Lessons learned from postmarketing withdrawals of expedited approvals for oncology drug indications.

In the past decade, there have been a record number of oncology therapy approvals by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Besides the EMA's conditional marketing authorisation programme and the FDA's Accelerated Approval Program, we observe a tendency towards fast approval for exploratory studies with non-randomised, uncontrolled designs and surrogate endpoints. This issue raises concerns about the robustness and effectiveness of accepted treatments, leaving patients and health-care professionals in a state of uncertainty. A substantial number of accelerated approvals have recently been withdrawn in the USA, with some still authorised in Europe, emphasising discrepancies in regulatory standards that affect both patients and society as a whole. We highlight examples of drugs, authorised on the basis of surrogate endpoints, that were later withdrawn due to an absence of overall survival benefit. Our findings address the challenges and consequences of accelerated approval pathways in oncology. In conclusion, this Policy Review calls for regulatory bodies to better align their procedures and insist on robust evidence, preferably through unbiased randomised controlled trials. Drug approval processes should prioritise patient benefit, overall survival, and quality of life to minimise risks and uncertainties for patients.

Illustrating the Financial Consequences of Outcome-Based Payment Models From a Payers Perspective: The Case of Autologous Gene Therapy Atidarsagene Autotemcel (Libmeldy®).

OBJECTIVES: To illustrate the financial consequences of implementing different managed entry agreements (managed entry agreements for the Dutch healthcare system for autologous gene therapy atidarsagene autotemcel [Libmeldy]), while also providing a first systematic guidance on how to construct managed entry agreements to aid future reimbursement decision making and create patient access to high-cost, one-off potentially curative therapies. METHODS: Three payment models were compared: (1) an arbitrary 60% price discount, (2) an outcome-based spread payment with discounts, and (3) an outcome-based spread payment linked to a willingness to pay model with discounts. Financial consequences were estimated for full responders (A), patients responding according to the predicted clinical pathway presented in health technology assessment reports (B), and unstable responders (C). The associated costs for an average patient during the time frame of the payment agreement, the total budget impact, and associated benefits expressed in quality-adjusted life-years of the patient population were calculated. RESULTS: When patients responded according to the predicted clinical pathway presented in health technology assessment reports (scenario B), implementing outcome-based reimbursement models (models 2 and 3) had lower associated budget impacts while gaining similar benefits compared with the discount (scenario 1, €8.9 million to €6.6 million vs €9.2 million). In the case of unstable responders (scenario C), costs for payers are lower in the outcome-based scenarios (€4.1 million and €3.0 million, scenario 2C and 3C, respectively) compared with implementing the discount (€9.2 million, scenario 1C). CONCLUSIONS: Outcome-based models can mitigate the financial risk of reimbursing atidarsagene autotemcel. This can be considerably beneficial over simple discounts when clinical performance was similar to or worse than predicted.

The Beneluxa Initiative domain task force health technology assessment: a comparison of member countries' past health technology assessments.

OBJECTIVE: This study aimed to compare assessments between Beneluxa Initiative member countries' assessments and identify alignments and divergences. METHODS: A retrospective comparative analysis was performed that investigated (i) number and type of assessed indications (for Austria (AT), Belgium (BE), Ireland (IE), and the Netherlands (NL)); (ii) added benefit conclusions (for BE, IE, and NL); and (iii) the main arguments underlying differences in conclusions (for BE, IE, and NL). Data were retrieved directly from agency representatives and from public HTA reports. European Medicines Agency approved indications were included for drugs assessed between 2016 and 2020, excluding veterinary drugs, generics, and biosimilars. RESULTS: Only 44 (10 percent) of the 444 included indications were assessed by all four member countries. Between any pair of two countries, the overlap was higher, from 63 (AT-NL) to 188 (BE-IE). Added benefit conclusions matched exactly in 62-74 percent of the indications, depending on the countries compared. In the remaining cases, most often a difference of one added benefit level was observed (e.g., higher vs. equal relative effect). Contradictory outcomes were very rare: only three cases were observed (lower vs. higher effect). When assessing the underlying arguments for seven cases with different outcomes, differences were attributable to slight differences in weighing of evidence and uncertainties rather than disagreement on aspects within the assessment itself. CONCLUSIONS: Despite high variability in European HTA procedures, collaboration on HTA between the Beneluxa Initiative member countries is very feasible and would likely not result in added benefit conclusions that would be very different from added benefit conclusions in national procedures.

