190:. These generally constitute a number of tests designed to determine the major toxicities of a novel compound prior to first use in humans. It is a legal requirement that an assessment of major organ toxicity be performed (effects on the heart and lungs, brain, kidney, liver and digestive system), as well as effects on other parts of the body that might be affected by the drug (e.g., the skin if the new drug is to be delivered on or through the skin). Such preliminary tests are made using
46:
2559:
110:
406:
rate" problem. Careful decision making during drug development is essential to avoid costly failures. In many cases, intelligent programme and clinical trial design can prevent false negative results. Well-designed, dose-finding studies and comparisons against both a placebo and a gold-standard treatment arm play a major role in achieving reliable data.
512:
244:
If a vaccine candidate or antiviral compound emerges from these tests with an acceptable toxicity and safety profile, and the manufacturer can further show it has the desired effect in clinical trials, then the NCE portfolio of evidence can be submitted for marketing approval in the various countries
240:
The process of defining characteristics of the drug does not stop once an NCE is advanced into human clinical trials. In addition to the tests required to move a novel vaccine or antiviral drug into the clinic for the first time, manufacturers must ensure that any long-term or chronic toxicities are
405:
covering the 1980s and 1990s found that only 21.5 percent of drugs that started Phase I trials were eventually approved for marketing. In the time period of 2006 to 2015, the success rate was 9.6%. The high failure rates associated with pharmaceutical development are referred to as the "attrition
400:
Candidates for a new drug to treat a disease might, theoretically, include from 5,000 to 10,000 chemical compounds. On average about 250 of these show sufficient promise for further evaluation using laboratory tests, mice and other test animals. Typically, about ten of these qualify for tests on
264:
A study covering clinical research in the 1980–1990s found that only 21.5% of drug candidates that started Phase I trials were eventually approved for marketing. During 2006–2015, the success rate of obtaining approval from Phase I to successful Phase III trials was under 10% on average, and 16%
252:
Most novel drug candidates (NCEs) fail during drug development, either because they have unacceptable toxicity or because they simply do not prove efficacy on the targeted disease, as shown in Phase II–III clinical trials. Critical reviews of drug development programs indicate that Phase II–III
318:
for a manufacturer having a drug approved through successful Phase III trials was $ 2.6 billion (in 2013 dollars), an amount increasing at an annual rate of 8.5%. Over 2003–2013 for companies that approved 8–13 drugs, the cost per drug could rise to as high as $ 5.5 billion, due mainly to
469:, for drug discovery. The COVID-19 High Performance Computing Consortium also aims to forecast disease spread, model possible vaccines, and screen thousands of chemical compounds to design a COVID-19 vaccine or therapy. In May 2020, the OpenPandemics – COVID-19 partnership between
2132:
228:
Phase III trials are large, pivotal trials to determine safety and efficacy in sufficiently large numbers of patients with the targeted disease. If safety and efficacy are adequately proved, clinical testing may stop at this step and the NCE advances to the
147:
of this NCE in humans. It is the function of drug development to assess all of these parameters prior to human clinical trials. A further major objective of drug development is to recommend the dose and schedule for the first use in a human clinical trial
477:
was launched. The partnership is a distributed computing project that "will automatically run a simulated experiment in the background which will help predict the effectiveness of a particular chemical compound as a possible treatment for COVID-19".
387:
attributes such as duration, success rates, and costs, and the forecasted sales, including cost of goods and marketing and sales expenses. Less objective aspects like quality of the management or novelty of the technology should be reflected in the
265:
specifically for vaccines. The high failure rates associated with pharmaceutical development are referred to as an "attrition rate", requiring decisions during the early stages of drug development to "kill" projects early to avoid costly failures.
2077:
2033:
364:, large capital expenditures, and long timelines. This makes the valuation of such projects and companies a challenging task. Not all valuation methods can cope with these particularities. The most commonly used valuation methods are
306:
to demonstrate its equivalence or superiority to an existing approved drug, possibly as high as $ 345 million. The average cost of conducting a 2015–16 pivotal Phase III trial on an infectious disease drug candidate was $ 22 million.
155:
In addition, drug development must establish the physicochemical properties of the NCE: its chemical makeup, stability, and solubility. Manufacturers must optimize the process they use to make the chemical so they can scale up from a
2122:
97:
to market the drug. The entire process—from concept through preclinical testing in the laboratory to clinical trial development, including Phase I–III trials—to approved vaccine or drug typically takes more than a decade.
