US Food and Drug Administration. Development & Approval Process (Drugs). https://www.fda.gov/Drugs/DevelopmentApprovalProcess/default.htm#Developing. Accessed 27 May 2018.
Hare JM, Bolli R, Cooke JP, Gordon DJ, Henry TD, Perin EC, et al. Phase II clinical research design in cardiology: learning the right lessons too well: observations and recommendations from the Cardiovascular Cell Therapy Research Network (CCTRN). Circulation. 2013;127(15):1630–5.
Pasqualetti G, Gori G, Blandizzi C, Del Tacca M. Healthy volunteers and early phases of clinical experimentation. Eur J Clin Pharmacol. 2010;66(7):647–53.
National Institutes of Health (NIH) Clinical Center. Patient recruitment: healthy volunteers. https://clinicalcenter.nih.gov/recruit/volunteers.html. Accessed 17 Oct 2018.
CenterWatch. Overview of Clinical Trials. https://www.centerwatch.com/clinical-trials/overview.aspx. Accessed 27 May 2018.
Franks ME, Macpherson GR, Figg WD. Thalidomide. Lancet. 2004;363(9423):1802–11.
Schmucker DL, O’Mahony MS, Vesell ES. Women in clinical drug trials. An update. Clin Pharmacokinet. 1994;27(6):411–7.
Schmucker DL, Vesell ES. Underrepresentation of women in clinical drug trials. Clin Pharmacol Ther. 1993;54(1):11–5.
Beierle I, Meibohm B, Derendorf H. Gender differences in pharmacokinetics and pharmacodynamics. Int J Clin Pharmacol Ther. 1999;37(11):529–47.
Fletcher CV, Acosta EP, Strykowski JM. Gender differences in human pharmacokinetics and pharmacodynamics. J Adolesc Health. 1994;15(8):619–29.
Harris RZ, Benet LZ, Schwartz JB. Gender effects in pharmacokinetics and pharmacodynamics. Drugs. 1995;50(2):222–39.
Kashuba AD, Nafziger AN. Physiological changes during the menstrual cycle and their effects on the pharmacokinetics and pharmacodynamics of drugs. Clin Pharmacokinet. 1998;34(3):203–18.
Thurmann PA, Hompesch BC. Influence of gender on the pharmacokinetics and pharmacodynamics of drugs. Int J Clin Pharmacol Ther. 1998;36(11):586–90.
Martin RM, Biswas PN, Freemantle SN, Pearce GL, Mann RD. Age and sex distribution of suspected adverse drug reactions to newly marketed drugs in general practice in England: analysis of 48 cohort studies. Br J Clin Pharmacol. 1998;46(5):505–11.
Rademaker M. Do women have more adverse drug reactions? Am J Clin Dermatol. 2001;2(6):349–51.
Stunkel L, Grady C. More than the money: a review of the literature examining healthy volunteer motivations. Contemp Clin Trials. 2011;32(3):342–52.
Hassar M, Pocelinko R, Weintraub M, Nelson D, Thomas G, Lasagna L. Free-living volunteer’s motivations and attitudes toward pharmacologic studies in man. Clin Pharmacol Ther. 1977;21(5):515–9.
Orme M, Harry J, Routledge P, Hobson S. Healthy volunteer studies in Great Britain: the results of a survey into 12 months activity in this field. Br J Clin Pharmacol. 1989;27(2):125–33.
Johnson RA, Rid A, Emanuel E, Wendler D. Risks of phase I research with healthy participants: a systematic review. Clin Trials. 2016;13(2):149–60.
Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006;355(10):1018–28.
Butler D, Callaway E. Scientists in the dark after French clinical trial proves fatal. Nature. 2016;529(7586):263–4.
European Medicines Agency (EMA). Guidelines on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products; 2007. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002988.pdf. Accessed 1 July 2018.
Ling J, Johnson KA, Miao Z, Rakhit A, Pantze MP, Hamilton M, et al. Metabolism and excretion of erlotinib, a small molecule inhibitor of epidermal growth factor receptor tyrosine kinase, in healthy male volunteers. Drug Metab Dispos. 2006;34(3):420–6.
Bonini S, Rasi G. First-in-human clinical trials—what we can learn from tragic failures. N Engl J Med. 2016;375(18):1788–9.
Chaudhary R, Garg J, Shah N, Sumner A. PCSK9 inhibitors: a new era of lipid lowering therapy. World J Cardiol. 2017;9(2):76–91.
