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[562], 'agency': [565, 742], "'requiring": [569], 'margin': [571, 577], 'safety': [573, 1809], 'reduced': [576], "error'": [579], 'burdensome': [582], '[106].': [583], 'possible': [587], 'discern': [589], 'which': [590, 1401], 'these': [592, 824, 988, 1141, 1165], 'positions': [593], 'most': [594, 916], 'accurately': [595, 1182], 'reflects': [596], 'reality': [597], "'quality'": [600], 'controversy.': [601], 'However,': [602, 1018], 'fact': [604, 915, 1094], 'strident': [606], 'debate': [607], 'being': [609, 1028], 'waged': [610], 'suggests': [611], 'issue': [614], 'import.Many': [616], 'would': [620], 'agree.': [621], 'Some,': [622], 'anticipating': [623], 'severe': [624], 'standards,': [626], 'taking': [628], 'upon': [630], 'themselves': [631], 'raise': [633], 'bar': [635, 1797], 'candidates.': [639], 'consulting': [642], 'practice': [643], 'seen': [646], 'surprising': [648], 'small': [654, 748], 'clients': [656], 'needlessly': [657], 'insisting': [658], 'non-clinical': [660], 'studies': [662, 792], 'performed': [664], 'according': [665], 'Good': [667], 'Laboratory': [668], 'Practice': [669], '(GLP)': [670], 'guidelines.': [671], 'perception': [673], 'GLP': [676, 701], 'means': [677], "'better'.": [678], 'Insofar': [679], 'GLPs': [681], 'dictate': [682], 'strict': [683], 'documentation': [684], 'quality': [686, 709, 903], 'assurance': [687], 'oversight,': [688], 'there': [689], 'kernel': [692], 'truth': [694], 'belief.': [697], 'reality,': [699], 'however,': [700], 'adherence': [702], 'provides': [703], 'marginal': [706], 'enhancement': [707], 'above': [710], 'conducted': [713], "'in": [714], 'spirit': [716], "GLP',": [718], 'is,': [720], "'GLP": [721], 'without': [722], 'extra': [724], "paperwork'.Such": [725], 'mindsets': [726], 'fueled': [728], 'our': [730, 1002, 1317, 1344, 1526], 'own': [731], 'collective': [732], 'paranoia,': [733], 'coupled': [734], 'general': [737], 'lack': [738, 1168], 'clarity': [740], 'expectations.': [743], 'understandable.': [746], 'A': [747, 1061, 1361], 'company': [750, 780], 'very': [752], 'few': [753, 1784], 'eggs': [754], 'basket': [758], 'can': [759, 803, 1191, 1369, 1388, 1442], 'ill': [760], 'afford': [761], 'risk': [763, 1394, 1415, 1702], 'measuring': [767], 'up': [768], 'arduous': [771], 'they': [774, 1019], 'perceive.': [775], 'fate': [777], 'bullet-proof': [783], 'submissions,': [785], 'also': [788], 'often': [789], 'spawns': [790], 'added': [791, 935], '(quantity)': [793], 'strengthen': [795], 'package.Generally,': [797], 'need': [799, 931], "'quantity'": [802], 'likened': [805], 'gauntlet': [808], 'airport': [812], 'security.': [813], 'Shoes': [814], 'liquids': [816], 'scrutinized': [818], 'because': [819], 'bad': [820, 859], 'things': [821, 860], 'related': [822, 861], 'items': [825], 'almost': [826], 'happened.': [827], 'Now': [828], 'consider': [829], 'hERG': [831], 'channel': [832], 'screening': [833], 'embedded': [835], 'virtually': [837], 'programs': [840], 'thorough': [844], 'human': [845, 1320, 1384], 'QTc': [846], 'contemplated': [850], 'every': [852], 'clinical': [855], 'Why?': [857], 'Because': [858], 'cardiac': [863], 'conduction': [864], 'abnormalities': [865], 'did': [866], 'happen.': [867], 'Patients': [868], 'died': [869], 'fatal': [871], 'arrhythmias': [872], 'when': [873], 