Advancing the utilization of real-world data and real-world evidence in clinical pharmacology and translational research-Proceedings from the ASCPT 2023 preconference workshop.

Real-world data (RWD) and real-world evidence (RWE) are now being routinely used in epidemiology, clinical practice, and post-approval regulatory decisions. Despite the increasing utility of the methodology and new regulatory guidelines in recent years, there remains a lack of awareness of how this approach can be applied in clinical pharmacology and translational research settings. Therefore, the American Society of Clinical Pharmacology & Therapeutics (ASCPT) held a workshop on March 21st, 2023 entitled "Advancing the Utilization of Real-World Data (RWD) and Real-World Evidence (RWE) in Clinical Pharmacology and Translational Research." The work described herein is a summary of the workshop proceedings.

Proposing a framework to quantify the potential impact of pharmacokinetic drug-drug interactions caused by a new drug candidate by using real world data about the target patient population.

Drug development teams must evaluate the risk/benefit profile of new drug candidates that perpetrate drug-drug interactions (DDIs). Real-world data (RWD) can inform this decision. The purpose of this study was to develop a predicted impact score for DDIs perpetrated by three hypothetical drug candidates via CYP3A, CYP2D6, or CYP2C9 in type 2 diabetes mellitus (T2DM), obesity, or migraine. Optum Market Clarity was analyzed to estimate use of CYP3A, CYP2D6, or CYP2C9 substrates classified in the University of Washington Drug Interaction Database as moderate sensitive, sensitive, narrow therapeutic index, or QT prolongation. Scoring was based on prevalence of exposure to victim substrates and characteristics (age, polypharmacy, duration of exposure, and number of prescribers) of those exposed. The study population of 14,163,271 adults included 1,579,054 with T2DM, 3,117,753 with obesity, and 410,436 with migraine. For T2DM, 71.3% used CYP3A substrates, 44.3% used CYP2D6 substrates, and 44.3% used CYP2C9 substrates. For obesity, 57.1% used CYP3A substrates, 34.6% used CYP2D6 substrates, and 31.0% used CYP2C9 substrates. For migraine, 64.1% used CYP3A substrates, 44.0% used CYP2D6 substrates, and 28.9% used CYP2C9 substrates. In our analyses, the predicted DDI impact scores were highest for DDIs involving CYP3A, followed by CYP2D6, and CYP2C9 substrates, and highest for T2DM, followed by migraine, and obesity. Insights from RWD can be used to estimate a predicted DDI impact score for pharmacokinetic DDIs perpetrated by new drug candidates currently in development. This score can inform the risk/benefit profile of new drug candidates in a target patient population.

Risk of mortality in older adults with loss of appetite: An analysis of Medicare fee-for-service data.

OBJECTIVES: Prior research suggested that loss of appetite (LOA) among adults with Medicare fee-for-service (FFS) insurance in the United States increased the risk of mortality within 1 year; those findings were not adjusted for risk factors and confounders. The objective of this study was to compare the risk of mortality among Medicare FFS beneficiaries with LOA to a control group without LOA while controlling or adjusting for age, comorbidities, body mass index (BMI), and weight loss. DESIGN: Retrospective and observational analysis of Medicare FFS health insurance claims data from October 1, 2015 to December 31, 2021. SETTING: Claims from all settings (e.g., hospital inpatient/outpatient, office, assisted living facility, skilled nursing facility, hospice, rehabilitation facility, home) were included in these analyses. PARTICIPANTS: The LOA group included all individuals aged 65-115 years with continuous Medicare FFS medical coverage (Parts A and/or B) for at least 12 months before a claim with ICD-10 diagnosis code "R63.0 Anorexia". The control group was drawn from individuals aged 65-115 years with continuous Medicare FFS coverage who did not have a diagnosis of R63.0. Individuals with LOA were matched 1:3 to those in the control group based on age, sex, and race/ethnicity. MEASUREMENTS: Mortality in the LOA group was compared to mortality in the control group using Kaplan-Meier and Cox regression analyses and stratified or adjusted in terms of Charlson Comorbidity Index (CCI), claims-based frailty index (CFI), BMI, and weight loss. RESULTS: The study population of 1,707,031 individuals with LOA and 5,121,093 controls without LOA was 61.7% female and 82.2% White. More individuals with LOA compared with the control group had a CCI score 5+ (52.4% vs. 19.4%), CFI score 5+ (31.6% vs. 6.4%), and BMI < 20 kg/m2 (11.2% vs. 2.1%). Median follow-up was 12 months (individuals with LOA) and 49 months (control group). In a matched population, the risk of mortality was significantly higher (unadjusted hazard ratio 4.40, 95% confidence interval 4.39-4.42) for individuals with LOA than the control group. Median survival time was 4 months (individuals with LOA) and 26 months (control group); differences in survival time remained when stratifying by CCI, BMI, and weight loss. CONCLUSION: Individuals with LOA had a substantially increased risk of death even after matching for age, sex, race/ethnicity, and adjusting for comorbidities. These findings highlight the burden of illness in older adults with LOA and the need for therapies.

