dataesr/scientific-paragraphs-categorization huggingface dataset:
Effect of Environmental Factors on Jumping Accelerometric Data The effect of location was always significant over all measurements. Influence of type of ground surface, environmental conditions (noise, horse being excited, and disturbed) were certainly involved in this effect. This result means that a sufficient number of horses must be recorded in each jumping test location to estimate this effect. Other effects were not always significant depending on each measurement. The main influence was successive number of jumps and sex. Month of birth and effect of morning/afternoon were significant only twice on duration variables. Heritability, Repeatability, Genetic, and Phenotypic Correlation Between Jumping Accelerometric Variables First, heritability (h 2 ) and (r) repeatability between jumps were estimated using univariate analysis (Table  3 ).
They all focused only on vertical and horizontal axis; no data were found on movement on the lateral axis. We focused the discussion on results in kinematics from literature that can be related to measurements obtained with accelerometric data. Indeed, studies of movement from video camera can derive acceleration values from the derivation of position landmarks. In addition, reciprocally, accelerometric data can provide variables such as jump duration, which is mechanically related to the distance measured by video: height of the center of gravity or length of the jump for example.
Ability of Early Measurements in Free Jumping to Predict Future Show Jumping Performance To predict the jumping ability of horses in competition from free jumping kinematics, literature very often uses too low a number of horses to calculate genetic correlation and is therefore focused on phenotypic correlation. In several publications  (Santamaria et al. , 2004a (Santamaria et al. , ,b, 2005 (Santamaria et al. , , 2006;; Bobbert et al. , 2005) , the team from Utrecht University managed an experimental design. They measured kinematic data on foals in free jumping and then raised them in two sets with and without training. At 4 years of age, the two groups were joined to start a year long common training program for show jumping. They were kinematically analyzed while free jumping at the beginning of the year and at the end, at the age of 5, they were analyzed during jumping tests under saddle.
CONCLUSION This study analyzed free jumping during regular breeding shows of young horses with an accelerometric device. For the first time, estimates of genetic correlation between biomechanical data and performance in a competition were calculated. We found that duration of jump was heritable and genetically correlated to jumping performance in a competition. Judgement scores during free jumping were also heritable and correlated to both performance in competition and jump duration measured by the device. The addition of jump duration measured by an accelerometric device in a selection plan must be further studied to replace or complement judgment scores. The advantage of such a measurement, is to be free from the subjectivity of judgement scores, and the calculated correlation cannot be overestimated by a priori knowledge of the judges on the quality of the sires of the horses.
, 2015; Mangipudy et al. , 2014; van Meer et al. , 2012). Other industry consortia have retrospectively investigated the concordance between animal toxicity data and human adverse effects. They concluded that when adverse effects were identified in humans, these were also identified in animals for between 48%  (Tamaki et al. , 2013)  and 71%  (Olson et al. , 2000)  of the dataset. More recently, a separate project has emphasised positive predictive values (PPV, the proportion of positive nonclinical findings that had positive clinical findings) as more relevant for prospective nonclinical to clinical translation  (Monticello et al. , 2017). For a dataset mainly consisting of small molecules (85%), mAbs (9%) and ADCs (3%), they found a PPV of 43%, which increased when the same target organ was identified in both the rodent and non-rodent toxicology species.
The NC3Rs/ABPI working group objectives The NC3Rs/ABPI working group comprised experts in nonclinical safety assessment, representing 25 global pharmaceutical and biotechnology companies, six contract research organisations (CROs) or consultants, two academic institutions and four regulatory bodies and was ledby the NC3Rs. The group shared pre-registration, non-public domain data on rodent and non-rodent species used for toxicity assessments with any drug candidate in current or former portfolios. Information was also collected on the key toxicities identified in each species within studies at different phases of drug development, both in terms of the specific target organs affected and the impact of the data on progression of the drug candidate. These data were collected with the aim of investigating the incidence in similarity of toxicities between species, in order to perform retrospective assessments as to whether there had been potential opportunities to reduce from two to one species at later stages of development.
g. , Fig. 2b ). 3) Information on the toxicity studies in each species, including details of study design (e. g. study type, Good Laboratory Practice (GLP) compliance status, dosing duration, route of administration and the total number of animals used), and summarised (high level) study results. High level study results included the presence or absence of any target organ toxicities; the impact this had on progression of the drug candidate (through internal decision making) was also noted. The list of drop-down options for the target organ toxicities and the impact of data from the study are described in Tables  2a  and 2b. Information on the nature, severity or incidence of toxicologicallyrelevant findings, achieved exposures or safety margins were not requested. 4) Several "retrospective", and potentially subjective, questions about the package of toxicity studies conducted were also included.
