Physician satisfaction with telemedicine and in-person visits in otolaryngology.

OBJECTIVES: To investigate the differential factors associated with physician satisfaction between telemedicine and in-person visits in otolaryngology. METHODS: Study data included 646 telemedicine and 365 in-person encounters delivered from May-June 2020 at a tertiary center outpatient setting. Encounter-specific physician satisfaction was rated by 15 otolaryngologists using Provider Satisfaction Questionnaire (range 0-100) consisted of 5 items (patient needs addressed, patient involvement, adequacy of information given, quality of emotion support provided, and general interaction satisfaction). A multivariable linear mixed-effects model was used to explore patient demographic and clinical factors associated with physician satisfaction. RESULTS: Physician satisfaction scores for telemedicine and in-person visits were 83.0 [95 % CI: 77.0-88.9] and 88.1 [95 % CI: 82.5-93.6], respectively. Among telemedicine visits, physician satisfaction scores were significantly higher for follow-up (vs. new), videoconference (vs. telephone) encounters, and English-speaking patients in a multivariable model. New encounters had significantly lower satisfaction subdomain scores for adequacy of information given to the patient (ß = -4.7 [95 % CI: -7.3 to -2.0], p = 0.001) and addressing the needs of the patient among telemedicine visits (ß = -4.1, [95 % CI: -7.1 to -1.1], p = 0.007) while there were no differences in satisfaction scores between new vs follow-up visits among in-person visits. For non-English speaking patients, the physician satisfaction scores were significantly lower for subdomain scores assessing active patient participation (ß = -13.1, [95 % CI: -13.1 to -17.4], p < 0.001) and emotional support given to the patient (ß = -7.8, [95 % CI: -11.0 to -4.5], p < 0.001) for telemedicine visits. CONCLUSIONS: Telemedicine has been broadly adopted as an alternative option to deliver care in otolaryngology since COVID-19 pandemic. Appropriate triaging based on patient and encounter characteristics may enhance physician satisfaction and overall experiences with telemedicine. Further efforts are needed to provide adequate interpretation and videoconference services during telemedicine visits.

Supraclavicular Artery Island Flap: Critical Appraisal and Comparison to Alternate Reconstruction.

OBJECTIVES/HYPOTHESIS: The supraclavicular artery island (SAI) flap may be a good option for selected head and neck reconstruction due to its reliability, ease of harvest, and favorable color match. The objective of this study was to examine the rates of complications for the SAI flap in head and neck oncologic reconstruction, with examination of risk factors and comparisons to alternative flaps often considered the gold-standard soft-tissue flaps for head and neck reconstruction: the pectoralis myocutaneous (PMC), radial forearm free flap (RFFF), and anterolateral thigh (ALT) flaps. STUDY DESIGN: Retrospective cohort study. METHODS: Consecutive SAI flaps were compared to PMC, RFFF, and ALT flaps (non-SAI flap group), all performed by the senior author from 2010 to 2018. The non-SAI flaps were included if an SAI flap could have been performed as an alternate flap. The groups were compared based on demographics, flap dimensions, site of reconstruction, operating time, total hospital stay, total hospital costs, and complications. RESULTS: One hundred seven SAI flaps and 194 non-SAI flaps were identified. SAI flaps were used less commonly than non-SAI flaps for mucosal defects (P < .001). The SAI flap dimensions were narrower but longer than non-SAI flaps (P < .001). SAI flaps had higher rates of total complications, partial flap necrosis, flap dehiscence at the recipient site, fistula, donor site dehiscence, and minor complications compared to non-SAI flaps (all P < .05). SAI flaps had higher rates of total complications, recipient site dehiscence, fistula, and minor complications in both the oral cavity and all mucosal sites compared to non-SAI flaps (all P < .05). SAI flaps for mucosal reconstruction were associated with higher rates of total complications (54% vs. 34%, P = .04), flap dehiscence at the recipient site (32% vs. 14%, P = .03), and major complications (21% vs. 5%, P = .02), compared to cutaneous reconstruction. Complications were equivalent between SAI flaps and non-SAI flaps for cutaneous reconstruction (all P > .05). Multivariate analysis showed that SAI flaps were associated with any postoperative complication (odds ratio [OR]: 3.47, 95% confidence interval [CI]: 1.85-6.54), partial flap necrosis (OR: 5.69, 95% CI: 1.83-17.7), flap dehiscence (OR: 5.36, 95% CI: 2.29-12.5), donor site complications (OR: 11.6, 95% CI: 3.27-41.0), and minor complications (OR: 5.17, 95% CI: 2.42-11.0). Within the SAI flap group, SAI flap length >24 cm was associated with postoperative complications on multivariate analysis (OR: 5.09, 95% CI: 1.02-25.5, P = .048). CONCLUSIONS: The SAI flap is best suited for cutaneous reconstruction of the face, neck, and parotid/temporal bone regions due to the favorable color match; the thin, pliable nature of the skin; ease of harvest; and equivalent complication rates compared to alternate soft-tissue flaps. However, the SAI flap is associated with more complications for oral cavity and mucosal site reconstruction when compared to RFFF and ALT flaps and should be used in selected cases that do not require complex folding. For all sites, flaps longer than 24 cm should be used with caution. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:S1-S14, 2022.