Stein EA, Mellis S, Yancopoulos GD, Stahl N, Logan D, Smith WB, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366(12):1108–18.
Dias CS, Shaywitz AJ, Wasserman SM, Smith BP, Gao B, Stolman DS, et al. Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins. J Am Coll Cardiol. 2012;60(19):1888–98.
Rosenwasser RF, Sultan S, Sutton D, Choksi R, Epstein BJ. SGLT-2 inhibitors and their potential in the treatment of diabetes. Diabetes Metab Syndr Obes. 2013;6:453–67.
Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644–57.
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.
Sahasrabudhe V, Saur D, Matschke K, Terra SG, Hickman A, Huyghe I, et al. A phase 1, randomized, placebo- and active-controlled crossover study to determine the effect of single-dose ertugliflozin on QTc interval in healthy volunteers. Clin Pharmacol Drug Dev. 2018;7:513–23.
Grunberger G, Camp S, Johnson J, Huyck S, Terra SG, Mancuso JP, et al. Ertugliflozin in patients with stage 3 chronic kidney disease and type 2 diabetes mellitus: the vertis renal randomized study. Diabetes Ther. 2018;9(1):49–66.
Emanuel EJ, Bedarida G, Macci K, Gabler NB, Rid A, Wendler D. Quantifying the risks of non-oncology phase I research in healthy volunteers: meta-analysis of phase I studies. BMJ. 2015;350:h3271.
Young TC, Srinivasan S, Vetter ML, Sethuraman V, Bhagwagar Z, Zwirtes R, et al. A systematic review and pooled analysis of select safety parameters among normal healthy volunteers taking placebo in phase 1 clinical trials. J Clin Pharmacol. 2017;57(9):1079–87.
Mallet C, Dubray C, Duale C. FAAH inhibitors in the limelight, but regrettably. Int J Clin Pharmacol Ther. 2016;54(7):498–501.
van Esbroeck ACM, Janssen APA, Cognetta AB 3rd, Ogasawara D, Shpak G, van der Kroeg M, et al. Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474. Science. 2017;356:1084–7.
DeGeorge JJ, Ahn CH, Andrews PA, Brower ME, Giorgio DW, Goheer MA, et al. Regulatory considerations for preclinical development of anticancer drugs. Cancer Chemother Pharmacol. 1998;41(3):173–85.
Hierro C, Azaro A, Argiles G, Elez E, Gomez P, Carles J, et al. Unveiling changes in the landscape of patient populations in cancer early drug development. Oncotarget. 2017;8(8):14158–72.
Roberts TG Jr, Goulart BH, Squitieri L, Stallings SC, Halpern EF, Chabner BA, et al. Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials. JAMA. 2004;292(17):2130–40.
Dagher RNRL, Morse DE, Pazdur R. Regulatory considerations for early clinical studies of anti-cancer drugs in healthy volunteers. J Clin Oncol. 2005;16:3101.
Gupta P, Gupta V, Gupta YK. Phase I clinical trials of anticancer drugs in healthy volunteers: need for critical consideration. Indian J Pharmacol. 2012;44(4):540–2.
Dixon WJ, Mood AM. A method for obtaining and analyzing sensitivity data. J Am Stat Assoc. 1948;43:109–26.
Skolnik JM, Barrett JS, Jayaraman B, Patel D, Adamson PC. Shortening the timeline of pediatric phase I trials: the rolling six design. J Clin Oncol. 2008;26(2):190–5.
Cannarile MA, Weisser M, Jacob W, Jegg AM, Ries CH, Ruttinger D. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J Immunother Cancer. 2017;5(1):53.
Wellek S, Blettner M. On the proper use of the crossover design in clinical trials: part 18 of a series on evaluation of scientific publications. Dtsch Arztebl Int. 2012;109(15):276–81.
Takahashi RH, Choo EF, Ma S, Wong S, Halladay J, Deng Y, et al. Absorption, metabolism, excretion, and the contribution of intestinal metabolism to the oral disposition of [14C]Cobimetinib, a MEK inhibitor, in humans. Drug Metab Dispos. 2016;44(1):28–39.
Scheers E, Leclercq L, de Jong J, Bode N, Bockx M, Laenen A, et al. Absorption, metabolism, and excretion of oral (1)(4)C radiolabeled ibrutinib: an open-label, phase I, single-dose study in healthy men. Drug Metab Dispos. 2015;43(2):289–97.
