Process of drug registration in Israel: the correlation between the number of discussions within the Ministry of Health and postapproval variations by EMA and/or FDA.

OBJECTIVES: US FDA and EMA allow facilitated regulatory pathways to expedite access to new treatments. Limited supportive data may result in major postapproval variations. In Israel, partly relying on Food and Drug Administration (FDA) and European Medicines Agency (EMA), clinical data are reviewed independently by the Advisory Committee of Drug Registration (ACDR). In this study, the correlation between the number of discussions at the ACDR and major postapproval variations is examined. DESIGN: This is an observational retrospective comparative cohort study. SETTING: Applications with FDA and/or EMA approval at time of assessment in Israel were included. The timeframe was chosen to allow a minimum of 3 years of postmarketing approval experience for potential major label variations. Data regarding the number of discussions at ACDR were extracted from protocols. Data on postapproval major variations were extracted from the FDA and EMA websites. RESULTS: Between 2014 and 2016, 226 (176 drugs) applications, met the study criteria. 198 (87.6%) and 28 (12.4%) were approved following single and multiple discussions, respectively. A major postapproval variation was recorded in 129 (65.2%) compared with 23 (82.1%) applications approved following single and multiple discussions, respectively (p=0.002). Increased risk for major variation was found for medicines approved following multiple discussions (HR=1.98, 95% CI: 1.26 to 3.09) with a median time of 1.2 years, applications approved based on phase II trials (HR=2.58, 95% CI: 1.72 to 3.87), surrogate endpoints (HR=1.99, 95% CI: 1.44 to 2.74) and oncologic indications (HR=2.48, 95% CI: 1.78 to 3.45). CONCLUSIONS: Multiple ACDR discussions associated with limited supportive data are predictive for major postapproval variations. Moreover, our findings demonstrate that approval by the FDA and/or EMA does not pave the way to automatic approval in Israel. In a substantial per cent of the cases, submission of the same clinical data resulted in different safety and efficacy considerations, requiring additional supporting data in some cases or even rejection of the application in others.

Increasing adverse drug reaction reporting-How can we do better?

Adverse drug reactions (ADRs) are associated with morbidity and mortality worldwide. Although national systems for reporting ADRs exist there is a low reporting rate. The aim of the current study was to evaluate an intervention plan for improving ADRs reporting among medical professionals (physicians and nurses). A multicentre intervention study was conducted, in which one medical centre was randomly assigned to the intervention group and two medical centres to the control group. The study consisted of 3 phases: baseline data collection, intervention and follow-up of the reporting rate. The questionnaire that was filled in at base line and at the end of study, contained questions about personal/professional demographic variables, and statements regarding knowledge of and behaviour toward ADRs reporting. The intervention program consisted of posters, lectures, distant electronic learning and reminders. An increase in the number of ADRs reports was noted in the intervention group (74 times higher than in the control group) during the intervention period, which was gradually decreased with as the study progressed (adjusted O.R = 74.1, 95% CI = 21.11-260.1, p<0.001). The changes in the "knowledge related to behaviour" (p = 0.01) and in the "behaviour related to reporting" (p<0.001) score was significantly higher in the intervention group. Specialist physicians and nurses (p<0.001), fulfilling additional positions (p<0.001) and those working in other places (p = 0.05) demonstrated a high rate of report. Lectures were preferable as a method to encourage ADRs reporting. The most convenient reporting tools were telephone and online reporting. Thus, implementation and maintenance of a continuous intervention program, by a pharmacovigilance specialist staff member, will improve ADRs reporting rates.

The effect of an intervention program on the knowledge and attitudes among medical staff regarding adverse drug reaction reporting.

PURPOSE: Adverse drug reactions (ADRs) are a growing important public health problem; however, underreporting of ADRs is very common. The aim of the current study was to explore the effect of an intervention program on the knowledge and attitudes among physicians and nurses regarding ADRs reporting. METHODS: A multicentre study consisted of three phases: filling out a questionnaire; an intervention program; filling out the same questionnaire again. The intervention program consisted of posters, lectures, and distant electronic learning. The questionnaire contained questions about personal/professional demographic variables, and statements regarding knowledge and attitudes regarding ADR reporting. RESULTS: The data revealed that the intervention program significantly elevated the "Objective knowledge" (P < 0.01) and "Practical knowledge" (P < 0.02) score as compared to the control group, while no significant differences were found regarding "Acquired knowledge" (P = 0.14). Seniority (P = 0.01) and experience in internal medicine (P = 0.05) were demonstrated as significant factors determining the knowledge of the staff. Obligation was the main motive for reporting in 80% of participants. After the intervention, no differences were found in the "Attitude related to the motive for reporting" or "Attitude related to the commitment to report", between the two groups. However, "Attitude related to the need to report" score significantly improved after the intervention (P = 0.04). CONCLUSIONS: The intervention program increased knowledge and attitudes regarding ADRs reports. Seniority had the most effect on the influence of the intervention program. The data from this study encourages the necessity to hold ongoing intervention programs in order to improve ADRs reporting rate.