Telemedicine in Otolaryngology During COVID-19: Patient and Physician Satisfaction.

OBJECTIVE: To examine patient and physician satisfaction with telemedicine in otolaryngology during COVID-19 and identify associated factors. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary care center. METHODS: Patient satisfaction was rated by patients (age ≥18 years) who had encounters from May to July 2020 (n = 407). Physician satisfaction was rated by 15 otolaryngologists for specific encounters delivered from May to June 2020 (n = 1011). Patient satisfaction was measured with a Press Ganey questionnaire and a Telemedicine Satisfaction Questionnaire. Mean Press Ganey satisfaction scores of telemedicine encounters during COVID-19 were compared with the pre-COVID-19 Press Ganey scores from in-person encounters (n = 3059) to test a noninferiority hypothesis. Physician satisfaction was measured with a Provider Satisfaction Questionnaire. RESULTS: The mean Press Ganey patient satisfaction score for telemedicine encounters was 94.5 (SD, 8.8), no worse than that for in-person encounters prior to COVID-19 at 93.7 (SD, 15.5; Δ = 0.8 [95% CI, -0.5 to 2.1, excluding the noninferiority margin of -1]). Encounters with videoconference (vs telephone) and patients reporting higher income were associated with higher Telemedicine Satisfaction Questionnaire scores. Physician satisfaction scores during COVID-19 with telemedicine encounters were overall high at 83.3 (95% CI, 77.5-89.1), slightly lower when compared with the scores with in-person encounters at 88.4 (95% CI, 82.5-94.3; Δ = -5.2 [95% CI, -6.6 to -3.8]). Encounters with videoconference (vs telephone) and patients with English as a preferred language and follow-up visits were associated with higher Provider Satisfaction Questionnaire scores. CONCLUSIONS: Telemedicine is a feasible alternative format in otolaryngology during COVID-19 with overall high patient and physician satisfaction. Patient satisfaction with telemedicine encounters during COVID-19 was no worse than in-person encounters prior to the pandemic. Physician satisfaction with telemedicine was relatively lower in comparison with in-person encounters.

Discordance Between Subjective and Objective Measures of Smell and Taste in US Adults.

OBJECTIVE: Examine the rates and factors associated with under- and overreporting of subjective changes in smell or taste as compared with objective measures. STUDY DESIGN: Cross-sectional analysis. SETTING: National Health and Nutrition Examination Survey (2013-2014). METHODS: We examined participants ≥40 years old who completed subjective questionnaires (smell, n = 3510; taste, n = 3089), validated objective 8-odor pocket smell tests, and NaCl/quinine taste tests. Over- and underreporting was determined by the difference in subjective and objective results. Univariate and multivariate logistic regression analyses incorporated sampling weights. RESULTS: A majority of participants correctly classified impairment: smell (73.7%; 95% CI, 71.2%-76.1%) and taste (78.3%; 95% CI, 75.6%-80.7%). Age ≥65 years (odds ratio, 2.23; P = .001) was associated with underreporting impairment, and persistent cold symptoms (odds ratio, 2.15; P = .001) were associated with overreporting smell impairment. Smoke, onion, and natural gas scents were incorrectly identified more frequently by individuals aged ≥65 years after Bonferroni correction. No factors were associated with under- and overreporting taste impairment. CONCLUSION: Although the concordance rate between subjective and objective assessment of smell and taste impairment remains high, we found that older age was associated with incorrect report of impairment. This suggests that the subjective perception of smell varies across demographical and clinical factors, and it is important to not overlook such factors in clinical practice. Potentially using a simplified odor assessment regularly in the clinical setting may aid in early detection and intervention.

