Evaluation of drug cost savings related to clinical trials from the perspective of a university hospital.

OBJECTIVES: Clinical trials are an opportunity for patients to access innovative therapy, but patient inclusion in clinical trials can also result in cost savings for hospitals. Our objective was to evaluate the economic impact of clinical trials drug cost savings in a French academic institution from the perspectives of both the French Health Insurance (FHI) and hospitals. METHODS: A retrospective, observational, cost saving analysis was performed on all the clinical trials initiated in our university hospital between 2015 and 2020. Only trials involving an investigational medicinal product were considered. Drug cost savings were defined as the best standard of care, defined in the protocol, whose cost was covered by a sponsor. RESULTS: Of the 646 trials undertaken during the 6 years analysed, 21% (212/646) led to cost savings, mostly driven by the industrial sponsor (92%, €6 984 283/€7 591 612) for a total of €7 591 612 (91% from the FHI's perspective (€6 959 115/€7 591 612)). Oncology trials generated 79.1% (€6 004 966/€7 591 612) of global cost savings, mostly driven by onco-haematology (33.1%, €1 983 146/€6 004 966), onco-pneumology (29.2%, €1 754 333/€6 004 966) and onco-dermatology (23.5%, €1 409 553/€6 004 966) followed by hepatogastroenterology trials (6.9%, €413 113/€6 004 966). Of the 162 drugs, the top 15 generated 75.3% (€5 715 479/€7 591 612) of savings and were grouped together: 12 antineoplastic agents (six per os and six intravenous) and three per os antiviral for hepatitis C. CONCLUSIONS: With ever-changing prices and new innovative treatments, such cost avoidance must be regularly evaluated. We provided objective evidence that clinical trials could achieve potential cost savings for the FHI and hospitals, in addition to the potential benefit to patients of having access to innovative investigational medicinal products.

Place of magistral preparations to continue the treatment if the drug is commercially stopped worldwide? A case report of a 10-year-old child with subacute sclerosing panencephalitis (SSPE) requiring inosiplex.

Subacute sclerosing panencephalitis (SSPE) is a late-onset and fatal viral disease caused by persistent infection of the central nervous system by measles virus (MeV). We present the case of a 10-year-old child from South Asia affected by SSPE, stabilized with a combination of intrathecal interferon-α2b (INF-α2b) injections and oral inosiplex and how we continued the treatment when inosiplex was commercially stopped worldwide.

Treatment of nonarteritic anterior ischemic optic neuropathy with an endothelin antagonist: ENDOTHELION (ENDOTHELin antagonist receptor in Ischemic Optic Neuropathy)-a multicentre randomised controlled trial protocol.

BACKGROUND: Nonarteritic anterior ischemic optic neuropathy (NAAION) is a major cause of blindness in individuals over 50 years of age, with no available effective treatment. The oral dual endothelin receptor antagonist, bosentan, increases retinal optic nerve head blood flow in healthy humans and glaucoma patients. The objective of this trial is to assess the efficacy of bosentan administered at the acute stage in improving outcomes in NAAION patients. METHODS: ENDOTHELION (ENDOTHELin antagonist receptor in Ischemic Optic Neuropathy) is a phase III, interventional, prospective, multicentre, placebo-controlled randomised double-blind clinical trial. The primary outcome is change in the visual field mean deviation (MD) at 3 months (Humphrey 30-2 SITA standard programme). Secondary outcomes include MD and visual acuity changes up to 24 months, changes in peripapillary retinal nerve fibre and macular ganglion cell layer thickness in the affected eye, as measured by optical coherence tomography, rate of NAAION bilateralisation at 2 years, and quality-of-life. Patients over 50 years of age presenting with typical NAAION of recent onset (less than 21 days) are randomly assigned to either 125 mg oral bosentan or placebo, twice a day, during 8 weeks. Besides visits during the treatment phase, patients attend follow-up visits at 2, 3, 6, 12 and 24 months. The inclusion of patients began in August 2015 at five French University hospital ophthalmology departments and two specialised ophthalmology centres. It is planned to include 86 patients in this trial. To date we have included 72 patients and 49 have completed the full follow-up process. DISCUSSION: An endothelin receptor antagonist is a potential approach to improving the anatomical and functional prognosis of patients with NAAION. This multicentre double-blind randomised controlled trial is an opportunity to assess (1) the effect of bosentan on the structure and function of the optic nerve in NAAION, at 3 months, (2) the effect of bosentan on the bilateralisation rate at 24 months and (3) the tolerance profile of bosentan in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT02377271 . Registered on March 3, 2015.

