dataesr/scientific-paragraphs-categorization huggingface dataset:
Articles focusing on the methodological aspects and/or providing guidance on the application of the multi-criteria decision analysis were not selected for this review. The following search terms were used: MCDA AND (benefit risk assessment OR risk benefit assessment OR BRA). Eligible articles were first selected based on their title and abstract, then based on the review of the full report. For each eligible study, we searched in CHMP, EMA, FDA websites and available reports to identify any evidence that the reported quantitative assessments where utilized in the regulatory process. In total 117 hits were found through the search of databases, out of which nine publications were selected. These articles are listed in Table  1. All of these papers had common objectives to compare the benefit-risk profile of several products using the quantitative, multi-criteria, decision analysis method and integrating data from several data sources of varied quality level.
High Performance Liquid Chromatography (HPLC) Analysis of Phenylephrine Hydrochloride and Tropicamide The HPLC system consisted of a Dionex UltiMate 3000 Series equipped with a quaternary pump, online degasser, autosampler, and photodiode array UV/vis detector. Data collection and analysis were performed using Chromeleon 7. 6. 2. (Dionex, France). The current method was adapted from literature and validated as per ICH Q2R1 guideline. Briefly, the separation was achieved on a Kinetex C18 column (5 µm, 4. 6 mm × 250 mm). The elution was isocratic at 1. 0 mL/min with a mobile phase of 72% (v/v) octane sulfonic acid buffer (pH 3. 5) and 28% (v/v) acetonitrile. The injection volume was 20 µL and UV detection was at 254 nm for TPC and 272 nm for PHE. Linearity was established in the concentration range of 8-120 µg/mL (r 2 > 0.
Formulations A, B, and C were compared with a control solution (CTRL) (phenylephrine 5% and tropicamide 0. 5%, in sterile water) and to commercially available eye drops (CED): Mydryaticum ® (tropicamide 0. 5%) and Néosynéphrine ® (phenylephrine hydrochloride 10%). In the case of commercial eye drops, a standard protocol used clinically was followed: four drops of each eye drop with a five-minute interval between each drop were instilled from t 0 to t 35min. The kinetic data of mydriasis were finally obtained by analyzing the images by open source processing program Image J  [34]. The flexible scale placed on the cheeks of the Rabbits allowed rescaling the photos to avoid distance bias between the objective of the camera and the head of the Rabbits that were free of movements. Diameters of the pupil were measured, and diameters minus reference diameter were plotted against time to express the dilatation of the pupil.
For the Picro-Red Sirius slices, collagen fiber birefringence was observed via a linearly polarizing filter (Olympus U-POT polarizer) set to obtain a black background. The polarized-slice pictures were taken at the healthy cartilage maximum birefringence intensity angle, and this angle was reproduced on subsequent slices  25, 26. The ROI, i. e. articular cartilage, was segmented from white light images, using ImageJ software (ImageJ 1. 53c, Wayne Rasband, NIH USA, http://image j. nih. gov/ij). This mask was applied to the polarized light images to isolate cartilage (Fig. 5 ). Different color thresholds (Red, Yellow, Green) were applied and the selected areas were compared to the total cartilage area. Since the birefringed color reflects the local state of the collagenous network (fiber size, density, spatial arrangement, etc), a variation in this color indicates a change in the network  27.
Data collection Data were obtained from the medical records of the patients and included the demographics (gender, age, weight, height), current treatments, medical history and the substances supposedly ingested by the patient. Throughout the text, the basic unit was the occurrence of a substance. An occurrence means the supposed ingestion of a defined substance, either a medicinal or a recreational substance. All drugs administered during the management of the patient from the pre-hospital setting to the admission to the ICU were not recorded.
Results of the pre-IND toxicology and non-clinical hepatic profile did not suggest a hepatic safety signal. However, as non-clinical studies cannot exclude hepatotoxicity in the clinic, careful liver test monitoring practices for ONA-ER were followed in the NCT02052128 and NCT02049190 studies and continue to be used in the NCT03909152 study. The concept behind reformulating onapristone was to attempt to achieve the efficacy seen in the previous phase II studies of breast cancer  [4, 6]  while reducing the risk of DILI. Off-target effects on hepatic glucocorticoid receptors (GRs) are a plausible cause for hepatotoxicity seen in clinical trials. Several lines of evidence support this hypothesis, including: onapristone cross-reactivity with GR in liver cytosol  [23] ; onapristone cross-reactivity with GR and other steroid receptors closely related to PR in non-hepatic tissues  [24] [25] [26] [27] ; and the recent demonstration that a closely related antiprogestin, ulipristal, specifically inhibits GR signaling in human liver cells  [28].
