Generic-reference and generic-generic bioequivalence of forty-two, randomly-selected, on-market generic products of fourteen immediate-release oral drugs.

BACKGROUND: The extents of generic-reference and generic-generic average bioequivalence and intra-subject variation of on-market drug products have not been prospectively studied on a large scale. METHODS: We assessed bioequivalence of 42 generic products of 14 immediate-release oral drugs with the highest number of generic products on the Saudi market. We conducted 14 four-sequence, randomized, crossover studies on the reference and three randomly-selected generic products of amlodipine, amoxicillin, atenolol, cephalexin, ciprofloxacin, clarithromycin, diclofenac, ibuprofen, fluconazole, metformin, metronidazole, paracetamol, omeprazole, and ranitidine. Geometric mean ratios of maximum concentration (Cmax) and area-under-the-concentration-time-curve, to last measured concentration (AUCT), extrapolated to infinity (AUCI), or truncated to Cmax time of reference product (AUCReftmax) were calculated using non-compartmental method and their 90% confidence intervals (CI) were compared to the 80.00%-125.00% bioequivalence range. Percentages of individual ratios falling outside the ±25% range were also determined. RESULTS: Mean (SD) age and body-mass-index of 700 healthy volunteers (28-80/study) were 32.2 (6.2) years and 24.4 (3.2) kg/m2, respectively. In 42 generic-reference comparisons, 100% of AUCT and AUCI CIs showed bioequivalence, 9.5% of Cmax CIs barely failed to show bioequivalence, and 66.7% of AUCReftmax CIs failed to show bioequivalence/showed bioinequivalence. Adjusting for 6 comparisons, 2.4% of AUCT and AUCI CIs and 21.4% of Cmax CIs failed to show bioequivalence. In 42 generic-generic comparisons, 2.4% of AUCT, AUCI, and Cmax CIs failed to show bioequivalence, and 66.7% of AUCReftmax CIs failed to show bioequivalence/showed bioinequivalence. Adjusting for 6 comparisons, 2.4% of AUCT and AUCI CIs and 14.3% of Cmax CIs failed to show bioequivalence. Average geometric mean ratio deviation from 100% was ≤3.2 and ≤5.4 percentage points for AUCI and Cmax, respectively, in both generic-reference and generic-generic comparisons. Individual generic/reference and generic/generic ratios, respectively, were within the ±25% range in >75% of individuals in 79% and 71% of the 14 drugs for AUCT and 36% and 29% for Cmax. CONCLUSIONS: On-market generic drug products continue to be reference-bioequivalent and are bioequivalent to each other based on AUCT, AUCI, and Cmax but not AUCReftmax. Average deviation of geometric mean ratios and intra-subject variations are similar between reference-generic and generic-generic comparisons. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01344070 (registered April 3, 2011).

Drug*placebo interaction effect may bias clinical trials interpretation: hybrid balanced placebo and randomized placebo-controlled design.

BACKGROUND: Conventional randomized placebo-controlled study design assumes the absence of drug*placebo interaction. We hypothesized the presence of such an interaction and that conventionally estimated drug effect might be biased. The objectives of the study were to determine the drug*placebo interaction effect (main) and compare conventionally estimated and interaction model-estimated drug effects (secondary). METHODS: We used a hybrid of balanced placebo and randomized placebo-controlled designs. Four hundred eighty healthy volunteers were randomized to three groups. The first received hydroxyzine (25 mg) described as hydroxyzine or placebo, the second received placebo described as hydroxyzine or placebo, and the third received hydroxyzine and placebo described as unknown; each in a randomized crossover design. Seven participants failed to crossover. Group assignment was concealed from participants and study coordinators. Coordinators were blinded to group and intervention assignment. Participants and coordinators were deceived as to study objectives. Main outcomes were mean area-under-the-curve of drowsiness (therapeutic outcome) and mouth-dryness (adverse outcome), self-reported on 100 mm visual analog scale over 7 h. Drug, placebo, placebo + interaction, and total effects were estimated using analysis of covariance by comparing received hydroxyzine/told placebo to received placebo/told placebo, received placebo/told hydroxyzine to received placebo/told placebo, received hydroxyzine/told hydroxyzine to received hydroxyzine/told placebo, and received hydroxyzine/told hydroxyzine to received placebo/told placebo, respectively. Drug effect was also conventionally estimated in the third group. RESULTS: Mean (SD) age was 31.4 (6.6) years, 65% were males. There was significant difference between placebo + interaction effect and placebo effect for both drowsiness and mouth-dryness with a mean difference (95% confidence interval) of 35.1 (5.6 to 64.6) and 23.8 (2.4 to 45.2) mm*hr, respectively. Total effect was larger than the sum of drug and placebo effects for drowsiness (139.7 (109.8 to 169.6) vs. 99.1 (68.2 to 130.0) mm*hr) and mouth-dryness (63.6 (41.1 to 86.1) vs. 34.7 (11.1 to 58.4) mm*hr). Conventionally estimated drug effect was larger than interaction model-estimated drug effect for drowsiness (69.2 (45.5 to 92.8) vs. (58.3 (31.6 to 85.0) mm*hr) and mouth-dryness (19.9 (5.3 to 34.5) vs. 9.5 (-9.2 to 28.1) mm*hr). CONCLUSIONS: There is significant and important drug*placebo interaction effect that may bias conventionally estimated drug effect. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT01501591 (registered December 25, 2011).