Theranostic AGuIX nanoparticles as radiosensitizer: A phase I, dose-escalation study in patients with multiple brain metastases (NANO-RAD trial).

BACKGROUND AND PURPOSE: Brain metastasis impacts greatly on patients' quality of life and survival. The phase I NANO-RAD trial assessed the safety and maximum tolerated dose of systemic administration of a novel gadolinium-based nanoparticle, AGuIX, in combination with whole brain radiotherapy in patients with multiple brain metastases not suitable for stereotactic radiotherapy. MATERIALS AND METHODS: Patients with measurable brain metastases received escalating doses of AGuIX nanoparticles (15, 30, 50, 75, or 100 mg/kg intravenously) on the day of initiation of WBRT (30 Gy in 10 fractions) in 5 cohorts of 3 patients each. Toxicity was assessed using NCI Common Terminology Criteria for Adverse Events v4.03. RESULTS: Fifteen patients with 354 metastases were included. No dose-limiting toxic effects were observed up to AGuIX 100 mg/kg. Plasma elimination half-life of AGuIX was similar for all groups (mean 1.3 h; range 0.8-3 h). Efficient targeting of metastases (T1 MRI enhancement, tumor selectivity) and persistence of AGuIX contrast enhancement were observed in metastases from patients with primary melanoma, lung, breast, and colon cancers. The concentration of AGuIX in metastases after administration was proportional to the injected dose. Thirteen of 14 evaluable patients had a clinical benefit, with either stabilization or reduction of tumor volume. MRI analysis showed significant correlation between contrast enhancement and tumor response, thus supporting a radiosensitizing effect. CONCLUSION: Combining AGuIX with radiotherapy for patients with brain metastases is safe and feasible. AGuIX specifically targets brain metastases and is retained within tumors for up to 1 week; ongoing phase II studies will more definitively assess efficacy.

The ABC taxonomy for medication adherence translated into French and German.

AIMS: We translated the ABC adherence taxonomy (i.e. 7 terms and their corresponding definitions) published by Vrijens et al. (2012) into French and German without changing the original meaning with the aim to promote a standardised taxonomy for medication adherence to French- and German-speaking researchers and clinicians. METHODS: A Delphi survey was performed. To generate round 1, we identified French and German synonyms for the 7 adherence terms through a literature search in PubMed. Investigators translated the original English definitions into French and German. Panellists were members of ESPACOMP-the International Society for Patient Medication Adherence; experts suggested by ESPACOMP members and first authors of medication adherence publications in French and German. Google forms were used to create online questionnaires. Delphi rounds were performed until consensus was reached. The consensus was defined according to the acceptance rate as moderate consensus (50-75%), consensus (>75-95%), and strong consensus (>95%). RESULTS: The literature search resulted in 4-6 (French) and 4-7 (German) items per English term. Delphi rounds were launched between November 2016 and April 2018. Three rounds sufficed to reach consensus on all terms and definitions from 26 French-speaking and 25 German-speaking panellists. Preferred terms for medication adherence are adhésion médicamenteuse (82%) in French and Medikamentenadhärenz (88%) in German. CONCLUSION: The use of a common terminology for medication adherence with translations in French and German will contribute to standardise the vocabulary, to harmonise research projects and ultimately ease comparison of study results among researchers and clinicians.

Intranasal sufentanil versus intravenous morphine for acute severe trauma pain: A double-blind randomized non-inferiority study.