To date, ONA-ER has advanced into two, completed phase 1-2 studies in female subjects with PR+ endometrial breast or ovarian cancer (NCT02052128,  Cottu et al. , 2018)   [8]  and in male subjects with PR+, castrate-resistant prostate cancer (NCT02049190; Jayaram et al. , 2017)  [18] , while a further phase II basket study has recently been initiated in women with PR+ recurrent gynecologic cancer (NCT03909152). In view of hepatotoxicity concerns from earlier clinical studies with onapristone and to better understand whether ONA-ER offers a suitable safety profile for continued evaluation in breast and gynecological cancers, we undertook a review of ONA-ER safety based on pooled data from a total of 88 subjects from NCT02052128  [8]  and NCT02049190. [18].
Methods To assess the hepatotoxic potential for ONA-ER in humans, this study evaluated two clinical studies in which ONA-ER was dosed between 10 and 50 mg BID for up to 60 weeks (NCT02052128, published as Cottu et al. , 2018; NCT02049190; clinical study records)  [8]. Pharmacokinetic parameters were compared between onapristone 100 mg QD (dosed as four times onapristone 25-mg capsules) and ONA-ER 50 mg BID within a dose-escalation component of a phase I-II clinical study in female subjects with endometrial carcinoma, breast cancer, or ovarian cancer  [8]. Blood samples were collected at 0, 1, 2, 3, 4, 6, 8, and 12 h (before next ONA-ER BID dose), and at 24 h (before next 100-mg dose in capsules) post-drug dosing, as well as at hour 0 on days 8, 29, and 57 (just before drug intake). No dose-limiting toxicity was observed with repeated liver biochemical tests in the phase I component of NCT02052128, which defined a recommended phase II dose level of ONA-ER of 50 mg BID.
The PK dataset from this clinical study enabled a direct comparison between C max and steady-state trough concentrations (C min-ss ) onapristone 100 mg QD (capsular form) and ONA-ER 50 mg BID. Figure  1  presents this comparison of the PK results. Figure  1  shows that dosing with ONA-ER 50 mg BID resulted in the day 1 median C max more than two times lower than the day 1 median C max for onapristone 100 mg QD, while at steady state (days 8, 29, 57), the median C min-ss for both formulations were similar: 1504 ng/mL vs 1835 ng/mL for onapristone 100 mg QD vs ONA-ER 50 mg BID, respectively. The reduced day 1 C max observed for ONA-ER 50 mg BID was associated with a delayed median time to C max of 2. 5 h vs 1 h for onapristone 100 mg QD, indicating a reduced absorption rate for the ER formulation.
Clinical Safety Review The databases of clinical trials AR18-CT-101 (NCT02052128, published as  Cottu et al. 2018 ) and AR18-CT-102 (NCT02049190; clinical study records) were reviewed and all subjects with either a hepatobiliary system organ class adverse event (AE) or elevation of any liverrelated laboratory tests including alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, gammaglutamyl transpeptidase (GGT), alkaline phosphatase (ALP), or lactic dehydrogenase were selected for additional evaluation  [8]. The cumulative exposure to ONA-ER for all subjects included in the AR18-CT-101 and AR18-CT-102 studies was estimated from the clinical databases. For crossover and dose escalation studies, the number of subjects who received a given treatment in any included study period was counted.
The safety cohort, if available, and assigned treatment cohorts were used to determine exposure in ongoing studies; if the safety population was not available, all subjects were included. A review of pooled safety data of AR18-CT-101 and AR18-CT-102 studies was also conducted to evaluate potential correlations between: the presentation of liver metastases and liver enzyme abnormalities; the presentation of bone metastases and liver enzyme abnormalities; and the use of ONA-ER alone or in combination with abiraterone (abiraterone acetate plus prednisone). The Common Terminology Criteria for Adverse Events (version 5. 0) was used to grade the aminotransferase elevations that occurred during the studies (Table  1 ).
