Trends in Use of Next-Generation Sequencing in Patients With Solid Tumors by Race and Ethnicity After Implementation of the Medicare National Coverage Determination.

Importance: In March 2018, Medicare issued a national coverage determination (NCD) for next-generation sequencing (NGS) to facilitate access to NGS testing among Medicare beneficiaries. It is unknown whether the NCD affected health equity issues for Medicare beneficiaries and the overall population. Objective: To examine the association between the Medicare NCD and NGS use by insurance types and race and ethnicity. Design, Setting, and Participants: A retrospective cohort analysis was conducted using electronic health record data derived from a real-world database. Data originated from approximately 280 cancer clinics (approximately 800 sites of care) in the US. Patients with advanced non-small cell lung cancer (aNSCLC), metastatic colorectal cancer (mCRC), metastatic breast cancer (mBC), or advanced melanoma diagnosed from January 1, 2011, through March 31, 2020, were included. Exposure: Pre- vs post-NCD period. Main Outcomes and Measures: Patients were classified by insurance type and race and ethnicity to examine patterns in NGS testing less than or equal to 60 days after diagnosis. Difference-in-differences models examined changes in average NGS testing in the pre- and post-NCD periods by race and ethnicity, and interrupted time-series analysis examined whether trends over time varied by insurance type and race and ethnicity. Results: Among 92 687 patients with aNSCLC, mCRC, mBC, or advanced melanoma, mean (SD) age was 66.6 (11.2) years, 51 582 (55.7%) were women, and 63 864 (68.9%) were Medicare beneficiaries. The largest racial and ethnic categories according to the database used and further classification were Black or African American (8605 [9.3%]) and non-Hispanic White (59 806 [64.5%]). Compared with Medicare beneficiaries, changes in pre- to post-NCD NGS testing trends were similar in commercially insured patients (odds ratio [OR], 1.03; 95% CI, 0.98-1.08; P = .25). Pre- to post-NCD NGS testing trends increased at a slower rate among patients in assistance programs (OR, 0.93; 95% CI, 0.87-0.99; P = .03) compared with Medicare beneficiaries. The rate of increase for patients receiving Medicaid was not statistically significantly different compared with those receiving Medicare (OR, 0.92; 95% CI, 0.84-1.01; P = .07). The NCD was not associated with statistically significant changes in NGS use trends by racial and ethnic groups within Medicare beneficiaries alone or across all insurance types. Compared with non-Hispanic White individuals, increases in average NGS use from the pre-NCD to post-NCD period were 14% lower (OR, 0.86; 95% CI, 0.74-0.99; P = .04) among African American and 23% lower (OR, 0.77; 95% CI, 0.62-0.96; P = .02) among Hispanic/Latino individuals; increases among Asian individuals and those with other races and ethnicities were similar. Conclusions and Relevance: The findings of this study suggest that expansion of Medicare-covered benefits may not occur equally across insurance types, thereby further widening or maintaining disparities in NGS testing. Additional efforts beyond coverage policies are needed to ensure equitable access to the benefits of precision medicine.

Shingles vaccination uptake in Massachusetts adults aged 50 years and older.

BACKGROUND: Shingles (herpes zoster), a medical condition caused by reactivation of latent varicella zoster virus and characterized by painful rash, will affect almost one third of Americans during their lifetime. A licensed vaccine (zoster vaccine live [ZVL]) was recommended for individuals ≥ 60 years old in 2008 to reduce shingles incidence. The Healthy People (HP) 2020 target for shingles vaccination in ≥ 60 year-olds was 30%; in 2014, it stood at 31.8% and in 2017 at 34.9%. While the national coverage target is met, variability remains across age, gender and ethnicity. Understanding factors influencing patient acceptance of the shingles vaccination is needed to help guide program activities and improve vaccination coverage in the adult population. PURPOSE: To understand Massachusetts consumers' knowledge, attitudes, behaviors, and barriers to obtaining a shingles vaccination. METHODS: We performed a telephone survey using a stratified sample of Massachusetts residents ≥ 50 years-old who i) responded to the 2012 Massachusetts Behavioral Risk Factor Surveillance System (n = 10,822), ii) agreed to a follow-up survey (n = 6,873), and iii) reported awareness of the shingles vaccination (n = 1,000; n = 529 vaccinated respondents (VR) and n = 471 non-vaccinated respondents (NVR)). Multivariable logistic regression identified factors independently associated with receiving shingles vaccination. RESULTS: Across both groups, most respondents (n = 989, 99%) were aware of shingles, perceived shingles as painful, and knew ofothers who had hadshingles. Multivariable logistic regression indicated an association between shingles vaccination and physician recommendation, influenza vaccination, and perception of shingles risk. CONCLUSIONS: More than half of the sub-sample reported not knowing about shingles vaccine, therefore, opportunities to increase awareness should be prioritized. Since provider recommendation and flu vaccination receipt had the greatest odds of increasing shingles vaccination, standard practice should include adding shingles to flu vaccine recommendations for age-eligible patients.

