Economic analysis of allogeneic hematopoietic stem cell transplantation in the Bone Marrow Transplant Center of Tunisia.

Introduction: New procedures and diagnostic tests in hematopoietic stem cell transplantation (HSCT) are associated with a significant increase in costs. The last cost estimate of allogeneic HSCT done in Tunisia was in 1996 and concerned only direct medical costs. Therefore, an updated cost analysis is needed. Objective: Analysis of direct costs during the first-year post-allogeneic HSCT in two groups of patients: Bone Marrow Transplant (Allo-BMT) and Peripheral Blood Stem Cell Transplant (Allo-PBSCT) and identification of factors leading to interindividual variations in costs in order to compare these costs with the budget allocated by the payer (CNAM). Methods: Pharmacoeconomic retrospective study, concerning patients who underwent allogeneic HSCT in 2013. Clinical and unit cost data were obtained from medical and administration records. Results:This study showed that the average direct cost of allogeneic HSCT in the population during the first year reached 56 638€. The average cost of Allo-BMT was 63 612€, and Allo-PBSCT was 45 966€ (p > 0.05). The initial hospitalization counted for 88% of total direct cost with an average cost of 41 441€ in Allo-BMT and 24 672€ in Allo-PBSCT (p < 0.05). Direct medical costs represented more than 70% of total direct costs, drugs, and laboratory tests occupied the largest share. Antifungals, antitumors, and antiviral drugs were the most expensive pharmaceutical classes with a mean cost, respectively, of 4 526€; 3 737€ and 3 268€. Some clinical criteria were significantly related to total direct costs like length of aplasia (p < 0.01) and GVHD (p < 0.05). However, the type of blood disease, its risk, length of mucositis, and the treatment protocol have no effect on the costs for all allogeneic patients. Conclusion: Our results showed that the costs of Allo HSCT have exceeded by far the budget allocated by the CNAM to the center, since the 90s to this day. That's why the total reimbursement mechanism should be revised.

Humoral and Cellular Immunogenicity of Six Different Vaccines against SARS-CoV-2 in Adults: A Comparative Study in Tunisia (North Africa).

BACKGROUND: The mass vaccination campaign against SARS-CoV-2 was started in Tunisia on 13 March 2021 by using progressively seven different vaccines approved for emergency use. Herein, we aimed to evaluate the humoral and cellular immunity in subjects aged 40 years and over who received one of the following two-dose regimen vaccines against SARS-CoV-2, namely mRNA-1273 or Spikevax (Moderna), BNT162B2 or Comirnaty (Pfizer-BioNTech), Gam-COVID-Vac or Sputnik V (Gamaleya Research Institute), ChAdOx1-S or Vaxzevria (AstraZeneca), BIBP (Sinopharm), and Coronavac (Sinovac). MATERIAL AND METHODS: For each type of vaccine, a sample of subjects aged 40 and over was randomly selected from the national platform for monitoring COVID-19 vaccination and contacted to participate to this study. All consenting participants were sampled for peripheral blood at 3-7 weeks after the second vaccine dose to perform anti-S and anti-N serology by the Elecsys® (Lenexa, KS, USA) anti-SARS-CoV-2 assays (Roche® Basel, Switzerland). The CD4 and CD8 T cell responses were evaluated by the QuantiFERON® SARS-CoV-2 (Qiagen® Basel, Switzerland) for a randomly selected sub-group. RESULTS: A total of 501 people consented to the study and, of them, 133 were included for the cellular response investigations. Both humoral and cellular immune responses against SARS-CoV-2 antigens differed significantly between all tested groups. RNA vaccines induced the highest levels of humoral and cellular anti-S responses followed by adenovirus vaccines and then by inactivated vaccines. Vaccines from the same platform induced similar levels of specific anti-S immune responses except in the case of the Sputnik V and the AstraZeneca vaccine, which exhibited contrasting effects on humoral and cellular responses. When analyses were performed in subjects with negative anti-N antibodies, results were similar to those obtained within the total cohort, except for the Moderna vaccine, which gave a better cellular immune response than the Pfizer vaccine and RNA vaccines, which induced similar cellular immune responses to those of adenovirus vaccines. CONCLUSION: Collectively, our data confirmed the superiority of the RNA-based COVID-19 vaccines, in particular that of Moderna, for both humoral and cellular immunogenicity. Our results comparing between different vaccine platforms in a similar population are of great importance since they may help decision makers to adopt the best strategy for further national vaccination programs.

COVID-19 Vaccines and Roles of the Health Regulatory Authority in Tunisia.

