Regulatory review time and pharmaceutical research and development

In the United States, all newly developed drugs undergo a lengthy review process conducted by the US Food and Drug Administration (FDA). These regulatory delays have direct immediate costs for drug manufacturers and patients waiting for treatment. Under certain market conditions, regulatory delays may also affect future research and development (R&D) strategies of pharmaceutical companies. To estimate the magnitude of this effect, we match data on drugs in the development pipeline in 2006 to data that we collect on FDA review times for all drugs approved between 1999 and 2005. Employing a rich and novel set of controls that affect drug R&D decisions and, potentially, regulatory review lags, we find that on average, three additional months of delay result in one fewer drug in development in that drug category. Our results suggest that the length of the regulatory delay matters for pharmaceutical firms' R&D decisions and that the firms are likely unable to pass on these costs onto consumers.     

Direct comparison of reproducibility and reliability in quantitative assessments of burn scar properties

IntroductionDetermining the efficacy of anti-scar technologies can be difficult as qualitative, subjective assessments are often utilized instead of systematic, objective measures. Perceptions regarding the reliability of instruments for quantitative measurements along with their high cost and increased data collection time may discourage their use, leading to use of scar scales which are relatively quick and low-cost. To directly evaluate the reliability of instruments for quantitative measurements of scar properties, instruments and two qualitative scales were compared by assessing a variety of cutaneous scars.MethodsScar height and surface texture were evaluated using a 3D scanner and a mold/cast technique. Scar color was evaluated by using a spectroscopy-based tool, the Mexameter®, and digital photography with image analysis. Scar biomechanics were evaluated using the BTC-2000?, Dermal Torque Meter (DTM®), and ballistometer®. The Vancouver Scar Scale (VSS) and Patient and Observer Scar Assessment Scale (POSAS) were used to qualitatively evaluate the same scar properties. Intraclass correlation coefficients (ICC) were used to determine inter- and intra-user reliability (poor, moderate, good, excellent) with all instruments and the kappa reliability statistic was used to asses inter-user reliability (poor, fair, moderate, good, very good) for VSS and POSAS. Time for measurement collection and after collection analysis was also recorded.ResultsThe Mexameter® was the most reliable method for evaluating erythema and pigmentation compared to digital photography and image processing, POSAS and VSS. Digital photography and analysis was more reliable than POSAS and VSS. Assessment of scar height was significantly more reliable when using a 3D scanner versus VSS and POSAS. The 3D scanner and mold-cast techniques also offered an additional benefit of providing an absolute value of scar height relative to the surrounding tissue. Intra-user reliability for all mechanical tests was moderate to good. Inter-user reliability was greater when using the BTC-2000? and ballistometer® versus the DTM®. All quantitative measurements took less than 90 s for collection, with the exception of the mold/cast technique.ConclusionNon-invasive instruments allow scar properties to be quantitatively assessed with high sensitivity and as a function of time and/or treatment without the need for biopsy collection. Overall, the reliability of scar assessments was significantly improved when quantitative instruments were utilized versus scar scales. Quantitative assessment of color and biomechanics were swift, requiring less than 90 s per measurement while assessments of texture and height required additional analysis time after collection. With proper training of clinical staff and well-defined protocols for measurement collection, reliable, quantitative assessments of scar properties can be collected with little disruption to the clinical workflow.     

Overview and update on molecular testing in non-small cell lung carcinoma utilizing endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) samples

Lung carcinoma remains one of the most frequent and aggressive human neoplasms. Fortunately, in the last decades, the increasing knowledge of the molecular mechanisms leading to cancer development has allowed the use of targeted therapies with improvement of prognosis in many patients. Clinical management has also changed after the introduction of endobronchialultrasonographic bronchoscopy that allows a conservative staging of lung tumors, avoiding the need of mediastinoscopy for lymph node staging. Lung pathologists and cytopathologists are facing the challenge of giving the more comprehensive prognostic and predictive information with ever smaller tissue or cytological samples. The aim of this review is to summarize the molecular testing for non-small cell lung carcinoma and how pathologists can contribute to the patient's outcome with a conscious management of biological samples.     