Smell and Taste Impairment in a Nationwide Sample of US Adults With Chronic Rhinosinusitis Symptoms.

OBJECTIVE: To estimate the prevalence of objectively confirmed olfactory and gustatory dysfunction in US adults reporting chronic rhinosinusitis (CRS) symptoms in a nationally representative database. STUDY DESIGN: Cross-sectional epidemiologic analysis. SETTING: Data were analyzed from the smell and taste component of the 2013-2014 NHANES data set (National Health and Nutrition Examination Survey). METHODS: Individuals reporting the presence of ≥2 cardinal CRS symptoms (nasal blockage, sinus pain, discolored mucus, and dysosmia) were identified as patients with a potential diagnosis of CRS. Associations were examined between the presence of CRS symptoms and both self-reported and objectively measured smell and taste. RESULTS: One-third (33%) of adults who have ≥2 CRS symptoms report subjective olfactory impairment, though only 18% of these adults have quantifiable olfactory dysfunction on objective testing. Of these adults, 27% report subjective taste impairment, but just 17% have quantifiable gustatory dysfunction on objective testing. The presence of ≥2 CRS symptoms was not significantly associated with objective olfactory or gustatory dysfunction, although the individual symptoms of subjective dysosmia and discolored mucus were associated with objectively confirmed olfactory dysfunction. CONCLUSION: The prevalence of objective olfactory and gustatory dysfunction was higher among adults reporting the presence of ≥2 CRS symptoms, but the differences were not statistically significant. Specific sinonasal symptoms, including discolored mucus and subjective smell dysfunction, were significantly associated with objective smell impairment.

Speech and Communicative Participation in Patients With Facial Paralysis.

Importance: Problems with speech in patients with facial paralysis are frequently noted by both clinicians and the patients themselves, but limited research exists describing how facial paralysis affects verbal communication. Objective: To assess the influence of facial paralysis on communicative participation. Design, Setting, and Participants: A nationwide online survey of 160 adults with unilateral facial paralysis was conducted from March 1 to June 1, 2017. To assess communicative participation, respondents completed the Communicative Participation Item Bank (CPIB) Short Form questionnaire and the Facial Clinimetric Evaluation (FaCE) Scale. Main Outcomes and Measures: The CPIB Short Form and the correlation between the CPIB Short Form and FaCE Scale. In the CPIB, the level of interference in communication is rated on a 4-point Likert scale (where not at all = 3, a little = 2, quite a bit = 1, and very much = 0). Total scores for the 10 items range from 0 (worst) to 30 (best). The FaCE Scale is a 15-item instrument that produces an overall score ranging from 0 (worst) to 100 (best), with higher scores representing better function and higher quality of life. Results: Of the 160 respondents, 145 (90.6%) were women and 15 were men (mean [SD] age, 45.1 [12.6] years). Most respondents reported having facial paralysis for more than 3 years. Causes of facial paralysis included Bell palsy (86 [53.8%]), tumor (41 [25.6%]), and other causes (33 [20.6%]), including infection, trauma, congenital defects, and surgical complications. The mean (SD) score on the CPIB Short Form was 0.16 (0.88) logits (range, -2.58 to 2.10 logits). The mean (SD) score of the FaCE Scale was 40.92 (16.05) (range, 0-83.3). Significant correlations were observed between the CPIB Short Form and overall FaCE Scale scores, as well as the Social Function, Oral Function, Facial Comfort, and Eye Comfort subdomains of the FaCE Scale, but not with the Facial Movement subdomain. Conclusions and Relevance: Patients with facial paralysis in this study sample reported restrictions in communicative participation that were comparable with restrictions experienced by patients with other known communicative disorders, such as laryngectomy and head and neck cancer. We believe that communicative participation represents a unique domain of dysfunction and can help quantify the outcome of facial paralysis and provide an additional frame of reference when assessing treatment outcomes.

