The development of a new medicine is a risky and costly undertaking that requires careful planning. This planning is largely applied to the operational aspects of the development and less so to the scientific objectives and methodology. The drugs that will be developed in the future will increasingly affect pathophysiological pathways that have been largely unexplored. Such drug prototypes cannot be immediately introduced in large clinical trials. The effects of the drug on normal physiology, pathophysiology, and eventually the desired clinical effects will need to be evaluated in a structured approach, based on the definition of drug development as providing answers to important questions by appropriate clinical studies. This review describes the selection process for biomarkers that are fit-for-purpose for the stage of drug development in which they are used. This structured and practical approach is widely applicable and particularly useful for the early stages of innovative drug development.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Black JW, Crowther AF, Shanks RG, Belf MD, Smith LH. 1.  et al. 1964. A new adrenergic: beta-receptor antagonist. Lancet 283:1080–81 [Google Scholar]
  2. Pilkington TRE, Lowe RD, Robinson BF, Titterington E. 2.  1962. Effect of adrenergic blockade on glucose and fatty-acid mobilisation in man. Lancet 280:316–17 [Google Scholar]
  3. Dornhorst AC, Robinson BF. 3.  1962. Clinical pharmacology of a beta-adrenergic-blocking agent (nethalide). Lancet 280:314–16 [Google Scholar]
  4. Prichard BNC, Gillam PMS. 4.  1969. Treatment of hypertension with propranolol. BMJ 1:7–16 [Google Scholar]
  5. Harris WS, Schoenfeld CD, Brooks RH, Weissler AM. 5.  1966. Effect of beta adrenergic blockers on the hemodynamic responses to epinephrine in man. Am. J. Cardiol. 17:484–92 [Google Scholar]
  6. Cohen AF. 6.  2010. Developing drug prototypes: pharmacology replaces safety and tolerability?. Nat. Rev. Drug Discov. 9:11856–65 [Google Scholar]
  7. Nissen SE, Tardif J-C, Nicholls SJ, Revkin JH, Shear CL. 7.  et al. 2007. Effect of torcetrapib on the progression of coronary atherosclerosis. N. Engl. J. Med. 356:1304–16 [Google Scholar]
  8. Clark RW, Sutfin TA, Ruggeri RB, Willauer AT, Sugarman ED. 8.  et al. 2004. Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib. Arterioscler. Thromb. Vasc. Biol. 24:490–97 [Google Scholar]
  9. Bots ML, Visseren FL, Evans GW, Riley WA, Revkin JH. 9.  et al. 2007. Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. Lancet 370:153–60 [Google Scholar]
  10. Forrest MJ, Bloomfield D, Briscoe RJ, Brown PN, Cumiskey A-M. 10.  et al. 2008. Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br. J. Pharmacol. 154:71465–73 [Google Scholar]
  11. McKenney JM, Davidson MH, Shear CL, Revkin JH. 11.  2006. Efficacy and safety of torcetrapib, a novel cholesteryl ester transfer protein inhibitor, in individuals with below-average high-density lipoprotein cholesterol levels on a background of atorvastatin. J. Am. Coll. Cardiol. 48:91774–81 [Google Scholar]
  12. Barter P, Caulfield M. 12.  2007. Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 357:212109–22 [Google Scholar]
  13. Zhao L, Jin W, Rader D, Packard C, Feuerstein. 13.  2009. A translational medicine perspective of the development of torcetrapib: Does the failure of torcetrapib development cast a shadow on future development of lipid modifying agents, HDL elevation strategies or CETP as a viable molecular target for atherosclerosis?. Biochem. Pharmacol. 78:315–25 [Google Scholar]
  14. Kenter MJH, Cohen AF. 14.  2006. Establishing risk of human experimentation with drugs: lessons from TGN1412. Lancet 368:95441387–91 [Google Scholar]
  15. Yusuf S, Flather M, Gent M. 15.  1997. Effects of RheothRx on mortality, morbidity, left ventricular function, and infarct size in patients with acute myocardial infarction. Circulation 96:1192–201 [Google Scholar]
  16. Schaer GL, Spaccavento LJ, Browne KF, Krueger KA, Krichbaum D. 16.  et al. 1996. Beneficial effects of RheothRx injection in patients receiving thrombolytic therapy for acute myocardial infarction: results of a randomized, double-blind, placebo-controlled trial. Circulation 94:3298–307 [Google Scholar]
  17. Jewell RC, Khor SP, Kisor DF, LaCroix KA, Wargin WA. 17.  1997. Pharmacokinetics of RheothRx injection in healthy male volunteers. J. Pharm. Sci. 86:7808–12 [Google Scholar]
  18. 18. Eur. Parliam. Counc 2001. Directive 2001/20/EC of the European Parliament and of the Council. Off. J. Eur. Communities L121:34–44 [Google Scholar]
