Abstract
Ray Lipicky (Director, LIPICKY, LLC, A Consulting Company; retires from FDA in February 2002) started one of his presentations with the following slide:
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Ackerman MJ (1998) The long QT syndrome: ion channel diseases of the heart. Mayo Clin Proc 73:250–269
Anderson ME, Al-Khatib SM, Roden DM, Califf RM (2002) Cardiac repolarization: current knowledge, critical gaps and new approaches to drug development and patient management. Am Heart J 144:769–781
Anon (2008) Guidance for industry diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. U.S. Department of Health and Humans Services, Food and Drug Administration, Center for Drug Evaluation and Research. www.fda.gov/downloads/drugs/GuidanceComplianceRegulatoryInformation/guidances/UCM071627.pdf. Accessed Dec 2008
Baldrick P, Bamford DG, Tattersall ML (1998) An assessment of two gastric transport models currently used in safety pharmacology testing. Hum Reprod Toxicol 17:1–7
Bass AS, Williams PD (2003) Status of international regulatory guidelines on safety pharmacology. In: Williams PD, Bass AS (eds) Safety Pharmacology, pp 9–20
Bass A, Kinter L, Williams P (2004a) Origins, practices and future on safety pharmacology. J Pharmacol Toxicol Methods 49:145–151
Bass AS, Vargas HM, Kinter LB (2004b) Introduction to nonclinical safety pharmacology and the Safety Pharmacology Society. J Pharmacol Toxicol Methods 49:141–144
Bass AS, Vargas HM, Valentin J-P, Kinter LB, Hammond T, Wallis R, Siegl PKS, Yamamoto K (2011) Safety pharmacology in 2010 and beyond: survey of significant events of the past 10 years and a roadmap to the immediate-, intermediate- and long-term future in recognition of the tenth anniversary of the Safety Pharmacology Society. J Pharmacol Toxicol Methods. doi:10.1016/j.vascn.2011.05.006
Batey AJ, Doe CPA (2003) A method for QT correction based on beat-to-beat analysis of the QT/RR interval relationship in conscious telemetered beagle dogs. J Pharmacol Toxicol Methods 48:1–9
Bunting PB, Siegl PKS (1994) Models used to assess cardiovascular function in general pharmacology. Drug Dev Res 32:256–259
Calamari D (2003) Strategic survey of therapeutic drugs in the rivers Po and Lambo in Northern Italy. Environ Sci Technol 37:1241–1248
Cavero I, Crumb W (2005) ICH S7B draft guideline on the non-clinical strategy for testing delayed cardiac repolarisation risk of drugs: a critical analysis. Expert Opin Drug Saf 4:509–530
Champeroux P, Martel E, Fowler JSL, Maurin A, Sola ML, Jude S, Elamrani F, Weyn AA, Laveissiere A, Lala P, Richard S (2009) Calculation of QT shift in non clinical safety pharmacology studies. J Pharmacol Toxicol Methods 59:73–85
Champeroux P, Ouillé A, Martel E, Fowler JSL, Maurin A, Jude S, Lala P, Guennec J-Y, Richard S (2010) Interference of the autonomic nervous system with drug induced QT prolongation: a point to consider in non-clinical safety studies. J Pharmacol Toxicol Methods 61:251–263
Chiu PJS (1994) Models used to assess renal function. Drug Dev Res 32:247–255
De Ponti F, Poluzzi E, Montanaro N (2001) Organising evidence on QT prolongation and occurrence of torsades de pointes with non-antiarrhythmic drugs: a call for consensus. Eur J Clin Pharmacol 57:185–209
Del Rio CL, Kijtawornrat A, Hamlin RL, Billman GE (2010) Beat-to beat changes in QT/RR relationships induced by ischemia on dogs prone to sudden death are modeled by QT-shortening, not lengthening. J Pharmacol Toxicol Methods 62:e45–e46
Deurinck M, Traebert M (2008) Body temperature-induced QT shortening in dogs: a case report. J Pharmacol Toxicol Methods 58:159
Gad SC (2004) Safety pharmacology in pharmaceutical development and approval. CRC Press, Boca Raton
Green MD (1995) An FDA perspective on general pharmacology studies to determine activity and safety. Drug Dev Res 35:158–160
Haggerty GC (1991) Strategy for and experience with neurotoxicity testing of new pharmaceuticals. J Am Coll Toxicol 10:677–687
Hammond TG, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Redfern WS, Sullivan AT, Camm AJ (2001) Methods of collecting and evaluating non-clinical cardiac electrophysiology data in pharmaceutical industry: results of an international survey. Cardiovasc Res 49:741–750