NAFLD and NASH are obesity-independent risk factors in COVID-19: Matched real-world results from the large PINC AI™ Healthcare Database.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are potential risk factors for severe pneumonia and other infections. Available data on the role of NAFLD/NASH in worsening outcomes for COVID-19 are controversial and might be confounded by comorbidities. METHODS: We used the PINC AI™ Healthcare Data Special Release (PHD-SR) to identify patients with COVID-19 (ICD-10) at approximately 900 hospitals in the United States. We performed exact matching (age, gender, and ethnicity) for patients with or without NAFLD/NASH, adjusting for demographics (admission type, region) and comorbidities (e.g., obesity, diabetes) through inverse probability of treatment weighting and then analysed hospitalisation-related outcomes. RESULTS: Among 513 623 patients with SARS-CoV-2 (COVID-19), we identified 14 667 with NAFLD/NASH who could be matched to 14 667 controls. Mean age was 57.6 (±14.9) years, 50.8% were females and 43.7% were non-Hispanic whites. After matching, baseline characteristics (e.g., age, ethnicity, and gender) and comorbidities (e.g., hypertension, obesity, diabetes, and cardiovascular disease) were well balanced (standard difference (SD) <.10), except for cirrhosis and malignancies. Patients with COVID-19 and NAFLD/NASH had higher FIB-4 scores, a significantly longer hospital length of stay (LOS) and intensive care LOS than controls (9.4 vs. 8.3 days, and 10.4 vs. 9.3, respectively), even after adjusting for cirrhosis and malignancies. Patients with COVID-19 and NAFLD/NASH also had significantly higher risk of needing invasive mandatory ventilation (IMV) (odds ratio 1.0727; 95% CI 1.0095-1.1400). Other outcomes were similar in both groups. CONCLUSIONS: In this large real-world cohort of patients hospitalised for COVID-19 in the United States, NAFLD/NASH were obesity-independent risk factors for complicated disease courses.

Clinical Pharmacology Applications of Real-World Data and Real-World Evidence in Drug Development and Approval-An Industry Perspective.

Since the 21st Century Cures Act was signed into law in 2016, real-world data (RWD) and real-world evidence (RWE) have attracted great interest from the healthcare ecosystem globally. The potential and capability of RWD/RWE to inform regulatory decisions and clinical drug development have been extensively reviewed and discussed in the literature. However, a comprehensive review of current applications of RWD/RWE in clinical pharmacology, particularly from an industry perspective, is needed to inspire new insights and identify potential future opportunities for clinical pharmacologists to utilize RWD/RWE to address key drug development questions. In this paper, we review the RWD/RWE applications relevant to clinical pharmacology based on recent publications from member companies in the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) RWD Working Group, and discuss the future direction of RWE utilization from a clinical pharmacology perspective. A comprehensive review of RWD/RWE use cases is provided and discussed in the following categories of application: drug-drug interaction assessments, dose recommendation for patients with organ impairment, pediatric plan development and study design, model-informed drug development (e.g., disease progression modeling), prognostic and predictive biomarkers/factors identification, regulatory decisions support (e.g., label expansion), and synthetic/external control generation for rare diseases. Additionally, we describe and discuss common sources of RWD to help guide appropriate data selection to address questions pertaining to clinical pharmacology in drug development and regulatory decision making.