  19. Ng R. 19.  2009. Drugs: From Discovery to Approval. Hoboken, NJ: Wiley, 2nd ed..
  20. 20. Eur. Med. Agency 1998. Note for guidance on general considerations for clinical trials (CPMP/ICH/291/95). Rep., London
  21. Lenfle S, Loch C. 21.  2009. Lost roots: how project management settled on the phased approach (and compromised its ability to lead change in modern enterprises) INSEAD Work. Pap., Fontainebleau, France
  22. De Meyer A, Loch CH, Pich MT. 22.  2002. Managing project uncertainty: from variation to chaos. IEEE Eng. Manag. Rev. 30:91–98 [Google Scholar]
  23. Cohen A. 23.  2007. Should we tolerate tolerability as an objective in early drug development?. Br. J. Clin. Pharmacol. 64:3249–52 [Google Scholar]
  24. Sheiner L. 24.  1997. Learning versus confirming in clinical drug development. Clin. Pharmacol. Ther. 61:3275–91 [Google Scholar]
  25. Danhof M, Alvan G, Dahl SG, Kuhlmann J, Paintaud G. 25.  2005. Mechanism-based pharmacokinetic-pharmacodynamic modeling—a new classification of biomarkers. Pharm. Res. 22:91432–37 [Google Scholar]
  26. Lalonde RL, Kowalski KG, Hutmacher MM, Ewy W, Nichols DJ. 26.  et al. 2007. Model-based drug development. Clin. Pharmacol. Ther. 82:121–32 [Google Scholar]
  27. Milligan PA, Brown MJ, Marchant B, Martin SW, van der Graaf PH. 27.  et al. 2013. Model-based drug development: a rational approach to efficiently accelerate drug development. Clin. Pharmacol. Ther. 93:6502–14 [Google Scholar]
  28. Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D. 28.  et al. 2014. Mortality and morbidity in patients receiving encainide, flecainide or placebo—the Cardiac Arrhythmia Suppression Trial. N. Engl. J. Med. 324:781–88 [Google Scholar]
  29. Dei Cas L, Manca C, Bernardini B, Vasini G, Visioli O. 29.  1982. Noninvasive evaluation of the effects of oral ibopamine (SB 7505) on cardiac and renal function in patients with congestive heart failure. J. Cardiovasc. Pharmacol. 4:436–40 [Google Scholar]
  30. Col J, Mievis E, Reynaert M. 30.  1983. Ibopamine in very severe congestive heart failure: pilot haemodynamic invasive assessment. Eur. J. Clin. Pharmacol. 24:3297–300 [Google Scholar]
  31. van Veldhuisen DJ, Man in't Veld AJ, Dunselman PHJM, Lok DJA, Dohmen HJM. 31.  et al. 1993. Double-blind placebo-controlled study of ibopamine and digoxin in patients with mild to moderate heart failure: results of the Dutch Ibopamine Multicenter Trial (DIMT). J. Am. Coll. Cardiol. 22:61564–73 [Google Scholar]
  32. Hampton JR, van Veldhuisen DJ, Kleber FX, Cowley AJ, Ardia A. 32.  et al. 1997. Randomised study of effect of ibopamine on survival in patients with advanced severe heart failure. Lancet 349:971–77 [Google Scholar]
  33. Yee KM, Struthers A. 33.  1997. Can drug effects on mortality in heart failure be predicted by any surrogate measure?. Eur. Heart J. 18:121860–64 [Google Scholar]
  34. Ho D, Moudgil T, Alam M. 34.  1989. Quantitation of human immunodeficiency virus type 1 in the blood of infected persons. N. Engl. J. Med. 321:241621–25 [Google Scholar]
  35. Atkinson AJ Jr, Colburn WA, DeGruttola VG, DeMets DL, Downing GJ. 35.  et al. 2001. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin. Pharmacol. Ther. 69:389–95 [Google Scholar]
  36. Peto R, Pike M, Armitage P, Breslow N, Cox D. 36.  et al. 1976. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. Br. J. Cancer 34:585–612 [Google Scholar]