Haverkamp W, Breithart G, Camm AJ, Janse MJ, Rosen MR, Antzelevitch C, Escande D, Franz M, Malik M, Moss A, Shah R (2000) The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Cardiovasc Res 47:219–233
Himmel HM, Hoffmann M (2010) QTc shortening with a new investigational cancer drug: a brief case study. J Pharmacol Toxicol Methods 62:72–81
Holbrook M, Malik M, Shah RR, Valentin J-P (2009) Drug induced shortening of the QT/QTc interval: an emerging safety issue warranting further modeling and evaluation in drug research and development? J Pharmacol Toxicol Methods 59:21–28
Holzgrefe HH, Cavero I, Gleason CR, Warner WA, Buchanan LV, Gill MW, Burkett DE, Durham SK (2007a) Novel probalistic method for precisely correcting the QT interval for heart rate in telemetered dogs and cynomolgus monkeys. J Pharmacol Toxicol Methods 55:159–175
Holzgrefe HH, Cavero I, Buchanan LV, Gill MW, Durham SK (2007b) Application of a probalistic method for the determination of drug-induced QT prolongation in telemetered cynomolgus monkeys: effects of moxifloxacin. J Pharmacol Toxicol Methods 55:244–254
Hondeghem LM, Carlsson L, Duker G (2001) Instability and triangulation of the action potential predict serious proarrhythmia, but action potential duration prolongation is antiarrhythmic. Circulation 103:2004–2013
Huggett DB, Khan IA, Foran CM, Schlenk D (2003) Determination of beta-adrenergic receptor blocking pharmaceuticals in United States wastewater effluent. Environ Pollut 121:199–205
Igarashi T, Nakane S, Kitagawa T (1995) Predictability of clinical adverse reactions of drugs by general pharmacology studies. J Toxicol Sci 20:77–92
Jackson CO (1970) Doctor Massengill’s elixir. In: Jackson CO (ed) Food and drug legislation in the new deal. Princeton University Press, Princeton, pp 151–174
Japanese Ministry of Health and Welfare (1995) Japanese guidelines for nonclinical studies of drugs manual 1995. Yakuji Nippo, Tokyo
Kinter LB (2003) Safety pharmacology of the renal and gastro-intestinal systems. In: Williams PD, Bass AS (eds) Safety pharmacology: a practical guide. TherImmune Research, Gaithersburg, pp 99–116
Kinter LB, Dixon LW (1995) Safety pharmacology program for pharmaceuticals. Drug Dev Res 35:179–182
Kinter LB, Johnson DK (1999) Remote monitoring of experimental endpoints in animals using radiotelemetry and bioimpedance technologies. In: Hendriksen CFM, Morton DB (eds) Proceedings of the international conference on humane endpoints in animal experiments for biomedical research. The Royal Society of Medicine Press, London, pp 58–65
Kinter LB, Johnson DK (2003) Safety pharmacology of the cardiovascular system. In: Williams PD, Bass AS (eds) Safety pharmacology: a practical guide. TherImmune Research, Gaithersburg, pp 67–98
Kinter LB, Valentin JP (2002) Safety pharmacology and risk assessment. Fundam Clin Pharmacol 16:175–182
Kinter LB, Gossett KA, Kerns WD (1994) Status of safety pharmacology in the pharmaceutical industry—1993. Drug Dev Res 32:208–216
Kinter LB, Murphy DJ, Mann WA, Leonard TB, Morgan DG (1997) Major organ systems toxicology: an integrated approach to pharmacodynamic safety assessment studies in animals. In: Williams PD, Hottendorf GH (Series eds), Sipes IG, McQueen CA, Gandolfi AJ (Vol eds) Comprehensive toxicology: toxicology testing and evaluation, vol 2. Elsevier, New York, pp 155–168
Kopin DW, Furlong ET, Meyer MT, Thurman EM, Zaugg SD, Barber LB, Buxton HT (2002) Pharmaceuticals, hormones, and other organic wastewater contaminants in U.S. streams 1999–2000: a national reconnaissance. Environ Sci Technol 36(6):1202–1211
Kramer K, Kinter LB (2003) Evaluation and application of radiotelemetry in small laboratory animals. Physiol Genomics 13:197–205
Kramer K, Mills PA, Kinter LB, Brockway BP (1998) History of laboratory telemetry and the state of the art of fully implanted radiotelemetry for monitoring laboratory animals. Lab Anim 27:40–46
Kurata M, Kanai K, Mizuguchi K, Yoshida M, Nakamura K, Furuga Y, Kinoue A, Totsuka K, Igarashi S (1997) Trends in safety pharmacology in the US and Europe. J Toxicol Sci 22:237–248
Lacroix P, Provost D (2000) Basic safety pharmacology: the cardiovascular system. Therapie 55:63–69
Leber P (2002) Regulatory issues. In: Davis KL, Charney D, Coyle JZ, Nemeroff C (eds) Neuropsychpharmacology: the fifth generation of progress. American College of Neuropsychopharmacology, Brentwood, pp 485–494
