Examining association between cohesion and diversity in collaboration networks of pharmaceutical clinical trials with drug approvals.
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ABSTRACT: Objective
Clinical trials ensure that pharmaceutical treatments are safe, efficacious, and effective for public consumption, but are extremely complex, taking up to 10 years and $2.6 billion to complete. One main source of complexity arises from the collaboration between actors, and network science methodologies can be leveraged to explore that complexity. We aim to characterize collaborations between actors in the clinical trials context and investigate trends of successful actors.Materials and methods
We constructed a temporal network of clinical trial collaborations between large and small-size pharmaceutical companies, academic institutions, nonprofit organizations, hospital systems, and government agencies from public and proprietary data and introduced metrics to quantify actors' collaboration network structure, organizational behavior, and partnership characteristics. A multivariable regression analysis was conducted to determine the metrics' relationship with success.Results
We found a positive correlation between the number of successful approved trials and interdisciplinary collaborations measured by a collaboration diversity metric (P < .01). Our results also showed a negative effect of the local clustering coefficient (P < .01) on the success of clinical trials. Large pharmaceutical companies have the lowest local clustering coefficient and more diversity in partnerships across biomedical specializations.Conclusions
Large pharmaceutical companies are more likely to collaborate with a wider range of actors from other specialties, especially smaller industry actors who are newcomers in clinical research, resulting in exclusive access to smaller actors. Future investigations are needed to show how concentrations of influence and resources might result in diminished gains in treatment development.
SUBMITTER: Lin G
PROVIDER: S-EPMC7810455 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC10690876 | biostudies-literature
Project description:ImportanceWhile there have been multiple assessments of clinical trials leading to anticancer drug approvals by the US Food and Drug Administration (FDA), the cumulative percentage of approvals based on trials with a limitation remains uncertain.ObjectiveTo assess the percentage of clinical trials with limitations in 4 domains-lack of randomization, lack of significant overall survival advantage, inappropriate use of crossover, and use of suboptimal control arms-that led to FDA approvals from June 30, 2014, to July 31, 2019.Design, setting, and participantsThis observational analysis included all anticancer drug indications approved by the FDA from June 30, 2014, through July 31, 2019. All indications were investigated, and each clinical trial was evaluated for design, enrollment period, primary end points, and presence of a limitation in the domains of interest. The standard-of-care therapy was determined by evaluating the literature and published guidelines 1 year prior to the start of clinical trial enrollment. Crossover was examined and evaluated for optimal use. The percentage of approvals based on clinical trials with any or all limitations of interest was then calculated.Main outcomes and measuresEstimated percentage of clinical trials with limitations of interest that led to an anticancer drug marketing authorization by the FDA.ResultsA total of 187 trials leading to 176 approvals for 75 distinct novel anticancer drugs by the FDA were evaluated. Sixty-four (34%) were single-arm clinical trials, and 123 (63%) were randomized clinical trials. A total of 125 (67%) had at least 1 limitation in the domains of interest; 60 of the 125 trials (48%) were randomized clinical trials. Of all 123 randomized clinical trials, 37 (30%) lacked overall survival benefit, 31 (25%) had a suboptimal control, and 17 (14%) used crossover inappropriately.Conclusions and relevanceTwo-thirds of cancer drugs are approved based on clinical trials with limitations in at least 1 of 4 essential domains. Efforts to minimize these limitations at the time of clinical trial design are essential to ensure that new anticancer drugs truly improve patient outcomes over current standards.
| S-EPMC7296449 | biostudies-literature
Project description:BackgroundThere is a natural assumption that quality and efficiency are optimized when providers consistently work together and share patients. Diversity in composition and recurrence of groups that provide face-to-face care to the same patients has not previously been studied.ObjectiveClaims data enable identification of the constellation of providers caring for a single patient. To indirectly measure teamwork and provider collaboration, we measure recurrence of provider constellations and cohesion among providers.DesignRetrospective analysis of commercial healthcare claims from a single insurer.ParticipantsPatients with claims for office visits and their outpatient providers. To maximize capture of provider panels, the cohort was drawn from the four regions with the highest plan coverage. Regional outpatient provider networks were constructed with providers as nodes and number of shared patients as links.Main measuresMeasures of cohesion and stability of provider constellations derived from the networks of providers to quantify patient sharing.ResultsFor 10,325 providers and their 521,145 patients, there were 2,641,933 collaborative provider pairs sharing at least one patient. Fifty-four percent only shared a single patient, and 19 % shared two. Of 15,449,835 unique collaborative triads, 92 % shared one patient, 5 % shared two, and 0.2 % shared ten or more. Patient constellations had a median of four providers. Any precise constellation recurred rarely-89 % with exactly two providers shared just one patient and only 4 % shared over two; 97 % of constellations with exactly three providers shared just one patient. Four percent of constellations with 2+ providers were not at all cohesive, sharing only the hub patient. In the remaining constellations, a median of 93 % of provider pairs shared at least one additional patient beyond the hub patient.ConclusionStunning variability in the constellations of providers caring for patients may challenge underlying assumptions about the current state of teamwork in healthcare.
