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We conclude that the regressive nature of the GDUFA fee structure penalizes small, new, and foreign firms while benefiting the large established firms. A progressive fee structure in line with other human drug user fees is needed to ensure a healthy generic drug industry.

In a randomised, double-blind, 3-way cross-over trial, the incidence of nausea associated with 2 doxycycline 100 mg formulations (Doryx' and Vibramycin') were compared. The original study cohort comprised 103 healthy male volunteers, with 97 subjects completing the trial. Subjects were randomly allocated to 1 of 3 treatment sequences and received a single dose of Doryx', Vibramycin' or placebo, with a 7-day washout prior to cross-over. At half-hourly intervals, from 0 to 2 h post-dose, subjects completed questionnaires to indicate if they felt nauseous. Data were analysed according to a log-linear method for the analysis of cross-over trials with categorical responses. Seventeen, 29 and 11 subjects experienced nausea with Doryx', Vibramycin' and placebo, respectively. A significantly greater number of volunteers indicated a positive response with Vibramycin' vs Doryx' and vs placebo; the positive response frequency was not significantly different for the Doryx' vs the placebo regimen. Treatment sequence had no significant effect on response, although a marked first-dose effect was noted; the first (vs the second and vs the third) regimen was 1.5-2 times more likely to induce a positive response.

Eighteen healthy, non-smoking, adult volunteers participated in single and multiple dose three-way crossover studies to evaluate a sustained-release, pellet-filled capsule of theophylline, Austyn. The effect of food on the bioavailability of the sustained-release capsule was investigated by administering 300 mg single doses of Austyn, with a high-fat meal and without food and a divided 300 mg dose of the reference product Elixophyllin elixir, given after fasting. Plasma theophylline concentrations were measured by fluorescence polarization immunoassay (FPIA) which had been validated against HPLC. The single dose study data showed that there were no significant differences (n = 18, ANOVA, p greater than 0.05) between the three regimens with respect to AUC0-infinity values (mg h l-1), (mean +/- SD); Elixophyllin fasting = 97.1 +/- 33.7, Austyn with food = 90.9 +/- 31.3, Austyn fasting = 91.2 +/- 33.8. Similarly, multiple dosing with rapid-release Nuelin tablets, Austyn capsules, and sustained-release Theo-Dur tablets demonstrated that there were no significant differences between regimens with respect to AUC0-24h, AUC0-12h, and AUC12-24h values calculated from the steady-state concentrations (5th day, 24 h sampling). However, the percentage fluctuation at steady-state over the total blood sampling period was significantly less for treatment with the sustained-release capsule. Austyn, compared with the sustained-release tablet, Theo-Dur (Austyn = 36.7 +/- 13.7 per cent, Theo-Dur = 53.1 +/- 14.1 per cent). The results of the single and multiple dose studies indicate that Austyn capsules demonstrate complete bioavailability, and good controlled release characteristics not influenced by concomitant intake of a high-fat meal and with no evidence of dose dumping.

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