Assessing Patient Participation Burden Based on Protocol Design Characteristics.

BACKGROUND: Although a number of studies have quantitatively measured investigative site burden to administer increasingly complex protocol designs, robust scholarly research has not been performed to quantify the burden that patients face as participants in clinical trials. METHODS: This paper presents the results of a cross-sectional pilot study conducted by the Tufts Center for the Study of Drug Development and ZS Associates among nearly 600 patients via an online survey conducted between February and March 2019. Respondents rated the perceived burden of 60 commonly administered protocol procedures. The association and relationship between overall patient burden-derived from aggregating mean perceived burden ratings for individual procedures-and performance (eg, screen failure and retention rates, clinical trial cycle times) for a cross-sectional sample of 137 individual protocols was assessed. Descriptive statistics, significance tests, and univariate analyses were performed. RESULTS: Strong positive, statistically significant associations were observed between a composite measure of patient burden and protocol-specific design and performance measures, most notably study visits above the tolerable mean and the study conduct duration from first patient first visit to last patient last visit. CONCLUSIONS: The study results suggest a new and viable approach to optimize protocol design and improve patient engagement.

Correction to: Adverse Drug Reaction Case Safety Practices in Large Biopharmaceutical Organizations from 2007 to 2017: An Industry Survey.

The correct name of the second author should be "Moritz Fehrle", and not "Mortiz Fehrle" as given in the original publication of the article.

Measuring the Impact of Patient Engagement and Patient Centricity in Clinical Research and Development.

BACKGROUND: Recently, drug development companies have sought out patient feedback to improve overall drug development. However, characterization of the overall impact and return on engaging with patients have not been determined. METHODS: The Drug Information Association (DIA), the Tufts Center for the Study of Drug Development (Tufts CSDD), and 17 other stakeholder organizations collaborated on a study to (1) quantify and define patient-centric initiatives (PCIs) utilized in clinical research and development and (2) to define evidence-based metrics and performance indicators that demonstrate return on engagement (ROE) of specific PCIs. We conducted a literature review, industry surveys, and in-depth interviews to determine and measure the impact of adopted PCIs. RESULTS: We identified and defined 30 PCIs used to engage with patients. We analyzed 121 case studies and created a comprehensive list of metrics assessing overall return to the organization and to patients. Advocacy Group Support and Involvement, Conducting Patient Advisory Panels, and Focus Groups were examples of PCIs with the lowest cost and largest impact with respect to quality, speed, and impact on the patient relative to other PCIs. CONCLUSION: The results from the literature review and use cases provide drug development teams with evidence and insights to help facilitate the adoption of specific PCIs within their organization and to help select those initiatives that would provide the highest impact to patients and development organizations. It is also hoped that the biopharmaceutical industry will apply the standardized metrics in the toolkit to systematically assess the overall return on engagement.

Development Times and Approval Success Rates for Drugs to Treat Infectious Diseases.