Paraganglioma Presenting as a Nasal Septal Mass: Case Report and Literature Review.

OBJECTIVES: To describe a rare case of a paraganglioma arising from the nasal septum and review the diagnosis and management of paragangliomas in the nasal cavity and paranasal sinuses. METHODS: We present a case of a 70-year-old female presenting with persistent nasal congestion and obstruction. Nasal endoscopy revealed a posterior septal mass approaching the sphenoid sinuses and partially obstructing the nasopharynx. A biopsy of the mass was taken, and histologic analysis confirmed a diagnosis of paraganglioma. RESULTS: The patient underwent an endoscopic resection of the tumor. There has been no evidence of disease recurrence after 3 months of follow-up. CONCLUSIONS: Paragangliomas arising from the nasal septum are exceedingly rare, but should be considered in the differential diagnosis in patients presenting with nasal septal masses. These tumors are typically benign, although few cases of malignant sinonasal paragangliomas have been reported. Treatment requires surgical excision with close follow-up as several cases of tumor recurrence have been reported.

Opportunities to integrate new approaches in genetic toxicology: an ILSI-HESI workshop report.

Genetic toxicity tests currently used to identify and characterize potential human mutagens and carcinogens rely on measurements of primary DNA damage, gene mutation, and chromosome damage in vitro and in rodents. The International Life Sciences Institute Health and Environmental Sciences Institute (ILSI-HESI) Committee on the Relevance and Follow-up of Positive Results in In Vitro Genetic Toxicity Testing held an April 2012 Workshop in Washington, DC, to consider the impact of new understanding of biology and new technologies on the identification and characterization of genotoxic substances, and to identify new approaches to inform more accurate human risk assessment for genetic and carcinogenic effects. Workshop organizers and speakers were from industry, academe, and government. The Workshop focused on biological effects and technologies that would potentially yield the most useful information for evaluating human risk of genetic damage. Also addressed was the impact that improved understanding of biology and availability of new techniques might have on genetic toxicology practices. Workshop topics included (1) alternative experimental models to improve genetic toxicity testing, (2) Biomarkers of epigenetic changes and their applicability to genetic toxicology, and (3) new technologies and approaches. The ability of these new tests and technologies to be developed into tests to identify and characterize genotoxic agents; to serve as a bridge between in vitro and in vivo rodent, or preferably human, data; or to be used to provide dose response information for quantitative risk assessment was also addressed. A summary of the workshop and links to the scientific presentations are provided.

An organizational approach for the assessment of DNA adduct data in risk assessment: case studies for aflatoxin B1, tamoxifen and vinyl chloride.

The framework analysis previously presented for using DNA adduct information in the risk assessment of chemical carcinogens was applied in a series of case studies which place the adduct information into context with the key events in carcinogenesis to determine whether they could be used to support a mutagenic mode of action (MOA) for the examined chemicals. Three data-rich chemicals, aflatoxin B1 (AFB1), tamoxifen (Tam) and vinyl chloride (VCl) were selected for this exercise. These chemicals were selected because they are known human carcinogens and have different characteristics: AFB1 forms a unique adduct and human exposure is through contaminated foods; Tam is a pharmaceutical given to women so that the dose and duration of exposure are known, forms unique adducts in rodents, and has both estrogenic and genotoxic properties; and VCl, to which there is industrial exposure, forms a number of adducts that are identical to endogenous adducts found in unexposed people. All three chemicals produce liver tumors in rats. AFB1 and VCl also produce liver tumors in humans, but Tam induces human uterine tumors, only. To support a mutagenic MOA, the chemical-induced adducts must be characterized, shown to be pro-mutagenic, be present in the tumor target tissue, and produce mutations of the class found in the tumor. The adducts formed by AFB1 and VCl support a mutagenic MOA for their carcinogenicity. However, the data available for Tam shows a mutagenic MOA for liver tumors in rats, but its carcinogenicity in humans is most likely via a different MOA.

Analysis of cartilage-polydioxanone foil composite grafts.

