Pre-ANDA strategy and Human Factors activities to de-risk pharmaceutical companies ANDA submission of drug-device combination products: case study of a formative Comparative Use Human Factors study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

The Clinical Significance of Fibrin Monomers.

INTRODUCTION: Fibrin monomer (FM) concentrations reflect pro-thrombin activity and have the potential to predict thrombotic events relatively earlier than other haemostatic markers. Most often, FM are compared with D-dimer (DD) as increased DD have been documented in disseminated intravascular coagulation (DIC), deep vein thrombosis (DVT) and pulmonary embolism. Although DD have a high sensitivity and negative predictive value, their specificity is much lower depending on the assay chosen, clinical pre-test probability and patient condition. There are limited reports investigating the utility of FM in hyper-coagulable patients. METHODS: We performed a literature search of FM concentrations in hyper-coagulable patients including those with DIC, acute ischaemic stroke, atrial fibrillation, acute myocardial infarction, venous thromboembolism (VTE) and cancer, as well as those who are pregnant or undergoing surgery. RESULTS: FM were increased in patients with DIC and those with malignancy. In contrast, detection of VTE or post-operative DVT development is likely enhanced using both FM and DD concentrations. Similarly, measuring FM concentrations with other biomarker levels may be more beneficial in patients suffering an acute myocardial infarction or acute ischaemic stroke. Lastly, FM concentrations vary substantially throughout pregnancy with no definitive role of FM as of yet. CONCLUSION: Utilizing FM concentrations to assess hyper-coagulable patients seems promising; however, there are limitations including variations in FM cut-off values, the effect of patient medications and the timing of FM measurement relative to an acute event. Thus, further investigation is required before a true advantage for FM as a haemostatic marker can be established.