Use of Real-World Evidence to Drive Drug Development Strategy and Inform Clinical Trial Design.

Interest in real-world data (RWD) and real-world evidence (RWE) to expedite and enrich the development of new biopharmaceutical products has proliferated in recent years, spurred by the 21st Century Cures Act in the United States and similar policy efforts in other countries, willingness by regulators to consider RWE in their decisions, demands from third-party payers, and growing concerns about the limitations of traditional clinical trials. Although much of the recent literature on RWE has focused on potential regulatory uses (e.g., product approvals in oncology or rare diseases based on single-arm trials with external control arms), this article reviews how biopharmaceutical companies can leverage RWE to inform internal decisions made throughout the product development process. Specifically, this article will review use of RWD to guide pipeline and portfolio strategy; use of novel sources of RWD to inform product development, use of RWD to inform clinical development, use of advanced analytics to harness "big" RWD, and considerations when using RWD to inform internal decisions. Topics discussed will include the use of molecular, clinicogenomic, medical imaging, radiomic, and patient-derived xenograft data to augment traditional sources of RWE, the use of RWD to inform clinical trial eligibility criteria, enrich trial population based on predicted response, select endpoints, estimate sample size, understand disease progression, and enhance diversity of participants, the growing use of data tokenization and advanced analytical techniques based on artificial intelligence in RWE, as well as the importance of data quality and methodological transparency in RWE.

Economic Evaluation of an Extended Telehealth Worksite Exercise Intervention to Reduce Lost Work Time from Low Back Pain in Career Firefighters.

Purpose Low back pain (LBP) is a leading cause of lost work time (LWT) in firefighters and is related to poor muscle endurance. Although exercise can improve muscle endurance, it must be continued to sustain benefits, and it is unknown if it can reduce LWT. This study conducted an economic evaluation of an extended worksite exercise intervention in career firefighters. Methods A randomized controlled trial allocated 264 firefighters to telehealth with remote instruction ("telehealth"), direct exercise supervision ("direct"), or brief education ("control"). The telehealth and direct groups performed worksite exercises twice weekly for 12 months. Outcomes included quality adjusted life years, LWT from LBP (24-h shifts), costs of LWT from LBP, and net monetary benefits. Results A total of 216 firefighters were included in the economic analysis (telehealth n = 71, direct n = 75, control n = 70). Sixteen experienced LWT from LBP (telehealth n = 4, direct n = 4, control n = 8). The mean number of 24-h shifts lost from LBP were 0.05 (telehealth), 0.28 (direct), and 0.43 (control). Mean study intervention costs per participant were $1984 (telehealth), $5269 (direct), and $384 (control). Net monetary benefit was $3573 for telehealth vs. direct, - $1113 for telehealth vs. control, and - $4686 for direct vs. control. Conclusions Worksite exercise reduced LWT from LBP in firefighters. Telehealth was less costly and more effective at reducing LWT from LBP than direct exercise supervision. If the costs of telehealth were further reduced, a positive net monetary benefit might also be achieved when compared to no intervention.Clinical trial registration: (clinicaltrials.gov): NCT02362243.

Comparison of Supervised and Telehealth Delivery of Worksite Exercise for Prevention of Low Back Pain in Firefighters: A Cluster Randomized Trial.

OBJECTIVE: This study assessed worksite exercise delivered by on-site supervision (supervised) or telehealth to reduce lost work time (LWT) related to low back pain (LBP) in firefighters. METHODS: A cluster randomized controlled trial assigned 264 career firefighters to supervised (n = 86) or telehealth (n = 95) back and core exercises 2×/week for 12 months, or control (n = 83). RESULTS: 58.0% (153/264) of participants reported LBP and 7.6% (20/264) reported LWT related to LBP (control n = 10, supervised n = 5, telehealth n = 5). Participants in the control group experienced 1.15 times as many hours of LWT as the supervised group, and 5.51 times as many hours of LWT as the telehealth group. CONCLUSIONS: Worksite exercise, delivered by on-site supervision or telehealth, can reduce LWT related to LBP in career firefighters.