Given the unstoppable spread of coronavirus disease (COVID-19), the development of a vaccine was needed to contain the pandemic. In such a situation of global emergency, regulatory authorities ensured timely, safe, and equitable access to the vaccine.This article aims to outline the roles of the Tunisian regulatory authority, the Directorate of Pharmacy and Medicines (DPM) at the Ministry of Health, in registration and procurement of the COVID-19 vaccine.Requirement to grant the Exceptional Provisional Authorizations of Marketing (EPAM) for COVID-19 vaccines was 27 days versus 869 days for conventional marketing authorizations (MAs). The DPM has optimized its activity through: early dialogue with manufacturers, online submission, the use of distance communication technologies. It has demonstrated unprecedented flexibility through the continuous and rolling review approach.Regulatory authorities in Tunisia and around the world have partnered with manufacturers to speed up administrative procedures while ensuring the quality, safety, and efficacy of vaccines.

Multi-Criteria Decision Analysis to Prioritize People for COVID-19 Vaccination When Vaccines Are in Short Supply.

COVID-19 pandemic underscored the need for a rapid tool supporting decision-makers in prioritizing patients in the immediate and overwhelming context of pandemics, where shortages in different healthcare resources are faced. We have proposed Multi-Criteria Decision Analysis (MCDA) to create a system of criteria and weights to prioritize uses of COVID-19 vaccines in groups of people at significantly higher risk of severe COVID-19 disease or death, when vaccines are in short supply, for use in Tunisia. The prioritization criteria and the levels within each criterion were identified based on available COVID-19 evidence with a focus on the criteria selected by Tunisian scientific committees. To determine the weights for the criteria and levels, reflecting their relative importance, a panel of frontline physicians treating COVID-19 were invited to participate in an online survey using 1,000 minds MCDA software (www.1000minds.com) which implements the PAPRIKA (Potentially All Pairwise RanKings of all possible Alternatives) method. Ten criteria and twenty-three levels have been selected for prioritizing the uses of COVID-19 vaccines in groups of people at significantly higher risk of severe disease or death. Among the invited physicians, sixty have completed the survey. The obtained scores were, in decreasing order of importance (mean weights in parentheses, summing to 100%). Obesity (16.2%), Age (12.7%), Chronic pulmonary diseases (10.8%), Chronic cardiovascular conditions (10.3%), Bone marrow or organ transplantation (10.1%), Immunodeficiency or Immunosuppression (9.6%), Diabetes (9%), Renal failure (8.4%), evolutive cancer (6.9%), and high blood pressure (6%). MCDA-based prioritization scoring system comprising explicit criteria and weights provides an adaptable and multicriteria approach that can assist policy-makers to prioritize uses of COVID-19 vaccines.

Regulatory Challenges in the COVID-19 Era: The Case of Tunisia.

In view of the possible disruptions in the manufacturing and supply of health products following the coronavirus disease 2019 (COVID-19) pandemic, the Tunisian medicines regulatory authority was mobilized to guarantee patient safety. Teleworking has become the ultimate way of service continuity. The planning was revised according to health priorities. Work procedures were set online. A minimum list of medicines known as "medicines of health and strategic interest" was established. The Directorate of Pharmacy and Medicines (DPM) has been working on updating medicines stock data. A provisional suspension of authorizations for medicines export for 1 mo was decided. A fast-track procedure allowing the validation of alternative sources of raw materials has been put in place. An appeal for a fast track manufacture of hydroalcoholic gel/solutions was launched. A Monitored Emergency Use of Unregistered and Investigational Interventions (MEURI) procedure has been adopted in order to dispense off-label prescriptions of hydroxychloroquine and azithromycin combination. Focus groups were organized in order to set up therapeutic trials exploring possible strategies of COVID-19 treatment, such as serotherapy and BCG vaccine. This proactive and anticipatory policy has made it possible to meet the health challenges dictated by this crisis.

Valuing health-related quality of life using a hybrid approach: Tunisian value set for the EQ-5D-3L.

OBJECTIVE: To develop a value set for EQ-5D-3L based on the societal preferences of the Tunisian population. METHODS: A representative sample of the Tunisian general population was obtained through multistage quota sampling involving age, gender and region. Participants (n = 327), aged above 20 years, were interviewed using the EuroQol Portable Valuation Technology in face-to-face computer-assisted interviews. Participants completed 10 composite time trade-off (cTTO) and 10 discrete choice experiments (DCE) tasks. Utility values for the EQ-5D-3L health states were estimated using regression modeling. The cTTO and DCE data were analyzed using linear and conditional logistic regression modeling, respectively. Multiple hybrid models were computed to analyze the combined data and were compared on goodness of fit measured by the Akaike information criterion (AIC). RESULTS: A total of 300 participants with complete data that met quality criteria were included. All regression models showed both logical consistency and significance with respect to the parameter estimates. A hybrid model accounting for heteroscedasticity presented the lowest value for the AIC among the hybrid models. Hence, it was used to construct the Tunisian EQ-5D-3L valuation set with a range of predicted values from - 0.796 to 1.0. CONCLUSION: This study provides utility values for EQ-5D-3L health states for the Tunisian population. This value set will be used in economic evaluations of health technologies and for Tunisian health policy decision-making.