  37. 37. U.S. Food Drug Adm 2004. Innovation or stagnation: challenge and opportunity on the critical path to new medical products Chall. Oppor. Rep., U.S. Dep. Health Hum. Serv., Rockville, MD
  38. 38. U.S. Food Drug Adm 2011. Guidance for industry: E16 biomarkers related to drug or biotechnology product development: context, structure and format of qualification submissions. Rep., U.S. Dep. Health Hum. Serv., Rockville, MD
  39. 39. U.S. Food Drug Adm 2005. Guidance for industry: pharmacogenomic data submissions Proced. Rep., U.S. Dep. Health Hum. Serv., Rockville, MD
  40. Lee JW, Devanarayan V, Barrett YC, Weiner R, Allinson J. 40.  et al. 2006. Fit-for-purpose method development and validation for successful biomarker measurement. Pharm. Res. 23:2312–28 [Google Scholar]
  41. 41. Expert Sci. Group 2006. Expert scientific group on phase one clinical trials. Final Rep., Nov. 30
  42. Appel S, Kumle A, Hubert M, Duvauchelle T. 42.  1997. First pharmacokinetic—pharmacodynamic study in humans with a selective 5-hydroxytryptamine4 receptor agonist. J. Clin. Pharmacol. 37:229–37 [Google Scholar]
  43. Wood P. 43.  2012. Tegaserod in the treatment of constipation-predominant irritable bowel syndrome. Do the risks outweigh the benefits?. Naunyn-Schmiedeberg's Arch. Pharmacol. 385:11–3 [Google Scholar]
  44. Al-Judaibi B, Chande N, Gregor J. 44.  2010. Safety and efficacy of tegaserod therapy in patients with irritable bowel syndrome or chronic constipation. Can. J. Clin. Pharmacol. 17:1e194–200 [Google Scholar]
  45. Chan KY, de Vries R, Leijten FPJ, Pfannkuche H-J, van den Bogaerdt AJ. 45.  et al. 2009. Functional characterization of contractions to tegaserod in human isolated proximal and distal coronary arteries. Eur. J. Pharmacol. 619:1–361–67 [Google Scholar]
  46. Tack J, Camilleri M, Chang L, Chey WD, Galligan JJ. 46.  et al. 2012. Systematic review: cardiovascular safety profile of 5-HT4 agonists developed for gastrointestinal disorders. Aliment. Pharmacol. Ther. 35:7745–67 [Google Scholar]
  47. de Visser S. 47.  2003. A question based approach to drug development PhD Thesis, Leiden Univ., Leiden, Neth.
  48. Morgan P, Van Der Graaf PH, Arrowsmith J, Feltner DE, Drummond KS. 48.  et al. 2012. Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival. Drug Discov. Today 17:9–10419–24 [Google Scholar]
  49. Copeland TE, Keenan PT. 49.  1998. Making real options real. McKinsey Q. 3:128–42 [Google Scholar]
  50. D'Souza F. 50.  2002. Putting real options to work to improve project planning. Harvard Manag. Update 7:83–6 [Google Scholar]
  51. Aronson JK, Ferner RE. 51.  2003. Joining the DoTS: new approach to classifying adverse drug reactions. BMJ 327:1222–25 [Google Scholar]
  52. van der Post JP, de Visser SJ, Schoemaker RC, Cohen AF, van Gerven JMA. 52.  2004. Pharmacokinetic/pharmacodynamic assessment of tolerance to central nervous system effects of a 3 mg sustained release tablet of rilmenidine in hypertensive patients. J. Psychopharmacol. 18:2221–27 [Google Scholar]
  53. Hoever P, Hay J, Rad M, Cavallaro M, van Gerven JM, Dingemanse J. 53.  2013. Tolerability, pharmacokinetics, and pharmacodynamics of single-dose almorexant, an orexin receptor antagonist, in healthy elderly subjects. J. Clin. Psychopharmacol. 33:3363–70 [Google Scholar]
  54. Van Poelgeest EP, Swart RM, Betjes MGH, Moerland M, Weening JJ. 54.  et al. 2013. Acute kidney injury during therapy with an antisense oligonucleotide directed against PCSK9. Am. J. Kidney Dis. 62:4796–800 [Google Scholar]