The study dosing duration within each of the phases above differed for individual drug candidates, as appropriate for each individual programme and drug modality. For example, a 4week study may have been conducted to support a small molecule for the FIH phase and a 13 or 26-week study for post-FIH, whilst a 13-week study may have been conducted for a mAb for FIH phase and a 26-week study for post-FIH. The studies suitable for inclusion in the questionnaire were restricted by the working group to general toxicology studies only (i. e. safety pharmacology, reproductive toxicity, genotoxicity or carcinogenicity studies were out of scope). Completed questionnaires were submitted by individual companies and data were collated and anonymised by NC3Rs before being analysed by the working group. Any data provided by CROs/consultants were provided (with permission) from Sponsors not otherwise involved in the working group (to avoid duplication).
A blinded exercise to investigate the potential to conduct post-FIH studies in a single nonclinical species An exercise was conducted to test the hypothesis that an assessment of the toxicities observed in two species during the FIH studies (data from the pre-FIH and FIH phases) could, in hindsight, inform on the requirement for two species toxicology testing for the longer-term post-FIH toxicity studies, or if reduction to a single species would have been acceptable without increasing risk of missing toxicity findings within the nonclinical safety decision-making. Panels of six to eight working group members reviewed results from the pre-FIH and FIH phase animal studies for drug candidates that had been tested in two species and had progressed to longer-term post-FIH studies (blinded to the latter data).
Working group decision Comparisons with the actual outcomes of the post-FIH toxicity studies # participants had access to pre-FIH and FIH toxicology data but were blind to the actual decision made and any post-FIH toxicology data. n/a: option not applicable for this category. Concordant: the working group majority consensus decision, based on the available data (which was a supplied summary of the whole data package) were consistent with the toxicities identified in the longer-term post-FIH toxicity studies. Non-concordant: the working group majority consensus decision, based on the available data (which was a supplied summary of the whole data package) were inconsistent with the toxicities identified in the longer-term post-FIH toxicity studies. a Decision to drop to one species could be considered as low impact on nonclinical assessment of risk to humans, as no effects were identified in either species, or only in the species chosen to progress, in the longer-term post-FIH toxicity studies.
b Decision to drop to one species could be considered as potential risk to human safety, as effects were identified in the species chosen to drop (missed potential toxicities). c Decision to retain two species could be considered as low impact on nonclinical assessment of risk to humans, as effects were identified in both species used in the longer-term post-FIH toxicity studies. d Decision to retain two species could be considered as low impact on nonclinical assessment of risk to humans, as effects were identified in only one, or neither species used in the longer-term post-FIH toxicity studies, however, this is a missed opportunity to reduce to one species. studies, along with the impact of data from each study on drug candidate progression (used for internal decision-making). The panels discussed the data to form a consensus opinion on whether the next (longer-term post-FIH) series of studies could have been performed in a single species, and to propose which species they would have chosen for these toxicity studies.
The use of one species was considered acceptable if there were either no, the same, or similar toxicities from the totality of data available from pre-FIH and FIH studies. The rodent, rather than non-rodent, would be the species progressed if appropriate (as per the current ICHS6(R1) guideline, but expanded for this exercise to include any drug modality). The use of one species was also considered acceptable where the toxicities in two species at FIH were classified as different, when the difference was the absence of toxicities in one species but presence of toxicities in the other; the most-sensitive species was progressed in such cases. The actual results from the longer-term post-FIH studies were then revealed and the views reached by the panel were assessed for concordance relative to the toxicities observed, as outlined in Table  3.
Overview of the dataset Data were collected from 18 different pharmaceutical and biotechnology companies, including some submitted through CROs/consultants. Five or more drug candidates (with a mean of ten) were submitted to the dataset by 15 companies. The analysed dataset consisted of 172 drug candidates that met the inclusion criteria: 92 small molecules, 46 mAbs, 15 recombinant proteins, 13 synthetic peptides and 6 ADCs (Fig. 1a ; comprising 53%, 27%, 9%, 8% and 3% of the total dataset, respectively). The dataset included the following demographic information: • The drug candidates were representative of a wide range of therapeutic areas, with oncology, central nervous system (CNS) and immunomodulatory indications being the most highly represented (Fig. 1b ). • Approximately one half (54%) of the drug candidates were defined as at the FIH stage (93/172 drug candidates), with 32 drug candidates at the pre-FIH stage (19%) and 47 drug candidates at the post-FIH stage (27%; Table  4 ).