Health technology assessment: Choice between a cytotoxic safety cabinet and an isolator for oncology drug reconstitution in Tunisia.

INTRODUCTION: In order to implement a centralized cytotoxic reconstitution unit (CCRU), a study was conducted to compare the implementation costs of a CCRU equipped with a cytotoxic safety cabinet (CSC) and one equipped with an isolator with negative pressure. MATERIALS AND METHODS: This study compares items such as infrastructure, air treatment and CCRU qualification costs, equipment's purchase and qualifications costs, as well as staff dressing costs. Two plans were elaborated according to the international recommendations in a way that they respond to the necessary requirements in both cases. Requests for quotes for the compared items were sent to different suppliers. RESULTS: The implementations' cost of a CCRU equipped with a CSC is cheaper than the one equipped with an isolator. The price of an isolator is much higher than a CSC; its qualification is also more expensive. However, the requirements and the costs for the air treatment and the dressing of the staff are less in the case of an isolator. The overall cost of the CCRU's implementation is approximately 1.3 times higher in the case of an isolator. However, by excluding the equipment purchase cost, the overall cost of a CSC's implementation becomes higher. CONCLUSION: For Tunisia, it seems that the CSC is the most adapted. However, this work should be completed by the comparison of the CCRU's operating costs in order to optimize the resources and figure out the cheapest system.

Physical and chemical stability of cytarabine in polypropylene syringes.

BACKGROUND: Cytarabine is widely used to treat leukemia and lymphoma. Currently, Cyrabol®, powder for injection, is one of the specialties marketed in Tunisia. However, no stability data when diluted with 0.9% NaCl are available. The aim of this study is to evaluate the physical and chemical stability of cytarabine (Cyrabol®) solution after dilution in 0.9% NaCl (1 mg/mL, 5 mg/mL and 10 mg/mL) in polypropylene syringes under different storage conditions. METHODS: Cytarabine solutions (1 mg/mL, 5 mg/mL and 10 mg/mL) in 0.9% NaCl were prepared in polypropylene syringes and stored for 28 days under different conditions. Cytarabine preparations in glass containers were prepared as a control to detect any adsorption. Chemical stability was assessed by a stability-indicating high-performance liquid chromatography method. The stability-indicating capacity of the method was proved by forced degradation tests. Linearity, precision and limit of detection and quantification were performed according to the International Conference on Harmonisation recommendations. Physical stability was checked by visual inspection. RESULTS: The method was proven to be a validated stability-indicating assay. At 2-8°C, all tested solutions were chemically stable for 28 days. However, at 25°C, the main degradation product gradually increased during the study and the chemical stability of 1 mg/mL, 5 mg/mL and 10 mg/mL solutions was 14 days, 8 days and 5 days, respectively. Similar results were observed in the glass containers. CONCLUSION: The highest physical and chemical stability of cytarabine diluted in 0.9% NaCl in polypropylene syringes was observed at 2-8°C. At 25°C, better stability was found in the 1 mg/mL solution compared with those at higher concentrations (5 mg/mL and 10 mg/mL).

Perception of hematologists and oncologists about the biosimilars: A prospective Tunisian study based on a survey.

INTRODUCTION: Biosimilar drugs have significantly shaken the global pharmaceutical market through a better access to the health care services. The aim of this study is to establish a state of play in Tunisia based on the knowledge and perceptions of doctors on biosimilars in order to identify the problems related to these drugs and to propose solutions for improvement. MATERIALS AND METHODS: In our study, we conducted a prospective, descriptive survey using a questionnaire, destinated to oncologists and hematologists with different grades, from both public and private sectors and from several regions. The questions focused on physicians' general knowledge of biosimilars and their comparison with reference on safety, quality, efficacy, and indication. Finally, we explored the proportion of physicians who are favorable to the policy encouraging biosimilar use. RESULTS: One hundred and seven doctors among 150 answered the questionnaire; 57% were oncologists and 43% were hematologists. About one over five physicians defines biosimilar as a chemical drug. About 29% do not differentiate between a biosimilar and a generic one. A percentage of 68 believe that a biosimilar can have all the indications of its reference following complementary clinical studies. On the other side, 68.2% support the policy encouraging these drugs. Last, only 3.7% of the practitioners believe that they are well informed about biosimilars. DISCUSSION: Our results are comparable to other surveys described in the literature. However, this is the first study that targets oncologists and hematologists specifically. CONCLUSION: Our study showed a lack of information from oncologists and hematologists about biosimilars in Tunisia. Thus, health authorities should carry out training programs on biosimilars and introduce clear and effective legislation in order to allow better access to health care services.