Exploring end of life priorities in Saudi males: usefulness of Q-methodology.

BACKGROUND: Quality end-of-life care depends on understanding patients' end-of-life choices. Individuals and cultures may hold end-of-life priorities at different hierarchy. Forced ranking rather than independent rating, and by-person factor analysis rather than averaging may reveal otherwise masked typologies. METHODS: We explored Saudi males' forced-ranked, end-of-life priorities and dis-priorities. Respondents (n = 120) rank-ordered 47 opinion statements on end-of-life care following a 9-category symmetrical distribution. Statements' scores were analyzed by averaging analysis and factor analysis (Q-methodology). RESULTS: Respondents' mean age was 32.1 years (range, 18-65); 52% reported average religiosity, 88 and 83% ≥ very good health and life-quality, respectively, and 100% ≥ high school education. Averaging analysis revealed that the extreme five end-of-life priorities were to, be at peace with God, be able to say the statement of faith, maintain dignity, resolve conflicts, and have religious death rituals respected, respectively. The extreme five dis-priorities were to, die in the hospital, not receive intensive care if in coma, die at peak of life, be informed about impending death by family/friends rather than doctor, and keep medical status confidential from family/friends, respectively. Q-methodology classified 67% of respondents into five highly transcendent opinion types. Type-I (rituals-averse, family-caring, monitoring-coping, life-quality-concerned) and Type-V (rituals-apt, family-centered, neutral-coping, life-quantity-concerned) reported the lowest and highest religiosity, respectively. Type-II (rituals-apt, family-dependent, monitoring-coping, life-quantity-concerned) and Type-III (rituals-silent, self/family-neutral, avoidance-coping, life-quality & quantity-concerned) reported the best and worst life-quality, respectively. Type-I respondents were the oldest with the lowest general health, in contrast to Type-IV (rituals-apt, self-centered, monitoring-coping, life-quality/quantity-neutral). Of the extreme 14 priorities/dis-priorities for the five types, 29, 14, 14, 50, and 36%, respectively, were not among the extreme 20 priorities/dis-priorities identified by averaging analysis for the entire cohort. CONCLUSIONS: 1) Transcendence was the extreme end-of-life priority, and dying in the hospital was the extreme dis-priority. 2) Quality of life was conceptualized differently with less emphasize on its physiological aspects. 3) Disclosure of terminal illness to family/close friends was preferred as long it is through the patient. 4) Q-methodology identified five types of constellations of end-of-life priorities and dis-priorities that may be related to respondents' demographics and are partially masked by averaging analysis.

Patients' perceived purpose of clinical informed consent: Mill's individual autonomy model is preferred.

BACKGROUND: Although informed consent is an integral part of clinical practice, its current doctrine remains mostly a matter of law and mainstream ethics rather than empirical research. There are scarce empirical data on patients' perceived purpose of informed consent, which may include administrative routine/courtesy gesture, simple honest permission, informed permission, patient-clinician shared decision-making, and enabling patient's self decision-making. Different purposes require different processes. METHODS: We surveyed 488 adults who were planning to undergo or had recently undergone written informed consent-requiring procedures. Perceptions of informed consent purpose (from norm and current practice perspectives) were explored by asking respondents to rank (1 = most reflective) 10 randomly-presented statements: "meaningless routine", "courtesy gesture" "litigation protection", "take away compensation rights", "inform patient', "make sure patient understand", "document patient's decision", "discover patient's preferences", "have shared decision", and "help patient decide". RESULTS: Respondents' mean (SD) age was 38.3 (12.5); 50.4% were males, 56.8% had ≥ college education, and 37.3% had undergone a procedure. From the norm perspective, the least reflective statement was "meaningless routine" (ranked 1-3 by 2.6% of respondents) and the most reflective statements were "help patient decide", "make sure patient understand", and "inform patient" (ranked 1-3 by 65%, 60%, and 48% of respondents with median [25%,75%] ranking scores of 2 [1,5], 3 [2,4], and 4 [2,5], respectively). Compared to their counterparts, males and pre-procedure respondents ranked "help patient decide" better, whereas females and post-procedure respondents ranked "inform patient" better (p = 0.007 to p < 0.001). Age was associated with better ranking of "help patient decide" and "make sure patient understand" statements (p < 0.001 and p = 0.002, respectively), which were ranked 1-3 by only 46% and 42% of respondents from the current practice perspective (median ranking score 4 [2,6], p < 0.001 vs. norm perspective for both). CONCLUSIONS: 1) the informed consent process is important to patients, however, patients vary in their views of its purpose with the dominant view being enabling patients' self decision-making, 2) males, pre-procedure, and older patients more favor a self decision-making purpose, whereas females and post-procedure patients more favor an information disclosure purpose, and 3) more self decision-making and more effective information disclosure than is currently practiced are desired. An informed consent process consistent with Mill's individual autonomy model may be suitable for most patients.