BACKGROUND: Intravenous morphine (IVM) is the most common strong analgesic used in trauma, but is associated with a clear time limitation related to the need to obtain an access route. The intranasal (IN) route provides easy administration with a fast peak action time due to high vascularization and the absence of first-pass metabolism. We aimed to determine whether IN sufentanil (INS) for patients presenting to an emergency department with acute severe traumatic pain results in a reduction in pain intensity non-inferior to IVM. METHODS AND FINDINGS: In a prospective, randomized, multicenter non-inferiority trial conducted in the emergency departments of 6 hospitals across France, patients were randomized 1:1 to INS titration (0.3 µg/kg and additional doses of 0.15 µg/kg at 10 minutes and 20 minutes if numerical pain rating scale [NRS] > 3) and intravenous placebo, or to IVM (0.1 mg/kg and additional doses of 0.05 mg/kg at 10 minutes and 20 minutes if NRS > 3) and IN placebo. Patients, clinical staff, and research staff were blinded to the treatment allocation. The primary endpoint was the total decrease on NRS at 30 minutes after first administration. The prespecified non-inferiority margin was -1.3 on the NRS. The primary outcome was analyzed per protocol. Adverse events were prospectively recorded during 4 hours. Among the 194 patients enrolled in the emergency department cohort between November 4, 2013, and April 10, 2016, 157 were randomized, and the protocol was correctly administered in 136 (69 IVM group, 67 INS group, per protocol population, 76% men, median age 40 [IQR 29 to 54] years). The mean difference between NRS at first administration and NRS at 30 minutes was -4.1 (97.5% CI -4.6 to -3.6) in the IVM group and -5.2 (97.5% CI -5.7 to -4.6) in the INS group. Non-inferiority was demonstrated (p < 0.001 with 1-sided mean-equivalence t test), as the lower 97.5% confidence interval of 0.29 (97.5% CI 0.29 to 1.93) was above the prespecified margin of -1.3. INS was superior to IVM (intention to treat analysis: p = 0.034), but without a clinically significant difference in mean NRS between groups. Six severe adverse events were observed in the INS group and 2 in the IVM group (number needed to harm: 17), including an apparent imbalance for hypoxemia (3 in the INS group versus 1 in the IVM group) and for bradypnea (2 in the INS group versus 0 in the IVM group). The main limitation of the study was that the choice of concomitant analgesics, when they were used, was left to the discretion of the physician in charge, and co-analgesia was more often used in the IVM group. Moreover, the size of the study did not allow us to conclude with certainty about the safety of INS in emergency settings. CONCLUSIONS: We confirm the non-inferiority of INS compared to IVM for pain reduction at 30 minutes after administration in patients with severe traumatic pain presenting to an emergency department. The IN route, with no need to obtain a venous route, may allow early and effective analgesia in emergency settings and in difficult situations. Confirmation of the safety profile of INS will require further larger studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT02095366. EudraCT 2013-001665-16.

A Randomised Controlled Trial to Test the Effectiveness of Planning Strategies to Improve Medication Adherence in Patients with Cardiovascular Disease.

BACKGROUND: Low levels of adherence to medication prescribed to treat and manage chronic disease may lead to maladaptive health outcomes. Theory-based, easy-to-administer interventions that promote patients' effective self-regulation of their medication-taking behaviour are needed if adherence is to be maximised. We tested the effectiveness of an intervention adopting planning techniques to promote medication adherence. METHODS: Outpatients with cardiovascular disease (N = 71) were allocated to either an experimental condition, in which participants were asked to form implementation intentions and coping plans related to their treatment, or to a no-planning control condition, in which participants received no treatment. Patients also completed self-report measures of medication adherence, self-efficacy, and beliefs in medication necessity and concerns. Measures were administered at baseline and at 6-week follow-up. RESULTS: Results revealed no overall main effect for the intervention on medication adherence. Post-hoc moderator analyses revealed that the intervention was effective in patients with lower necessity beliefs compared to those with higher necessity beliefs. CONCLUSION: While current findings have promise in demonstrating the conditional effects of planning interventions, there is a need to replicate these findings by manipulating planning and beliefs independently and testing their direct and interactive effects on medication adherence.

Why Do Patients with Chronic Inflammatory Rheumatic Diseases Discontinue Their Biologics? An Assessment of Patients' Adherence Using a Self-report Questionnaire.