2177:
2172:
2102:
434:
designation to expedite development and regulatory review of candidate drugs for which preliminary clinical evidence shows the drug candidate may substantially improve therapy for a serious disorder.
2187:
1672:
2107:
2192:
2137:
2023:
2201:
2152:
2057:
291:
cost estimate of 2015–16 trials for development of 10 anti-cancer drugs was $ 648 million. In 2017, the median cost of a pivotal trial across all clinical indications was $ 19 million.
2067:
2013:
2182:
2117:
314:) to market—from discovery through clinical trials to approval—is complex and controversial. In a 2016 review of 106 drug candidates assessed through clinical trials, the total
2092:
1611:
1024:
2142:
1365:
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196:
methods (e.g., with isolated cells), but many tests can only use experimental animals to demonstrate the complex interplay of metabolism and drug exposure on toxicity.
2062:
2167:
2162:
524:
402:
2206:
225:
Phase II trials are used to get an initial reading of efficacy and further explore safety in small numbers of patients having the disease targeted by the NCE.
2127:
2112:
2047:
2038:
2018:
1700:
2028:
1765:
1552:
1234:
1633:
199:
The information is gathered from this preclinical testing, as well as information on CMC, and submitted to regulatory authorities (in the US, to the
2542:
2299:
2087:
2082:
1521:
871:
135:. These have promising activity against a particular biological target that is important in disease. However, little is known about the safety,
1468:
1442:
2157:
1943:
1299:
599:
2147:
236:
Phase IV trials are post-approval trials that are sometimes a condition attached by the FDA, also called post-market surveillance studies.
794:
Ciociola AA, Cohen LB, Kulkarni P (May 2014). "How drugs are developed and approved by the FDA: current process and future directions".
2239:
520:
438:
1743:
1843:"Model-Informed Drug Discovery and Development: Current Industry Good Practice and Regulatory Expectations and Future Perspectives"
2517:
530:
2593:
2537:
416:
676:
1585:
995:
45:
241:
well-defined, including effects on systems not previously monitored (fertility, reproduction, immune system, among others).
1183:"Estimated Costs of Pivotal Trials for Novel Therapeutic Agents Approved by the US Food and Drug Administration, 2015-2016"
279:
One 2010 study assessed both capitalized and out-of-pocket costs for bringing a single new drug to market at about US$ 1.8
875:
680:
516:
502:
421:
200:
78:
948:"Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: A review"
2512:
1991:
442:
384:
320:
299:
295:
1510:
Boris Bogdan and Ralph
Villiger, "Valuation in Life Sciences. A Practical Guide", 2008, 2nd edition, Springer Verlag.
513:
International
Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use
1791:
497:
454:
846:"Early Drug Discovery and Development Guidelines: For Academic Researchers, Collaborators, and Start-up Companies"
554:"Early Drug Discovery and Development Guidelines: For Academic Researchers, Collaborators, and Start-up Companies"
2583:
1936:
2507:
2348:
274:
204:
123:
82:
2588:
2489:
1981:
327:
414:
Novel initiatives include partnering between governmental organizations and industry, such as the
European
2232:
2464:
2449:
326:
Alternatives to conventional drug development have the objective for universities, governments, and the
31:
1528:
1127:"Research and Development Spending to Bring a Single Cancer Drug to Market and Revenues After Approval"
2532:
2469:
2363:
2272:
1929:
1405:
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474:
430:
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to collaborate and optimize resources. An example of a collaborative drug development initiative is
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187:
94:
74:
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2411:
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2294:
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315:
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131:(NCEs, also known as new molecular entities or NMEs) are compounds that emerge from the process of
128:
90:
62:
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2437:
2406:
1692:
1653:
1486:
1346:
1107:
1076:
Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR, Schacht AL (March 2010).
1058:
844:
Strovel J, Sittampalam S, Coussens NP, Hughes M, Inglese J, Kurtz A, et al. (July 1, 2016).
819:
552:
Strovel J, Sittampalam S, Coussens NP, Hughes M, Inglese J, Kurtz A, et al. (July 1, 2016).
492:
165:
261:
trials), and because of inadequate financing, trial design weaknesses, or poor trial execution.
1892:
747:"In vitro toxicity model: Upgrades to bridge the gap between preclinical and clinical research"
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561:
169:
157:
1841:
Marshall S, Madabushi R, Manolis E, Krudys K, Staab A, Dykstra K, Visser SA (February 2019).
