Assessing the net financial benefits of employing digital endpoints in clinical trials.

In the last few decades, developers of new drugs, biologics, and devices have increasingly leveraged digital health technologies (DHTs) to assess clinical trial digital endpoints. To our knowledge, a comprehensive assessment of the financial net benefits of digital endpoints in clinical trials has not been conducted. We obtained data from the Digital Medicine Society (DiMe) Library of Digital Endpoints and the US clinical trials registry, ClinicalTrials.gov. The benefit metrics are changes in trial phase duration and enrollment associated with the use of digital endpoints. The cost metric was obtained from an industry survey of the costs of including digital endpoints in clinical trials. We developed an expected net present value (eNPV) model of the cash flows for new drug development and commercialization to assess financial value. The value measure is the increment in eNPV that occurs when digital endpoints are employed. We also calculated a return on investment (ROI) as the ratio of the estimated increment in eNPV to the mean digital endpoint implementation cost. For phase II trials, the increase in eNPV varied from $2.2 million to $3.3 million, with ROIs between 32% and 48% per indication. The net benefits were substantially higher for phase III trials, with the increase in eNPV varying from $27 million to $40 million, with ROIs that were four to six times the investment. The use of digital endpoints in clinical trials can provide substantial extra value to sponsors developing new drugs, with high ROIs.

New Estimates on the Cost of a Delay Day in Drug Development.

Two frequently cited figures by clinical research insiders and observers - the cost of missing a day to generate prescription drug sales and the cost of a day to conduct a clinical trial - are outdated and based on anecdotal evidence. In late 2023, the Tufts Center for the Study of Drug Development conducted empirical research to gather more accurate and granular estimates and to test whether average sales per day have changed over time. 645 drugs launched since 2000, and 409 clinical trial budgets were drawn from commercially available and proprietary data sets and analyzed. The results indicate that a single day equals approximately $500,000 in lost prescription drug or biologic sales, with daily prescription sales for infectious, hematologic, cardiovascular, and gastrointestinal diseases among the highest. The results also show that each year, the average sales per day of prescription drugs and biologics has decreased by approximately $80,000-$100,000. The estimated direct daily cost to conduct a clinical trial is approximately $40,000 per day for phase II and III clinical trials, with those in respiratory, rheumatology, and dermatology having the highest relative daily direct costs.

Assessing the Financial Value of Decentralized Clinical Trials.

BACKGROUND: Deployment of remote and virtual clinical trial methods and technologies, referred to collectively as decentralized clinical trials (DCTs), represents a profound shift in clinical trial practice. To our knowledge, a comprehensive assessment of the financial net benefits of DCTs has not been conducted. METHODS: We developed an expected net present value (eNPV) model of the cash flows for new drug development and commercialization to assess the financial impact of DCTs. The measure of DCT value is the increment in eNPV that occurs, on average, when DCT methods are employed in comparison to when they are not. The model is populated with parameter values taken from published studies, Tufts CSDD benchmark data, and Medable Inc. data on DCT projects. We also calculated the return on investment (ROI) in DCTs as the ratio of the increment in eNPV to the DCT implementation cost. RESULTS: We found substantial value from employing DCT methods in phase II and phase III trials. If we assume that DCT methods are applied to both phase II and phase III trials the increase in value is $20 million per drug that enters phase II, with a seven-fold ROI. CONCLUSIONS: DCTs can provide substantial extra value to sponsors developing new drugs, with high returns to investment in these technologies. Future research on this topic should focus on expanding the data to larger datasets and on additional aspects of clinical trial operations not currently measured.

Evaluating the Feasibility and Validity of a New Tool to Assess Organizational Preparedness and Capabilities to Support Patient Engagement in Drug Development.

Interest in patient-centric initiatives to engage patients as partners in clinical research and inform drug development strategy, planning and execution has increased exponentially during the past decade. Adoption, use, organizational approach and infrastructure supporting patient-centric initiatives, however, varies widely from company to company. The Drug Information Association (DIA) in collaboration with the Tufts Center for the Study of Drug Development (Tufts CSDD) at the Tufts University School of Medicine developed and validated an assessment tool that companies can use to evaluate their organization's patient engagement preparedness and capabilities within the context of industry-wide practices. This paper discusses the development of the tool, the assessment experience, and implications for further refinement of the assessment process. Specifically, the team conducted an extensive literature review, compiled and analyzed case studies and gathered input from a working group of 18 biopharmaceutical companies. To validate the assessment tool and demonstrate its feasibility, the DIA-CSDD Tufts team conducted a pilot implementation involving onsite and virtual in-depth interviews among 14 biopharmaceutical companies. A subsequent paper will report on the findings from the 14 companies assessed.