Guideline summary review: an evidence-based clinical guideline for the diagnosis and treatment of low back pain.

BACKGROUND CONTEXT: The North American Spine Society's (NASS) Evidence Based Clinical Guideline for the Diagnosis and Treatment of Low Back Pain features evidence-based recommendations for diagnosing and treating adult patients with nonspecific low back pain. The guideline is intended to reflect contemporary treatment concepts for nonspecific low back pain as reflected in the highest quality clinical literature available on this subject as of February 2016. PURPOSE: The purpose of the guideline is to provide an evidence-based educational tool to assist spine specialists when making clinical decisions for adult patients with nonspecific low back pain. This article provides a brief summary of the evidence-based guideline recommendations for diagnosing and treating patients with this condition. STUDY DESIGN: This is a guideline summary review. METHODS: This guideline is the product of the Low Back Pain Work Group of NASS' Evidence-Based Clinical Guideline Development Committee. The methods used to develop this guideline are detailed in the complete guideline and technical report available on the NASS website. In brief, a multidisciplinary work group of spine care specialists convened to identify clinical questions to address in the guideline. The literature search strategy was developed in consultation with medical librarians. Upon completion of the systematic literature search, evidence relevant to the clinical questions posed in the guideline was reviewed. Work group members utilized NASS evidentiary table templates to summarize study conclusions, identify study strengths and weaknesses, and assign levels of evidence. Work group members participated in webcasts and in-person recommendation meetings to update and formulate evidence-based recommendations and incorporate expert opinion when necessary. The draft guideline was submitted to an internal and external peer review process and ultimately approved by the NASS Board of Directors. RESULTS: Eighty-two clinical questions were addressed, and the answers are summarized in this article. The respective recommendations were graded according to the levels of evidence of the supporting literature. CONCLUSIONS: The evidence-based clinical guideline has been created using techniques of evidence-based medicine and best available evidence to aid practitioners in the diagnosis and treatment of adult patients with nonspecific low back pain. The entire guideline document, including the evidentiary tables, literature search parameters, literature attrition flowchart, suggestions for future research, and all of the references, is available electronically on the NASS website at https://www.spine.org/ResearchClinicalCare/QualityImprovement/ClinicalGuidelines.aspx.

Impact of liposomal bupivacaine on opioid use, hospital length of stay, discharge status, and hospitalization costs in patients undergoing total hip arthroplasty.

Aims: Effective postsurgical analgesia hastens recovery, reduces hospital length of stay (LOS), and decreases hospitalization costs for total hip arthroplasty (THA). Improving these outcomes is critical for value-based surgical bundled payment programs such as the Medicare Comprehensive Care for Joint Replacement and similar programs for commercial insurance providers. This study compared clinical outcomes and hospitalization costs for patients undergoing THA with and without liposomal bupivacaine (LB).Materials and methods: This retrospective, comparative cohort study used data from the Premier Healthcare Database from the 10 hospitals with highest use of LB for THA from January 2011 through April 2017. A cohort undergoing THA with LB at those hospitals was compared with a propensity-score matched cohort at those hospitals who had THA without LB. Descriptive, univariate, and multivariable analyses compared post-surgical inpatient opioid consumption, hospital LOS, discharge status, same-hospital readmissions, and total hospitalization costs. Analyses were performed using the Pearson Chi-square test (categorical variables) and Wilcoxon or Student t-test (continuous variables).Results: For patients with Medicare (with LB, n = 3622; without LB, n = 3610) and commercial insurance (with LB, n = 2648; without LB, n = 2709), use of LB was associated with lower post-surgical inpatient opioid consumption (105 and 81 mg, respectively; p < 0.0001), a 0.7-day shorter LOS (p < 0.0001), a 1.6-1.7-fold increased likelihood of home discharge (p < 0.0001), and no increase in readmissions (p ≥ 0.103). Total hospitalization costs were $561 lower with LB in the Medicare population (p < 0.0001) and $41 higher with LB in the commercial population (p = 0.7697).Limitations: Hospitalization costs were estimated from the hospital chargemaster. Findings from these 10 hospitals may not represent other US hospitals.Conclusions: At select hospitals, THA with LB was associated with reduced post-surgical inpatient opioid consumption, shorter hospital LOS, increased likelihood of home discharge, and lower hospitalization costs. Post-surgical pain management with LB may help hospitals in value-based bundled payment programs.

