Background: "Patient experience data" (PED) refers to the systematic collection of meaningful data relating to the experiences, perspectives, needs, and priorities of patients. PED can augment traditional clinical trial data in the FDA's review of product applications. Section 3001 of the 2016 21st Century Cures Act requires the FDA to make a public statement about the PED considered in the approval of a drug application. Here, we present one of the first assessments of PED consideration during drug application approval, as reported by the FDA under Sec. 3001 of the Cures Act. Methods: FDA reported use of PED in the Review Documentation of the 59 new molecular entities (NMEs) approved in 2018 were collected, indexed, and cross-referenced against information regarding FDA review and product regulatory designation. The data reported in the PED tables were quantitatively described and visualized. Results: Of the 59 approved NMEs in 2018, 48 include a table that summarized whether PED was or was not used during the FDA drug review. Thirty-four of those 48 approvals (70.8%) reported using PED in the drug review. Patient-reported outcomes (PROs) represented the most significant source of PED and were used in 60.4% of approved drug reviews. Additional findings, including PED use by FDA review division and by FDA regulatory designation, are described. Conclusions: This assessment is a first step to better understanding how FDA considers PED in regulatory decision making. This analysis should help develop a baseline regarding FDA use of PED and may inform decisions to ensure patients' experiences are adequately heard in future drug development.

Background: "Patient experience data" (PED) refers to the systematic collection of meaningful data relating to the experiences, perspectives, needs, and priorities of patients. PED can augment traditional clinical trial data in the FDA's review of product applications. Section 3001 of the 2016 21st Century Cures Act requires the FDA to make a public statement about the PED considered in the approval of a drug application. Here, we present one of the first assessments of PED consideration during drug application approval, as reported by the FDA under Sec. 3001 of the Cures Act. Methods: FDA reported use of PED in the Review Documentation of the 59 new molecular entities (NMEs) approved in 2018 were collected, indexed, and cross-referenced against information regarding FDA review and product regulatory designation. The data reported in the PED tables were quantitatively described and visualized. Results: Of the 59 approved NMEs in 2018, 48 include a table that summarized whether PED was or was not used during the FDA drug review. Thirty-four of those 48 approvals (70.8%) reported using PED in the drug review. Patient-reported outcomes (PROs) represented the most significant source of PED and were used in 60.4% of approved drug reviews. Additional findings, including PED use by FDA review division and by FDA regulatory designation, are described. Conclusions: This assessment is a first step to better understanding how FDA considers PED in regulatory decision making. This analysis should help develop a baseline regarding FDA use of PED and may inform decisions to ensure patients' experiences are adequately heard in future drug development.

Background: Since 2008, the US Food and Drug Administration (FDA) has required that drug manufacturers conduct postmarket cardiovascular outcomes trials (CVOTs) for approved type 2 diabetes mellitus (T2DM) drugs. The utility and impact of these studies in determining atherosclerotic cardiovascular risk was reviewed during an FDA Advisory Committee Meeting held on October 24, 2018. Drug manufacturers and patient advocates at this meeting contended that the FDA-required CVOT studies discouraged private sector investment into developing novel T2DM drugs. Here, we explore these contentions by reviewing private sector investment in T2DM drug development from 2000 through 2008, followed by a deductive analysis of how associated events-including the implementation of the CVOT requirement-may have precipitated any observed changes. Methods: We collected and analyzed industry-sponsored interventional trials for T2DM initiated between January 1, 2000, and December 31, 2017, and compared observed trends with those seen across all trials, specific diseases, and against patent filings of novel antidiabetic agents. Results: The analysis shows a marked decline in initiated T2DM clinical trials from 2008 through 2017. Possible influencing factors, including the 2008 financial crisis and a slow in the discovery of novel antidiabetic agents may have contributed, but could not fully account for this decline in T2DM studies. Conclusions: These observations are consistent with the statements made by industry representatives and patient advocates at the 2018 Advisory Committee meeting. As the FDA reconsiders postmarket requirements for T2DM products, these observations underscore the importance of considering more efficient postmarket study structures to assess cardiovascular safety beyond mandatory CVOTs.