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628:
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458:
140:
106:
Broadly, the process of drug development can be divided into preclinical and clinical work.
632:
77:
on microorganisms and animals, filing for regulatory status, such as via the United States
2442:
2416:
2329:
615:
Everts, Maaike; Cihlar, Tomas; Bostwick, J. Robert; Whitley, Richard J. (6 January 2017).
616:
245:
where the manufacturer plans to sell it. In the United States, this process is called a "
1409:
852:. Eli Lilly & Company and the National Center for Advancing Translational Sciences.
715:
560:. Eli Lilly & Company and the National Center for Advancing Translational Sciences.
383:
The most important value drivers are the cost of capital or discount rate that is used,
109:
2502:
2401:
1986:
1966:
1869:
1842:
1673:"Portfolio Decisions in Early Development: Don't Throw Out the Baby with the Bathwater"
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1182:
1151:
1126:
972:
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923:
898:
771:
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215:
186:
Many aspects of drug development focus on satisfying the regulatory requirements for a
132:
86:
70:
723:
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1490:
823:
369:
342:
303:
149:
66:
1696:
1657:
1350:
1198:
1142:
1078:"How to improve R&D productivity: the pharmaceutical industry's grand challenge"
1062:
617:"Accelerating Drug Development: Antiviral Therapies for Emerging Viruses as a Model"
207:(IND) application. If the IND is approved, development moves to the clinical phase.
2315:
1282:
Taylor D (2015). "The
Pharmaceutical Industry and the Future of Drug Development".
1250:
1111:
582:
Taylor D (2015). "The
Pharmaceutical Industry and the Future of Drug Development".
507:
373:
335:
176:
1597:
1566:
Stratmann HG (September 2010). "Bad
Medicine: When Medical Research Goes Wrong".
1007:
963:
914:
449:, industry, and nine universities pooled resources to access supercomputers from
179:. Together, these processes are known in preclinical and clinical development as
2262:
1971:
1952:
1291:
591:
487:
377:
254:
173:
1519:
Nielsen, Nicolaj Hoejer "Financial valuation methods for biotechnology", 2010.
1366:"The cost of creating a new drug now $ 5 billion, pushing Big Pharma to change"
845:
553:
2389:
2341:
2279:
1481:
349:
258:
144:
1333:
1316:
762:
640:
17:
1394:"Busting the billion-dollar myth: how to slash the cost of drug development"
462:
389:
1878:
1427:
1342:
1268:
1235:"Innovation in the pharmaceutical industry: New estimates of R&D costs"
1216:
1160:
1103:
981:
932:
857:
815:
780:
648:
565:
298:
was US$ 25 million for a Phase I safety study, $ 59 million for a Phase II
222:
Phase I trials, usually in healthy volunteers, determine safety and dosing.
1041:
Wang Y (2012). "Extracting knowledge from failed development programmes".
731:
2289:
2248:
1317:"Key cost drivers of pharmaceutical clinical trials in the United States"
807:
339:
192:
136:
702:
Kessler DA, Feiden KL (March 1995). "Faster evaluation of vital drugs".
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1688:
1649:
1259:
1054:
319:
international geographic expansion for marketing and ongoing costs for
1820:
1721:
164:
scale. They further examine the product for suitability to package as
1370:
466:
288:
113:
Timeline showing the various drug approval tracks and research phases
1418:
1393:
1094:
1077:
152:" or First Human Dose , previously also known as "first-in-man" ).
360:
The nature of a drug development project is characterised by high
108:
1467:
Lee, Alpha; Chodera, John; von Delft, Frank (27 September 2021).
1443:"Moonshot is the spanner in the Covid-19 works the country needs"
172:, aerosol, intramuscular injectable, subcutaneous injectable, or
446:
365:
338:
project started in March 2020 with the goal of developing an un-
2221:
1925:
899:"Phase II Trials in Drug Development and Adaptive Trial Design"
1921:
450:
161:
1469:"Why we are developing a patent-free Covid antiviral therapy"
1181:
Moore TJ, Zhang H, Anderson G, Alexander GC (November 2018).
2217:
1792:"Sixteen supercomputers tackle coronavirus cures in the US"
160:
producing milligrams, to manufacturing on the kilogram and
27:
Process of bringing a new pharmaceutical drug to the market
2133:
Nucleoside and nucleotide reverse-transcriptase inhibitors
1823:. The COVID-19 High Performance Computing Consortium. 2020
1634:"Extracting Knowledge from Failed Development Programmes"
1916:
1315:
Sertkaya A, Wong HH, Jessup A, Beleche T (April 2016).