Impact of treatment with liposomal bupivacaine on hospital costs, length of stay, and discharge status in patients undergoing total knee arthroplasty at high-use institutions.

Aims: Post-surgical pain experienced by patients undergoing total knee arthroplasty (TKA) can be severe. Enhanced recovery after surgery programs incorporating multimodal analgesic regimens have evolved in an attempt to improve patient care while lowering overall costs. This study examined clinical and economic outcomes in hospitals using liposomal bupivacaine (LB) for pain control following TKA.Methods: This retrospective observational study utilized hospital chargemaster data from the Premier Healthcare Database from January 2011 through April 2017 for the 10 hospitals with the highest number of primary TKA procedures using LB. Within these hospitals, patients undergoing TKA who received LB were propensity-score matched in a 1:1 ratio to a control group not receiving LB. Outcomes included hospital length of stay (LOS), discharge status, 30-day same-hospital readmissions, total hospitalization costs, and opioid consumption; only patients with Medicare or commercial insurance as the primary payer for TKA were considered.Results: The study population included 20,907 Medicare-insured patients (LB = 10,411; control =10,496) and 12,505 patients with commercial insurance (LB = 6,242; control = 6,263). Overall, LOS was 0.6 days shorter with LB (p < 0.0001), and patients who received LB were 1.6-times more likely to be discharged home (p < 0.0001). Total hospitalization costs for the TKA procedure were lower with LB for patients with both Medicare (-$616; P < 0.0001) and commercial insurance (-$775; p < 0.0001). Opioid consumption was lower with LB in both payer populations (p < 0.0001). No significant differences for 30-day readmissions were found.Limitations: Costs were estimated using Premier charge-to-cost ratios and limited to goods and services recorded in the chargemaster. Findings from these 10 hospitals may not be representative of other US hospitals.Conclusions: In a sub-set of 10 US hospitals with the highest use of LB for TKA, LB use was associated with shorter hospital LOS, increased home discharge, lower total hospitalization costs, and decreased opioid use after TKA.

A comparison of approaches to identify possible cases of local anesthetic systemic toxicity in the FDA Adverse Event Reporting System (FAERS) database.

BACKGROUND: Local anesthetic systemic toxicity (LAST) is a rare but potentially serious adverse event . METHODS: Data from the US Food and Drug Administration Adverse Event Reporting System were examined for liposomal bupivacaine (LB), bupivacaine, or other injectable local anesthetics. Possible LAST cases were identified based on MedDRA system organ classes (Approach 1), a recent publication (Approach 2), and a novel approach based on LAST literature (Approach 3). Disproportionality analyses compared possible LAST cases for LB and bupivacaine with other injectable local anesthetics. RESULTS: Approaches 1, 2, and 3 identified 75, 42, and 29 possible LAST cases associated with LB, respectively, compared with 9,595, 3,422, and 549 for other injectable local anesthetics. The proportional reporting ratios (95% CI) for LB versus other injectable local anesthetics for the 3 approaches were 1.9 (1.6-2.3), 2.9 (2.2-3.9), and 1.6 (1.1-2.2), respectively. Based on sales data, the estimated incidence of possible LAST with LB was 0.1 per 10,000 uses; literature estimates for LAST with other injectable local anesthetics were 0 to 18 per 10,000 uses. CONCLUSIONS: Our findings suggest the estimated incidence of possible LAST cases with LB is similar to, or less than, the reported incidence with other injectable local anesthetics.