'CYP3A4': [874, 887], 'substrates': [875], 'potential': [878, 1414], 'elicit': [880], 'QT': [881], 'prolongation': [882], 'taken': [884], 'potent': [886], 'enzyme': [888], 'inhibitors.': [889], 'history': [891], 'withdrawals': [894, 1807], 'replete': [896], 'similar': [898], 'examples': [899], '[107].The': [900], 'quantity': [905, 975], 'merely': [907], 'two': [908], 'edges': [909], 'same': [912], 'sword.': [913], 'requirements': [919, 990], 'additional': [921, 989], 'work': [922, 977], 'support': [924, 1443], 'filing': [926], 'emanated': [928], 'ensure': [933, 1006], 'some': [934], 'element': [936], 'For': [939], 'example,': [940], 'now': [943], 'demonstrate': [946], 'integrity': [948], 'bioanalytical': [950], 'methods': [951], 'performing': [953], 'incurred': [954], 'sample': [955, 1884], 'reanalyses.': [956], 'requirement': [958], 'itself': [959, 1296], 'particularly': [962, 1500], 'onerous,': [963], 'but': [964], 'just': [966], 'one': [967], 'many': [969, 1163], 'add': [971, 1021], 'overall': [974, 1097], 'necessary': [978], 'filing.The': [985], 'intent': [986], 'laudable.': [992], 'They': [993], 'foster': [994], 'confidence': [995, 1315, 1461], 'understand': [998], 'character': [1000], 'help': [1005, 1518], 'used': [1011], 'safely': [1013], 'effectively': [1015], 'possible.': [1017], 'timelines': [1023], 'expenses.So': [1025], 'asked': [1029], 'more,': [1032], 'better,': [1036], 'less.': [1042], 'How': [1043], 'rationalize': [1046, 1070], 'continued,': [1048], 'let': [1049], 'alone': [1050], 'expanding,': [1051], 'financial': [1059, 1549, 1558, 1562, 1941, 1950, 1954], 'environment?': [1060], 'better': [1062], 'question': [1063], 'may': [1064], 'be,': [1065], 'how': [1066, 1354], 'it?The': [1071], 'ADME:': [1074], 'IIThe': [1076], 'probability': [1077, 1425], 'making': [1081, 1368, 1516], 'depressingly': [1086], 'low.': [1087], 'Impressive': [1088], 'success': [1090, 1427], 'rates': [1091], 'belie': [1092], 'rate': [1100], 'Phase': [1102, 1131, 1152, 1448, 1679], 'through': [1104], 'approval': [1105], 'still': [1107], '90%': [1108], 'primary': [1111], 'driver': [1112], 'simply': [1114], 'shifted': [1115], 'pharmacology.': [1119], 'Remarkably,': [1120], 'recent': [1122], 'analysis': [1123], 'found': [1124], '66%': [1126], 'III': [1132, 1680], 'insufficient': [1136], 'efficacy': [1137, 1170, 1328], '[5].': [1138], 'Given': [1139], 'compounds': [1142], 'had': [1143], 'activity': [1145], 'favorable': [1146], 'enough': [1147], 'justify': [1149], 'progression': [1150, 1222], 'III,': [1153], 'left': [1156], 'uncomfortable': [1159], 'realization': [1160], 'cases': [1166], 'least': [1173], 'partly': [1174], 'deficiencies': [1177], 'PK,': [1179, 1814], 'PK/pharmacodynamic': [1183], '(PK/PD),': [1184], 'performance.': [1185], 'where': [1188], 'make': [1192], 'inroads': [1194], 'optimizing': [1196, 1725], 'development.Advanced': [1200], 'PK/PD': [1201, 1246, 1374, 1420, 1440, 1510], 'strategies': [1202], 'sophisticated': [1206], 'modeling': [1207], 'tools': [1208], 'account': [1212, 1377], 'complex': [1215], 'biological': [1216, 1275, 1351], 'variables': [1217], 'contribute': [1219], 'disease': [1221], 'response': [1225], 'intervention.': [1228], 'Quantitative': [1229, 1821], 'Systems': [1231], 'Pharmacology': [1232], '(QSP)': [1233], 'tremendous': [1236], 'impact': [1237], 'front.': [1240], 'QSP': [1241, 1293, 