1917:
International Union of Basic and
Clinical Pharmacology
2078:
Dual serotonin and norepinephrine reuptake inhibitors
30:"Drug research" redirects here. For the journal, see
1821:"The COVID-19 High Performance Computing Consortium"
36:
2488:
2425:
2382:
2308:
2255:
2004:
1959:
428:to enhance innovation of drug development, and the
321:Phase IV trials for continuous safety surveillance
1768:. US Food and Drug Administration. 4 January 2018
253:clinical trials fail due mainly to unknown toxic
89:on humans, and may include the step of obtaining
1746:. US Food and Drug Administration. 23 April 2018
1724:. European Innovative Medicines Initiative. 2020
2123:Non-nucleoside reverse-transcriptase inhibitors
1847:CPT: Pharmacometrics & Systems Pharmacology
1233:DiMasi JA, Grabowski HG, Hansen RW (May 2016).
1025:"Clinical development success rates: 2006–2015"
453:, combined with cloud computing resources from
1612:"Clinical Development Success Rates 2006-2015"
1284:Issues in Environmental Science and Technology
745:Madorran E, Stožer A, Bevc S, Maver U (2020).
584:Issues in Environmental Science and Technology
403:Tufts Center for the Study of Drug Development
2233:
1937:
8:
621:Annual Review of Pharmacology and Toxicology
310:The full cost of bringing a new drug (i.e.,
1815:
1813:
1722:"About the Innovative Medicines Initiative"
952:Contemporary Clinical Trials Communications
69:has been identified through the process of
2240:
2226:
2218:
1944:
1930:
1922:
1228:
1226:
839:
837:
835:
833:
671:
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665:
1868:
1858:
1785:
1783:
1480:
1417:
1332:
1258:
1206:
1176:
1174:
1172:
1170:
1150:
1093:
971:
922:
770:
751:Bosnian Journal of Basic Medical Sciences
2300:Separation of prescribing and dispensing
1125:Prasad V, Mailankody S (November 2017).
796:The American Journal of Gastroenterology
2083:Selective serotonin reuptake inhibitors
541:
1551:: CS1 maint: archived copy as title (
1544:
1019:
1017:
633:10.1146/annurev-pharmtox-010716-104533
1596:(6): 14. June 1, 2003. Archived from
1006:(6): 14. June 1, 2003. Archived from
181:chemistry, manufacturing, and control
7:
1286:. Royal Society of Chemistry: 1–33.
903:JACC. Basic to Translational Science
586:. Royal Society of Chemistry: 1–33.
577:
575:
547:
545:
300:randomized controlled efficacy study
1030:. BIO Industry Analysis. June 2016.
294:The average cost (2013 dollars) of
2173:Bcr-Abl tyrosine-kinase inhibitors
872:"Vaccine Product Approval Process"
439:United States Department of Energy
25:
2188:Neurokinin 1 receptor antagonists
2063:Dipeptidyl peptidase-4 inhibitors
1441:Whipple, Tom (October 23, 2021).
724:10.1038/scientificamerican0395-48
401:humans. A study conducted by the
61:is the process of bringing a new
2558:
2557:
2518:List of pharmaceutical companies
2178:Cannabinoid receptor antagonists
531:List of pharmaceutical companies
44:
2538:Pharmacies in the United States
2007:and development of drug classes
1586:"R&D costs are on the rise"
1568:Analog Science Fiction and Fact
1199:10.1001/jamainternmed.2018.3931
1143:10.1001/jamainternmed.2017.3601
996:"R&D costs are on the rise"
515:, a consensus between the U.S.
417:Innovative Medicines Initiative
366:risk-adjusted net present value
296:each stage of clinical research
102:New chemical entity development
1251:10.1016/j.jhealeco.2016.01.012
1082:Nature Reviews. Drug Discovery
677:"The Drug Development Process"
1:
2024:Angiotensin receptor blockers
964:10.1016/j.conctc.2018.08.001
915:10.1016/j.jacbts.2019.02.005
876:Food and Drug Administration
681:Food and Drug Administration
517:Food and Drug Administration
503:Pharmaceutical manufacturing
422:Food and Drug Administration
79:Food and Drug Administration
2513:Pharmacy benefit management
2202:Melatonin receptor agonists
2153:Thalidomide and its analogs
2108:Memantine and related drugs
2058:Cyclooxygenase 2 inhibitors
1590:Medical Marketing and Media
1364:Herper M (11 August 2013).