Zollinger M, Lozac’h F, Hurh E, Emotte C, Bauly H, Swart P. Absorption, distribution, metabolism, and excretion (ADME) of (1)(4)C-sonidegib (LDE225) in healthy volunteers. Cancer Chemother Pharmacol. 2014;74(1):63–75.
Galgatte UC, Jamdade VR, Aute PP, Chaudhari PD. Study on requirements of bioequivalence for registration of pharmaceutical products in USA, Europe and Canada. Saudi Pharm J. 2014;22(5):391–402.
Carrington C. Oral targeted therapy for cancer. Aust Prescr. 2015;38(5):171–6.
Narasimhan NI, Dorer DJ, Niland K, Haluska F, Sonnichsen D. Effects of food on the pharmacokinetics of ponatinib in healthy subjects. J Clin Pharm Ther. 2013;38(6):440–4.
Lau YY, Gu W, Lin T, Song D, Yu R, Scott JW. Effects of meal type on the oral bioavailability of the ALK inhibitor ceritinib in healthy adult subjects. J Clin Pharmacol. 2016;56(5):559–66.
Kletzl H, Giraudon M, Ducray PS, Abt M, Hamilton M, Lum BL. Effect of gastric pH on erlotinib pharmacokinetics in healthy individuals: omeprazole and ranitidine. Anticancer Drugs. 2015;26(5):565–72.
Narasimhan NI, Dorer DJ, Davis J, Turner CD, Sonnichsen D. Evaluation of the effect of multiple doses of lansoprazole on the pharmacokinetics and safety of ponatinib in healthy subjects. Clin Drug Investig. 2014;34(10):723–9.
Chi KN, Spratlin J, Kollmannsberger C, North S, Pankras C, Gonzalez M, et al. Food effects on abiraterone pharmacokinetics in healthy subjects and patients with metastatic castration-resistant prostate cancer. J Clin Pharmacol. 2015;55(12):1406–14.
Goldwater R, Hussaini A, Bosch B, Nemeth P. Comparison of a novel formulation of abiraterone acetate vs. the originator formulation in healthy male subjects: two randomized, open-label, crossover studies. Clin Pharmacokinet. 2017;56(7):803–13.
Solymosi T, Otvos Z, Angi R, Ordasi B, Jordan T, Molnar L, et al. Novel formulation of abiraterone acetate might allow significant dose reduction and eliminates substantial positive food effect. Cancer Chemother Pharmacol. 2017;80(4):723–8.
Markus R, Chow V, Pan Z, Hanes V. A phase I, randomized, single-dose study evaluating the pharmacokinetic equivalence of biosimilar ABP 215 and bevacizumab in healthy adult men. Cancer Chemother Pharmacol. 2017;80(4):755–63.
Hettema W, Wynne C, Lang B, Altendorfer M, Czeloth N, Lohmann R, et al. A randomized, single-blind, Phase I trial (INVICTAN-1) assessing the bioequivalence and safety of BI 695502, a bevacizumab biosimilar candidate, in healthy subjects. Expert Opin Investig Drugs. 2017;26(8):889–96.
Tajima N, Martinez A, Kobayashi F, He L, Dewland P. A phase 1 study comparing the proposed biosimilar BS-503a with bevacizumab in healthy male volunteers. Pharmacol Res Perspect. 2017;5(2):e00286.
Knight B, Rassam D, Liao S, Ewesuedo R. A phase I pharmacokinetics study comparing PF-06439535 (a potential biosimilar) with bevacizumab in healthy male volunteers. Cancer Chemother Pharmacol. 2016;77(4):839–46.
Pivot X, Deslypere JP, Park LS, Kim MJ, Lee W, Lee J. A randomized phase I study comparing the pharmacokinetics of HD201, a trastuzumab biosimilar, with european union-sourced herceptin. Clin Ther. 2018;40(3):396–405.
Camacho LH. Current status of biosimilars in oncology. Drugs. 2017;77(9):985–97.
Abbas R, Leister C, El Gaaloul M, Chalon S, Sonnichsen D. Ascending single-dose study of the safety profile, tolerability, and pharmacokinetics of bosutinib coadministered with ketoconazole to healthy adult subjects. Clin Ther. 2012;34(9):2011–9.
Abbas R, Boni J, Sonnichsen D. Effect of rifampin on the pharmacokinetics of bosutinib, a dual Src/Abl tyrosine kinase inhibitor, when administered concomitantly to healthy subjects. Drug Metab Pers Ther. 2015;30(1):57–63.