Quantifying Patient Subpopulation Disparities in New Drugs and Biologics Approved Between 2007 and 2017.

BACKGROUND: Tufts CSDD conducted a study to quantify the magnitude of participant subgroup demographic disparities in industry-funded pivotal trials and establish baseline participant diversity measures. METHODS: Eleven years of data on pivotal trials of all novel drugs and biologics approved between 2007 and 2017 (n = 341 drugs and n = 757 pivotal trials) was compiled and analyzed. RESULTS: The availability of reported participant demographic subgroup data was poor-most notably participant ethnicity with 63% of pivotal trials supporting all approved treatments missing data. The availability of data on participant race and ethnicity did not improve between 2007 and 2017. Participants of Black or of African Descent were the subgroup most highly under-represented. Three times as many participants in this demographic subgroup should have been enrolled in pivotal trials to achieve representation as dictated by disease prevalence rates and population census figures. Although variation was observed between disease conditions, under-representation of Black/African Descent participants occurred in nearly all conditions. Participants from indigenous communities were also highly under-represented. Asian participants were highly over-represented in pivotal trials. Approximately 14% more Hispanic/Latinx participants should have been enrolled in clinical trials to achieve population-proportional representation. CONCLUSIONS: The results suggest that participant demographic disclosure practices are falling short and that insufficient diversity in clinical trials is limiting the value of guidance on medical treatment dosing and response. The study findings supplement the FDA's Drug Trial Snapshot Reports and offer insight into the magnitude of, and trends in, participant demographic subgroup disparities.

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.

US Physician and Nurse Proclivity to Refer Their Patients Into Clinical Trials.

BACKGROUND: Clinical research awareness, familiarity, referral proclivity, and practice have been assessed to varying degrees among US-based physicians specializing in oncology but very few studies have assessed these attitudes and behaviors among US physicians and nurses outside of oncology. METHODS: To address this gap, the Tufts Center for the Study of Drug Development (Tufts CSDD) conducted a study of 589 US-based physicians and 1255 US-based nurses. RESULTS AND CONCLUSIONS: US health care providers have very limited exposure to clinical research in medical and nursing school and in professional meetings. Very high percentages of multispecialty nurses and doctors view clinical trials as health care options, are interested in referring their patients into appropriate clinical trials, and are comfortable providing clinical trial information to, and discussing clinical trial opportunities with, their patients. Yet US physicians and nurses refer very small numbers of patients each year largely because of the inability to access clinical trial information, and the lack of sufficient information and time to evaluate and confidently discuss clinical trial options with their patients. Several factors are predictors of referral behavior, including proximity to research activity and past involvement in clinical research as an investigator, study coordinator, or study volunteer. The results of this study offer new insights into addressing low referral rates among US health care providers.

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).

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.

Insights and Best Practices for Planning and Implementing Patient Advisory Boards.

A growing number of organizations-including pharmaceutical and biotechnology companies, foundations and associations-are routinely implementing patient advisory boards (PAB) given their high reported value for minimal relative investment. Organizations are typically implementing PABs to solicit patient voices and perspectives on a variety of areas such as protocol designs, clinical trial medicine kit designs, informed consent form designs, technology solutions, and patient communication materials. The Center for Information and Study on Clinical Research Participation (CISCRP) has planned, executed, and facilitated more than 30 PABs. In this article, the authors share lessons learned and best practices with regard to structure, format, and process for organizations wishing to adopt and implement PABs. The authors also provide metrics on the adoption and impact of PABs.

New Benchmarks Characterizing Growth in Protocol Design Complexity.