1292:10.1039/9781782622345-00001
1239:Journal of Health Economics
1000:Medical Marketing and Media
946:Fogel DB (September 2018).
897:Van Norman GA (June 2019).
592:10.1039/9781782622345-00001
443:National Science Foundation
2610:
2068:Direct thrombin inhibitors
2005:Case studies of discovery
1893:"OpenPandemics – COVID-19"
1790:Shankland S (2020-03-23).
1744:"Critical Path Initiative"
498:Pharmaceutical engineering
455:Hewlett Packard Enterprise
426:"Critical Path Initiative"
302:, and $ 255 million for a
272:
121:
29:
2553:
2183:CCR5 receptor antagonists
1482:10.1146/knowable-092721-1
287:million, respectively. A
257:(50% failure of Phase II
2508:Investigational New Drug
2349:Pharmaceutical chemistry
2295:Pharmacological activity
2118:Neuraminidase inhibitors
1392:Maxmen A (August 2016).
1334:10.1177/1740774515625964
763:10.17305/bjbms.2019.4378
275:Cost of drug development
205:Investigational New Drug
124:Pre-clinical development
83:investigational new drug
2490:Pharmaceutical industry
2309:Pharmaceutical sciences
2093:HIV-protease inhibitors
2014:5α-Reductase inhibitors
1043:Pharmaceutical Medicine
328:pharmaceutical industry
304:pivotal Phase III trial
32:Drug Research (journal)
2594:Life sciences industry
2143:Proton pump inhibitors
1766:"Breakthrough Therapy"
1187:JAMA Internal Medicine
1131:JAMA Internal Medicine
878:(FDA). 30 January 2018
114:
2465:Pharmacist prescriber
2450:Consultant pharmacist
1671:Herschel, M. (2012).
1619:BIO Industry Analysis
850:Assay Guidance Manual
683:(FDA). 4 January 2018
558:Assay Guidance Manual
410:Computing initiatives
129:New chemical entities
112:
65:to the market once a
2533:Pharmacies of Norway
2470:Pharmacy informatics
2364:Pharmacoepidemiology
2273:Prehistoric medicine
2098:Integrase inhibitors
2073:Direct Xa inhibitors
1600:on October 18, 2016.
1010:on October 18, 2016.
808:10.1038/ajg.2013.407
475:World Community Grid
431:Breakthrough Therapy
247:new drug application
231:new drug application
218:involve four steps:
188:new drug application
95:new drug application
75:preclinical research
2480:Veterinary pharmacy
2412:Pharmacy technician
2374:Pharmacocybernetics
2268:History of pharmacy
1410:2016Natur.536..388M
716:1995SciAm.272c..48K
704:Scientific American
437:In March 2020, the
334:, an international
316:capital expenditure
312:new chemical entity
91:regulatory approval
63:pharmaceutical drug
2475:Specialty pharmacy
2438:Community pharmacy
2407:Pharmacy residency
2168:Tubulin inhibitors
1860:10.1002/psp4.12372
1689:10.1007/BF03256895
1650:10.1007/BF03256897
1055:10.1007/BF03256897
493:Drug repositioning
115:
2571:
2570:
2528:Pharmacy in China
2455:Hospital pharmacy
2433:Clinical pharmacy
2369:Pharmacovigilance
2285:Prescription drug
2215:
2214:
2163:TRPV1 antagonists
2103:Lipase inhibitors
1473:Knowable Magazine
1301:978-1-78262-189-8
1193:(11): 1451–1457.
1137:(11): 1569–1575.
601:978-1-78262-189-8
283:billion and $ 870
158:medicinal chemist
56:
55:
16:(Redirected from
2601:
2584:Drug development
2561:
2560:
2523:Medication costs
2498:Drug development
2460:Nuclear pharmacy
2337:Pharmacogenomics
2325:Pharmacodynamics
2321:Pharmacokinetics
2242:
2235:
2228:
2219:
2207:Renin inhibitors
2053:c-Met inhibitors
1977:Drug development
1946:
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1699:. Archived from
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1632:Wang Y. (2012).