Consenting options for posthumous organ donation: presumed consent and incentives are not favored.

BACKGROUND: Posthumous organ procurement is hindered by the consenting process. Several consenting systems have been proposed. There is limited information on public relative attitudes towards various consenting systems, especially in Middle Eastern/Islamic countries. METHODS: We surveyed 698 Saudi Adults attending outpatient clinics at a tertiary care hospital. Preference and perception of norm regarding consenting options for posthumous organ donation were explored. Participants ranked (1, most agreeable) the following, randomly-presented, options from 1 to 11: no-organ-donation, presumed consent, informed consent by donor-only, informed consent by donor-or-surrogate, and mandatory choice; the last three options ± medical or financial incentive. RESULTS: Mean(SD) age was 32(9) year, 27% were males, 50% were patients' companions, 60% had ≥ college education, and 20% and 32%, respectively, knew an organ donor or recipient. Mandated choice was among the top three choices for preference of 54% of respondents, with an overall median[25%,75%] ranking score of 3[2,6], and was preferred over donor-or-surrogate informed consent (4[2,7], p < 0.001), donor-only informed consent (5[3,7], p < 0.001), and presumed consent (7[3,10], p < 0.001). The addition of a financial or medical incentive, respectively, reduced ranking of mandated choice to 7[4,9], p < 0.001, and 5[3,8], p < 0.001; for donor-or-surrogate informed consent to 7[5,9], p < 0.001, and 5[3,7], p = 0.004; and for donor-only informed consent to 8[6,10], p < 0.001, and 5[3,7], p = 0.56. Distribution of ranking score of perception of norm and preference were similar except for no-organ donation (11[7,11] vs. 11[6,11], respectively, p = 0.002). Compared to females, males more perceived donor-or-surrogate informed consent as the norm (3[1,6] vs. 5[3,7], p < 0.001), more preferred mandated choice with financial incentive option (6[3,8] vs. 8[4,9], p < 0.001), and less preferred mandated choice with medical incentive option (7[4,9] vs. 5[2,7], p < 0.001). There was no association between consenting options ranking scores and age, health status, education level, or knowing an organ donor or recipient. CONCLUSIONS: We conclude that: 1) most respondents were in favor of posthumous organ donation, 2) mandated choice system was the most preferred and presumed consent system was the least preferred, 3) there was no difference between preference and perception of norm in consenting systems ranking, and 4) financial (especially in females) and medical (especially in males) incentives reduced preference.

Interaction between drug and placebo effects: a cross-over balanced placebo design trial.

BACKGROUND: The total effect of a medication is the sum of its drug effect, placebo effect (meaning response), and their possible interaction. Current interpretation of clinical trials' results assumes no interaction. Demonstrating such an interaction has been difficult due to lack of an appropriate study design. METHODS: 180 adults were randomized to caffeine (300 mg) or placebo groups. Each group received the assigned intervention described by the investigators as caffeine or placebo, in a randomized crossover design. 4-hour-area-under-the-curve of energy, sleepiness, nausea (on 100 mm visual analog scales), and systolic blood pressure levels as well as caffeine pharmacokinetics (in 22 volunteers nested in the caffeine group) were determined. Caffeine drug, placebo, placebo-plus-interaction, and total effects were estimated by comparing outcomes after, receiving caffeine described as placebo to receiving placebo described as placebo, receiving placebo described as caffeine or placebo, receiving caffeine described as caffeine or placebo, and receiving caffeine described as caffeine to receiving placebo described as placebo, respectively. RESULTS: The placebo effect on area-under-the-curve of energy (mean difference) and sleepiness (geometric mean ratio) was larger than placebo-plus-interaction effect (16.6 [95% CI, 4.1 to 29.0] vs. 8.4 [-4.2 to 21.0] mm*hr and 0.58 [0.39 to 0.86] vs. 0.69 [0.49 to 0.97], respectively), similar in size to drug effect (20.8 [3.8 to 37.8] mm*hr and 0.49 [0.30 to 0.91], respectively), and its combination with the later was larger than total caffeine effect (29.5 [11.9 to 47.1] mm*hr and 0.37 [0.22 to 0.64]). Placebo-plus-interaction effect increased caffeine terminal half-life by 0.40 [0.12 to 0.68] hr (P=0.007). CONCLUSIONS: Drug and placebo effects of a medication may be less than additive, which influences the interpretation of clinical trials. The placebo effect may increase active drug terminal half-life, a novel mechanism of placebo action. TRIAL REGISTRATION: ClinicalTrials.gov identification number - NCT00426010.