We gathered data from three pipeline databases and other public sources on development stage and clinical trial metrics for 1,914 investigational drugs, biologics, and vaccines and 2,769 clinical trials intended to treat a wide variety of infectious diseases. We included new molecular entities (NMEs), new formulations, and new combinations. Clinical trial times decreased from 2000-2008 to 2009-2017, varied by disease class, and were longer for trials with more subjects or more sites. Clinical approval success rates were higher for this set of diseases than those in the published literature for drugs across all therapeutic categories. NMEs to treat HIV had a success rate (16.0%) that was similar to those for drugs in general, whereas NME success rates for influenza and pneumonia were much higher (48.1% and 50.5%, respectively).

Assessing Patient Participation Burden Based on Protocol Design Characteristics.

BACKGROUND: Although a number of studies have quantitatively measured investigative site burden to administer increasingly complex protocol designs, robust scholarly research has not been performed to quantify the burden that patients face as participants in clinical trials. METHODS: This paper presents the results of a cross-sectional pilot study conducted by the Tufts Center for the Study of Drug Development and ZS Associates among nearly 600 patients via an online survey conducted between February and March 2019. Respondents rated the perceived burden of 60 commonly administered protocol procedures. The association and relationship between overall patient burden-derived from aggregating mean perceived burden ratings for individual procedures-and performance (eg, screen failure and retention rates, clinical trial cycle times) for a cross-sectional sample of 137 individual protocols was assessed. Descriptive statistics, significance tests, and univariate analyses were performed. RESULTS: Strong positive, statistically significant associations were observed between a composite measure of patient burden and protocol-specific design and performance measures, most notably study visits above the tolerable mean and the study conduct duration from first patient first visit to last patient last visit. CONCLUSIONS: The study results suggest a new and viable approach to optimize protocol design and improve patient engagement.

Adverse Drug Reaction Case Safety Practices in Large Biopharmaceutical Organizations from 2007 to 2017: An Industry Survey.

INTRODUCTION: Drug safety remains a top global public health concern. An increase in the number of data sources available has increased the complexity of pharmacovigilance operations, so the US FDA has created draft guidance focusing on optimizing drug safety data for well-characterized medicines. However, to date, no data demonstrating changes in reports have been presented. OBJECTIVES: This study provided data assessing changes in individual case safety reports (ICSRs) and aggregate reports (ARs) for large biopharmaceutical companies from 2007 to 2017. This study also evaluated current trends on the use of advanced machine and deep learning in order to process all data captured for ICSRs as well as opinions from industry thought leaders on creating a sustainable case-processing operation. METHODOLOGY: Using data captured from Navitas Life Science's annual pvnet® benchmark, we calculated workload indicators characterizing pharmacovigilance operations for large biopharmaceutical organizations. Workload indicators included the number of ICSRs by organization, the number of ARs, and the number and types of data sources used. We also conducted structured in-depth interviews with seven biopharmaceutical executives to discover the reasons for changes in workload indicators across time as well as current strategies for increasing efficiencies in drug safety reporting. RESULTS: The median number of ICSRs increased from 84,960 cases in 2007 to over 200,000 cases in 2017; this increase was largely attributable to an increase in both nonserious cases and follow-up cases. Member companies reported using 12 ± 3 data sources for case identification. The number of ARs also increased from a median of 70 reports in 2007 to 258 reports in 2017. To address these increases, 61% of the biopharmaceutical organizations we surveyed planned to adopt machine learning for full ICSR processing; however, as of 2018, none of the organizations surveyed had mechanisms in place. CONCLUSION: This study demonstrated that pharmacovigilance departments are currently burdened by ever-increasing case volumes. With increased guidance from regulatory agencies, as well as improvements in artificial intelligence and natural language processing, biopharmaceutical organizations must determine the most resource-efficient and sustainable methods to process the growing volume of cases.

Evaluating the Completeness of ClinicalTrials.gov.

