UNASSIGNED: This article presents a strategy that a Drug Delivery Device Developer (DDDD) has adopted to support Abbreviated New Drug Application (ANDA) submissions of drug-device combination products. As per the related FDA guidance, a threshold analysis should be compiled. If \'other differences\' between the Reference Listed Drug (RLD) and the generic drug devices are identified, a Comparative Use Human Factors (CUHF) study may be requested.
UNASSIGNED: The DDDD performed task analysis and physical comparison to assess the pen injector design differences. Then, a formative CUHF study with 25 participants simulating injections using both RLD and the generic pen injectors was conducted.
UNASSIGNED: After each participant completed four simulated injections, similar type and rates of use error between the RLD (0.70) and generic (0.68) pen injectors were observed.
UNASSIGNED: DDDDs can support pharmaceutical companies in the ANDA submission strategy of their drug-device combination product by initiating comparative task analysis and physical comparison of the device as inputs for the threshold analysis. If \'other differences\' are identified, a formative CUHF study can be performed. As shown in our case study, this approach can be leveraged to support the sample size calculation and non-inferiority margin determination for a CUHF study with the final combination product.

Development of generic extended-release (ER) formulations is challenging. Especially under fed conditions, the risk of failure in bioequivalence trials is high because of long gastric residence times and susceptibility to food effects. We describe the development of a generic trazodone ER formulation that was aided with a biorelevant dissolution evaluation. Trazodone hydrochloride 300-mg monolithic matrix tablets were dissolved both in USP and EMA compliant conditions and in the StressTest device that simulated both physicochemical and mechanical conditions of the gastrointestinal passage. The final formulation was tested against the originator, Trittico XR 300 mg, in a randomized cross-over bioequivalence trial with 44 healthy volunteers, in agreement with EMA guidelines. Initially developed formulations dissolved trazodone similarly to the originator under standard conditions (f2 factor above 50), but their dissolution kinetics differed significantly in the biorelevant tests. The formulation was optimized by the addition of low-viscosity hypromellose and mannitol. The final formulation was approved for the bioequivalence trial. Calculated Cmax were 1.92 ± 0.77 and 1.92 ± 0.63 [μg/mL], AUC0-t were 27.46 ± 8.39 and 29.96 ± 9.09 [μg∙h/mL], and AUC0-∞ were 28.22 ± 8.91 and 30.82 ± 9.41 [μg∙h/mL] for the originator and test formulations, respectively. The 90% confidence intervals of all primary pharmacokinetic parameters fell within the 80-125% range. In summary, biorelevant dissolution tests supported successful development of a generic trazodone ER formulation pharmaceutically equivalent with the originator under fed conditions. Employment of biorelevant dissolution tests may decrease the risk of failure in bioequivalence trials of ER formulations.

BACKGROUND: Official drug prices have been set by the government and revised every other year in Japan. However, most drug prices are revised based on the price divergence rate of official and delivery prices every other year. This paper overviews how the drug price revision process works and reveals factors associated with price cutting, based on the price divergence rate.
METHODS: Drugs approved as new molecular entities from 2005 to 2014 were selected for price cutting analysis, based on the price divergence rate. Logistic regression assessed the determinants of whether drugs were targeted for price cutting in 2016. Additionally, generic drugs approved from 2009 to 2013 and their off-patent drugs were also analyzed by multiple linear regression analysis to reveal determinants related to price divergence rates.
RESULTS: From the targeted on-patent drugs, 90% were targeted for price revision based on the price divergence rate. Of these drugs, 23% were targeted for price cutting. Drugs whose characteristics are larger sales, lower cost/patient, being followers, and being longer in the market were more likely to be targeted for price cutting. The number of generic manufacturers is directly proportional to the price cutting of both generic and off-patent branded drugs.
CONCLUSIONS: As drug price revision policy is under reconstruction in Japan, the characteristics of drugs targeted for price cutting shown in this study should be considered for establishing drug price revision policies that reflect market conditions adequately.

BACKGROUND: Bioequivalence testing for locally acting gastrointestinal drugs is a challenging issue for both regulatory authorities and pharmaceutical industries. The international regulatory framework has been characterized by the lack of specific bioequivalence tests that has generated a negative impact on the market competition and drug use in clinical practice. Areas covered: This review article provides an overview of the European Union and United States regulatory frameworks on bioequivalence criteria for locally acting gastrointestinal drugs, also discussing the most prominent scientific issues and advances that has been made in this field. A focus on oral modified release mesalamine formulations will be also provided, with practical examples of the regulatory pathways followed by pharmaceutical companies to determine bioequivalence. Expert commentary: The development of a scientific rationale to demonstrate bioequivalence in this field has been complex and often associated with uncertainties related to scientific and regulatory aspects. Only in recent years, thanks to advanced knowledge in this field, the criteria for bioequivalence assessment are undergoing substantial changes. This new scenario will likely result in a significant impact on pharmaceutical companies, promoting more competition through a clearer regulatory approach, conceived for streamlining the demonstration of therapeutic equivalence for locally acting gastrointestinal drugs.

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Generic prescribing is a sound approach to contain health care costs. However, little is known about physicians\' prescribing patterns in the Thai context.
OBJECTIVE: To explore physicians\' generic prescription patterns in district hospitals.
METHODS: Data was collected from three of the eight district hospitals between January and December 2008 (final response rate 37.5%). All participating hospitals were between 30 and 60-bed capacity. The researchers reviewed 10% of total outpatient prescriptions in each hospital.
RESULTS: A total of 14,500 prescriptions were evaluated. The majority of patients were under universal health coverage (4,367; 30.1%), followed by senior citizens\' health insurance (2,734; 18.9%), and civil servant medical benefit schemes (2,419; 16.7%). Ten thousand six hundred and seventy-one prescriptions (73.6% of total prescriptions) had at least one medication. Among these, each prescription contained 2.85 (SD=1.69) items. The majority of prescriptions (7,886; 73.9%) were prescribed by generic name only. Drugs prescribed by brand names varied in their pharmacological actions. They represented both innovator and branded-generic items. Interestingly, a large number of them were fixed-dose combination drugs. All brand name prescriptions were off patented. In addition, none of the brand-name drugs prescribed were categorized as narrow therapeutic range or any other drug that had been reported to have had problems with generic substitution.
CONCLUSIONS: The majority of prescriptions in this sample were written by generic names. There is room for improvement in brand name prescribing patterns.

In 2010/2011, regional commissioners withdrew payment for the fixed-dose combination Combivir, forcing a switch to component drugs. This was deemed clinically acceptable and annual savings of £44 k expected. We estimated the true costs of switching and examined patient outcomes. Information for 46 patients using Combivir was extracted from case notes for each clinical contact in the 12 months pre- and post-switch (clinician seen, tests, antiretrovirals). Post-switch care costs £93/patient more annually versus pre-switch (95% CI £424 to £609), yielding £4278/year more post-switch for all patients. Drug and pathology costs were more expensive post-switch and extra clinical visits required. None of these results were statistically significant. Forty-two per cent of patients switched directly or in the subsequent year to an alternative fixed-dose combination rather than generics. Costs in this group were significantly higher post-switch driven by drug cost. Six patients (13%) reported problems with the switch including confusion around dosing and new side effects. As less-expensive generic antiretroviral drugs become available, it may appear cheaper to switch from fixed-dose combinations to component drugs. However, the additional clinical costs involved may outweigh the initial cost savings of the drugs and switching may cause confusion for some patients, risking loss of adherence.