Evaluation of Liver Test Abnormalities Observed in Phase I and Phase I-II Studies A total of 88 subjects have been dosed with ONA-ER in two oncology studies: (a) in AR18-CT-101 (phase I-II; NCT02052128) and (b) AR18-CT-102 (phase I-II; NCT02049190) (Table  2 )  [8, 18]. Drug-induced liver injury remains a diagnosis of exclusion after evaluating for various toxic, infectious, metabolic, and autoimmune causes of liver injury  [32]. The lack of a definitive laboratory or radiologic test and the presence of non-specific histopathological findings can make DILI a challenging diagnosis  [33]. For this reason, and to monitor safety and tolerability, a safety data review committee (DRC) was established, involving five independent members (two oncologists, one pharmacovigilance specialist [chair], one statistician, one clinical pharmacologist), as well as the lead principal investigator.
Two subjects (0003-0002 and 0014-0005) underwent a dose reduction or interruption because of elevated liver enzymes. For subject 0003-0002, review of the pharmacovigilance CIOMS I form for this subject revealed that the liver disease was obstructing the biliary duct and was treated with a biliary drain/stent 2 days after stopping ONA-ER. This explains the causation and the immediate resolution of liver enzyme events. For subject 0014-0005, at the day 29 visit, the subject complained of mild abdominal pain, Table  5  Liver-related onapristone extended release (ONA-ER) grade 3-4 treatment-emergent adverse events (TEAEs) in the safety dataset (n = 88) Safety population = all subjects who received at least one dose of ONA-ER in clinical studies: AR18-CT-101 and AR18-CT-102. ONA-ER related adverse events = (a) related to ONA-ER for AR18-CT-101 and AR18-CT-102 or (b) ONA-ER plus abiraterone/prednisone for AR18-CT-102.
H. L. ) concluded that this hepatic event was unlikely to be related to ONA-ER (< 25% probability based on the US Drug-Induced Liver Injury Network scoring system)  [38]  largely due to the negative re-challenge response to ONA-ER that was continued without further incident. The clinical study AR18-CT-102 (NCT02049190) was a phase I-II study in male subjects (n = 36) with castrationresistant prostate cancer, in which all subjects had histologically confirmed adenocarcinoma of the prostate that had progressed on abiraterone or enzalutamide  [18]. Subjects were divided among seven treatment cohorts who were dosed with: ONA-ER BID: 10, 20, 30, 40, or 50 mg; ONA-ER 30 mg BID plus abiraterone (abiraterone acetate 1000 mg plus prednisone 5 mg BID); or ONA-ER 50 mg BID plus abiraterone. There were no serious AEs related to liver biochemistry tests, including 15 subjects who received abiraterone in combination with ONA-ER.
1 ). An extendedrelease tablet (ONA-ER) was selected for clinical evaluation. As reported above, ONA-ER 50 mg BID appears to achieve the PK goals of the re-formulation program. Typical pre-IND toxicology studies preliminary to the IND review, as well as a non-clinical hepatic profile found no hepatotoxicity signals or lethalities, a result that enabled new clinical studies, AR18-CT-101 (NCT02052128)  [8]  and AR18-CT-102 (NCT02049190)  [18] , to be initiated. Out of 88 subjects in clinical studies AR18-CT-101 (NCT02052128) and AR18-CT-102 (NCT02049190), five subjects (four with breast cancer and one with endometrial cancer) developed significant elevations in liver tests and serum bilirubin suggesting cholestatic injury. However, the role of progressive malignant disease with liver metastases was considered, by the DRC, a more likely cause in all four of the subjects with breast cancer.
0% (ALT) and 9. 5% (AST) of subjects without known liver metastases. The only grade 3-4 ALT elevation, and three out of four grade 3-4 AST elevations, occurred in subjects with liver metastases. Gamma-glutamyl transpeptidase elevation has low specificity for liver disease, thus the significance of 9. 0% of subjects with grade 3-4 elevations is not clear. Although no clinical signal of significant hepatotoxicity is manifest in the current liver safety database, it cannot be ruled out because of the relatively small total number of patients and the high prevalence of liver metastases. Thus, careful liver test monitoring is proposed for the planned larger phase II-III studies. It is recommended that grade 3 AST, ALT, or bilirubin elevation be managed by study drug interruption, then re-starting at a lower dose once the values resolve to grade 1 or less (ONA-ER investigator's brochure).
