug technologies programme or its continuation. They may delay patients’ access to the necessary treatment or cause its discontinuation. In view of the above it seems advisable to simplify the procedure of treatment continuation in order to reduce the burden associated with the hospital’s and the attending physician’s obligation to fill in a vast number of forms necessary to obtain the Minister of Health’s consent.

However, the example of vandetanib (Caprelsa^®) demonstrates that the discussed procedure ensures access to medications which are the only ones recommended in clinical guidelines for a given indication due to their established efficacy and an adequate safety profile. There is no publicly financed therapy for the treatment of patients with aggressive and symptomatic, unresectable locally advanced or metastatic medullary thyroid cancer. This indicates the presence of an unmet medical need in this area. Vandetanib is currently financed under the emergency access to drug technologies programme, but despite the positive recommendation of the Agency for Health Technology Assessment for vandetanib, the Minister of Health has not decided to place this medicine on the Reimbursement List.  

Making vandetanib available under the emergency access to drug technologies programme generates positive effects. Patients receiving the drug experience clinical benefits, which is supported not only by clinical trial outcomes and experts’ opinions, but also by real-world effectiveness confirmed by applications for continuation of treatment under the said programme. According to recommendation of AHTAPols, it is justified to include vandetanib in the Reimbursement List. This decision will at the same time release funds currently allocated to finance the medicine under the emergency programme and enable hospitals to allocate them on other products and services. Most importantly, however, it will remove the existing limitations to treatment. It should be noted that generally the negotiations with the Ministry of Health regarding the setting of the official selling price within the standard reimbursement process result in the reduction of the medicine’s price. Therefore, the cost remains the same, but more patients can be treated than if the medicine was financed under the emergency access to drug technologies programme. In addition, the need to submit further applications for treatment continuation under the emergency access to drug technologies programme together with the required documents may cause treatment discontinuation and generate uncertainty as to whether therapy can be resumed.

To sum up, it appears advisable to introduce a number of improvements into the procedure of emergency access to drug technologies programme with the objective of facilitating access to effective treatments for patients in whom the available reimbursed therapeutic options have been exhausted. At the same time, it is recommendable to enter such drugs into the Reimbursement List without delay, especially if clinical benefit resulting from their use was confirmed not only in randomized clinical trials, but also in patients undergoing therapy under the emergency access programme, and the Agency for Health Technology Assessment issued positive recommendation in standard reimbursement process. This also seems to be the intention of the legislators as a provision was included in the Act pursuant to which pharmaceutical companies are called to submit reimbursement applications for such medications.

Conflict of interest:

This research was supported by Sanofi-Aventis Sp. z o.o., Warsaw, Poland.