Comparative Expedited Regulatory Programs of U.S Food & Drug Administration and Project Orbis Partners.

Project Orbis was initiated in May 2019 by the Oncology Center of Excellence to facilitate faster patient access to innovative cancer therapies by providing a framework for concurrent submissions and review of oncology products among international partners. Since its inception, Australia's Therapeutic Goods Administration (TGA), Canada's Health Canada (HC), Singapore's Health Sciences Authority (HSA), Switzerland's Swissmedic (SMC), Brazil's National Health Surveillance Agency (ANVISA), United Kingdom's Medicines and Healthcare Products Regulatory Agency (MHRA), and most recently Israel's Ministry of Health (IMoH) Medical Technologies, Health Information, Innovation and Research (MTIIR) Directorate, have joined Project Orbis. While each country has its own expedited review pathways to bring promising therapies to patients, there are some similarities and differences in pathways and timelines. FDA's fast-track designation and MHRA's marketing authorization under exceptional circumstances (MAEC) allow non-clinical and limited clinical evidence to support approval under these programs. HC's Extraordinary Use New Drug (EUND) pathway allows granting exceptional use authorization with limited clinical evidence. ANVISA, HSA, MTIIR, and TGA do not have standard pathways that allow non-clinical evidence and limited clinical evidence. While there is no definite regulatory pathway for HSA, the current framework for approval does allow flexibility in the type of data (non-clinical or clinical) required to demonstrate the benefit-risk profile of a product. HSA may register a product if the agency is satisfied that the overall benefit outweighs the risk. All Project Orbis Partner (POP) countries have similar programs to the FDA accelerated approval program except ANVISA. Although HSA and MTIIR do not have defined pathways for accelerated approval programs, there are opportunities to request accelerated approval per these agencies. All POP countries have pathways like the FDA priority review except MHRA. Priority review timelines for new drugs range from 120 to 264 calendar days (cd). Standard review timelines for new drugs range from 180 to 365 cd.

Integrating real-world data to accelerate and guide drug development: A clinical pharmacology perspective.

Pharmaceutical products in the current accelerated drug development landscape can benefit from tools beyond data generated from randomized control trials. We have seen an abundance of real-world data (RWD) and real-world evidence, driven by the digitalization of healthcare systems and an increased awareness that has inspired a heightened interest in their potential use. Literature review suggest leveraging RWD as a promising tool to answer key questions in the areas of clinical pharmacology and translational science. RWD may increase our understanding regarding the impact of intrinsic (e.g., liver, renal impairment, or genetic polymorphisms) and extrinsic (e.g., food consumption or concomitant medications) factors on the clearance of administered drugs. Changes in clearance may lead to clinically relevant changes in drug exposure that may require clinical management strategies, such as change in dose or dosing regimen. RWD can be leveraged to potentially bridge the gaps among research, development, and clinical care. This paper highlights promising areas of how RWD have been used to complement clinical pharmacology throughout various phases of drug development; case examples will include dose/regimen extrapolation, dose adjustments for special populations (organ impairment, pediatrics, etc.), and pharmacokinetic/pharmacodynamic models to assess impact of prognostic factors on outcomes. In addition, this paper will also juxtapose limitations and promises of utilizing RWD to answer key scientific questions in drug development and articulate challenges posed by quality issues, data availability, and integration from various sources as well as the increased need for multidimensional-omics data that can better guide the development of personalized and predictive medicine.

Changes in overactive bladder medication following bariatric surgery: segmented regression analysis.

PURPOSE: Bariatric surgery has shown reductions in overactive bladder (OAB) symptoms; however, the impacts on OAB treatment is unknown. The goal of our study is to evaluate the impact of bariatric surgery on OAB medication utilization. METHODS: We used IBM® MarketScan® commercial databases from 2005 to 2018. We included patients aged ≥ 18 years with 360 days of continuous enrollment before and after bariatric surgery (Roux-en-Y Gastric Bypass and Sleeve Gastrectomy) with at least one fill of an OAB medication in the 360 days prior to bariatric surgery. We evaluated all included patients and stratified by surgery type and patient sex. Segmented regression analyses were used to assess the proportion of patients on OAB medications before and after bariatric surgery. We replicated our findings using hip or knee replacement surgery as a negative control. RESULTS: Among the included patients (n = 3069), 92.2% were females, 58.6% underwent Roux-en-Y Gastric Bypass. Immediately following bariatric surgery, the proportion of patients treated with an OAB medication reduced from 34.8 to 14.1% (p < 0.001) resulting in a 59.5% relative reduction. Patients who underwent Roux-en-Y Gastric Bypass vs. Sleeve Gastrectomy (63.8% vs. 55.1%) relative reduction (p = 0.009)) and females versus males [62.3% vs. 52.9% relative reduction (p < 0.001)] had a more pronounced reduction in OAB medication use. There was slight decrease in OAB medication use in the negative control analysis. CONCLUSIONS: A reduction in OAB medication use following bariatric surgery may be associated with a reduction in OAB symptoms suggesting an additional benefit of bariatric surgery.

Changes in Prescribing by Provider Type Following a State Prescription Opioid Restriction Law.