Saudi views on consenting for research on medical records and leftover tissue samples.

BACKGROUND: Consenting for retrospective medical records-based research (MR) and leftover tissue-based research (TR) continues to be controversial. Our objective was to survey Saudis attending outpatient clinics at a tertiary care hospital on their personal preference and perceptions of norm and current practice in relation to consenting for MR and TR. METHODS: We surveyed 528 Saudis attending clinics at a tertiary care hospital in Saudi Arabia to explore their preferences and perceptions of norm and current practice. The respondents selected one of 7 options from each of 6 questionnaires. RESULTS: Respondents' mean (SD) age was 33 (11) years, 42% were males, 56% were patients, 84% had ≥ secondary school education, and 10% had previously volunteered for research. Respectively, 40% and 49% perceived that the norm is to conduct MR and TR without consent and 38% and 37% with general or proposal-specific consent; the rest objected to such research. There was significant difference in the distribution of choices according to health status (patients vs. companions) for MR (adjusted Kruskal-Wallis test P = 0.03) but not to age group, gender, education level, or previous participation in research (unadjusted P = 0.02 - 0.59). The distributions of perceptions of current practice and norm were similar (unadjusted Marginal Homogeneity test P = 0.44 for MR and P = 0.89 for TR), whereas the distributions of preferences and perceptions of norm were different (adjusted P = 0.09 for MR and P = 0.02 for TR). The distributions of perceptions of norm, preferences, and perceptions of current practice for MR were significantly different from those of TR (adjusted P < 0.009 for all). CONCLUSIONS: We conclude that: 1) there is a considerable diversity among Saudi views regarding consenting for retrospective research which may be related to health status, 2) the distribution of perceptions of norm was similar to the distribution of perceptions of current practice but different from that of preferences, and 3) MR and TR are perceived differently in regard to consenting.

Bioeqivalence assessment of two domperidone 1 tablet formulations.

A randomized, single-dose, crossover study was conducted to assess the bioavailability of two domperidone (CAS 57808-66-9) tablet formulations, Domperidone (test) and a commercially available original preparation (reference) under fasting conditions. A 10 mg dose of each formulation was administered to 36 healthy male volunteers with a one-week washout period, 17 blood samples were collected over 48 h, plasma concentrations of domperidone were analyzed by a locally validated LC-MS-MS assay, and the pharmacokinetic parameters were determined by the standard non-compartmental method. Mean +/- SD maximum concentration (C(max)), time to reach maximum concentration (T(max)), areas under the curve (AUC(0 --> t and AUC(0 --> infininty)), and elimination constant (K(el)) were 17.13 +/- 9.62 and 17.67 +/- 7.97 ng/ml, 0.87 +/- 0.58, and 0.89 +/- 0.33 h, 73.12 +/- 43.37 and 71.45 +/- 35.41 ng x h/ml, 90.32 +/- 48.55 and 87.08 +/- 40.29 ng x h/ml, and 0.069 +/- 0.046 and 0.068 +/- 0.048 h(-1) for the test and reference formulation, respectively. The parametric 90% confidence intervals on the mean difference between log-transformed values of the two formulations were within the acceptable bioequivalence range for AUC(0 --> t) (87.84% to 109.60%), AUC(0 --> infinity) (89.05% to 111.67%) and C(max) (83.28% to 107.50%). ANOVA revealed significant subject's effect for AU4C(0 --> t), AUC((0 -->infinity), C(max), and t1/2 with a ratio of the inter-subject to intra-subject coefficient of variation of 2.10, 1.55, 1.10, and 1.02, respectively. The results indicate that the two formulations are equivalent in relation to the extent and rate of absorption and confirm the previously reported marked intra-individual variations in the pharmacokinetics of domperidone.