OBJECTIVE: Concerns have been raised about nonadherence behavior among patients with chronic inflammatory rheumatic diseases (CIRD) receiving biologics. This nonadherence may be caused by various factors. The main objective was to explain why patients discontinue their biologics of their own accord. METHODS: A quantitative and descriptive study was performed using a self-report questionnaire that was sent through the Internet to members of different patient associations. Sociodemographic data, medical and therapeutic history, management of biologic administration, previous experiences, and patients' beliefs and perceptions about treatment efficacy and side effects were studied to explain self-discontinuation (SD). RESULTS: A total of 581 patients answered the questionnaire between June 16, 2012, and July 4, 2012, including patients with ankylosing spondylitis (351/581, 60.4%), rheumatoid arthritis (196/581, 33.7%), psoriatic arthritis (30/581, 5.2%), and other CIRD (4/581, 0.7%). More than 1000 different biologics were described by the 581 patients, with a median of 2 lines per patient. Eighty-six patients discontinued their biologics of their own accord (14.8%). In a multivariate analysis, factors that were significantly related to SD were low level of pain, more than 1 line of biologics tried, self-administration of biologics, negative beliefs about the treatment, and a lack of medical and social support. CONCLUSION: Five predictive factors of this SD were identified, which should be assessed in routine with patients with CIRD receiving biologic treatment: pain, treatment history, self-administration of injections, negative beliefs about treatment, and a lack of perceived medical and social support.

[Hereditary angiœdema treatments: Recommendations from the French national center for angiœdema (Bordeaux consensus 2014)]. / Traitements des angiœdèmes héréditaires : recommandations du centre de référence national des angiœdèmes (consensus 2014 de Bordeaux).

INTRODUCTION: Treatment of hereditary angiœdema (HAE), associated or not with C1Inh deficiency, has dramatically changed these last five years. Four new therapeutic options are now available in France. The French Reference Centre for Angioedema has a consensus meeting to give recommendations about their use. METHODS: The proposals were based on a CREAK survey and a comprehensive review of the literature done by 4 experts. These proposals were submitted to a vote at a national CREAK meeting (Bordeaux, March 2014). Fifty-one participants, 15 experts and one expert-patient have participated. The consensus concerned HAE patients with or without C1Inh deficiency. Were excluded children, patients with acquired AE and with drug induced AE. RESULTS: Proposals were done for 4 cases: acute attack treatment, short-term prophylaxis, long-term prophylaxis and pregnant women. The drugs cited were: C1Inh concentrate, icatibant, tranexamic acid, danazol and chlormadinone acetate. CONCLUSION: Consensual proposals were obtained during this meeting. They will be now widely diffused.

Influence of intention to adhere, beliefs and satisfaction about medicines on adherence in solid organ transplant recipients.

INTRODUCTION: Nonadherence to immunosuppressive (IS) therapy is associated with poor outcomes. Identifying factors predicting poor adherence is therefore essential. The primary objective of this study was to test whether parameters of a model adapted from the theory of planned behavior, and more specifically attitudes that are influenced by beliefs and satisfaction with medication, could predict adherence in solid organ transplant patients. METHODS: Adherence was assessed with a self-reported medication adherence scale and IS blood trough concentrations over 6 months, in four transplant units. Satisfaction and beliefs were assessed using the Treatment Satisfaction with Medicines Questionnaire (SATMED-Q) and Beliefs about Medicines Questionnaire (BMQ), respectively. Theory of planned behavior was assessed with a specific questionnaire exploring intentions, subjective norms, attitudes and perceived behavioral control. Treatment characteristics and socioeconomic data were also collected. RESULTS: One hundred and fifty-three solid organ transplant patients were enrolled, including lung (n=33), heart (n=43), liver (n=42), and kidney (n=44) patients. Satisfaction and positive beliefs about medication were higher in adherent than those in nonadherent patients. Factors independently associated with an increased risk of nonadherence were negative general beliefs about medications (odds ratio [OR]=0.89 [0.83-0.97]), living alone (OR=2.78 [1.09-7.09]), heart transplantation (OR=3.49 [1.34-9.09]), and being on everolimus (OR=5.02 [1.21-20.8]). CONCLUSION: Negative beliefs toward medications were shown to be an independent risk factor of poor adherence. Therefore, the BMQ could be an effective, easy to implement tool, for use in everyday practice, to identify patients needing interventions to improve adherence to IS.