BACKGROUND: Many states have implemented opioid days' supply restriction policies, leading to reductions in opioid prescribing. Although research within certain provider types exist, no study has evaluated a restriction policy by various provider types. OBJECTIVE: To evaluate changes in opioid utilization following a days' supply restriction policy stratified by provider type: surgery, emergency medicine, primary care, specialty care, and dentistry. DESIGN: Interrupted time series (ITS) PARTICIPANTS: Opioid prescription claims of patients in a private health plan serving a large Florida employer from 1/1/2015 to 3/31/2019. Provider types were determined using the Healthcare Provider Taxonomy Code associated with the national provider identifier (NPI). INTERVENTIONS: Florida's opioid restriction policy implemented on July 1, 2018. MAIN MEASURES: Changes in mean morphine milligram equivalent (MMEs), mean days' supply, and mean number of units dispensed per opioid prescription before and after policy implementation. KEY RESULTS: There were 10,583 opioid initial prescriptions dispensed. Treating providers were classified as surgery (16.4%; n = 1732), emergency care (14.3%; n = 1516), primary care (21.2%; n = 2241), specialty care (11.4%; n = 1207), and dentistry providers (23.7%; n = 2511). Significant reductions in mean days' supply were observed across most provider types ranging from 14% reduction for dentistry providers to 41% reduction for specialty care providers. Significant changes were observed for emergency care and specialty care providers with a 30% (p = 0.001)and 29% (p < 0.001) reduction in mean MME, respectively, and a 27% (p = 0.040) reduction in mean number of units dispensed in emergency care providers, after implementation. Pre-implementation trends in opioid prescribing varied by provider type impacting the effects of the opioid days' supply restriction policy. CONCLUSIONS: Pre-policy opioid prescribing varied by provider type with a differential impact on mean MMEs, mean days' supply, and mean number of units dispensed per prescription following implementation.

Changes in utilization of immediate-release, extended-release, and liquid formulation medications relative to bariatric surgery: a segmented regression analysis.

BACKGROUND: Changes in gut anatomy following bariatric surgery impacts medication absorption, often requiring changes in medication formulations. OBJECTIVES: To assess changes in utilization of extended-release (ER), immediate-release (IR), and liquid formulations 360 days before and after bariatric surgery. SETTING: Large U.S. administrative claims database of privately insured beneficiaries, January 2005 through December 2018. METHODS: We included patients aged ≥18 years with 360 days of continuous enrollment before and after date of bariatric surgery (Roux-en-Y gastric bypass [RYGB] or sleeve gastrectomy [SG]). The proportion of each formulation (ER, IR, or liquid) of oral prescription medications filled during the study period were assessed in twelve 30-day windows before and after bariatric surgery and stratified by bariatric surgery type. Segmented regression analysis was used to assess filled medication categorized by formulation before and after bariatric surgery overall and RYGB relative to SG. RESULTS: Among 122,866 included patients, there were increases in the proportion of patients on each formulation before and after surgery attributed to proton pump inhibitors, opioids, antiemetics, and ursodiol. After removing these acutely used medications, we found a 40% immediate reduction in patients on ER medications (P < .0001), 15% immediate reduction in patients on IR medications (P < .0001), and a nonsignificant increase in patients on liquid formulations (P = .1340). CONCLUSION: Despite reductions in ER formulations, many patients continued on this formulation which may potentially contribute to poor outcomes.

Chronic Opioid Therapy: A Scoping Literature Review on Evolving Clinical and Scientific Definitions.

The management of chronic noncancer pain (CNCP) with chronic opioid therapy (COT) is controversial. There is a lack of consensus on how COT is defined resulting in unclear clinical guidance. This scoping review identifies and evaluates evolving COT definitions throughout the published clinical and scientific literature. Databases searched included PubMed, Embase, and Web of Science. A total of 227 studies were identified from 8,866 studies published between January 2000 and July 2019. COT definitions were classified by pain population of application and specific dosage/duration definition parameters, with results reported according to PRISMA-ScR. Approximately half of studies defined COT as "days' supply duration >90 days" and 9.3% defined as ">120 days' supply," with other days' supply cut-off points (>30, >60, or >70) each appearing in <5% of total studies. COT was defined by number of prescriptions in 63 studies, with 16.3% and 11.0% using number of initiations or refills, respectively. Few studies explicitly distinguished acute treatment and COT. Episode duration/dosage criteria was used in 90 studies, with 7.5% by Morphine Milligram Equivalents + days' supply and 32.2% by other "episode" combination definitions. COT definitions were applied in musculoskeletal CNCP (60.8%) most often, and typically in adults aged 18 to 64 (69.6%). The usage of ">90 days' supply" COT definitions increased from 3.2 publications/year before 2016 to 20.7 publications/year after 2016. An increasing proportion of studies define COT as ">90 days' supply." The most recent literature trends toward shorter duration criteria, suggesting that contemporary COT definitions are increasingly conservative. PERSPECTIVE: This study summarized the most common, current definition criteria for chronic opioid therapy (COT) and recommends adoption of consistent definition criteria to be utilized in practice and research. The most recent literature trends toward shorter duration criteria overall, suggesting that COT definition criteria are increasingly stringent.