  55. Lee JW, Weiner RS, Sailstad JM, Bowsher RR, Knuth DW. 55.  et al. 2005. Method validation and measurement of biomarkers in nonclinical and clinical samples in drug development: a conference report. Pharm. Res. 224499–511
  56. van der Graaf PH. 56.  2012. CPT: pharmacometrics and systems pharmacology. CPT Pharmacometrics Syst. Pharmacol. 1:e8 [Google Scholar]
  57. van Meer L, Moerland M, Cohen AF, Burggraaf J. 57.  2013. Urinary kidney biomarkers for early detection of nephrotoxicity in clinical drug development. Br. J. Clin. Pharmacol. 77:947–57 [Google Scholar]
  58. de Visser SJ, van der Post JP, de Waal PP, Cornet F, Cohen AF, van Gerven JMA. 58.  2003. Biomarkers for the effects of benzodiazepines in healthy volunteers. Br. J. Clin. Pharmacol. 55:139–50 [Google Scholar]
  59. de Visser SJ, van der Post JP, Pieters MSM, Cohen AF, van Gerven JMA. 59.  2001. Biomarkers for the effects of antipsychotic drugs in healthy volunteers. Br. J. Clin. Pharmacol. 51:119–32 [Google Scholar]
  60. Zuurman L, Ippel AE, Moin E, van Gerven JMA. 60.  2009. Biomarkers for the effects of cannabis and THC in healthy volunteers. Br. J. Clin. Pharmacol. 67:15–21 [Google Scholar]
  61. Dumont GJH, de Visser SJ, Cohen AF, van Gerven JMA. 61.  2005. Biomarkers for the effects of selective serotonin reuptake inhibitors (SSRIs) in healthy subjects. Br. J. Clin. Pharmacol. 59:5495–510 [Google Scholar]
  62. Zoethout RWM, Delgado WL, Ippel AE, Dahan A, van Gerven JMA. 62.  2011. Functional biomarkers for the acute effects of alcohol on the central nervous system in healthy volunteers. Br. J. Clin. Pharmacol. 71:3331–50 [Google Scholar]
  63. Rijnbeek B, de Visser SJ, Franson KL, Cohen AF, van Gerven JMA. 63.  2003. REM sleep effects as a biomarker for the effects of antidepressants in healthy volunteers. J. Psychopharmacol. 17:2196–203 [Google Scholar]
  64. Pleuvry BJ, Maddison SE, Odeh RB, Dodson ME. 64.  1980. Respiratory and psychological effects of oral temazepam in volunteers. Br. J. Anaesth. 52:9901–6 [Google Scholar]
  65. van Steveninck AL, Schoemaker HC, Pieters MSM, Kroon R, Breimer DD, Cohen AF. 65.  1991. A comparison of the sensitivities of adaptive tracking, eye movement analysis and visual analog lines to the effects of incremental doses of temazepam in healthy volunteers. Clin. Pharmacol. Ther. 50:2172–80 [Google Scholar]
  66. Khalili-Mahani N, van Osch MJP, Baerends E, Soeter RP, de Kam M. 66.  et al. 2011. Pseudocontinuous arterial spin labeling reveals dissociable effects of morphine and alcohol on regional cerebral blood flow. J. Cereb. Blood Flow Metab. 31:51321–33 [Google Scholar]
  67. van der Post J, de Waal PP, de Kam ML, Cohen AF, van Gerven JMA. 67.  2004. No evidence of the usefulness of eye blinking as a marker for central dopaminergic activity. J. Psychopharmacol. 18:1109–14 [Google Scholar]
  68. Strougo A, Zuurman L, Roy C, Pinquier JL, van Gerven JMA. 68.  et al. 2008. Modelling of the concentration–effect relationship of THC on central nervous system parameters and heart rate—insight into its mechanisms of action and a tool for clinical research and development of cannabinoids. J. Psychopharmacol. 22:7717–26 [Google Scholar]
