Bayesian Complex Innovative Trial Designs (CIDs) and Their Use in Drug Development for Rare Disease.

As the temporal, financial, and ethical cost of randomized clinical trials (RCTs) continues to rise, researchers and regulators in drug discovery and development face increasing pressure to make better use of existing data sources. This pressure is especially high in rare disease, where traditionally designed RCTs are often infeasible due to the inability to recruit enough patients or the unwillingness of patients or trial leaders to randomly assign anyone to placebo. Bayesian statistical methods have recently been recommended in such settings for their ability to combine disparate data sources, increasing overall study power. The use of these methods has received a boost in the United States thanks to a new willingness by regulators at the Food and Drug Administration to consider complex innovative trial designs. These designs allow trialists to change the nature of the trial (eg, stop early for success or futility, drop an underperforming trial arm, incorporate data on historical controls, etc) while it is still running. In this article, we review a broad collection of Bayesian techniques useful in rare disease research, indicating the benefits and risks associated with each. We begin with relatively innocuous methods for combining information from RCTs and proceed on through increasingly innovative approaches that borrow strength from increasingly heterogeneous and less carefully curated data sources. We also offer 2 examples from the very recent literature illustrating how clinical pharmacology principles can make important contributions to such designs, confirming the interdisciplinary nature of this work.

Impact of a new levonorgestrel intrauterine system, Levosert(®), on heavy menstrual bleeding: results of a one-year randomised controlled trial.

OBJECTIVE: To evaluate a new levonorgestrel-releasing intrauterine system (LNG-IUS) called Levosert(®) for the treatment of heavy menstrual bleeding (HMB) in comparison to the reference product Mirena(®). METHODS: A multicentre, randomised, controlled trial, in non-menopausal women diagnosed with functional HMB (defined as menstrual blood loss [MBL] ≥ 80 mL) randomised to either Levosert(®) or Mirena(®) and followed for up to one year. MBL was evaluated using a validated modified version of the Wyatt pictogram. RESULTS: A total of 280 women were randomised (141 to Levosert(®) and 139 to Mirena(®)). During the one-year treatment period, both Levosert(®) and Mirena(®) dramatically decreased MBL and increased haemoglobin and ferritin levels. There were no statistically significant differences between Levosert(®) and Mirena(®) regarding any of the parameters evaluated during the study. Similar bleeding patterns were observed in both groups. Levosert(®) was inserted with the same ease as Mirena(®). Both treatments were associated with identical expulsion rates and no perforations occurred in either treatment group. CONCLUSION: Levosert(®), a new LNG-IUS designed to release the same daily amount of LNG as Mirena(®), is highly effective in the treatment of HMB. No differences were observed between Levosert(®) and Mirena(®) regarding all evaluated outcomes, including safety profile.

Systemic bioavailability of topical diclofenac sodium gel 1% versus oral diclofenac sodium in healthy volunteers.

Systemic bioavailability and pharmacodynamics of topical diclofenac sodium gel 1% were compared with those of oral diclofenac sodium 50-mg tablets. In a randomized, 3-way crossover study, healthy volunteers (n = 40) received three 7-day diclofenac regimens: (A) 16 g gel applied as 4 g to 1 knee 4 times daily (4 g on surface area 400 cm(2)), (B) 48 g gel applied as 4 g per knee 4 times daily to 2 knees plus 2 g gel per hand applied 4 times daily to 2 hands (12 g on 1200 cm(2)), and (C) 150 mg oral diclofenac applied as 50-mg tablets 3 times daily. Thirty-nine participants completed all 3 regimens. Systemic exposure was greater with oral diclofenac (AUC(0-24), 3890 +/- 1710 ng x h/mL) than with topical treatments A (AUC(0-24), 233 +/- 128 ng x h/mL) and B (AUC(0-24), 807 +/- 478 ng x h/mL). Oral diclofenac inhibited platelet aggregation, cyclooxygenase-1 (COX-1), and COX-2. Topical diclofenac did not inhibit platelet aggregation and inhibited COX-1 and COX-2 less than oral diclofenac. Treatment-related adverse events were mild and limited to application site reactions with diclofenac sodium gel 1% (n = 4) and gastrointestinal reactions with oral diclofenac (n = 3). Systemic exposure with diclofenac sodium gel 1% was 5- to 17-fold lower than with oral diclofenac. Systemic effects with topical diclofenac were less pronounced.

Systemic exposure and implications for lung deposition with an extra-fine hydrofluoroalkane beclometasone dipropionate/formoterol fixed combination.