| S-EPMC4238195 | biostudies-literature
Project description:BackgroundMedical devices can be useful in a variety of diseases, but few devices have been specifically approved for use in children. The 2007 Pediatric Medical Device Safety and Improvement Act was passed to stimulate pediatric device development. The current state of trial evidence underpinning the approval of pediatric devices remains poorly described.MethodsWe identified all high-risk (ie, class III) devices approved through the premarket approval or humanitarian device exemption pathways for therapeutic use in children between 2008 and 2011. We collected key information on clinical trial design (randomization, blinding, controls, and types of end points) as well as age distribution of trial participants. We also identified US Food and Drug Administration (FDA)-mandated postmarketing trials.ResultsTwenty-two devices were approved for use in children via the premarket approval pathway and 3 via the humanitarian device exemption pathway. Twenty-two (88%) qualified as pediatric despite minimum approval ages of ≥18 years (the FDA Center for Devices and Radiologic Health considers patients 18-21 years old as pediatric). Most devices were approved on the basis of nonrandomized (59%), open-label (68%) studies with surrogate effectiveness end points (86%). Overall, 21 (84%) devices were not studied in any patients <18 years of age. Postmarketing studies were mandated by the FDA for 19 (76%) devices, although only 3 (18%) required enrollment of pediatric patients.ConclusionsMost high-risk pediatric devices are approved on the basis of trials in patients ≥18 years old, with few pediatric patients exposed to the devices before market availability. Few postmarketing studies require additional study in pediatric patients.
| S-EPMC4531281 | biostudies-literature
Project description:BackgroundIt has been suggested that the results from fragile trials are less likely to translate into benefit in routine clinical practice.MethodsWe searched the Food and Drug Administration (FDA) archives to identify drug approvals for solid organ malignancies between 2010 and 2019. We calculated the Fragility Index (FI) supporting each approval, using methods to account for time-to-event. We compared FI and trial and approval characteristics using Mann-Whitney U and Kruskal-Wallis test. Using logistic regression, we examined study characteristics associated with withdrawal of consent or lost to follow-up (WCLFU) exceeding the calculated FI.ResultsThe median FI among 125 included studies was 23 (range 1-322). The FI was ≤10 in 35 studies (28%), 11-20 in 21 (17%), and >20 in 69 (55%). The median FI/Nexp was 7.7% (range 0.1-51.7%). The median FI was significantly lower among approvals processed through the accelerated vs regular pathway (5.5 vs 25, p = 0.001), but there was no difference in median FI/Nexp. The WCLFU exceeded FI in 42% of studies. Overall survival endpoints were more likely to have a WCLFU exceeding FI (OR 3.16, p = 0.003). WCLFU exceeding FI was also associated with a lesser magnitude of effect (median HR 0.69 vs 0.55, p < 0.001). In a sensitivity analysis including only studies with 1:1 randomization, 51% of studies had WCLFU >FI.ConclusionThe median FI among all trials was 23, and WCLFU exceeded FI in 42%. Comparative trials in solid tumors supporting approval through the accelerated pathway are more fragile compared to trials approved through the regular pathway, an observation likely explained by a lower sample size in the experimental arm.
| S-EPMC8366090 | biostudies-literature
Project description:Community cohesion plays a critical role in the determination of an individual's health in social science. Intriguingly, a community structure of gene networks indicates that the concept of community cohesion could be applied between the genes as well to overcome the limitations of single gene-based biomarkers for precision oncology. Here, we develop community cohesion scores which precisely quantify the community ability to retain the interactions between the genes and their cellular functions in each individualized gene network. Using breast cancer as a proof-of-concept study, we measure the community cohesion score profiles of 950 case samples and predict the individualized therapeutic targets in 2-fold. First, we prioritize them by finding druggable genes present in the community with the most and relatively decreased scores in each individual. Then, we pinpoint more individualized therapeutic targets by discovering the genes which greatly contribute to the community cohesion looseness in each individualized gene network. Compared with the previous approaches, the community cohesion scores show at least four times higher performance in predicting effective individualized chemotherapy targets based on drug sensitivity data. Furthermore, the community cohesion scores successfully discover the known breast cancer subtypes and we suggest new targeted therapy targets for triple negative breast cancer (e.g. KIT and GABRP). Lastly, we demonstrate that the community cohesion scores can predict tamoxifen responses in ER+ breast cancer and suggest potential combination therapies (e.g. NAMPT and RXRA inhibitors) to reduce endocrine therapy resistance based on individualized characteristics. Our method opens new perspectives for the biomarker development in precision oncology.