  69. de Haas SL, de Visser SJ, van der Post JP, de Smet M, Schoemaker RC. 69.  et al. 2007. Pharmacodynamic and pharmacokinetic effects of TPA023, a GABAA α2,3 subtype-selective agonist, compared to lorazepam and placebo in healthy volunteers. J. Psychopharmacol. 21:4374–83 [Google Scholar]
  70. Chen X, de Haas S, de Kam M, van Gerven J. 70.  2012. An overview of the CNS-pharmacodynamic profiles of nonselective and selective GABA agonists. Adv. Pharmacol. Sci. 2012:134523 [Google Scholar]
  71. Liem-Moolenaar M, Zoethout RWM, de Boer P, Schmidt M, de Kam ML. 71.  et al. 2010. The effects of the glycine reuptake inhibitor R213129 on the central nervous system and on scopolamine-induced impairments in psychomotor and cognitive function in healthy subjects. J. Psychopharmacol. 24:111671–79 [Google Scholar]
  72. Klumpers LE, Fridberg M, de Kam ML, Little PB, Jensen NO. 72.  et al. 2013. Peripheral selectivity of the novel cannabinoid receptor antagonist TM38837 in healthy subjects. Br. J. Clin. Pharmacol. 76:6846–57 [Google Scholar]
  73. Zuurman L, Roy C, Schoemaker RC, Amatsaleh A, Guimaeres L. 73.  et al. 2010. Inhibition of THC-induced effects on the central nervous system and heart rate by a novel CB1 receptor antagonist AVE1625. J. Psychopharmacol. 24:3363–71 [Google Scholar]
  74. Jacobs GE, van Gerven JMA, de Kam ML, Elassaiss-Schaap J, Ruigt G. 74.  et al. 2011. A pharmacological tool to assess vasopressinergic co-activation of the hypothalamus–pituitary–adrenal axis more integrally in healthy volunteers. J. Psychopharmacol. 25:3361–69 [Google Scholar]
  75. Jacobs GE, Hulskotte EGJ, van Gerven JMA, Zuurman L, de Kam ML. 75.  et al. 2011. Desmopressin as a pharmacological tool in vasopressinergic hypothalamus–pituitary–adrenal axis modulation: neuroendocrine, cardiovascular and coagulatory effects. J. Psychopharmacol. 25:3353–60 [Google Scholar]
  76. Smarius LJCA, Jacobs GE, Hoeberechts-Lefrandt DHM, de Kam ML, van der Post JP. 76.  et al. 2008. Pharmacology of rising oral doses of 5-hydroxytryptophan with carbidopa. J. Psychopharmacol. 22:4426–33 [Google Scholar]
  77. Kemme MJB, Burggraaf J, Schoemaker RC, Cohen AF, Blauw GJ. 77.  2000. No evidence for functional involvement of 5-HT2B receptors in serotonin-induced vasodilatation in the human forearm. 36699–703
  78. Moerland M, Kemme M, Dijkmans A, Bergougnan L, Burggraaf J. 78.  2011. Modulation of vasoactivity and platelet aggregation by selective 5-HT receptor antagonism in humans. 58575–80
  79. van Gerven JMA, Roncari G, Schoemaker RC, Massarella J, Keesmaat P. 79.  et al. 1997. Integrated pharmacokinetics and pharmacodynamics of Ro 48–8684, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects. Br. J. Clin. Pharmacol. 44:5487–93 [Google Scholar]
  80. Weber O, Willmann S, Bischoff H, Li V, Vakalopoulos A. 80.  et al. 2012. Prediction of a potentially effective dose in humans for BAY 60–5521, a potent inhibitor of cholesteryl ester transfer protein (CETP) by allometric species scaling and combined pharmacodynamic and physiologically-based pharmacokinetic modelling. Br. J. Clin. Pharmacol. 73:2219–31 [Google Scholar]
  81. Boettcher M-F, Heinig R, Schmeck C, Kohlsdorfer C, Ludwig M. 81.  et al. 2012. Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60–5521, a potent inhibitor of cholesteryl ester transfer protein. Br. J. Clin. Pharmacol. 73:2210–18 [Google Scholar]

Data & Media loading...

Supplemental Material

Supplementary Data

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error