This study presents an analytical investigation into the mechanical behavior of a cartilage-polydioxanone (PDS) plate composite grafts. Numerical methods are used to provide a first-order, numerical model of the flexural stiffness of a cartilage-PDS graft. Flexural stiffness is a measure of resistance to bending and is inversely related to the amount of deformation a structure may experience when subjected to bending forces. The cartilage-PDS graft was modeled as a single composite beam. Using Bernoulli-Euler beam theory, a closed form equation for the theoretical flexural stiffness of the composite graft was developed. A parametric analysis was performed to see how the flexural properties of the composite model changed with varying thicknesses of PDS foil. The stiffness of the cartilage-PDS composite using 0.15-mm-thick PDS was four times higher than cartilage alone. The composite with a 0.5-mm-thick PDS graft was only 1.7 times stiffer than the composite with the 0.15-mm-thick PDS graft. Although a thicker graft material will yield higher flexural stiffness for the composite, the relationship between composite stiffness and PDS thickness is nonlinear. After a critical point, increments in graft thickness produce gradually smaller improvements in flexural stiffness. The small increase in stiffness when using the thicker PDS foils versus the 0.15 mm PDS foil may not be worth the potential complications (prolonged foreign body reaction, reduction in nutrient diffusion to cartilage) of using thicker artificial grafts.

In vitro testicular toxicity models: opportunities for advancement via biomedical engineering techniques.

To address the pressing need for better in vitro testicular toxicity models, a workshop sponsored by the International Life Sciences Institute (ILSI), the Health and Environmental Science Institute (HESI), and the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), was held at the Mt. Washington Conference Center in Baltimore, MD, USA on October 26-27, 2011. At this workshop, experts in testis physiology, toxicology, and tissue engineering discussed approaches for creating improved in vitro environments that would be more conducive to maintaining spermatogenesis and steroidogenesis and could provide more predictive models for testicular toxicity testing. This workshop report is intended to provide scientists with a broad overview of relevant testicular toxicity literature and to suggest opportunities where bioengineering principles and techniques could be used to build improved in vitro testicular models for safety evaluation. Tissue engineering techniques could, conceivably, be immediately implemented to improve existing models. However, it is likely that in vitro testis models that use single or multiple cell types will be needed to address such endpoints as accurate prediction of chemically induced testicular toxicity in humans, elucidation of mechanisms of toxicity, and identification of possible biomarkers of testicular toxicity.

Genotoxicity of nanomaterials: refining strategies and tests for hazard identification.

A workshop addressing strategies for the genotoxicity assessment of nanomaterials (NMs) was held on October 23, 2010 in Fort Worth Texas, USA. The workshop was organized by the Environmental Mutagen Society and the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute. The workshop was attended by more than 80 participants from academia, regulatory agencies, and industry from North America, Europe and Japan. A plenary session featured summaries of the current status and issues related to the testing of NMs for genotoxic properties, as well as an update on international activities and regulatory approaches. This was followed by breakout sessions and a plenary session devoted to independent discussions of in vitro assays, in vivo assays, and the need for new assays or new approaches to develop a testing strategy for NMs. Each of the standard assays was critiqued as a resource for evaluation of NMs, and it became apparent that none was appropriate without special considerations or modifications. The need for nanospecific positive controls was questioned, as was the utility of bacterial assays. The latter was thought to increase the importance of including mammalian cell gene mutation assays into the test battery. For in-vivo testing, to inform the selection of appropriate tests or protocols, it was suggested to run repeated dose studies first to learn about disposition, potential accumulation, and possible tissue damage. It was acknowledged that mechanisms may be at play that a standard genotoxicity battery may not be able to capture.

Summary of the HESI consortium studies exploring circulating inhibin B as a potential biomarker of testis damage in the rat.

The Developmental and Reproductive Toxicity Technical Committee of the Health and Environmental Sciences Institute hosted a working consortium of companies to evaluate a new commercially available analytic assay for Inhibin B in rat serum or plasma. After demonstrating that the kit was stable and robust, the group performed a series of independent pathogenesis studies (23 different compound/investigator combinations) designed to examine the correlation between the appearance of lesions in the testis and changes in circulating levels of Inhibin B. These studies were reported individually in the previous articles in this series (this issue), and are discussed in this paper. For roughly half of these exposures, lesions appeared well before Inhibin B changed. A few of the studies showed a good correlation between seminiferous tubule damage and reduced circulating Inhibin B levels, while for seven exposures, circulating Inhibin B was reduced with no detectable alteration in testis histology. Whether this indicates a prodromal response or a false-positive signal will require further investigation. These exceptions could plausibly suggest some value of circulating Inhibin B as a useful biomarker in some circumstances. However, for roughly half of these exposures, Inhibin B appeared to be a lagging biomarker, requiring significant damage to the seminiferous tubules before a consistent and credible reduction in circulating levels of Inhibin B was observed.