Lumbar degenerative spondylolisthesis: factors associated with the decision to fuse

BACKGROUND CONTEXTThe indication to perform a fusion and decompression surgery as opposed to decompression alone for lumbar degenerative spondylolisthesis (LDS) remains controversial. A variety of factors are considered when deciding on whether to fuse, including patient demographics, radiographic parameters, and symptom presentation. Likely surgeon preference has an important influence as well.PURPOSEThe aim of this study was to assess factors associated with the decision of a Canadian academic spine surgeon to perform a fusion for LDS.STUDY DESIGN/SETTINGThis study is a retrospective analysis of patients prospectively enrolled in a multicenter Canadian study that was designed to evaluate the assessment and surgical management of LDS.PATIENT SAMPLEInclusion criteria were patients with: radiographic evidence of LDS and neurogenic claudication or radicular pain, undergoing posterior decompression alone or posterior decompression and fusion, performed in one of seven, participating academic centers from 2015 to 2019.OUTCOME MEASURESPatient demographics, patient-rated outcome measures (Oswestry Disability Index [ODI], numberical rating scale back pain and leg pain, SF-12), and imaging parameters were recorded in the Canadian Spine Outcomes Research Network (CSORN) database. Surgeon factors were retrieved by survey of each participating surgeon and then linked to their specific patients within the database.METHODSUnivariate analysis was used to compare patient characteristics, imaging measures, and surgeon variables between those that had a fusion and those that had decompression alone. Multivariate backward logistic regression was used to identify the best combination of factors associated with the decision to perform a fusion.RESULTSThis study includes 241 consecutively enrolled patients receiving surgery from 11 surgeons at 7 sites. Patients that had a fusion were younger (65.3±8.3 vs. 68.6±9.7 years, p=.012), had worse ODI scores (45.9±14.7 vs. 40.2±13.5, p=.007), a smaller average disc height (6.1±2.7 vs. 8.0±7.3 mm, p=.005), were more likely to have grade II spondylolisthesis (31% vs. 14%, p=.008), facet distraction (34% vs. 60%, p=.034), and a nonlordotic disc angle (26% vs. 17%, p=.038). The rate of fusion varied by individual surgeon and practice location (p<.001, respectively). Surgeons that were fellowship trained in Canada more frequently fused than those who fellowship trained outside of Canada (76% vs. 57%, p=.027). Surgeons on salary fused more frequently than surgeons remunerated by fee-for-service (80% vs. 64%, p=.004). In the multivariate analysis the clinical factors associated with an increased odds of fusion were decreasing age, decreasing disc height, and increasing ODI score; the radiographic factors were grade II spondylolisthesis and neutral or kyphotic standing disc type; and the surgeon factors were fellowship location, renumeration type and practice region. The odds of having a fusion surgery was more than two times greater for patients with a grade II spondylolisthesis or neutral and/or kyphotic standing disc type (opposed to lordotic standing disc type). Patients whose surgeon completed their fellowship in Canada, or whose surgeon was salaried (opposed to fee-for-service), or whose surgeon practiced in western Canada had twice the odds of having fusion surgery.CONCLUSIONSThe decision to perform a fusion in addition to decompression for LDS is multifactorial. Although patient and radiographic parameters are important in the decision-making process, multiple surgeon factors are associated with the preference of a Canadian spine surgeon to perform a fusion for LDS. Future work is necessary to decrease treatment variability between surgeons and help facilitate the implementation of evidence-based decision making.     