Medications and glucose-6-phosphate dehydrogenase deficiency: an evidence-based review.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect and one of the most common genetic disorders worldwide, with an estimated 400 million people worldwide carrying a mutation in the G6PD gene that causes deficiency of the enzyme. Although drug-induced haemolysis is considered the most common adverse clinical consequence of G6PD deficiency, significant confusion exists regarding which drugs can cause haemolytic anaemia in patients with G6PD deficiency. In the absence of consensus among physicians, patients are subject to conflicting advice, causing uncertainty and distress. In the current review we aimed, by thorough search of the medical literature, to collect evidence on which to base decisions either to prohibit or allow the use of various medications in patients with G6PD deficiency. A literature search was conducted during May 2009 for studies and case reports on medication use and G6PD deficiency using the following sources: MEDLINE (1966-May 2009), PubMed (1950-May 2009), the Cochrane database of systematic reviews (2009), and major pharmacology, internal medicine, haematology and paediatric textbooks. After assessing the literature, we divided medications into one of three groups: medications that should be avoided in individuals with G6PD deficiency, medications that were considered unsafe by at least one source, but according to our review can probably be given safely in normal therapeutic dosages to individuals with G6PD deficiency as evidence does not contravene their use, and medications where no evidence at all was found to contravene their use in G6PD-deficient patients. It is reasonable to conclude that, over time, many compounds have been wrongly cited as causing haemolysis because they were administered to patients experiencing an infection-related haemolytic episode. We found solid evidence to prohibit only seven currently used medications: dapsone, methylthioninium chloride (methylene blue), nitrofurantoin, phenazopyridine, primaquine, rasburicase and tolonium chloride (toluidine blue). Regarding all other medications, our review found no evidence to contravene their use in normal therapeutic doses to G6PD-deficient patients. There is a need for evidence-based global consensus regarding medication use in G6PD-deficient patients.

Appropriate antibiotic prescribing pattern in hospitalized children.

This study analyzes prospectively the antibiotic prescription habits in terms of appropriateness of use and cost pattern effects in the paediatric wards of two different university hospital patient set-ups. Data on demographics, discharge diagnosis, antibiotic utilization and costs were collected prospectively from the children's individual electronic charts at Rambam Health Care Campus (R) and Kaplan Medical Centre (K) in Israel. A total of 505 and 497 children from R and K units, respectively, were screened. Of the surveyed population, 239 and 330 children in the R and K units were hospitalized due to infectious diseases. The antibiotic appropriateness for the R and K units were 84% and 91%, respectively (p>0.5). Total antibiotics Defined Daily Dose (DDD) and Drug Utilization 90% (DU90%) index were 241.7 and 217.5 for the R unit and 388 and 349.2 for the K unit, (p<0.001). Drug Cost 90% indices (DC90%) for the two units were NIS 6,023.5 and NIS 5,955.8; respectively. This study generates up-to-date information on the antimicrobial prescription habits in two different hospitals and suggests that antibiotic treatment in both hospitals appears to be appropriate. Significant lower median antibiotic cost was depicted in the K admission unit in comparison to the R admission unit (11.3 NIS - 40.0 NIS; p<0.01), respectively. Drug use evaluations are useful indicators for following trends of drug prescription, optimizing antibiotic usage and controlling expenditure.

Cigarette smoking and infection.