Involvement of Patients and Medical Professionals in the Assessment of Relative Effectiveness: A Need for Closer Cooperation.

OBJECTIVES: Involvement of patients and medical professionals in assessment of relative effectiveness (relative effectiveness assessment) contributes to an efficient and effective health technology assessment (HTA) process and supports acceptance and implementation of the outcome. This study aimed to analyze stakeholder involvement in assessing relative effectiveness and how the parties involved value this collaboration. METHODS: This is a document analysis of all drug assessments completed in 2019 (20) by the public HTA agency of The Netherlands, enriched with semistructured interviews with employees of the HTA agency (18) and representatives of patient (5) and medical (11) associations involved in these assessments. Data were analyzed, coded, and categorized. RESULTS: In almost half of the assessments, there was no coordination with the medical associations at the start of the relative effectiveness assessment and no patient associations involved in this phase. During the assessment procedure, patient and medical associations were always asked to comment on the draft report. Nevertheless, the strict 5-day deadline that the HTA agency uses as a response period often hampered a proper response and involvement. According to interviewees of the HTA agency, this leads to a great diversity in the substantive quality of their input. Patient and medical associations indicated that the HTA agency relies too much on "paper knowledge," which leads to a (perceived) lack of alignment with clinical practice. CONCLUSIONS: The limited involvement results in a lack of coordination and mutual trust. Optimizing involvement of patients and medical professionals in HTA practice requires effort from all parties involved. Procedural adjustments and better coordination, especially at the start of the assessment, would probably improve cooperation.

Patient experiences and views on pharmaceutical care during adjuvant endocrine therapy for breast cancer: A qualitative study.

OBJECTIVE: The use of adjuvant endocrine therapy (AET) after primary treatment of hormone receptor-positive breast cancer reduces the risk of recurrence and mortality. However, non-adherence is still common. Limited consideration has been given to how users deal with AET and the role of pharmaceutical care. Therefore, this study aims to obtain insight into the needs and wishes of women using AET regarding pharmaceutical care and eHealth. METHODS: This is a qualitative explorative study comprising semi-structured interviews (n = 16) and a focus group (n = 5) among women who use or used AET after primary early-stage breast cancer (EBC) treatment using a thematic analysis approach. RESULTS: Three themes emerged from the interviews and focus group: (1) experiences with AET use, (2) experiences with provided information and (3) needs and wishes regarding pharmaceutical care. Most women were highly motivated to use AET and indicated to have received useful information on AET. However, many expressed a strong need for more elaborate tailored and timely provided information on AET. They acknowledged the accessibility of pharmacists but reported that currently, pharmacists are hardly involved in AET care. Several women considered eHealth useful to obtain counselling and reliable information. CONCLUSION: Women need more comprehensive information and follow-up in primary setting after initial cancer treatments. A more elaborate role for the pharmacy and eHealth/mHealth, especially with regard to counselling on side effects and side effect management, could potentially improve pharmaceutical care.

Cost-Based Price Calculation of Mexiletine for Nondystrophic Myotonia.

OBJECTIVES: Mexiletine is a long-known drug used for the treatment of arrhythmias and repurposed in the 1980s for patients with nondystrophic myotonia (NDM). Recently, the price of mexiletine in Europe increased significantly after registration as an orphan drug for NDM. This led to international discussions on affordability and willingness to reimburse mexiletine in the absence of background information that would justify such a price. Our objective was to calculate a cost-based price for mexiletine for adult patients with NDM based on detailed information on development costs. METHODS: We calculated a fair price based on a cost-based pricing model for commercial mexiletine to treat adults with NDM using a recent European drug-pricing model as a framework to include actual costs incurred. Three scenarios were applied: 1 with minimum estimated costs, 1 with maximum estimated costs, and 1 with costs as if mexiletine was innovative. RESULTS: The calculated fair price of mexiletine per patient per year (PPPY) is €452 for the minimum scenario and €1996 for the maximum scenario. By using hypothetical R&D costs used for innovative drugs, the price would be €6685 PPPY. In Europe, the list price of mexiletine ranges from €30 707-60 730 PPPY, based on 600 mg daily. CONCLUSIONS: The current list price for mexiletine in Europe is manifold higher than any scenario of the cost-based models. Accounting for the reduced costs for clinical development in a repurposing scenario, the cost-based pricing model provides a fair commercial price range, which can be used as benchmark for pricing negotiations and/or reimbursement decisions.