BACKGROUND: To date, although studies have been conducted to assess compliance with listing clinical trial information, to our knowledge there is nothing in the literature examining the completion and accuracy of clinical trial site information on ClinicalTrials.gov . METHODS: We compared clinical trial information originating from ClinicalTrials.gov to a widely subscribed and well-established commercial clinical trial database, Informa Pharma Intelligence's Trialtrove, as Trialtrove includes information from ClinicalTrials.gov among its more than 30,000 sources. We assessed breast cancer, non-small cell lung cancer, type 2 diabetes mellitus, and pain clinical trials submitted to ClinicalTrials.gov . We compared the number of trials associated with each disease indication for each database, and we conducted a head-to-head comparison of certain data fields of clinical trial information found in both databases for clinical trials with identical National Clinical Trial (NCT) numbers. RESULTS: As of January 17, 2017, Trialtrove captured 31% more clinical trials (10,786 trials) in the selected disease indications than did ClinicalTrials.gov (7,419 trials) using identical Medical Subject Headings (MeSH) terms for breast cancer, non-small cell lung cancer, type 2 diabetes mellitus, and pain. Clinical trial site information was identical in 48% of clinical trials, while country information was identical in 82% of clinical trials, and patient enrollment figures identical for 86% of clinical trials. Clinical trial status, Phase, and start year differed across the 2 datasets. CONCLUSION: This study provides a baseline to compare the completeness of trial information required by the NIH and HHS with respect to reporting practices on ClinicalTrials.gov . While one cannot determine which database is more accurate: ClinicalTrials.gov or Trialtrove, wide variation exists in clinical trial site and country information for trials with identical NCT numbers suggesting that caution should be used when relying solely on ClinicalTrials.gov to assess the clinical trial landscape.

Cost Drivers of a Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia Phase 3 Clinical Trial.

Background: Studies indicate that the prevalence of multidrug-resistant infections, including hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), has been rising. There are many challenges associated with these disease conditions and the ability to develop new treatments. Additionally, HABP/VABP clinical trials are very costly to conduct given their complex protocol designs and the difficulty in recruiting and retaining patients. Methods: With input from clinicians, representatives from industry, and the US Food and Drug Administration, we conducted a study to (1) evaluate the drivers of HABP/VABP phase 3 direct and indirect clinical trial costs; (2) to identify opportunities to lower these costs; and (3) to compare (1) and (2) to endocrine and oncology clinical trials. Benchmark data were gathered from proprietary and commercial databases and used to create a model that calculates the fully loaded (direct and indirect) cost of typical phase 3 HABP/VABP endocrine and oncology clinical trials. Results: Results indicate that the cost per patient for a 200-site, 1000-patient phase 3 HABP/VABP study is $89600 per patient. The cost of screen failures and screen failure rates are the main cost drivers. Conclusions: Results indicate that biopharmaceutical companies and regulatory agencies should consider strategies to improve screening and recruitment to decrease HABP/VABP clinical trial costs.

Baseline Assessment of a Global Clinical Investigator Landscape Poised for Structural Change.

Mergers and acquisitions, the convergence of clinical research into clinical practice, more effective site selection and management practices, and efforts to improve investigator competence and credentials are all expected to contribute to consolidation in the global investigative site landscape during the coming 3 to 5 years. Tufts CSDD conducted an analysis of the FDA's Bioresearch Monitoring Information System (BMIS) to gather baseline data with which to monitor this anticipated structural change. More than half-a-million records were analyzed on clinical investigators who have filed at least 1 form 1572 with the FDA annually between 2008 and 2015. The results show that the global landscape of unique FDA-regulated principal investigators remains highly fragmented, nascent, and unstable. Principal investigators who file the lowest volume of 1572 forms each year make up the highest proportion of the global landscape, and one-third of all principal investigators each year are first-time filers. Each year, 40% of principal investigators drop out of the clinical research enterprise. However, there are signs that the landscape is beginning to scale and mature, particularly among investigators in North America. In addition, the rate of globalization is slowing and shifting, where recent growth in the number of active principal investigators in Europe has outpaced that in North America and in the rest of world. The implications of this study and future areas of research are discussed.

A Survey of Adverse Event Reporting Practices Among US Healthcare Professionals.