BACKGROUND AND OBJECTIVES: Foster is a fixed combination of beclometasone dipropionate/formoterol (BDP/F). It is formulated as an extra-fine solution and delivered via a pressurized metered-dose inhaler (pMDI) using a hydrofluoroalkane (HFA) propellant. The aims of this study were to compare the systemic exposure to BDP, to its active metabolite beclometasone-17-monopropionate (B17MP) and to formoterol after administration of BDP/F versus separate administration of a chlorofluorocarbon (CFC) formulation of BDP and formoterol HFA, and to explore a possible relationship between pharmacokinetic and pharmacodynamic findings. METHODS: In this open-label, crossover, placebo-controlled study, 12 healthy male subjects received a single dose of BDP/F 400 microg/24 microg (four inhalations of Foster BDP/F 100 microg/6 microg), single doses of BDP CFC 1000 microg (four inhalations of Becotide Forte 250 microg) plus formoterol 24 microg (four inhalations of Atimos 6 microg) via separate MDIs, or placebo. Continuous pharmacokinetic variables for BDP, B17MP, formoterol, cortisol and potassium were evaluated. Cardiovascular effects, peak flow measurements and tolerability were also examined. RESULTS: Exposure to BDP was not significantly different between active treatment arms, but lower systemic exposure to B17MP was observed with the fixed combination than with the separate components (area under the plasma concentration-time curve [AUC] from time zero to infinity [AUC(infinity)] 5280 vs 8120 pg.h/mL; p = 0.001). Despite a lower total systemic exposure to B17MP with the fixed combination, B17MP plasma concentrations during the first 30 minutes after administration, indicative of pulmonary absorption, were 86% higher with BDP/F than with the separate components (AUC from 0 to 30 minutes [AUC(30 min)] 353 vs 190 pg x h/mL; p = 0.003). Twenty-four-hour serum cortisol concentrations were significantly higher with BDP/F than with BDP and formoterol administered separately (2.26 vs 1.90 microg x h/mL; p < 0.01). No significant differences in the pharmacokinetic parameters of formoterol and no clinically relevant differences in serum potassium and cardiovascular or spirometric parameters were observed between the treatments. Both active treatments were well tolerated. CONCLUSION: These pharmacokinetic data show that with a BDP dose from Foster that is 2.5 times less than a BDP dose from Becotide Forte, pulmonary absorption is 86% higher; however, systemic exposure is 35% lower, resulting in less cortisol suppression for a similar BDP dosage.

Pharmacokinetic profile of a new controlled-release isosorbide-5-mononitrate 60 mg scored tablet (Monoket Multitab).

The influences of food, tablet splitting, and fractional dosing on the pharmacokinetics of a new controlled-release double-scored tablet containing 60 mg isosorbide-5-mononitrate (Monoket Multitab) were investigated in healthy male volunteers. Food interaction was evaluated after single dose administration under fasted conditions and after a standard high-fat breakfast. The effect of tablet splitting was assessed at steady-state, after 5 days of once daily dosing with the tablet taken intact or trisected. The influence of fractional dosing was assessed after 1 and 6 days of daily regimen of 40 mg in the morning (2/3 of a tablet) and 20 mg in the evening (1/3 of a tablet). The pharmacokinetics of isosorbide-5-mononitrate after taking the tablet intact or in three fragments were very similar with a mere 10% increase of maximum plasma concentration (C(max)) for the latter, while the time to peak (T(max)) decreased from 5 to 4 h and areas under the concentration vs. time curves (AUCs) were virtually unchanged. Morning trough concentration reached 53 and 46 ng/ml, respectively. Administration of the intact tablet after a high-fat breakfast increased C(max) by 18% and AUC by 21%, and slightly delayed T(max) from 5 to 6h. During fractional dosing, morning and evening C(max) reached 364 and 315 ng/ml on the first day, and 373 and 300 ng/ml on the 6th day, respectively. The ratio of AUC(0-24 h) on the last day to AUC(infinity) on the first day, was 82.1% (confidence limits 71.7-94.1%) possibly resulting from peripheral volume expansion. The release characteristics of Monoket Multitab are thus moderately influenced by concomitant intake of food and to a very minor extent by tablet breaking. Fractional dosing allows to achieve lower peak and higher morning trough levels, while total exposure is comparable to that during once daily dosing (AUC(0-24 h, s.s.) of 5.55+/-1.78 and 5.71+/-1.08 microg h/ml).