Exploring the opportunities for alignment of regulatory postauthorization requirements and data required for performance-based managed entry agreements.

Performance-based managed entry agreements (PB-MEAs) might allow patient access to new medicines, but practical hurdles make competent authorities for pricing and reimbursement (CAPR) reluctant to implement PB-MEAs. We explored if the feasibility of PB-MEAs might improve by better aligning regulatory postauthorization requirements with the data generation of PB-MEAs and by active collaboration and data sharing. Reviewers from seven CAPRs provided structured assessments of the information available at the European Medicines Agency (EMA) Web site on regulatory postauthorization requirements for fifteen recently authorized products. The reviewers judged to what extent regulatory postauthorization studies could help implement PB-MEAs by addressing uncertainty gaps. Study domains assessed were: patient population, intervention, comparators, outcomes, time horizon, anticipated data quality, and anticipated robustness of analysis. Reviewers shared general comments about PB-MEAs for each product and on cooperation with other CAPRs. Reviewers rated regulatory postauthorization requirements at least partly helpful for most products and across domains except the comparator domain. One quarter of responses indicated that public information provided by the EMA was insufficient to support the implementation of PB-MEAs. Few PB-MEAs were in place for these products, but the potential for implementation of PB-MEAs or collaboration across CAPRs was seen as more favorable. Responses helped delineate a set of conditions where PB-MEAs may help reduce uncertainty. In conclusion, PB-MEAs are not a preferred option for CAPRs, but we identified conditions where PB-MEAs might be worth considering. The complexities of implementing PB-MEAs remain a hurdle, but collaboration across silos and more transparency on postauthorization studies could help overcome some barriers.

Response and Adherence to Nilotinib in Daily practice (RAND study): an in-depth observational study of chronic myeloid leukemia patients treated with nilotinib.

INTRODUCTION: This comprehensive observational study aimed to gain insight into adherence to nilotinib and the effect of (non)adherence on exposure (Cmin) and treatment outcomes. METHODS: Chronic myeloid leukemia (CML) patients using nilotinib were followed for 12 months. Adherence was measured by Medication Event Monitoring System (MEMS), pill count, and Medication Adherence Report Scale (MARS-5). Nilotinib Cmin and patient-reported outcomes (i.e., quality of life, side effects, beliefs, satisfaction) were measured at baseline, 3, 6, and 12 months. RESULTS: Sixty-eight patients (57.5 ± 15.0 years, 49% female) participated. Median adherence to nilotinib (MEMS and pill count) was ≥ 99% and adherence < 90% was rare. Self-reported nonadherence (MARS-5) increased in the first year of treatment to a third of patients. In line with the strong beliefs in the necessity of taking nilotinib, forgetting to take a dose was more prevalent than intentionally adjusting/skipping doses. Nilotinib Cmin were generally above the therapeutic target in 95% of patients. Patients reported a variety of side effects, of which fatigue was most frequent. The mean Cmin was higher in patients who reported severe itching and fatigue. The overall 1-year MMR rate ranged from 47 to 71%. CONCLUSION: Substantial nonadherence (< 90%) to nilotinib was rare and nilotinib Cmin were generally above the therapeutic target. Lack of response in our group of patients was not related to nonadherence or inadequate Cmin. Nevertheless, a considerable number of patients experienced difficulties in adhering to the twice daily fasted dosing regimen, emphasizing the importance of continuous support of medication adherence in CML. CLINICAL TRIAL REGISTRATION: NTR3992 (Netherlands Trial Register, www.trialregister.nl ).

Feasibility of and patients' perspective on nilotinib dried blood spot self-sampling.