Analytic evaluation of a human ELISA kit for measurement of inhibin B in rat samples.

BACKGROUND: A cross-laboratory analytic evaluation of a commercially available human inhibin B ELISA for measuring inhibin B in rat serum and plasma has been undertaken. METHODS: Dilution linearity, spiked recovery, intra- and inter-assay precision, functional sensitivity, matrix effects, and frozen stability were assessed across five laboratories. Reference ranges were generated for male Sprague Dawley and Han Wistar rats. RESULTS: Acceptable performance was defined as an overall assay coefficient of variation ≤ 20% with an intraday LLOQ ≤ 20 pg/ml. Intra- and inter-assay precision and functional sensitivity (≤6.4 pg/ml) generally met these criteria, but with occasional evidence of greater variability, particularly at lower concentrations. Dilution linearity was acceptable with occasional low recovery. Acceptable recovery of kit calibrators from rat serum confirmed the absence of matrix effects. Matched serum and plasma samples gave comparable results. The signal increased on freezing, remained constant for ≥3 freeze-thaw cycles and was generally stable for at least 8 weeks. Mean inhibin B ranged from 33.5 to 140.6 pg/ml in adult rats across laboratories, with some evidence for a decline from 6 to 9 weeks of age. Power calculations using preliminary reference range data indicated 10 animals/group would generally detect a 40% decrease in inhibin B at AstraZeneca, but laboratories with lower control values would require larger groups. CONCLUSIONS: The assay meets the analytical performance criteria; however, precision at the low end of the standard curve, biological variability, and low control values observed in some laboratories indicate that the utility of the assay may be limited in some laboratories.

Validation of alternative tests for developmental and reproductive toxicology testing: an ILSI Health and Environmental Sciences Institute perspective.

The current political and societal climate is driving the science of toxicology towards developing non-animal testing methodologies. Though alternative and in vitro tests have always been a mainstay for toxicological testing, technological advances in the last decade have allowed toxicologists to move rapidly towards a better understanding of the relevance of in vitro endpoints for traditional apical endpoints. Non-animal research using new technologies have illuminated toxicologists on the mechanisms of protection and adverse health outcomes. In this context, the "validation" of alternative and in vitro tests has taken on significant importance, particularly in regard to satisfying safety concerns of drugs and chemicals in a regulatory setting. The purpose of this chapter is to briefly review the impetus for the development of alternative and in vitro tests, discuss the projects underway at the ILSI Health and Environmental Sciences Institute (HESI) that are oriented towards this topic, and summarize the processes for formal validation. It should be noted that though there are validated assays and tests, these are under constant evaluation by scientific researchers as our understanding of the underlying biological processes continues to evolve.

Incidence and nature of testicular toxicity findings in pharmaceutical development.

BACKGROUND: Testicular toxicity (TT) is a sporadic and challenging issue in pharmaceutical drug development. Efforts to develop TT screening assays or biomarkers have been overshadowed by consortium efforts to predict drug-induced toxicities such as hepatic injury, which are encountered more frequently. METHODS: To gauge the current state of the field and to prioritize future TT activities, the International Life Sciences Institute-Health and Environmental Sciences Institute Developmental and Reproductive Toxicology (DART) Technical Committee sponsored a survey to better understand the incidence and nature of TT findings encountered during drug development. RESULTS: Highlights from the 16 survey respondents include: (1) Although preclinical TT was encountered relatively infrequently, half of the participants observed repeated problems with TT during pharmaceutical development, (2) despite control measures such as use of sexually mature animals to diminish confounding effects of spurious lesions, interpretation of TT remains a challenge, (3) "traditional" evaluation tools such as hormonal monitoring and newer approaches such as -omics are utilized to investigate testicular changes, and (4) an understanding of the risk and relevance of TT findings is achieved through joint consideration of factors such as species specificity, potential mode of action, and safety margins. CONCLUSIONS: TT remains a relatively uncommon but persistent challenge in pharmaceutical development. Although current preclinical TT approaches appear to be effective in limiting the occurrence of pharmaceutical candidate attrition in clinical trials, improved biomarker or screening platforms would allow companies to identify TT at an earlier stage, thus decreasing the time and resources expended on safety evaluation of pharmaceutical candidates.