Bioequivalence evaluation of two rosiglitazone tablet formulations.

A randomized, two-period, two-sequence, crossover study was conducted on 28 healthy male volunteers to compare the bioavailability of two rosiglita-zone (CAS 122320-73-4) tablet formulations, a test and a commercially available original preparation (reference), under fasting conditions. The two preparations were given in a dose of 8 mg with a 7-day washout period between the two preparations. Eighteen blood samples were collected over 24 h, plasma rosiglitazone concentrations were determined by locally validated high performance liquid chromatography (HPLC) assay, and pharmacokinetic parameters were analyzed by the standard non-compartmental method. The mean+/-SD of AUC0-->t, AUC0-->infinity, Cmax, Tmax, and t1/2 were 4.80+/-1.89 and 4.76 +/-1.94 microg x h/ml, 5.17+/-2.11 and 5.08 +/- 2.27 microg x h/ml, 0.93+/-0.24 and 0.99+/-0.34 microg/ml, 1.0 +/-0.4 and 0.8+/-0.5 h, and 5.0+/-2.0 and 5.0+/-2.0 h for the test and reference formulation, respectively. ANOVA did not show significant formulation, period, or sequence effect for any of the pharmacokinetic parameters. The 90 % confidence intervals of the mean differences between log-transformed values of the two formulations were 93.09 % to 109.73 %, 94.04 % to 111.70 %, and 89.70 % to 103.24 % for AUC0-->t, AUC-->infinity, and Cmax, respectively. It is concluded that the two formulations are equivalent in relation to the rate and extent of absorption.

Bioequivalence evaluation of two formulations of fluconazole 150 mg capsule in healthy Arab men.

A randomized crossover study was conducted on 26 healthy Arab males to compare the bioavailability of two formulations of fluconazole 150 mg capsules, Fluconazole (test) and Diflucan (reference). The formulations were administered after an overnight fast with a washout period of 2 weeks. Twenty blood samples (per period) were collected over 168 h, plasma fluconazole concentrations were determined by locally validated high performance liquid chromatography (HPLC) assay and pharmacokinetic parameters were analysed by the standard non-compartmental method. The mean +/- SD maximum concentration (C(max)), time to reach maximum concentration (T(max)), area under the curve (AUC(0-->t) and AUC(0-->infinity)) and elimination half-life (t(1/2)) were 3.17+/-0.47 and 3.24+/-0.59 microg/ml, 2.62+/-2.01 and 2.65+/-1.63 h, 149.52+/-29.49 and 151.36+/-25.84 microg.h/ml, 163.57+/-29.9 and 164.89+/-26.46 microg.h/ml, and 36.81+/-5.72 and 36.56+/-5.36 h for the test and reference drug, respectively. These values are similar to previously reported values in other ethnic groups. The parametric 90% confidence intervals on the mean of the difference (test-reference) between the log-transformed values of the two formulations were 95.484% to 101.035%, 96.382% to 101.245% and 94.621% to 102.074% for AUC(0-->t), AUC(0-->infinity) and C(max), respectively. The results indicate that the two formulations are equivalent in the rate and extent of absorption. Further, a review of the literature indicates that there is no apparent ethnic variation in the absorption and elimination rates of fluconazole.

Bioequivalence of two oral formulations of nizatidine capsules in healthy male volunteers.

PURPOSE: The purpose of this randomized, crossover study was to compare the bioavailability of a generic and an innovator formulation of nizatidine 300 mg capsules under fasting conditions. METHODS: Twenty blood samples per period were collected from 20 healthy, Arab male volunteers over 16 h, plasma nizatidine concentrations were determined by HPLC assay, and pharmacokinetic parameters were determined by the non-compartmental method. RESULTS: Mean+/-SD C(max), T(max), AUC(0-->t), AUC(0-->infinity), and t1/2 were 2.96+/-0.54 and 3.28+/-0.68 microg/ml, 1.31+/-0.70 and 0.93+/-0.38 h, 9.04+/-1.66 and 9.03+/-1.94 microg x h/ml, 9.17+/-1.64 and 9.12+/-1.94 microg x h/ml, and 1.64+/-0.21 and 1.58+/-0.22 h for the generic and innovator formulation, respectively. The parametric 90% confidence intervals on the mean of the difference between log-transformed values were 98.06% to 103.21%, 98.74% to 103.71%, and 83.37% to 101.34%, for AUC(0-->t), AUC(0-->infinity), and C(max), respectively. CONCLUSION: The results indicate that these two formulations are equivalent in the rate and extent of absorption.