PURPOSE: To obtain insight into the feasibility of, and the patients' perspective on, dried blood spot (DBS) self-sampling by patients with chronic myeloid leukemia (CML) using nilotinib. METHODS: Sixty-eight patients with CML using nilotinib participated in this multicenter observational study. Patients were asked to perform blood sampling by means of the DBS method at home just before drug intake (trough level) and to complete a questionnaire including demographics and five questions on their experience with DBS self-sampling. RESULTS: Sixty-one patients (57.5 ± 15.0 years, 49% female) provided 178 DBS samples of which 137 (77%) proved useful in clinical practice. Twenty percent of the samples were rejected because the spot size was too small for analysis. A further 3% were taken at the wrong time. Unsuitable DBS samples were provided by 23 patients. Their educational level was significantly lower than that of patients whose samples were all suitable (p = 0.041). Patients considered DBS self-sampling easy and not painful, and three quarters of the patients performed DBS sampling without additional assistance. Patients' belief in the reliability of DBS self-sampling was moderate to high. It was preferred over venous sampling by 37% of the patients, whereas 39% had no preference. CONCLUSION: DBS self-sampling by CML patients is feasible in clinical practice provided that patients, particularly those with a lower educational level, are adequately instructed about sample collection with emphasis on timing and volume of sample collection.

Needs for information and reasons for (non)adherence in chronic myeloid leukaemia: Be aware of social activities disturbing daily routines.

OBJECTIVES: To obtain insight into patients' reasons for medication (non)adherence in chronic myeloid leukaemia (CML) and needs and wishes regarding information and communication. METHODS: A mixed-method study on the basis of a questionnaire and semi-structured interviews. The CML patient advocacy group asked patients to participate. RESULTS: Sixty-one patients (54 ± 12 years, 43% male) using imatinib, dasatinib or nilotinib participated. Fifteen patients (25%) reported to miss an intake at least once a month. Most were not worried about missing an intake and did not discuss missed intakes with their healthcare provider (HCP). Social activities disturbing daily routines and the wish to avoid side effects resulted in nonadherence. Patients wanted extensive and understandable information provided timely on all aspects of CML treatment, in particular on side effects, and a more supportive HCP attitude. CONCLUSIONS: Nonadherence to CML medication does not cause concern in all patients and is not discussed pro-actively. HCP have a clear role in supporting medication adherence in CML and must be aware that social activities disturbing daily routines contribute to nonadherence. HCP should discuss (non)adherence in a direct manner, motivate patients to play an active role in managing their medication and timely provide extensive and understandable information on all aspects of CML.

Supporting adherence to oral anticancer agents: clinical practice and clues to improve care provided by physicians, nurse practitioners, nurses and pharmacists.

BACKGROUND: Healthcare provider (HCP) activities and attitudes towards patients strongly influence medication adherence. The aim of this study was to assess current clinical practices to support patients in adhering to treatment with oral anticancer agents (OACA) and to explore clues to improve the management of medication adherence. METHODS: A cross-sectional, observational study among HCPs in (haemato-)oncology settings in Belgium and the Netherlands was conducted in 2014 using a composite questionnaire. A total of 47 care activities were listed and categorised into eight domains. HCPs were also asked about their perceptions of adherence management on the items: insight into adherence, patients' communication, capability to influence, knowledge of consequences and insight into causes. Validated questionnaires were used to assess beliefs about medication (BMQ) and shared decision making (SDM-Q-doc). RESULTS: In total, 208 HCPs (29% male) participated; 107 from 51 Dutch and 101 from 26 Belgian hospitals. Though a wide range of activities were reported, certain domains concerning medication adherence management received less attention. Activities related to patient knowledge and adverse event management were reported most frequently, whereas activities aimed at patient's self-efficacy and medication adherence during ongoing use were frequently missed. The care provided differed between professions and by country. Belgian physicians reported more activities than Dutch physicians, whereas Dutch nurses and pharmacists reported more activities than Belgian colleagues. The perceptions of medication adherence management were related to the level of care provided by HCPs. SDM and BMQ outcomes were not related to the care provided. CONCLUSIONS: Enhancing the awareness and perceptions of medication adherence management of HCPs is likely to have a positive effect on care quality. Care can be improved by addressing medication adherence more directly e.g., by questioning patients about (expected) barriers and discussing strategies to overcome them, by asking for missed doses and offering (electronic) reminders to support long-term medication adherence. A multidisciplinary approach is recommended in which the role of the pharmacist could be expanded.