| S-EPMC11018546 | biostudies-literature
Project description:ImportanceGovernment and the pharmaceutical industry make substantive contributions to pharmaceutical innovation. This study compared the investments by the National Institutes of Health (NIH) and industry and estimated the cost basis for assessing the balance of social and private returns.ObjectivesTo compare NIH and industry investments in recent drug approvals.Design, setting, and participantsThis cross-sectional study of NIH funding associated with drugs approved by the FDA from 2010 to 2019 was conducted from May 2020 to July 2022 and accounted for basic and applied research, failed clinical candidates, and discount rates for government spending compared with analogous estimates of industry investment.Main outcomes and measuresCosts from the NIH for research associated with drug approvals.ResultsFunding from the NIH was contributed to 354 of 356 drugs (99.4%) approved from 2010 to 2019 totaling $187 billion, with a mean (SD) $1344.6 ($1433.1) million per target for basic research on drug targets and $51.8 ($96.8) million per drug for applied research on products. Including costs for failed clinical candidates, mean (SD) NIH costs were $1441.5 ($1372.0) million per approval or $1730.3 ($1657.6) million per approval, estimated with a 3% discount rate. The mean (SD) NIH spending was $2956.0 ($3106.3) million per approval with a 10.5% cost of capital, which estimates the cost savings to industry from NIH spending. Spending and approval by NIH for 81 first-to-target drugs was greater than reported industry spending on 63 drugs approved from 2010 to 2019 (difference, -$1998.4 million; 95% CI, -$3302.1 million to -$694.6 million; P = .003). Spending from the NIH was not less than industry spending considering clinical failures, a 3% discount rate for NIH spending, and a 10.5% cost of capital for the industry (difference, -$1435.3 million; 95% CI, -$3114.6 million to $244.0 million; P = .09) or when industry spending included prehuman research (difference, -$1394.8 million; 95% CI, -$3774.8 million to $985.2 million; P = .25). Accounting for spillovers of NIH-funded basic research on drug targets to multiple products, NIH costs were $711.3 million with a 3% discount rate, which was less than the range of reported industry costs with 10.5% cost of capital.Conclusions and relevanceThe results of this cross-sectional study found that NIH investment in drugs approved from 2010 to 2019 was not less than investment by the pharmaceutical industry, with comparable accounting for basic and applied research, failed clinical trials, and cost of capital or discount rates. The relative scale of NIH and industry investment may provide a cost basis for calibrating the balance of social and private returns from investments in pharmaceutical innovation.
| S-EPMC10148199 | biostudies-literature
Project description:ImportanceDiverse, representative enrollment in pivotal clinical trials is vital to sufficiently power subgroup analyses and ensure equity and validity of trial results.ObjectiveTo evaluate the racial/ethnic representation, trends, and disparities in clinical trials leading to US Food and Drug Administration (FDA) ophthalmology drug approvals from 2000 to 2020.Design, setting, and participantsThis cohort study used data from participants in clinical trials of drugs for neovascular age-related macular degeneration (AMD), open-angle glaucoma (OAG), and expanded indications for diabetic retinopathy (DR) from January 1, 2000, to December 31, 2020. Trial data were sourced from FDA reviews, ClinicalTrials.gov, and relevant linked studies. National expected racial/ethnic proportions were sourced from public National Eye Institute prevalence data as well as published rates scaled using US Census Bureau data.Main outcomes and measuresThe primary outcome measures were the distribution of and change over time in the racial/ethnic proportion of participants in clinical trials leading to FDA approval of drugs for AMD, OAG, and DR.ResultsDuring the 20-year period, 31 clinical trials were identified for 13 medications with 18 410 participants. The distribution of trial participants was different from the expected trial distribution for most approvals with regard to race/ethnicity (12 drugs) and sex (10 drugs). Compared with the first decade (2000-2010), trials conducted in the second decade (2011-2020) showed increases in enrollment of Asian (odds ratio [OR], 2.30; 95% CI, 1.97-2.68; P < .001) and Hispanic or Latinx participants (OR, 1.74; 95% CI, 1.49-2.03; P < .001) for AMD, Asian participants (OR, 2.21; 95% CI, 1.46-3.42; P < .001) for DR, and Black (OR, 1.60; 95% CI, 1.43-1.78; P < .001) and Hispanic or Latinx participants (OR, 10.31; 95% CI, 8.05-13.35; P < .001) for OAG. There was a decrease in Black participants in DR trials (OR, 0.58; 95% CI, 0.42-0.79; P < .001). Based on these trends, the enrollment incidence ratio is expected to worsen by 2050, with overrepresentation of white participants vs underrepresentation of Black and Hispanic or Latinx participants in trials of drugs for AMD (1.08 vs 0.04 vs 0.77), DR (1.83 vs 0.87 vs 0.59), and OAG (1.62 vs 0.90 vs 0.37).Conclusions and relevanceIn this cohort study, Black, Hispanic or Latinx, and other non-White participants were underrepresented in clinical trials leading to FDA ophthalmology drug approvals compared with the expected disease burden and racial/ethnic distribution in the US. Although there was meaningful improvement from 2000 to 2020, further efforts to increase minority enrollment in clinical trials seem to be warranted.