The number of nonclinical species used For the majority of drug candidates, toxicology studies were conducted in either one or two species for the entire package, with drug candidates reaching varying stages of development (as described in section 3. 1). For a small number of drug candidates (8/133), initial toxicology studies were conducted in two species, whilst studies supporting later stages of development were conducted in only one species. No drug candidates within the database used more than two species within the package.
Blinded exercise investigating the potential for post-FIH studies to be conducted in a single nonclinical species There were 38 drug candidates that had used two species at the FIH stage and progressed to longer-term post-FIH studies: 35 of these (23 small molecules, 6 mAbs, 2 recombinant proteins and 4 synthetic peptides) were assessed within an exercise to determine if, retrospectively (and with the benefit of hindsight), single species toxicology testing could have been considered for the longer-term (post-FIH) studies based on FIH data. There were insufficient data for the remaining 3 drug candidates, and therefore these were excluded from the exercise. The panels of working group members decided it should have been possible to decrease to one species for the longer-term studies for 14 small molecules, 5 mAbs and 3 synthetic peptides (Table  7a ).
Discussion The primary purpose of the expert working group was to identify if there are wider opportunities for use of a single nonclinical species in toxicology programmes, regardless of drug modality, relevant regulatory guidance and/or phase of drug development. To enable this, data were provided by eighteen different pharmaceutical and biotechnology companies, mainly based in the USA and Europe (53 and 44% of drug candidates in the dataset, respectively) and Japan, generally representing larger multi-national companies. In order to reduce potential for selection bias, contributors were asked to provide information for their most recent drug candidates to have completed at least one of three phases of development (pre-FIH, FIH or post-FIH). Information was subsequently supplied on molecules for a wide variety of therapeutic indications, spread across the three development phases.
Whilst this could not entirely exclude the possibility of some selection bias regarding the most recent molecules, this is a common limitation of these types of data-sharing activities and as such should be viewed as providing a snap-shot of current industry practice. Additionally, the small sample sizes for some of the drug modalities and development phases has limited the conclusions that can be drawn. Nevertheless, the balance of drug modalities that data were provided for (53% small molecules and 47% biologics) and their associated range of therapeutic indications were considered by the working group as a reasonable representation of the industry, especially since two-thirds of the data were derived from drug candidates in active development at the time of the review. For drug candidates that were no longer in development, nonclinical toxicology findings were responsible for 87% of drug candidates terminated pre-FIH, and for 43% of drug candidates stopped at the FIH stage.
Nonclinical species used for development of small molecules The small molecules were being developed following ICHM3(R2) in general, or in conjunction with ICHS9 for drug candidates for advanced cancer indications. These guidelines generally expect two species to be used for toxicity testing (rodents and non-rodents), with no explicit wording around opportunities for reducing to one species, other than case-by-case approaches within ICHS9. The species used for toxicity testing of small molecules in the dataset reflect those of other industry reviews  (Baldrick, 2008; Butler et al. , 2017) , in that rat, dog and NHP are the predominant species used (92%, 65% or 32% of small molecules, respectively). Interestingly, minipig was used for only one small molecule, which would appear to be an under-representation of the use of this species for toxicology testing across the industry  (Colleton et al.
, 2016; Heining and Ruysschaert, 2016; Monticello et al. , 2017). Discussion within the working group indicated that some companies currently use, or are considering use of, minipig as the non-rodent species for toxicology testing, and therefore it is unclear why minipig data for only one drug candidate was submitted. It is possible that the retrospective nature of the dataset may not reflect a more recent transition to using minipig as a non-rodent species for toxicology testing and this may warrant more investigation. There were three examples of a small molecule tested in a single species only. For two of these, only pre-FIH studies were conducted (in rodent) and development was stopped due to the toxicology findings, prior to the start of studies in a non-rodent, a common approach taken for early toxicity screening  (Roberts et al.
Further information provided indicated that as no orthologous target existed in any nonclinical species, the rat was used to assess offtarget toxicities at and above anticipated human exposures. For the remaining 14 mAbs, 12 recombinant proteins, 10 synthetic peptides and 5 ADCs (53% of the drug candidates following ICHS6(R1) within the dataset) toxicity studies were performed in two species. For mAbs, this equates to 30% of the mAbs within the dataset with crossreactivity to two species, consistent with working group member experience, but not previously published from a cross-industry perspective. Of the eleven different companies which submitted mAb data, seven provided data on drug candidates that were tested in two species. Multiple pharmacologically-relevant species for biologics raises a 3Rs challenge: when two species toxicology with biologics is required, this results in higher animal use overall.