Adherence to oral anticancer agents: Healthcare providers' perceptions, beliefs and shared decision making in Belgium and the Netherlands.

BACKGROUND: Little is known about healthcare providers' (HCPs) perceptions of adherence management of oral anticancer agents (OACA). The study aims to explore HCPs perceptions of OACA and adherence. METHODS: A cross-sectional, multi-center observational study among HCPs in hemato-oncology settings in Belgium and the Netherlands was conducted. Physicians, nurse practitioners, nurses and pharmacists were asked to complete questionnaires on their perception of patient adherence and its management (PAMQ) and their beliefs about OACA (BMQ-Specific). Physicians were also asked to complete a questionnaire on their perception of shared decision making (SDM-Q-Doc). RESULTS: The sample consisted of 254 HCPs. Variations were found between HCPs on the PAMQ: 56%, 50%, 28% and 23% of, respectively, physicians, nurse practitioners, nurses and pharmacists reported to know the level of adherence of their patients and 59%, 53%, 43% and 10% of, respectively, physicians, nurse practitioners, nurses and pharmacists think that patients discuss adherence with them. 70%, 82%, 63% and 62% of, respectively, physicians, nurse practitioners, nurses and pharmacists reported to have knowledge of causes of non-adherence, while 78%, 87%, 76% and 80% of them reported to have knowledge of consequences of non-adherence. 81%, 92%, 83% and 67% of, respectively, physicians, nurse practitioners, nurses and pharmacists felt able to influence adherence. Lower concerns beliefs were associated with a higher total score on the PAMQ [ß (SE)=-0.85 (0.24); CI -1.33--0.38]. Physicians scored a mean of 75 on the SDM-scale. CONCLUSIONS: A considerable part of the HCPs states they do not know the adherence of their patients, nor do they think patients discuss adherence with them. However, they feel to have knowledge of adherence and perceive to be able to influence adherence of their patients.

Study protocol of the RAND-study: a multicenter, prospective cohort study investigating response and adherence to nilotinib treatment in chronic myeloid leukemia.

BACKGROUND: The antitumor drug nilotinib has a large inter- and intra individual variability in pharmacokinetics. Adherence to treatment may substantially influence plasma levels and has been recognized as the most important determinant of treatment failure in chronic myeloid leukemia (CML). A better understanding of the various factors contributing to the efficacy of treatment is essential for the development of interventions to optimize the treatment of chronic phase CML (CP-CML) with a protein kinase inhibitor like nilotinib. METHODS/DESIGN: In this multicenter prospective observational cohort study 70 adult patients with CP-CML starting treatment with nilotinib will be followed up for at least 12 months. Response to treatment is evaluated after 3, 6 and 12 months. Adherence is primarily assessed by counting the daily intake of nilotinib capsules by means of a medication event monitoring system (MEMS). Before the start of nilotinib treatment and after 3, 6 and 12 months, patients are asked to fill in a comprehensive questionnaire including topics on quality of life, side effects, attitude towards disease and medication, the patients' appreciation of information received about the medication, and discontinuation, and trough plasma levels of nilotinib are measured. DISCUSSION: The present study aims to get more insight into the efficacy of treatment with nilotinib and the various aspects that govern optimal response, of which adherence is a primary endpoint. We hypothesize that patients who experience inadequate response levels to nilotinib are less adherent. In addition, their plasma levels of nilotinib may be lower. We expect that our findings will be useful for health care professionals to support patients with the use of nilotinib in order to derive optimal benefit from their medication. TRIAL REGISTRATION: Netherlands Trial Registry NTR3992.

Adherence and patients' experiences with the use of oral anticancer agents.