| S-EPMC8063130 | biostudies-literature
Project description:ObjectiveStatistical significance drives interpretation of randomized controlled trials (RCTs). We examined the type S error risk-claiming a new drug is falsely beneficial-and exaggeration ratio-how estimated effects differ from true effects-to re-emphasize direction and magnitude of treatment effects.Study design and settingWe systematically reviewed RCTs supporting Food and Drug Administration (FDA) approval of cancer drugs between 2007 and 2016. We extracted data for overall survival (OS), progression-free survival (PFS), and response outcomes from FDA reviews. We estimated type S error risks and exaggeration ratios by considering replicated RCTs of equal size and a range of true effects.ResultsWe analyzed 42 RCTs for 39 approved drugs. Across 38 RCTs reporting OS, the median type S error risk was 0.00% (Q1-Q3, 0.00-0.01%) and 3.56% (0.40-6.74%), for true hazard ratios of 0.7 and 0.9, respectively, indicating confidence in effect direction. The corresponding exaggeration ratios were 1.09 (1.01-1.11) and 1.30 (1.13-1.42), indicating median overestimations of 9% and 30%. Similar results held for PFS and response outcomes.ConclusionsThe type S error risk and exaggeration ratio provide additional insights into the replicability of RCTs. Our analyses also quantify the winner's curse, in which pivotal RCTs tend toward overoptimism.
| S-EPMC8978539 | biostudies-literature
Project description:BackgroundProportionate female representation in health research is necessary for scientific rigor and health equity. We aimed to assess the representation of women in clinical trials leading to U.S. Food and Drug Administration (FDA) cancer drug approvals.Materials and methodsTrials supporting FDA cancer drug approvals between July 2008 and June 2018 were sourced from PubMed and ClinicalTrials.gov. The ratio of female to male trial enrollment was compared with cancer incidence and mortality in the U.S. using International Agency for Research on Cancer data. Reproductive tract and breast cancers were excluded. Odds ratios (ORs) and 95% confidence intervals (CIs) comparing trial enrollment with population incidence and mortality were calculated.ResultsA total of 186 trials leading to 170 FDA cancer drug approvals showed slight female underrepresentation compared with overall cancer incidence in the U.S. (OR, 0.97; 95% CI, 0.95-0.98, p < .0001). Female enrollment for drugs approved between 2008-2013 and 2014-2018 was unchanged (OR, 1.02; 95% CI, 0.99-1.05, p = .25). There was slight female underrepresentation in hematological trials (OR, 0.95; 95% CI, 0.91-0.998; p = .040 for leukemia; OR, 0.95; 95% CI, 0.90-0.997; p = .040 for lymphoma) and significant female underrepresentation in colorectal (OR, 0.72; 95% CI, 0.69-0.76; p < .0001), pancreas (OR, 0.85; 95% CI, 0.78-0.93; p = .0004), lung (OR, 0.77; 95% CI, 0.75-0.80; p < .0001), kidney (OR, 0.63; 95% CI, 0.60-0.67; p < .0001), and thyroid cancer trials (OR, 0.26; 95% CI, 0.23-0.28; p < .0001) compared with U.S. incidence.ConclusionFemale underrepresentation has persisted within solid organ tumor trials but is less notable in hematologic trials. Additional work is required to identify drivers of such disparity.Implications for practiceAdequate gender representation in clinical trials is a matter of health equity. This study demonstrates that women remain underrepresented in trials across hematological and solid organ trials compared with cancer incidence and mortality in women, with the disparity worse in a number of solid organ tumor types. There are thus still significant improvements to be made regarding adequate representation of women in trials. Studies exploring the reasons for ongoing disparity in gender representation are warranted to help clinicians to rectify this.
| S-EPMC7873318 | biostudies-literature