Multi-dimensional clinical phenotyping of a national cohort of adult cystic fibrosis patients

BackgroundCystic Fibrosis (CF) is a multi-systemic disorder resulting from genetic variation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene which can result in bronchiectasis, chronic sinusitis, pancreatic malabsorption, cholestatic liver disease and distal intestinal obstructive syndrome. This study generates multi-dimensional clinical phenotypes that capture the complexity and spectrum of the disease manifestations seen in adult CF patients using statistically robust techniques.MethodsPre-transplant clinical data from adult (age ≥18 years) CF patients (n = 992) seen in six regionally distinct US CF centers between 1/1/2014 and 6/30/2015 were included. Demographic, spirometry, nutritional, microbiological and therapy data were used to generate clusters using the Random Forests statistical-learning and Partitioning around Medoids (PAM) clustering algorithms. Five commonly measured demographic, physiological and nutritional parameters were needed to create the final phenotypes that are highly similar to a regionally matched group of patients from the CF Foundation Patient RegistryResultsThis approach identified high-risk phenotypes with expected characteristics including high rates of pancreatic insufficiency, diabetes and Pseudomonas aeruginosa colonization. It also identified unexpected populations including a) a male-dominated, well-nourished group with good lung function with a high prevalence of severe genotypes (i.e. 60% subjects had two minimal function CFTR variations), b) and an older, “survivor” phenotype that had high rates of chronic P. aeruginosa infection.ConclusionsThis study identified recognizable phenotypes that capture the clinical complexity in a statistically robust manner and which may aide in the identification of specific genetic and environmental factors responsible for these disease manifestation patterns.     

Economic evaluation methods used in home-visiting interventions: A systematic search and review

Home-visiting interventions are used to improve outcomes for families experiencing disadvantage. As scarce resources must be allocated carefully, appropriate methods are required to provide accurate information on the effect of these programmes. We aimed to investigate: economic evaluation/analysis methods used in home-visiting programmes for children, young people and families, study designs and methods suitable in situations where randomised-controlled-trials are not feasible, and type of costs included in analyses, including any implementation costs stated. A systematic search and review was conducted of existing full economic evaluation/analysis methods in home-visiting programmes for children, young people and/or families. We included studies published in English between January 2000 and mid-November 2020. Of the 4,742 papers sourced, 60 were retained for full-text review, and 21 included. Economic-analysis methods found in the included studies were: within trial economic evaluation, economic evaluation using decision analytic modelling (i.e. cost-utility, cost-benefit analysis), cost comparison and cost-consequence. Studies incorporating return on investment and budget impact analysis were also found. Study designs suitable when randomisation was not feasible included parallel cluster randomised trials and using pre-post intervention data. Costs depended mainly on study context and only one study reported implementation costs. We hope this information will help guide future economic evaluations of home-visiting interventions.     

Is diagnostic peritoneal lavage for blunt trauma obsolete?

Diagnostic peritoneal lavage was 97 percent accurate, with a 2 percent false positive rate and a 1 percent false negative rate in this series of 414 patients. The ease, safety, and accuracy of diagnostic peritoneal lavage justify its continued use in evaluating these patients. Recent studies show computerized tomography (CT) can be highly accurate in detecting intra-abdominal injuries after blunt trauma. We reviewed our experience with diagnostic peritoneal lavage (DPL) to evaluate whether the accuracy, safety, speed, and cost justified its continued use. Four hundred fifteen DPLs were performed on 414 patients from February 1, 1983, through December 31, 1987. All DPLs were done by the open technique. The lavage was considered grossly positive if 10 cc gross blood were aspirated. If there were greater than 100,000 red blood cells (RBC)/mm3, greater than 500 white blood cells (WBC)/mm3, elevated amylase or bilirubin, or bacteria or vegetable fibers the lavage was microscopically positive. There were no cases with elevated bilirubin, amylase, or presence of bacteria. All four cases with "rare vegetable fibers" were false positive. Six DPLs were for penetrating trauma to the lower chest or back. There were 291 negative lavages, including five false negatives (1%), and 124 positive DPLs, including seven false positives (2%), resulting in a crude accuracy of 97 percent. Three of the five false negative lavages had a ruptured diaphragm as the only intra-abdominal injury. There was one minor complication. DPL was usually performed in the trauma resuscitation room during the secondary survey. At our institution, the total fees for DPL are +185 less than the fees for CT. DPL is accurate, rapid, safe, and avoids the disruption of patient care that results in the radiology suite. DPL remains our procedure of choice for evaluating blunt abdominal trauma in the adult.