A rapidly growing number of oral anticancer agents has become available in oncology and hematology. Though these introductions have several benefits, medication adherence is an issue of concern. Little is known about the factors influencing adherence to treatment with oral anticancer agents in daily practice. Material and methods. In this observational, multicenter study including 216 patients, carried out between October 2010 and March 2012, the use of oral anticancer drugs was assessed by means of a telephonic pill count, a questionnaire and a review of the patient's medical file and pharmacy medication records. Parameters collected were patients' demographics, treatment characteristics, beliefs and attitude towards disease and medicines, self-reported adherence, side effects, quality of life and satisfaction about information. Patients off treatment filled out a questionnaire about the reasons for discontinuation. Optimal adherence was defined as ≥ 95%-≤ 105%. Results. The mean adherence rate (AR) (n = 177) was 99.1% with 20.3% of patients having a sub-optimal AR (< 95%, > 105%) consisting both of under- and over-adherence. Multivariate analyses showed that being on a cyclic dosing regimen (rather than a continuous regimen), not living alone and being highly educated increased the chances of optimal adherence (ORs = 4.88, 4.59 and 2.53, respectively). In addition, optimal adherence was found to be less common in patients reporting treatment control (OR = 0.77). One third of 79 patients off treatment reported their experienced side effects as one of the reasons for discontinuation. Discussion. Although most patients are fully adherent to oral anticancer agents, there is a substantial number tending to non-adherence. Patients living alone and those on a continuous dosing regimen are most likely to adhere sub-optimally. Interventions to improve adherence should specifically address these patients and be tailored to the needs of the individual patient.

The impact of an 'evergreening' strategy nearing patent expiration on the uptake of biosimilars and public healthcare costs: a case study on the introduction of a second administration form of trastuzumab in The Netherlands.

In this paper, we explore dynamic market share and public healthcare costs of trastuzumab's evergreening (subcutaneous) variant during introduction of trastuzumab's competitive biosimilar variants in the Netherlands. We used a time series design to assess dynamic market share of trastuzumab's evergreening variant after introducing trastuzumab's biosimilar variants, focusing on the number of treatments and patients. The public healthcare costs of this evergreening strategy were estimated using administrative claims data. Our results show that the original trastuzumab was completely replaced by the subcutaneous and biosimilar variants. The uptake of the subcutaneous form peaked at 50% market share but after the introduction of biosimilars progressively reduced to a market share of 20%, resulting in a more competitive market structure. The public healthcare costs for trastuzumab significantly decreased after the introduction of the biosimilars. After the introduction of the biosimilars, a substantial price drop is visible, with the subcutaneous version, still under patent, also falling sharply in price but less strongly than the iv/biosimilar version. As the costs are publicly funded, we recommend a more explicit societal debate to consider if the potential benefits of subcutaneous Herceptin® (and other similar medicines) are worth the additional costs, and at which price it should be reimbursed as the part of the benefit package.

Framework for Multistakeholder Patient Registries in the Field of Rare Diseases: Focus on Neurogenetic Diseases.

Progress in genetic diagnosis and orphan drug legislation has opened doors to new therapies in rare neurogenetic diseases (RNDs). Innovative therapies such as gene therapy can improve patients' quality of life but come with academic, regulatory, and financial challenges. Registries can play a pivotal role in generating evidence to tackle these, but their development requires multidisciplinary knowledge and expertise. This study aims to develop a practical framework for creating and implementing patient registries addressing common challenges and maximizing their impact on care, research, drug development, and regulatory decision making with a focus on RNDs. A comprehensive 3-step literature and qualitative research approach was used to develop the framework. A qualitative systematic literature review was conducted, extracting guidance and practices leading to the draft framework. Subsequently, we interviewed representatives of 5 established international RND registries to add learnings from hands-on experiences to the framework. Expert input on the draft framework was sought in digital multistakeholder focus groups to refine the framework. The literature search; interviews with 5 registries; and focus groups with patient representatives (n = 4), clinicians (n = 6), regulators, health technology assessment (HTA) bodies and payers (n = 7), industry representatives (n = 7), and data/information technology (IT) specialists (n = 5) informed development of the framework. It covers the interests of different stakeholders, purposes for data utilization, data aspects, IT infrastructure, governance, and financing of rare disease registries. Key principles include that data should be rapidly accessible, independent, and trustworthy. Governance should involve multiple stakeholders. In addition, data should be highly descriptive, machine-readable, and accessible through a shared infrastructure and not spread over multiple isolated repositories. Sustainable and independent financing of registries is deemed important but remains challenging because of a lack of widely supported funding models. The proposed framework will guide stakeholders in establishing or improving rare disease registries that fulfill requirements of academics and patients as well as regulators, HTA bodies, and commercial parties. There is a need for more clarity regarding quality requirements for registries in regulatory and HTA context. In addition, independent financing models for registries should be developed, as well as well-defined policies on technical uniformity in health data.