Lipicky R To the heart of the matter: cardiac safety of non-cardiac drugs. http://spo.escardio.org/eslides/view.aspx?eevtid=40&fp=201
Lu HR, van Bergen P, Vlaminckx E, Rohrbacher J, Hermans A, van Ammel K, Towrd R, Pugley MK, Gallacher DJ (2008a) Drug-induced QT shortening and fibrillation: through or not thorough QT, that is the question? Heart 94:e1
Lu HR, Vlaminckx E, Hermans AN, Rohrbacher J, van Ammel K, Toward R, Pugsley M, Gallacher DJ (2008b) Predicting drug-induced changes in QT interval and arrhythmias: QT-shortening drugs points to gaps in the ICHS7B guidelines. Br J Pharmacol 154:1427–1438
Lufy J, Bode G (2002) Integration of safety pharmacology endpoints into toxicology studies. Fundam Clin Pharmacol 16:91–103
Lumley CE (1994) General pharmacology, the international regulatory environment, and harmonization guidelines. Drug Dev Res 32:223–232
Malik M, Camm AJ (2001) Evaluation of drug-induced QT interval prolongation. Implications for drug approval and labelling. Drug Saf 24:323–351
Marshall E (2001a) Volunteer’s death prompts review. Science 292:2226–2227
Marshall E (2001b) Procedures faulted in fatal asthma trial. Science 293:405–406
Mattsson JL, Spencer PJ, Albee RR (1996) A performance standard for chemical and functional observation battery examinations of rats. J Am Coll Toxicol 15:239–254
Miller HI (2000) Gene therapy’s trials and tribulations. The Scientist 14:16–18
Mojaverian P (1996) Evaluation of gastrointestinal pH and gastric residence time via the Heidelberg radiotelemetry capsule: pharmacological application. Drug Dev Res 38:73–85
Morgan DG, Kelvin AS, Kinter LB, Fish CJ, Kerns WD, Rhodes G (1994) The application of toxicokinetic data to dosage selection in toxicology studies. Toxicol Pathol 22:112–123
Mortin LI, Horvath CJ, Wygand MS (1997) Safety pharmacology screening: practical problems in drug development. Int J Toxicol 16:41–65
Moser VC (1991) Application of a neurobehavioral screening battery. J Am Coll Toxicol 10:661–669
Moss AJ (1999) The QT interval and torsade de pointes. Drug Saf 21:5–10
Murphy DJ (1994) Safety pharmacology of the respiratory system: techniques and study design. Drug Dev Res 32:237–246
Murphy DJ (2002) Assessment of respiratory function in safety pharmacology. Fundam Clin Pharmacol 16:183–196
Olsen H, Betton G, Robimson D, Thomas K, Monro A, Kolaja G, Lilly P, Sanders J, Sipes G, Braken W, Dorato M, Van Deun K, Smith P, Berger B, Heller A (2000) Concordance of the toxicity of pharmaceuticals in humans and animals. Regul Toxicol Pharmacol 32:56–67
Omosu M, Komine I, Becker RH, Schölkens BA (1988) General pharmacology of Ramipril. Arzneimittel Forsch Drug Res 38:1309–1317
Porsolt RD, Lemaire M, Durmuller N, Roux S (2002) New perspectives in CNS safety pharmacology. Fundam Clin Pharmacol 16:197–207
Porsolt RD, Picard S, Lacroix P (2005) International safety pharmacology guidelines (ICH S7A and S7B): where do we go from here? Drug Dev Res 64:83–89
Proakis AG (1994) Regulatory considerations on the role of general pharmacology studies in the development of therapeutic agents. Drug Dev Res 32:233–236
Pugsley MK, Curtis MJ (2007) Safety pharmacology methods: anticipating the transition from long QT (LQTS) to short QT syndromes (SQTS)? J Pharmacol Toxicol Methods 56:87–90
Pugsley MK, Authier S, Curtis MJ (2008) Principles of safety pharmacology. Br J Pharmacol 154:1382–1399
Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, Siegl PKS, Strang I, Sullivan AT, Wallis R, Camm AJ, Hammond TG (2003) Relationships between preclinical cardiac electrophysiology clinical QT interval prolongation, and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res 58:1–44
Regan N, Sutton MR, Waldron G, Alexandrou A (2008) Multiple mechanisms of QTc shortening. J Pharmacol Toxicol Methods 58:158
Ross JF, Mattsson JL, Fix AS (1998) Expanded clinical observations in toxicology studies: historical perspectives and contemporary issues. Regul Toxicol Pharmacol 28:17–26
Sarlo K, Clark ED (1995) Evaluating chemicals as respiratory allergens: using a tier approach for risk assessment. Methods Immunotoxicol 2:411–426
Shah RR (2005a) Drugs, QT interval prolongation and ICH E14. Drug Saf 28:115–125
Shah RR (2005b) Drugs, QTc interval prolongation and final ICH E14 guideline. Drug Saf 28:1009–1028