However, when only one pharmacologically relevant species is identified, this tends to be the NHP, (as confirmed in the current dataset). Whilst overall animal use would be lower, especially as smaller group sizes are generally employed (compared to rodent studies), selection of the NHP as the toxicology species should always be a balance between robust scientific justification (including demonstrable lack of suitability of any other species) and ethical considerations. Multi-species cross-reactive drug candidates offer other options to reduce NHP use during development, through early toxicity screening in rodents and potentially by reduction to a single rodent species for longer-term post-FIH toxicity studies. In addition, rodent crossreactivity would allow additional evaluations without NHP use, in particular reproductive, developmental or juvenile toxicity assessments, if warranted.
In order to progress this work, a larger dataset of drug candidates from individual drug modalities would be required, where FIH and post-FIH toxicology data were available. Other information that would also aid future evaluation could include broader details regarding the drug candidate and nonclinical information such as primary, secondary and safety pharmacology data, species relevance justification, toxicity findings including nature, severity and incidence, dose relationship, exposure data and safety margins, expected/exaggerated pharmacology, NOAELs in the different species and which species data drove the clinical safety margins. Such information from drug candidates that have conducted FIH and longer-term post-FIH toxicology packages in two species would allow investigation of the nature of any new toxicities in the longer-term studies and their relevance to human safety.
Additionally, access to human safety data would allow for the most complete analysis of animal species decisions for post-FIH toxicology studies. Such an approach would enable expansion of both the similarity at FIH exercise and the blinded prospective exercise. A future prospective exercise could also be considered, similar to that currently being conducted to assess species usage for carcinogenicity studies (ICHS1, 2016). A hypothetical decision to use a single or two species is defined and justified ahead of testing and the data subsequently obtained from both species would be used to determine whether the correct decision would have been made from a reasonably sized database.
Concluding remarks and recommendations The primary purpose of a nonclinical safety assessment during early drug development is to identify potential hazards for human risk assessment. While animal studies are currently embedded in the drug development process, the data presented herein provides evidence that under certain conditions single species toxicology programmes could be considered more widely, without being detrimental to human safety. However, this would require a major change in strategy, by some companies and/or regulatory agencies, especially for small molecule testing. The goal of this industry survey was to gather data on the species used for repeat dose general toxicology studies conducted for human pharmaceuticals, using the current and relevant regulatory guidelines. The dataset covers small molecules and different classes of biologics across a wide range of therapeutic indications, many of which were still in active development.
For the vast majority of small molecules, a two species (rodent and non-rodent) approach is typical, consistent with regulatory guidance (ICHM3 (R2) and ICHS9). The majority of single species approaches described were used to support testing of biologics (currently typically using the NHP), based on the recommendation that toxicology testing should only be conducted in a pharmacologically relevant species (ICHS6(R1)). The high specificity and species selectivity of biologics and associated lower likelihood of off-target toxicities, also contribute to acceptability of single species toxicology programmes. The dataset did contain mAbs for which two species approaches (rodent and non-rodent) were used, when cross-reactivity to multiple species was demonstrated. The data indicated that for many of these biologics, toxicities were similar between the species, indicating that a single species (preferably the rodent) may be sufficient to identify relevant toxicities in these cases.
The dataset also contained drug candidates for other drug modalities for which a two species (rodent and non-rodent) approach is typical -therapeutic proteins/peptides and ADCs that have aspects of both small molecules and biologics and thus follow principles of both ICHM3(R2) and ICHS6(R1). There were cases where, as supported by various guidelines, toxicology studies in two species were conducted for the FIH stage, with longer-term toxicity studies only being conducted in a single species. The data review by the working group showed that, with the benefit of hindsight and purposely working outside the relevant regulatory guidelines on species recommendations for individual drug modalities, it may have been possible for more of the drug candidates to also take this approach, without detrimental impact on human risk assessment.
Generally, there was no trend towards one species being consistently more sensitive than another, which is in line with expectations given the wide range of targets, indications and pharmacologies likely represented in the dataset. However, the above conclusion was reached without access to the full datasets available for the drug candidates. Even within the working group, consensus was reached on the decision for each drug candidate only after much debate and differences of opinion. Ensuring that toxicities of potential human relevance have been adequately identified and the risks appropriately managed is challenging and the level of discussion required in justification of potentially smaller packages of data may be a factor in the retention of two species approaches. The challenge of designing the most appropriate toxicology testing programme for any novel human pharmaceutical is compounded by the lack of data-sharing between companies.