Tanaka C, Yin OQ, Smith T, Sethuraman V, Grouss K, Galitz L, et al. Effects of rifampin and ketoconazole on the pharmacokinetics of nilotinib in healthy participants. J Clin Pharmacol. 2011;51(1):75–83.
Nguyen L, Holland J, Ramies D, Mamelok R, Benrimoh N, Ciric S, et al. Effect of renal and hepatic impairment on the pharmacokinetics of cabozantinib. J Clin Pharmacol. 2016;56(9):1130–40.
Schnell D, Buschke S, Fuchs H, Gansser D, Goeldner RG, Uttenreuther-Fischer M, et al. Pharmacokinetics of afatinib in subjects with mild or moderate hepatic impairment. Cancer Chemother Pharmacol. 2014;74(2):267–75.
Wiebe S, Schnell D, Kulzer R, Gansser D, Weber A, Wallenstein G, et al. Influence of renal impairment on the pharmacokinetics of afatinib: an open-label, single-dose study. Eur J Drug Metab Pharmacokinet. 2017;42(3):461–9.
Olsson H, Petri N, Erichsen L, Malmberg A, Grundemar L. Effect of degarelix, a gonadotropin-releasing hormone receptor antagonist for the treatment of prostate cancer, on cardiac repolarisation in a randomised, placebo and active comparator controlled thorough QT/QTc trial in healthy men. Clin Drug Investig. 2017;37(9):873–9.
de Jong J, Hellemans P, Jiao JJ, Huang Y, Mesens S, Sukbuntherng J, et al. Ibrutinib does not prolong the corrected QT interval in healthy subjects: results from a thorough QT study. Cancer Chemother Pharmacol. 2017;80(6):1227–37.
Abbas R, Hug BA, Leister C, Gaaloul ME, Chalon S, Sonnichsen D. A phase I ascending single-dose study of the safety, tolerability, and pharmacokinetics of bosutinib (SKI-606) in healthy adult subjects. Cancer Chemother Pharmacol. 2012;69(1):221–7.
Lindauer A, Di Gion P, Kanefendt F, Tomalik-Scharte D, Kinzig M, Rodamer M, et al. Pharmacokinetic/pharmacodynamic modeling of biomarker response to sunitinib in healthy volunteers. Clin Pharmacol Ther. 2010;87(5):601–8.
Garrett M, Poland B, Brennan M, Hee B, Pithavala YK, Amantea MA. Population pharmacokinetic analysis of axitinib in healthy volunteers. Br J Clin Pharmacol. 2014;77(3):480–92.
Gupta A, Jarzab B, Capdevila J, Shumaker R, Hussein Z. Population pharmacokinetic analysis of lenvatinib in healthy subjects and patients with cancer. Br J Clin Pharmacol. 2016;81(6):1124–33.
Goel V, Hurh E, Stein A, Nedelman J, Zhou J, Chiparus O, et al. Population pharmacokinetics of sonidegib (LDE225), an oral inhibitor of hedgehog pathway signaling, in healthy subjects and in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2016;77(4):745–55.
Lacy S, Yang B, Nielsen J, Miles D, Nguyen L, Hutmacher M. A population pharmacokinetic model of cabozantinib in healthy volunteers and patients with various cancer types. Cancer Chemother Pharmacol. 2018;81(6):1071–82.
The Center for Information & Study on Clinical Research Participation (CISCRP). https://www.ciscrp.org/. Accessed 27 May 2018.
Bloom D, Beetsch J, Harker M, Hesterlee S, Moreira P, Patrick-Lake B, et al. The rules of engagement: cTTI recommendations for successful collaborations between sponsors and patient groups around clinical trials. Ther Innov Regul Sci. 2018;52(2):206–13.
Yin D, Barker KB, Li R, Meng X, Reich SD, Ricart AD, et al. A randomized phase 1 pharmacokinetic trial comparing the potential biosimilar PF-05280014 with trastuzumab in healthy volunteers (REFLECTIONS B327-01). Br J Clin Pharmacol. 2014;78(6):1281–90.
Xu H, O’Gorman M, Tan W, Brega N, Bello A. The effects of ketoconazole and rifampin on the single-dose pharmacokinetics of crizotinib in healthy subjects. Eur J Clin Pharmacol. 2015;71(12):1441–9.
Patel P, Howgate E, Martin P, Carlile DJ, Aarons L, Zhou D. Population pharmacokinetics of the MEK inhibitor selumetinib and its active N-desmethyl metabolite: data from 10 phase I trials. Br J Clin Pharmacol. 2018;84(1):52–63.