Clinical trials in which subjects received onapristone extended release (ONA-ER) BID twice daily, QD once daily a Phase I of NCT02052128 (AR18-CT-101) was published as Cottu et al. [9]  b All subjects had histologically confirmed adenocarcinoma of the prostate that had progressed on abiraterone or enzalutamide. NCT02049190 was published as Jayaram et al. [18]  c Abiraterone acetate 1000 mg QD was dosed with prednisone 5 mg BID Study Study title Dosage and dosage subjects (n) Study of Onapristone in Patients with Advanced Castration-resistant Prostate Cancer (a) ONA-ER BID: 10, 20, 30, 40, 50 mg (n = 21) (b) ONA-ER 30 mg BID + abiraterone 1000 mg (n = 5) c (c) ONA-ER 50 mg BID + abiraterone 1000 mg (n = 10) c.
3. 4. 1 Phase I-II Study in Female Subjects with Progesterone Receptor-Expressing Cancers (Study AR18-CT-101; NCT02052128; Cottu et al. 2018; Context Therapeutics, Study on File) AR18-CT-101 (NCT02052128) was a phase I-II study of female subjects (n = 58, n = 52 received ONA-ER) with PR-expressing cancers [8]. Five subjects, four with breast cancer and one with endometrial cancer, developed signifi- cant elevations in liver tests and serum bilirubin suggesting cholestatic injury. All four subjects with breast cancer had grade 3 liver test elevations in conjunction with rapid disease progression (Table.
The small-angle X-ray diffraction (SAXD) samples were prepared using a similar method; however, 0. 90 mg of lipids was dissolved in hexane/ethanol (2:1) and sprayed over an area of 10 × 10 mm 2 on the polycarbonate filters and equilibrated at 85 °C for 30 min for a single cycle. A single, higher equilibration temperature was possible for the SAXD samples due to the lipid's greater adhesive strength with these filters. The samples were hydrated in a 100% H 2 O humid environment for at least ∼18 h before measuring. D16 Neutron Diffractometer Measurements. Neutron diffraction experiments were performed on the D16 neutron diffractometer at the Institut Laue-Langevin, Grenoble, France. The measurement and data analysis procedure have been described previously. 21, 22 In brief, the incoming slit-collimated beam (wavelength 4.
The scattering data were reduced, background-subtracted, and the peaks were fitted using the data processing software LAMP. 29 While converting 2θ into to qspacing, a rearranged Bragg equation was used π θ λ = q 4 sin (1) When in the lamellar phase, a series of peaks at equal q-distances to one another are detected. The repeat distance (d) of the lamellar phase can be calculated from the positions of the peaks as π = d n q 2 n ( 2 ) with n as the order number of the diffraction peak located at position q n. Scattering Length Density (SLD) Calculations. Scattering curves were analyzed with a similar method that has been reported previously. 20, 21 In short, all diffraction orders were fitted with a Gaussian function to determine the scattering intensity (I). The I of the peaks were used to calculate the structure factor amplitude (|F n |) for that order.
Since the EDD profiles compare the samples at different temperatures, the overall scattering intensity is expected to change. As a result, each peak intensity was normalized in relation to the scan's overall peak intensity. The EDD phase signs were identified using the method previously reported. 20 As our models do not swell upon hydration, in the previous study, a continuous Fourier was determined from mixtures forming a similar LPP with small variations in repeat distance. When taking the same phase signs, our F n values fitted to the continuous Fourier, indicating that the LPP in this measurement had the same phase signs with the previous study. EDD profiles at a given position in the unit cell were calculated using eq 5. Modeling the LPP Neutron Diffraction Distribution. Due to the large error that is inherent with the SLD and EDD profiles, it is important to distinguish true SLD distributions from that caused by data truncation error.
Comparing the SLD intensity between the two hydration states, when the sample was hydrated in 8:92 D 2 O/H 2 O, the water scattering is reduced to 0, leaving the only contribution from the lipids, hence the reduced scattering values. In the 100:0 D 2 O model, approximately an equal number of water molecules were included at each of the headgroup regions. In addition, both hydration conditions included a small broader peak between 2. 75 and 2. 95 nm from the center, representing the ester group of the CER EOS. The oxygen in the ester bond contributes to a greater SLD value at that position (CO 12. 45 fm), as opposed to the neutral contribution to the methylene group it otherwise replaces in an acyl chain (CH 2 -0. 83 fm). From these theoretical SLD contributions, the F n for each order was calculated (Figure  4B ; red dots) and compared with the values derived from the experimental data (green dots).