Parenteral Nutrition Complications in Children Undergoing Bone Marrow Transplantation.

BACKGROUND: Parenteral nutrition (PN) seems to be a practical solution to face the negative nutritional effects of bone marrow transplantation. OBJECTIVE: Report and describe all observed PN-related complications in children undergoing allogenic bone marrow transplantation in a tertiary center and determine the possible risk factors. MATERIALS AND METHODS: This was a retrospective and observational study including 51 allografted children 2 to 17 years of age. We collected from medical patient records any noticed PN-related complications using an assessment causality method. The independent risk factors for complications were investigated by multivariate analysis. RESULTS: A total of 92% of patients (n=47) developed a total of 136 complications attributable to PN. The incidence rate of complications was 5 for 100 patient days of PN. Infectious complications (32.3%) and electrolytic disorders (27.9%) were the most common conditions identified during our study. Multivariate analysis showed that the duration of PN exposure, age, and hyperglycemia were the risk factors for the onset of these complications. CONCLUSIONS: Although we have noticed multiple complications attributable to PN, a certain causal link is difficult to establish in this particular context. Emphasizing enteral nutrition in bone marrow graft protocols would be the best way to avoid these complications.

Direct cost analysis of the second year post-allogeneic hematopoietic stem cell transplantation in the Bone Marrow Transplant Centre of Tunisia.

Background: Hematopoietic stem cell transplantation (HSCT) is a medically complicated therapy with a long recovery time. In Tunisia, the National Health Insurance Fund (CNAM) covers only the first year post-transplantation, after which the costs are borne by the hospital. Objective: Describe complications that can occur during the second year post-allogeneic HSCT and calculate direct costs in different groups of patients. Methods: In this pharmacoeconomic study, medical records of the second year post-allogeneic HSCT were collected. Studied variables included frequent observed complications and medical and non-medical direct costs. Results: The average total direct cost in the population during the second year post-transplantation was $11,571, 97% of which represents direct medical costs Drugs accounted for the largest share (80%) of total direct costs, dominated by the cost of antifungals (52%) and antivirals (26%) drug . Cytomegalovirus status was seen in 9.3% of patients and was associated with a seven-fold increase in direct costs (p < 0.001).​​In patients who developed chronic GVHD, the average direct cost was three times higher than for those who did not (p = 0.032). Conclusion: Given the importance of direct costs in the post-transplantation period a review of the hospital financing mechanism and a new convention with the CNAM is crucial.​​.

Progesterone for Luteal Phase Support in In Vitro Fertilization: Comparison of Vaginal and Rectal Pessaries to Vaginal Capsules: A Randomized Controlled Study.

BACKGROUND: In IVF, Luteal phase support is usually performed using vaginal progesterone. A part of patients using this route reports being uncomfortable with this route. We tried to study whether the rectal route could be an effective alternative and associated with less discomfort. PATIENTS AND METHODS: A prospective randomized controlled study. All patient were eligible for IVF treatment for infertility. After oocyte pickup, 186 patients were allocated to one the following protocols for luteal phase support: (i) rectal pessaries group: natural progesterone pessaries administered rectally 200 mg three times a day, (ii) vaginal pessaries group: natural progesterone pessaries administered vaginally 200 mg three times a day), and (iii) vaginal capsules group: natural micronized progesterone capsules administered vaginally 200 mg three times a day. On the day of pregnancy test, patients were asked to fill in a questionnaire conducted by an investigator in order to assess the tolerability and side effects of the LPS treatment taken. The primary endpoint was the occurrence of perineal irritation. RESULTS: Fifty eight patients were assigned to the rectal pessaries group, 68 patients to the vaginal pessaries group, and 60 patients to the vaginal capsules group. All patients adhered to their allocated treatment. Implantation and clinical pregnancy rates per transfer did not differ between the three groups. Perineal irritation, which was our primary endpoint, was the same for all the three groups (respectively 1.7 % versus 5.9 % versus 11.7%). Regarding the other side effects, more patients experienced constipation and flatulence with the rectal route, whereas more patients reported vaginal discharge in the vaginal capsules group. CONCLUSION: Rectal administration for luteal phase support is effective and well accepted alternative to vaginal route.