INTRODUCTION: The under-reporting of adverse drug events (ADEs) is an international health concern. A number of studies have assessed the root causes but, to our knowledge, little information exists relating under-reporting to practices and systems used for the recording and tracking of drug-related adverse event observations in ambulatory settings, institutional settings, and retail pharmacies. OBJECTIVES: Our objective was to explore the process for reporting ADEs in US hospitals, ambulatory settings, and retail pharmacies; to explore gaps and inconsistencies in the reporting process; and to identify the causes of under-reporting ADEs in these settings. METHODS: The Tufts Center for the Study of Drug Development (Tufts CSDD) interviewed 11 thought leaders and conducted a survey between May and August 2014 among US-based healthcare providers (HCPs) in diverse settings to assess their experiences with, and processes for, reporting ADEs. RESULTS: A total of 123 individuals completed the survey (42 % were pharmacists; 27 % were nurses; 15 % were physicians; and 16 % were classified as 'other'). HCPs indicated that the main reasons for under-reporting were difficulty in determining the cause of the ADE, given that most patients receive multiple therapies simultaneously (66 % of respondents); that HCPs lack sufficient time to report ADEs (63 % of respondents); poor integration of ADE-reporting systems (53 % of respondents); and uncertainty about reporting procedures (52 % of respondents). DISCUSSION: The results of this pilot study identify that key factors contributing to the under-reporting of ADEs relate to a lack of standardized process, a lack of training and education, and a lack of integrated health information technologies.

Mobile Nurse Services in Clinical Trials: Usage and Industry Perceptions.

BACKGROUND: With the pharmaceutical industry's increased attention on enhancing patient experiences during their participation in clinical trials, the use of mobile nurse (MN) services to support the conduct of clinical trial assessments in the home (or in alternative locations other than in investigational sites) has been gaining momentum. METHODS: Because no quantitative data capturing industry-wide practices are available, in July 2014, Tufts Center for the Study of Drug Development and Hoffman-La Roche conducted an online survey to gather data on the prevalence and utilization of MN services in clinical trials taking into account the following factors: industry perceptions of the business model, risks barriers to adoption, vendor landscape, cost, and prospects for future growth. A total of 113 respondents answered the survey, with 53 respondents answering all questions. RESULTS: The use of MN services in clinical trials is an established and growing business practice. Utilization of MN services has so far been most prevalent in North America, followed by Western Europe. Sponsor companies that have adopted this model have done so mainly to improve patient retention and protocol compliance, as well as improve access to rare patients. Most of the companies surveyed work directly with vendors specializing in home nurse services. Experience with vendors was considered favorable in most cases. CONCLUSIONS: Building effective partnerships with 1 to 2 vendors is considered a key factor for long-term success.

The Impact of Protocol Amendments on Clinical Trial Performance and Cost.

BACKGROUND: Tufts Center for the Study of Drug Development (Tufts CSDD), in collaboration with 15 pharmaceutical companies and contract research organizations, gathered data on substantial global protocol amendments to better understand how to manage and to reduce the significant unplanned expense and delays associated with major changes to finalized protocol designs. METHODS: Data from 836 phase I-IIB/IV protocols were analyzed to understand amendment prevalence. Impact assessments were based on data from 136 randomly selected amendments. Data from 52 protocols were analyzed to derive estimates of the direct cost to implement amendments. RESULTS: Tufts CSDD found that 57% of protocols had at least one substantial amendment, and nearly half (45%) of these amendments were deemed "avoidable." Phase II and III protocols had a mean number of 2.2 and 2.3 global amendments, respectively. Protocols with one or more global amendments tended to be larger in scope, with longer patient recruitment durations and overall study durations compared with those without a global amendment. Protocols with at least one substantial amendment had fewer actual screened and enrolled patients relative to the original baseline plan than did those protocols without an amendment. The median direct cost to implement a substantial amendment was US$141,000 for a phase II protocol and $535,000 for a phase III protocol. CONCLUSIONS: The study findings provide insights into optimizing development planning, protocol design, and clinical trial management practices.

Evaluating AE Reporting of Two Off-Patent Biologics to Inform Future Biosimilar Naming and Reporting Practices.