Research Agenda for the Prevention of Pain and Its Impact: Report of the Work Group on the Prevention of Acute and Chronic Pain of the Federal Pain Research Strategy.

After the 2011 Institute of Medicine report on chronic pain, the Interagency Pain Research Coordinating Committee (IPRCC) was created to enhance research efforts among federal agencies. The IPRCC and Office of Pain Policy at the National Institutes of Health collaborated to identify gaps in knowledge and address them via a Federal Pain Research Strategy (FPRS). Interdisciplinary work groups (WGs) were established to make research recommendations in 5 areas: prevention of acute and chronic pain, acute pain and acute pain management, transition from acute to chronic pain, chronic pain and chronic pain management, and disparities in pain and pain care; cross-cutting issues were also considered. The objective was to provide guidance on current research and to make recommendations about addressing identified gaps. Findings from the Prevention of Acute and Chronic Pain WG are summarized in this article. The WG created subgroups to develop recommendations on specific aspects of prevention of acute and chronic pain, including: public education, primary prevention, secondary prevention, tertiary prevention, transition from acute to chronic pain, and cross-cutting mediators. No formal literature review was conducted; however, external advisors were available and consulted as needed. Seven key research priorities were identified. The one deemed "greatest near-term value" was to optimize public health strategies to educate patients on managing pain; that deemed "most impactful" was to determine an association between patient and intervention factors. Other recommendations were related to the epidemiology of acute pain from health care procedures, the epidemiology of acute pain from work-related injuries, safety and effectiveness of management of pain associated with health care procedures, optimizing approaches to acute postsurgical pain, and safety and effectiveness of early interventions for tertiary prevention. Stakeholders, including federally sponsored research programs, researchers, health care providers, policy makers, patients, and others should work together to implement recommendations and address important gaps. PERSPECTIVE: The FPRS Steering Committee created 5 WGs to identify research needs and make recommendations in key areas of research. This article reports the results of one-the Prevention of Acute and Chronic Pain group. Several research priorities emerged, and recommendations made to fill existing knowledge gaps.

Medication, equipment, and supply costs for common interventions providing extended post-surgical analgesia following total knee arthroplasty in US hospitals.

AIMS: To estimate the cost to hospitals of materials (i.e. medications, equipment, and supplies) required to administer common interventions for post-surgical analgesia after total knee arthroplasty (TKA), including single-injection peripheral nerve block (sPNB), continuous peripheral nerve block (cPNB), periarticular infiltration of multi-drug cocktails, continuous epidural analgesia, intravenous patient-controlled analgesia (IV PCA), and local infiltration of bupivacaine liposome injectable suspension (BLIS). MATERIALS AND METHODS: This analysis was conducted using a mixed methods approach combining published literature, publicly available data sources, and administrative data, to first identify the materials required to administer these interventions, and then estimate the cost to the hospital of those materials. Medication costs were estimated primarily using the Wholesale Acquisition Costs (WAC), the cost of reusable equipment was obtained from published sources, and costs for disposable supplies were obtained from the US Government Services Administration (GSA) database. Where uncertainty existed about the technique used when administering these interventions, costs were calculated for multiple scenarios reflecting different assumptions. RESULTS: The total cost of materials (i.e. medications, equipment, and supplies) required to provide post-surgical analgesia was $41.88 for sPNB with bupivacaine; $756.57 for cFNB with ropivacaine; $16.38 for periarticular infiltration with bupivacaine, morphine, methylprednisolone, and cefuroxime; $453.84 for continuous epidural analgesia with fentanyl and ropivacaine; $178.94 for IV PCA with morphine; and $319.00 for BLIS. LIMITATIONS: This analysis did not consider the cost of healthcare providers required to administer these interventions. In addition, this analysis focused on the cost of materials and, therefore, did not consider aspects of relative efficacy or safety, or how the choice of intervention for post-surgical analgesia might impact outcomes such as length of stay, re-admissions, discharge status, adverse events, or total hospitalization costs. CONCLUSIONS: This study provided an estimate of the costs to hospitals for materials required to administer commonly used interventions for post-surgical analgesia after TKA.