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286:
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141:pharmacokinetics
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2417:Pharmacy school
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2330:Pharmacometrics
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2246:
2216:
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2196:
2138:PDE5 inhibitors
2128:NS5A inhibitors
2113:mTOR inhibitors
2042:
2006:
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1960:Steps in design
1955:
1950:
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1522:"Archived copy"
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1419:10.1038/536388a
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1321:Clinical Trials
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551:
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484:
412:
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362:attrition rates
358:
284:
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216:Clinical trials
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87:clinical trials
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2589:Drug discovery
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2503:Drug discovery
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2055:
2050:
2048:Cephalosporins
2045:
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2021:
2019:ACE inhibitors
2016:
2010:
2008:
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2001:
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1984:
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1967:Drug discovery
1963:
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370:decision trees
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346:antiviral drug
332:COVID Moonshot
273:Main article:
270:
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211:Clinical phase
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150:first-in-human
133:drug discovery
122:Main article:
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2034:Beta-blockers
2032:
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2029:Antiandrogens
2027:
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2020:
2017:
2015:
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2003:
1993:
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2497:
2316:Pharmacology
1976:
1897:. Retrieved
1887:
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1850:
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1836:
1825:. Retrieved
1800:. Retrieved
1795:
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1760:
1748:. Retrieved
1738:
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1716:
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1701:the original
1683:(2): 77–84.
1680:
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1644:(2): 91–96.
1641:
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1621:. June 2016.
1618:
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1593:
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1536:. Retrieved
1529:the original
1515:
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1494:. Retrieved
1472:
1462:
1450:. Retrieved
1446:
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1375:. Retrieved
1369:
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508:Generic drug
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415:
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396:Success rate
392:estimation.
382:
374:real options
359:
336:open-science
325:
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255:side effects
251:
243:
239:
233:(NDA) stage.
214:
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177:formulations
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118:Pre-clinical
105:
85:to initiate
58:
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2383:Professions
2263:Compounding
2197:antagonists
1982:Preclinical
1972:Hit to lead
1953:Drug design
1895:. IBM. 2020
1798:. ViacomCBS
1260:10161/12742
958:: 156–164.
488:Drug design
378:comparables
174:intravenous
2578:Categories
2390:Pharmacist
2342:Toxicology
2280:Medication
2088:Gliflozins
1827:2020-04-27
1772:24 January
1750:24 January
1728:24 January
1707:2012-06-12
1538:2014-11-25
1496:1 November
1452:5 November
654:2 November
537:References
473:and IBM's
390:cash flows
350:SARS-CoV-2
259:cardiology
249:" or NDA.
145:metabolism
1677:Pharm Med
1638:Pharm Med
1491:244170138
1447:The Times
1245:: 20–33.
824:205100166
641:0362-1642
463:Microsoft
420:. The US
356:Valuation
348:to treat
203:), as an
2563:Category
2290:Pharmacy
2249:Pharmacy
2158:Triptans
2043:agonists
1987:Clinical
1879:30411538
1802:27 April
1697:15782597
1658:17171991
1574:(9): 20.
1547:cite web
1428:27558048
1351:24308679
1343:26908540
1269:26928437
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933:31312766
882:21 March
858:22553881
816:24796999
781:31621554
687:21 March
649:27483339
566:22553881
482:See also
368:(rNPV),
340:patented
193:in vitro
166:capsules
137:toxicity
2543:History
2256:General
2148:Statins
1870:6389350
1406:Bibcode
1377:17 July
1208:6248200
1152:5710275
1112:1299234
973:6092479
924:6609997
874:. U.S.
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732:7871409
712:Bibcode
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519:(FDA),
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170:tablets
93:with a
81:for an
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1992:Phases
1899:18 May
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465:, and
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289:median
285:
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1693:S2CID
1654:S2CID
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1532:(PDF)
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1487:S2CID
1347:S2CID
1108:S2CID
1059:S2CID
1028:(PDF)
820:S2CID
525:Japan
385:phase
376:, or
2443:shop
2395:List
2193:5-HT
2039:Beta
1901:2020
1875:PMID
1804:2020
1796:CNET
1774:2020
1752:2020
1730:2020
1572:CXXX
1553:link
1498:2021
1454:2021
1424:PMID
1379:2016
1339:PMID
1296:ISBN
1265:PMID
1213:PMID
1157:PMID
1100:PMID
978:PMID
929:PMID
884:2020
854:PMID
812:PMID
777:PMID
728:PMID
689:2020
656:2021
645:PMID
637:ISSN
596:ISBN
562:PMID
447:NASA
343:oral
269:Cost
1865:PMC
1855:doi
1685:doi
1646:doi
1477:doi
1414:doi
1402:536
1329:doi
1288:doi
1255:hdl
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