Developmental toxicology: new directions workshop: refining testing strategies and study designs.

In April 2009, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute's (HESI) Developmental and Reproductive Toxicology Technical Committee held a two-day workshop entitled "Developmental Toxicology-New Directions." The third session of the workshop focused on ways to refine animal studies to improve relevance and predictivity for human risk. The session included five presentations on: (1) considerations for refining developmental toxicology testing and data interpretation; (2) comparative embryology and considerations in study design and interpretation; (3) pharmacokinetic considerations in study design; (4) utility of genetically modified models for understanding mode-of-action; and (5) special considerations in reproductive testing for biologics. The presentations were followed by discussion by the presenters and attendees. Much of the discussion focused on aspects of refining current animal testing strategies, including use of toxicokinetic data, dose selection, tiered/triggered testing strategies, species selection, and use of alternative animal models. Another major area of discussion was use of non-animal-based testing paradigms, including how to define a "signal" or adverse effect, translating in vitro exposures to whole animal and human exposures, validation strategies, the need to bridge the existing gap between classical toxicology testing and risk assessment, and development of new technologies. Although there was general agreement among participants that the current testing strategy is effective, there was also consensus that traditional methods are resource-intensive and improved effectiveness of developmental toxicity testing to assess risks to human health is possible. This article provides a summary of the session's presentations and discussion and describes some key areas that warrant further consideration.

Need and potential value of the Pig-ain vivo mutation assay-a HESI perspective.

The Health and Environmental Sciences Institute (HESI), a global branch of the International Life Sciences Institute (ILSI), initiated a project committee entitled "Relevance and Follow-up of Positive Results from In Vitro Genetic Toxicity Testing (IVGT)" with the overall objective of improving the scientific basis for the interpretation of results from genetic toxicology testing. The IVGT committee has also recognized the need to develop follow-up strategies for determining the relevance of in vitro test results to human health, and moving genetic toxicology testing from the sole purpose of hazard identification toward a more quantitative risk assessment approach. In this context, a group of experts evaluated the potential utility of the emerging in vivo mutational assessment model commonly known as the Pig-a gene mutation assay to follow-up positive in vitro genetic toxicology findings and to generate robust dose-response data for quantitative assessment of the in vivo mutagenicity. The IVGT experts participating in this effort represented academia, industry, and government agencies from across the globe and addressed such issues as the optimal sample size and experimental design for generating robust dose-response data. This expert group concluded that the emerging Pig-a gene mutation assay holds great promise as an in vivo mutagenicity assay, either as a stand-alone study or integrated into repeat-dose toxicology studies, and therefore supports further validation of the model.

Current and future needs for developmental toxicity testing.

A review is presented of the use of developmental toxicity testing in the United States and international regulatory assessment of human health risks associated with exposures to pharmaceuticals (human and veterinary), chemicals (agricultural, industrial, and environmental), food additives, cosmetics, and consumer products. Developmental toxicology data are used for prioritization and screening of pharmaceuticals and chemicals, for evaluating and labeling of pharmaceuticals, and for characterizing hazards and risk of exposures to industrial and environmental chemicals. The in vivo study designs utilized in hazard characterization and dose-response assessment for developmental outcomes have not changed substantially over the past 30 years and have served the process well. Now there are opportunities to incorporate new technologies and approaches to testing into the existing assessment paradigm, or to apply innovative approaches to various aspects of risk assessment. Developmental toxicology testing can be enhanced by the refinement or replacement of traditional in vivo protocols, including through the use of in vitro assays, studies conducted in alternative nonmammalian species, the application of new technologies, and the use of in silico models. Potential benefits to the current regulatory process include the ability to screen large numbers of chemicals quickly, with the commitment of fewer resources than traditional toxicology studies, and to refine the risk assessment process through an enhanced understanding of the mechanisms of developmental toxicity and their relevance to potential human risk. As the testing paradigm evolves, the ability to use developmental toxicology data to meet diverse critical regulatory needs must be retained.