The Tufts Center for the Study of Drug Development and Medidata Solutions Inc analyzed data from 9737 protocols and 130,601 investigative site contracts associated with these protocols to derive updated benchmarks characterizing protocol complexity. The results of the study indicate that protocol design complexity continues to grow rapidly. Nearly all phase I, II, and III complexity measures associated with protocol execution increased significantly (eg, P < .0001) from 2001-2005 to 2011-2015. These measures include the number of unique and total procedures performed per patient over the course of a study, the site work effort to administer protocol procedures, the number of study volunteer visits, and the total number of procedures performed per study volunteer visit. The total cost per planned study volunteer per visit also increased significantly (eg, P < .0001) as did the total cost per study volunteer across all planned study visits. Phase I protocols remain the most complex and the most demanding to execute. Phase III protocols have seen the most substantial growth in protocol complexity. Phase IV protocols saw only modest increases in executional complexity during the 10-year time horizon. The implications of the study findings are discussed.

Assessing the Financial Benefits of Faster Development Times: The Case of Single-source Versus Multi-vendor Outsourced Biopharmaceutical Manufacturing.

PURPOSE: The extent to which new drug developers can benefit financially from shorter development times has implications for development efficiency and innovation incentives. We provided a real-world example of such gains by using recent estimates of drug development costs and returns. METHODS: Time and fee data were obtained on 5 single-source manufacturing projects. Time and fees were modeled for these projects as if the drug substance and drug product processes had been contracted separately from 2 vendors. The multi-vendor model was taken as the base case, and financial impacts from single-source contracting were determined relative to the base case. FINDINGS: The mean and median after-tax financial benefits of shorter development times from single-source contracting were $44.7 million and $34.9 million, respectively (2016 dollars). The after-tax increases in sponsor fees from single-source contracting were small in comparison (mean and median of $0.65 million and $0.25 million). IMPLICATIONS: For the data we examined, single-source contracting yielded substantial financial benefits over multi-source contracting, even after accounting for somewhat higher sponsor fees.

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.

Examining and Enabling the Role of Health Care Providers as Patient Engagement Facilitators in Clinical Trials.

PURPOSE: The Tufts Center for the Study of Drug Development conducted a study among practicing physicians and nurses (health care providers) across multiple specialties to assess their attitudes and experiences with referring patients into clinical trials and to supplement the body of scholarly research focused primarily on referral practices among oncology-based health care providers. METHODS: A total of 755 physicians and 1255 nurses completed online surveys in late 2015 and early 2016. FINDINGS: The results of the study indicate that a high percentage of multispecialty nurses and physicians is interested in referring their patients to appropriate clinical trials, are familiar with the clinical trial process, and are comfortable providing clinical trial information to, and discussing clinical trial opportunities with, their patients. Study results also indicate, however, that health care providers refer only a small number of patients each year largely because of the inability to access clinical trial information and the lack of sufficient information and time to evaluate and confidently discuss clinical trial options with their patients. IMPLICATIONS: Many reasons for choosing not to refer patients appear addressable, particularly through effective but presently -underused communication leveraging social media communities and using liaisons who can act as a bridge between clinical care and clinical research.

Analysis of Review Times for Recent 505(b)(2) Applications.

BACKGROUND: Annual review statistics released by the Food and Drug Administration (FDA) and a number of studies indicate that the review process improvements introduced under various versions of the Prescription Drug Use Fee Act (PDUFA) have been successful in decreasing average times for marketing approval of new molecular entities (NMEs). Similar statistics are not available, however, for non-NME new drug applications. These application types, such as those covered under section 505(b)(2) of the Food and Drug and Cosmetic Act, represent more than half of all new drug application (NDA) submissions annually and they are primarily based on previously approved drugs. To our knowledge, this is the first study to gather review statistics on 505(b)(2) designations. METHODS: For this study, we analyzed total review times and review designations for 284 505(b)(2) NDA approvals between 2009 and 2015. RESULTS: Our results show that overall, the 505(b)(2) regulatory pathway results in longer review time than for NMEs despite the intent of the 505(b)(2) designation to simplify and streamline the review process. Several illustrative examples and the implications are discussed. CONCLUSIONS: For drug developers, the important take home message is that-as for any program at the FDA-shorter review times and fewer FDA requirements under a 505(b)(2) designation should not be anticipated or expected. The study results serve as benchmark data providing insights into regulatory submission strategy and planning.

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.