Background: Since 2008, the US Food and Drug Administration (FDA) has required that drug manufacturers conduct postmarket cardiovascular outcomes trials (CVOTs) for approved type 2 diabetes mellitus (T2DM) drugs. The utility and impact of these studies in determining atherosclerotic cardiovascular risk was reviewed during an FDA Advisory Committee Meeting held on October 24, 2018. Drug manufacturers and patient advocates at this meeting contended that the FDA-required CVOT studies discouraged private sector investment into developing novel T2DM drugs. Here, we explore these contentions by reviewing private sector investment in T2DM drug development from 2000 through 2008, followed by a deductive analysis of how associated events-including the implementation of the CVOT requirement-may have precipitated any observed changes. Methods: We collected and analyzed industry-sponsored interventional trials for T2DM initiated between January 1, 2000, and December 31, 2017, and compared observed trends with those seen across all trials, specific diseases, and against patent filings of novel antidiabetic agents. Results: The analysis shows a marked decline in initiated T2DM clinical trials from 2008 through 2017. Possible influencing factors, including the 2008 financial crisis and a slow in the discovery of novel antidiabetic agents may have contributed, but could not fully account for this decline in T2DM studies. Conclusions: These observations are consistent with the statements made by industry representatives and patient advocates at the 2018 Advisory Committee meeting. As the FDA reconsiders postmarket requirements for T2DM products, these observations underscore the importance of considering more efficient postmarket study structures to assess cardiovascular safety beyond mandatory CVOTs.

Autonomic and sensory nerves containing a variety of neurotransmitters innervate the lungs and control airway diameter. Pulses of electric field stimulation (EFS) cause release of all neurotransmitters where their effects on smooth muscle tone can be measured. The primary neurotransmitter driving airway contraction is acetylcholine (ACh). We therefore developed a pharmacokinetic (PK) model which treats EFS pulses as doses of ACh being administered to the trachea. This PK model builds outward from first principles using computational methods to describe this system. Understanding the functional role of the multiple neurotransmitter systems in the airways may inform the rational use of drugs in the treatment of asthma, COPD, and other airway diseases. We hypothesized that ACh‐induced tracheal contraction caused by electric stimulation of nerves can be modeled using a simple one‐compartment PK model.Isolated tracheal rings from CF‐1 wild‐type mice were exposed to EFS pulses known to activate neurotransmitter release (1.0 ms duration, 80 V, 1–30 Hz). Rings were pre‐treated with 100 μM capsaicin and 10 μM indomethacin to eliminate the effects of sensory nerves and endogenous prostaglandins, respectively. Contractile responses were blocked by the muscarinic ACh receptor antagonist atropine. These responses were modeled using the open‐source R package RxODE. The one‐compartment PK model was fit using three unknown parameters: absorption constant (ka,), elimination constant (ke), and dose.EFS caused atropine‐sensitive contraction, consistent with activation of airways by ACh released from parasympathetic nerves. Iterative solving of the differential equations defined by the model produced best‐fit parameters that accurately described the experimental data. From these data, the model was re‐run using global average values calculated to fit all samples at all frequencies to determine model accuracy (ka = 0.1597 s−1, ke = 0.8242 s−1, dose = 1.5 × 10−6 M). The average error across all samples and frequencies was 23.5 ± 3.87%. Stimulation at 15 Hz had the lowest average error of 5.91 ± 2.23%. A separate model incorporating presynaptic inhibition at muscarinic‐2 receptors and saturation of ACh metabolism had a lower average error 21.7 ± 3.52%, but was not statistically (p > 0.05) different from the simple one‐compartment model.The one‐compartment PK model, based only on first‐order absorption and elimination constants, was a reasonable model to approximate the experimental data. Future in vitro and computational experiments will expand the model to incorporate sensory nerve activity. A more complete model may provide new insights into potential mechanisms of neuronal control of airways, allow for the rational use of drugs in treating lung diseases, and enable in silico assessment of novel therapeutics.Support or Funding InformationState of Nebraska Research Fund Grant LB595This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.