Shah RR (2010) Drug-induced QT interval shortening: potential harbinger of proarrythmia and regulatory perspectives. Br J Pharmacol 159:58–69
Spence S, Soper K, Hoe C-M, Coleman J (1998) The rate-corrected QT interval of conscious beagle dogs: a formula based on analysis of covariance. Toxicol Sci 45:247–258
Thomas SHL (1994) Drugs, QT interval abnormalities and ventricular arrhythmias. Adverse Drug React Toxicol Rev 13:77–102
Vargas HM, Bass AS, Breidenbach A, Feldman HS, Gintant GA, Harmer AR, Heath B, Hoffmann P, Lagrutta A, Leishman D, McMayhon N, Mittelstadt S, Polonchuk L, Pugsley MK, Salata JJ, Valentin J-P (2008) Scientific review and recommendations on preclinical cardiovascular safety evaluation of biologics. J Pharmacol Toxicol Methods 58:72–76
Viskin S (1999) Long QT syndromes and torsade de pointes. Lancet 354:1625–1633
Wakefield ID, Pollard C, Redfern WS, Hammond TG, Valentin J-P (2002) The application of in vitro methods to safety pharmacology. Fundam Clin Pharmacol 16:209–218
Webster R, Leischman D, Walker D (2002) Towards a drug concentration effect relationship for QT prolongation and torsades de pointes. Curr Opin Drug Discov Devel 5:116–126
Williams PD (1990) The role of pharmacological profiling in safety assessment. Regul Toxicol Pharmacol 12:238–252
Williams PD, Bass AS (2003) Safety pharmacology: a practical guide. TherImmune Research, Gaithersburg
Zbinden G (1979) Pharmacological methods in toxicology. Pergamon, Elmsford, p 613
Zbinden G (1984) Neglect of function and obsession with structure in toxicity testing. In: Proceedings of the 9th international congress of pharmacology, vol 1, pp 43–49
Online Links
E14: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs (Step 5, May 2005). http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/Step4/E14_Guideline.pdf
E14 Implementation Working Group Questions & Answers (Current Version June 2008). http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/Q_As/E14_Q_As_step4pdf.pdf
Final Concept Paper E14: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs; Additional Q & As document (Endorsed by the Steering Committee, April 2010). http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/Q_As/E14_Q__As_Final_Concept_Paper_March_15_2010x.pdf
M3(R2): Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (Step 5; June 2009). http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M3_R2/Step4/M3_R2__Guideline.pdf
M3(R2) Implementation Working Group on the M3(R2) Guideline: Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (Current version June 2011). http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M3_R2/Q_As/ M3_R2_Q_AStep4.pdf
Points to Consider on the Assessment of the Potential for QT Interval Prolongation by Non-Cardiovascular Medicinal Products; CPMP/SWP/986/96; published December 1997; replaced by ICH S7A and taken off EMEA website
S6(R1): Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (Step 5, July 1997). http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S6_R1/Step4/S6_R1_Guideline.pdf
Final Concept Paper S6(R1): Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (Revision of the ICH S6 Guideline) (Endowed by the Steering Committee, June 2008). http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S6_R1/Concept_papers/S6_R1__Concept_Paper.pdf
S7A: Safety Pharmacology Studies for Human Pharmaceuticals (Step 5, November 2000). http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S7A/Step4/S7A_Guideline.pdf
S7B: The Non-Clinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals (Step 5, May 2005). http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S7B/Step4/S7B_Guideline.pdf
Final Concept Paper S7B: The Non-Clinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals (Endorsed by the Steering Committee, May 2001). http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S7B/Concept_papers/S7B_Concept_Paper.pdf
S9: Nonclinical Evaluation for Anticancer Pharmaceuticals (Step 5, October 2009). http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S9/Step4/S9_Step4_Guideline.pdf
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Hock, F.J. (2013). Status of Safety Pharmacology and Present Guidelines. In: Vogel, H.G., Maas, J., Hock, F.J., Mayer, D. (eds) Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-25240-2_1
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