BACKGROUND: Infectious diseases may rival cancer, heart disease, and chronic lung disease as sources of morbidity and mortality from smoking. We reviewed mechanisms by which smoking increases the risk of infection and the epidemiology of smoking-related infection, and delineated implications of this increased risk of infection among cigarette smokers. METHODS: The MEDLINE database was searched for articles on the mechanisms and epidemiology of smoking-related infectious diseases. English-language articles and selected cross-references were included. RESULTS: Mechanisms by which smoking increases the risk of infections include structural changes in the respiratory tract and a decrease in immune response. Cigarette smoking is a substantial risk factor for important bacterial and viral infections. For example, smokers incur a 2- to 4-fold increased risk of invasive pneumococcal disease. Influenza risk is severalfold higher and is much more severe in smokers than nonsmokers. Perhaps the greatest public health impact of smoking on infection is the increased risk of tuberculosis, a particular problem in underdeveloped countries where smoking rates are increasing rapidly. CONCLUSIONS: The clinical implications of our findings include emphasizing the importance of smoking cessation as part of the therapeutic plan for people with serious infectious diseases or periodontitis, and individuals who have positive results of tuberculin skin tests. Controlling exposure to secondhand cigarette smoke in children is important to reduce the risks of meningococcal disease and otitis media, and in adults to reduce the risk of influenza and meningococcal disease. Other recommendations include pneumococcal and influenza vaccine in all smokers and acyclovir treatment for varicella in smokers.

High fasting glucose levels as a predictor of worse clinical outcome in patients with coronary artery disease: results from the Bezafibrate Infarction Prevention (BIP) study.

BACKGROUND: A high fasting glucose level may be a marker not only for microvascular complications, but also for macrovascular complications. We evaluated the clinical significance of a high fasting glucose level (> or =110 mg/dL), detected either at baseline or during follow-up, in the Bezafibrate Infarction Prevention (BIP) study. METHODS: The BIP study was a secondary prevention prospective double-blind study comparing bezafibrate to placebo. A total of 3122 patients with documented coronary artery heart disease who were aged 45 to 74 years and had a total cholesterol level between 180 and 250 mg/dL, low-density lipoprotein cholesterol level < or =180 mg/dL, a high-density lipoprotein cholesterol level < or =45 mg/dL, a triglyceride level < or =300 mg/dL, and a fasting glucose < or =160 mg/dL were randomized to receive 400 mg of bezafibrate daily or placebo. RESULTS: The primary end point of the BIP study was fatal myocardial infarction, non-fatal myocardial infarction, or sudden death. Secondary end points included hospitalization for unstable angina, percutaneous transluminal coronary angioplasty, and coronary artery bypass grafting. At baseline, 330 patients (11%) had diabetes mellitus, and 293 patients (9%) had an impaired fasting blood glucose level (IFG). During 6.2 years of follow-up, diabetes mellitus developed in 186 patients (6%), IFG developed in 366 patients (12%), and 62% of patients remained with normal fasting glucose levels (NFG). Patients with diabetes mellitus and IFG both at baseline or developing during follow-up had a significantly higher rate of secondary end points than paients with NFG (P <.0001). Bezafibrate treatment reduced secondary end points only in patients with NFG (P =.04). CONCLUSION: Diabetes mellitus and IFG were common in the BIP study and were predictive of a worse clinical outcome that was not attenuated with bezafibrate treatment.

[Drug related taste disturbances: emphasis on the elderly].

BACKGROUND: Taste disturbances are common among the elderly due to physiologic changes, diseases, and medications. As many as 11% of elderly persons using multiple drugs report taste aberrations. The main danger of taste decline and disturbance in the old is food-anhedonia, causing loss of body weight via decreased calorie and nutrient intake. GOALS: To overview drug related taste disturbances emphasizing the elderly. METHODS: Review of Hebrew and English medical literature. RESULTS: Taste-disturbances can be divided into hypogeusia [diminished sense of taste], ageusia [absence of taste], and the 2 types of dysgeusia [taste distortion]: aliageusia [food related] and phantogeusia [taste illusions]. The mechanisms by which drugs impair taste are numerous, and may be related to drug chemical structure. The treatment of taste disturbances is empiric and has limited success. Treatments include: shifting drugs within the same class, zinc replacement (proven to enhance taste sensation for sweet, bitter and salty flavors), palliative measures (use of mints, sugarless chewing-gums, and bicarbonate mouthwashes), niacin and vitamin A ameliorate hypo and dysgeusia. CONCLUSIONS: Disturbed taste sensation is common among the elderly, and should be considered whenever unexplained nutritional decline is present. Scrupulous drug screening is mandatory, and other intervention modalities can be beneficial.