1844], 'marriage': [1244], 'systems': [1248, 1823], 'biology': [1249], 'involves': [1251], 'integrating': [1252], 'input': [1253], 'key': [1256, 1521], 'disciplines': [1257], 'characterize': [1259], 'interaction': [1261], 'physiological': [1267], 'system,': [1268], 'linking': [1269], 'information': [1270], 'various': [1272], 'levels': [1273], 'complexity,': [1276], 'investigating': [1278], 'interplay': [1280], 'vast': [1283], 'array': [1284], 'biochemical': [1286], 'networks': [1287], '[108].': [1288], 'Ultimately,': [1289], 'value': [1291, 1397], 'manifest': [1295], 'improved': [1298], 'decisions,': [1300], 'driven': [1301], 'refined': [1304], 'predictions': [1305, 1318, 1345, 1375, 1512], 'phases': [1308], 'development.To': [1312], 'engender': [1313], 'greater': [1314], 'performance': [1322], 'enable': [1324], 'us': [1325], 'address': [1327, 1519], 'issues': [1329, 1753], 'earlier': [1330], 'much': [1339], 'precision': [1342, 1508], 'accuracy.': [1349], 'Myriad': [1350], 'factors': [1352, 1416], 'determine': [1353], 'behaves': [1357], 'individual.': [1360], 'radical': [1362], 'improvement': [1363], 'decision': [1367, 1515, 1708], 'realized': [1371], 'enhanced': [1373], 'diversity': [1380], 'defines': [1382], 'population.': [1385], 'effort': [1387], 'assisted': [1390], 'quantitative': [1392], '(probabilistic)': [1393], 'analysis.': [1395], 'instrument,': [1400], 'technique': [1404], 'quantifying': [1406], 'uncertainty,': [1407], 'stems': [1408], 'ability': [1411], 'evaluate': [1413], '(e.g.,': [1417], 'analysis),': [1421], 'derive': [1423], 'guide': [1429], 'strategy': [1431], 'decisions': [1432, 1453], '[6].A': [1433], 'solid,': [1434], 'comprehensive': [1435], 'package': [1437], 'sound': [1439], 'underpinnings': [1441], 'aggressive': [1445], 'transitions': [1446], 'I,': [1449, 1617], 'allowing': [1450], 'important': [1451], 'go/no-go': [1452], 'based': [1454], 'proof-of-principle': [1456], 'made': [1459], 'quickly': [1463], 'possible,': [1468], 'streamlining': [1469], 'research': [1471], 'process,': [1472], 'improving': [1473, 1704], 'efficiency': [1475], 'timelines,': [1477], 'reducing': [1479], 'attrition.Thus,': [1480], 'seems': [1482], 'clear': [1483], 'continue': [1487], 'play': [1489], 'active': [1491], 'expanding': [1493], 'development,': [1499], 'helping': [1502], 'improve': [1504, 1514], 'accuracy': [1506], 'model': [1511], 'quest': [1527], 'therapeutic': [1531, 1836], 'interventions': [1532], 'bear': [1534], 'unmet': [1536], 'medical': [1537], 'needs.Financial': [1538], 'competing': [1540, 1932], 'interests': [1541, 1933], 'disclosureThe': [1542, 1934], 'author': [1543, 1935], 'relevant': [1546, 1938], 'affiliations': [1547, 1939], 'involvement': [1550, 1942], 'organization': [1553, 1945], 'entity': [1555, 1947], 'interest': [1559, 1951], 'conflict': [1563, 1955], 'subject': [1566, 1958], 'matter': [1567, 1959], 'materials': [1569, 1961], 'discussed': [1570, 1962], 'manuscript.': [1573, 1965], 'includes': [1575, 1967], 'employment,': [1576, 1968], 'consultancies,': [1577, 1969], 'honoraria,': [1578, 1970], 'stock': [1579, 1971], 'ownership': [1580, 1972], 'options,': [1582, 1974], 'expert': [1583, 1975], 'testimony,': [1584, 1976], 'grants': [1585, 1977], 'patents': [1587, 1979], 'received': [1588, 1980], 'pending,': [1590, 1982], 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