Assessing medication adherence: options to consider.

BACKGROUND: Adherence to chronic therapy is a key determinant of patient health outcomes in chronic disease. However, only about 50 % of patients adhere to chronic therapy. One of the challenges in promoting adherence is having an accurate understanding of adherence rates and the factors that contribute to non-adherence. There are many measures available to assess patient medication adherence. AIM OF THE REVIEW: This review aims to present the commonly used indirect methods available for measuring medication adherence in routine healthcare and research studies. METHOD: A literature review on medication adherence measures in patient populations with chronic conditions taking chronic medications was conducted through Medline (2003-2013). A complementary manual search of references cited in the retrieved studies was performed in order to identify any additional studies. RESULTS: Of the 238 initial Medline search results, 57 full texts were retrieved. Forty-seven articles were included as a result of the manual search. Adherence measures identified were: self-report (reported in 50 publications), electronic measures (33), pharmacy refills and claims data (26) and pill counts (25). Patient self-report, electronic measures, pharmacy refill and claims data were the most commonly used measures of adherence in research, routine practice, epidemiological and intervention studies. These methods, and their strengths and limitations have been described in this paper. CONCLUSION: A multitude of indirect measures of adherence exist in the literature, however, there is no "gold" standard for measuring adherence to medications. Triangulation of methods increases the validity and reliability of the adherence data collected. To strengthen the adherence data collected and allow for comparison of data, future research and practice interventions should use an internationally accepted, operational standardized definition of medication adherence and clearly describe the medication adherence methods used.

Comparison between two generic questionnaires to assess satisfaction with medication in chronic diseases.

OBJECTIVE: The objective of this work was to compare two generic questionnaires assessing patients' satisfaction with medication. In addition we tested whether satisfaction can predict adherence to medication regimens in patients with chronic diseases, and which dimensions of satisfaction are most involved. METHODS: This prospective, observational study was conducted over one year in a heterogeneous population of patients with various chronic diseases. Satisfaction with medication was assessed by using the TSQM® vII and the SatMed-Q® questionnaires, and adherence to treatment was assessed with the Morisky-Green questionnaire. Clinical pharmacists interviewed patients to collect clinical, demographic and therapeutic data. RESULTS: 190 patients were enrolled. Both questionnaires showed excellent reliability and correlation was high (R=0.70; p<0.001). Adherence was correlated with satisfaction with medication whether assessed with the SatMed-Q® (R=0.23; p=0.002) or the TSQM® (R=0.17; p=0.02). Among different dimensions of satisfaction, convenience of use and side effects are prominent predictors of adherence. CONCLUSION: Adherence is related to the patient's satisfaction with medication whether assessed with the TSQM® vII or the SatMed-Q®. Therefore, these simple questionnaires could be used as predictive tools to identify patients whos' adherence needs to be improved.

Development of a pharmacist collaborative care program for pulmonary arterial hypertension.

Patients with Pulmonary Arterial Hypertension (PAH) require multidisciplinary care. Involving pharmacists in PAH multidisciplinary care teams may enhance patient education and improve medication use. We describe the implementation of a Pharmacist Collaborative Care Program (PCCP) in a PAH referral centre in Grenoble, France. Initiated in 2007, the PCCP program includes a pharmacist intervention whose goals are educational, psychosocial, and technical. During patient interviews, pharmacists make an 'educational diagnosis' and provide a patient-specific education session. Patient skills are evaluated at the end of the session. Pharmacists provide feedback to nurses and physicians through a standardized report form and discussion during medical rounds and PAH group meetings. Pharmacists re-evaluate patients' skills every 3-6 months during multidisciplinary clinical evaluations. The PCCP program for PAH is an established practice in Grenoble and may inform future patient education programs involving pharmacists in France, where legislation has recently been passed to standardize patient education.