Historical studies of voluntary, spontaneous drug reports show poor attribution of adverse events to generic versions of commonly prescribed medications. As biosimilars enter the market place, it may be similarly difficult to accurately attribute adverse events to their respective reference products. At this time, lack of global consensus with regard to biosimilar naming conventions may result in drug reporting confusion, misattribution of adverse events and insufficient active monitoring of safety signals. Now, with the first biosimilar approval in the USA and many biosimilars expected to be launched globally in the near future, US Food and Drug Administration (FDA) guidance on biosimilar naming conventions will be essential. To inform the FDA and the global drug development community, the Tufts Center for the Study of Drug Development (Tufts CSDD) examined primary suspect reports sent to the FDA's Adverse Event Reporting System (FAERS) from US reporters for two biologics that have lost patent exclusivity--somatropin and human insulin--and extracted 4703 insulin reports and 6487 somatropin reports from FAERS. The results show that reporting practices are inconsistent between the two biologics that were evaluated and that manufacturer identifiability and traceability are lacking. Ways to improve biosimilar naming conventions and improve reporting practices are suggested.

Regulatory Definitions and Good Pharmacovigilance Practices in Social Media: Challenges and Recommendations.

Social media presents new challenges to the biopharmaceutical industry for conducting pharmacovigilance activities. The authors reviewed worldwide regulatory guidance documents related to monitoring of adverse events posted on social media sites and identified gaps in current regulatory definitions for pharmacovigilance. Points to consider for addressing these gaps are made to offer standards for industry consideration and a potential framework for guidance from global health authorities.

Identifying and Quantifying the Accuracy of Product Name Attribution of US-Sourced Adverse Event Reports in MedWatch of Somatropins and Insulins.

BACKGROUND: As of 2014, the US FDA was considering policy options to promote accurate attribution of adverse events for biosimilars. In order to assess the identification and traceability of biologics from multiple sources, Tufts University's Center for the Study of Drug Development conducted a study reviewing the current FDA Adverse Event Reporting System (FAERS) for reports related to insulin and growth hormone products. METHODS: For this study, all primary suspect reports that were received by FAERS for human growth hormone (hGH) and human insulin between the fourth quarter of 2005 and the third quarter of 2013 were extracted and analyzed. RESULTS: The rates of "accurate" brand (ie, identifiable) drug names were generally high, with a higher incidence for hGH drugs than for insulin drugs (92% of hGH primary suspect reports vs 84% of insulin primary suspect reports). Lot number completion rates were generally low, with a higher incidence for insulin drugs than for hGH drugs (37% of insulin primary suspect reports vs 13% of hGH primary suspect reports). There were 13.5% of insulin reports that could not be linked to manufacturers, while 7.5% of hGH reports could not be linked to a manufacturer. CONCLUSIONS: The completion and accuracy rates of FAERS data on biologics observed in this study are consistent with those observed in earlier studies and suggest that traceability in adverse event reports can be improved through more consistent use of brand names or other product specific identifiers and through more frequent inclusion of lot numbers.

Quantifying the magnitude and cost of collecting extraneous protocol data.

Although most research professionals believe that protocol designs contain a growing number of unnecessary and redundant procedures generating unused data, incurring high cost, and jeopardizing study success, there are no published studies systematically examining this issue. Between November 2011 and May 2012, Tufts Center for the Study of Drug Development conducted a study among a working group of 15 pharmaceutical companies in which a total of 25,103 individual protocol procedures were evaluated and classified using clinical study reports and analysis plans. The results show that the typical later-stage protocol had an average of 7 objectives and 13 end points of which 53.8% are supplementary. One (24.7%) of every 4 procedures performed per phase-III protocol and 17.7% of all phase-II procedures per protocol were classified as "Noncore" in that they supported supplemental secondary, tertiary, and exploratory end points. For phase-III protocols, 23.6% of all procedures supported regulatory compliance requirements and 15.9% supported those for phase-II protocols. The study also found that on average, $1.7 million (18.5% of the total) is spent in direct costs to administer Noncore procedures per phase-III protocol and $0.3 million (13.1% of the total) in direct costs are spent on Noncore procedures for each phase-II protocol. Based on the results of this study, the total direct cost to perform Noncore procedures for all active annual phase-II and phase-III protocols is conservatively estimated at $3.7 billion annually, not including the indirect costs associated with collecting and managing Noncore procedure data and the ethical costs of exposing study volunteers to unnecessary risks associated with conducting extraneous procedures.