Outcomes The main measurement will be paracetamol blood concentration. Curves will be established for each patient, and we will determine and compare for each route of administration and for each patient AUC0-t, AUC0-∞, Cmax, Vd, and t1/2. Data will also permit us to compare PK characteristics between all of the patients. Secondary evaluation criteria will be pain evaluation by Numeric Pain Rate Scale (NPRS) throughout the duration of the protocol and clinical evaluation of safety by the nurse.
Protocol steps The study design is described in Fig. 1. All the study was design in the respect of the SPIRIT and CONSORT advice of Additional files 1 and 2. All steps are outlined in Fig. 2  with the SPIRIT advice. Pre-inclusion Patients will be screened by investigators according to eligibility criteria. Patients will sign a consent form after receiving oral and written information from a physician investigator involved in this project. After inclusion, they will be randomly assigned using block randomization (using Ennov clinical® software based on a list prepared by the study statistician) to SC before IV paracetamol injection or IV before SC with a washout period of 24 h between the two injections. This washout period was determined since the half-life of paracetamol has been commonly reported (Summary of product characteristics) as ranging from 1 to 4 h depending on the administration route.
Pharmacokinetic data Pharmacokinetic sampling procedure Blood samples (2 ml) will be collected in dry tubes free of gel at 0. 75, 1, 1. 5, 2, 4, and 8 h after paracetamol IV administration or 0. 25, 0. 5, 0. 75, 1, 1. 5, 2, 4, 6, and 8 h after SC administration. The samples will be rapidly transported to the laboratory. Assay method After centrifugation, serum samples will be immediately used for quantification of acetaminophen with the EMIT tox TM Acetaminophen Assay, which is a homogeneous enzyme immunoassay performed in AU 5800 clinical chemistry systems (Beckman Coulter, France). The limit of quantification is 0. 12 mg/L. Precision is better than 6% for three quality control levels. The quantitative analyses will be conducted according to the principles of Good Laboratory Practice. PK calculations Paracetamol concentrations obtained after IV and SC administration will be analyzed using a one-compartment open model (because paracetamol PK is known to be linear).
Data analysis The PK parameters AUC0-t, AUC0-∞, Cmax, Vd, and t 1/2 , whose distributions are known to be approximately log-normal, will be described for the two modes of administration in the form of geometric means with geometric coefficients of variation. Tmax will be summarized by a median and quartiles. The parameters AUC0-t, AUC0-∞, Cmax, Vd, and t 1/2 will then be log-transformed and compared between the two modes of administration using a linear regression model taking into account the following effects: treatment sequence (IV-SC or SC-IV), subjects (nested in the treatment sequence), treatment period (period 1 or period 2), and mode of administration (IV or SC). For each parameter, the difference between the two modes of administration will be tested based on the P value associated with the treatment effect.
A non-parametric test (Wilcoxon signed-rank test) will be used for Tmax. The bioequivalence between the two modes of administration will be tested for AUC0-t, AUC0-∞, and Cmax based on the 90% confidence interval of the ratio of the geometric means (SC vs IV). According to the recommendations of the European Medicines Agency  [13] , we can conclude bioequivalence if the confidence interval is fully within the range 80-125%. Pain scores will be compared between the two modes of administration by paired t-tests or Wilcoxon signedrank tests, depending on the form of the distribution. Data will be analyzed based on a per protocol analysis. Statistical significance will be set at P < 0. 05. Data will be analyzed at the Biostatistics and Clinical Research Unit of Caen University Hospital, with SPSS and R software.
Adverse events data Information on all adverse events will be collected, from consent to the end of patient participation, and reported to the sponsor. Serious adverse reactions (SAR) will be qualified as expected or unexpected by the sponsor. Expected SAR related to paracetamol are thrombocytopenia, leucopenia, neutropenia, hypersensitivity, hypotension, increased transaminases, malaise, tachycardia, flushing, pruritus, and erythema. Other SAR will be considered as unexpected. A Data Safety Monitoring Board (DSMB) will review the safety independently. The DSMB will include three experts: one pharmacologist, one physician pain specialist, and one dermatologist. The sponsor will request DSMB advice in case of suspected unexpected SAR or any new safety information. The DSMB is charged with providing advice to the sponsor recommendations that include (a) continuation of the study, (b) continuation with modification, and (c) termination of the study.