Skip to main content
SpringerLink
Log in

ICH S8: History and Perspectives

  • Chapter
  • First Online:
Global Approach in Safety Testing

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 5))

Abstract

An important aspect of drug safety evaluation is determination of potential adverse effects on immune function. Drug-induced immune dysfunction can present as increased susceptibility to infections and tumors (especially virally induced), hypersensitivity reactions such as drug allergy and autoimmunity, and various inflammation-like phenomena. Although immunotoxicity test methods have been developed to assess environmental chemicals, these had not been applied systematically in drug development prior to promulgation of guidance documents by EMA and FDA. EMA and FDA guidances/guidelines differed in certain important respects, and ICH S8 was written to resolve these somewhat conflicting approaches. The key issue resolved in ICH S8 was whether functional immunotoxicity assays should be conducted routinely or when there was a cause for concern. An important result of ICH S8 is that drug developers can no longer ignore signs of compound-related adverse effects on immunity. ICH S8 provides a systematic approach to determining the need for immunotoxicity testing and includes discussion on appropriate methodology. Based on current experience with ICH S8, the issue of including immune function parameters in standard toxicity testing remains unresolved and may be addressed in future revisions of the document. In addition, guidance on unintended immunostimulation may be needed based on recent experiences in clinical drug development.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Auer J (1911) Lethal cardiac anaphylaxis in the rabbit. J Exp Med 14:476–496

    Article  PubMed  CAS  Google Scholar 

  • Auerbach C (1958) Radiomimetic substances. Radiat Res 9:33–47

    Article  PubMed  CAS  Google Scholar 

  • Bekesi JG, Holland JF, Anderson HA, Fischbein AS, Rom W, Wolff MS, Selikoff IJ (1978) Lymphocyte function of Michigan dairy farmers exposed to polybrominated biphenyls. Science 199:1207–1209

    Article  PubMed  CAS  Google Scholar 

  • Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, Lee S, Plavina T, Scanlon JV, Sandrock A, Bozic C (2012) Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 366:1870–1880

    Article  PubMed  CAS  Google Scholar 

  • Burleson GR, Burleson FG (2008) Animal models of host resistance. In: Herzyk DJ, Bussiere JL (eds) Immunotoxicology strategies for pharmaceutical safety assessment. Wiley, Hoboken, NJ, pp 163–177

    Google Scholar 

  • Centers for Disease Control and Prevention (CDC) (2004) Tuberculosis associated with blocking agents against tumor necrosis factor-alpha – California, 2002–2003. Morb Mortal Wkly Rep 53:683–686

    Google Scholar 

  • Cunha BA (1995) Pulmonary tuberculosis and steroids. Chest 107:1486–1487

    Article  Google Scholar 

  • Cunningham AJ (1965) A method of increased sensitivity for detecting single antibody-forming cells. Nature 207:1106–1107

    Article  PubMed  CAS  Google Scholar 

  • De Waal EJ, Timmerman HH, Dortant PM, Kranjc MAM, Van Loveren H (1995) Investigation of a screening battery for immunotoxicity of pharmaceuticals within a 28-day oral toxicity study using azathioprine and cyclosporin A as model compounds. Regul Toxicol Pharmacol 21:327–338

    Article  PubMed  Google Scholar 

  • De Waal EJ, De Jong WH, Van der Vleit H, Verlaan B, Van Loveren H (1996) An immunotoxicity screening study on salmeterol in rats. Int J Immunopharmacol 18:523–528

    Article  PubMed  Google Scholar 

  • De Waal EJ, Van Loveren H, Vos JG (1997) Practice of tiered testing for immunosuppression in rodents. Drug Info J 31:1317–1323

    Article  Google Scholar 

  • De Waal EJ, Van der Laan J-W, Van Loveren H (1998) Effects of prolonged exposure to morphine and methadone on in vivo parameters of immune function in rats. Toxicology 129:201–210

    Article  PubMed  Google Scholar 

  • Dean JH, Luster MI, Boorman GA, Lauer LD (1982) Procedures available to examine the immunotoxicity of chemicals and drugs. Pharmacol Rev 34:137–148

    PubMed  CAS  Google Scholar 

  • Dixon WG, Hyrich KL, Watson KD, Lunt M, Galloway J, Ustianowski A, Symmons DPM (2010) Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR). Ann Rheum Dis 69:522–528

    Article  PubMed  CAS  Google Scholar 

  • Draize JH, Woodward G, Calvery HO (1944) Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. J Pharm Exp Ther 61:377–390

    Google Scholar 

  • European Agency for the Evaluation of Medical Products (2000) Committee for Proprietary Medicinal Products. Note for guidance on repeated dose toxicity. European Agency for the Evaluation of Medical Products, London

    Google Scholar 

  • Eyers S, Weatherall M, Jefferies S, Beasley R (2011) Paracetamol in pregnancy and the risk of wheezing in offspring: a systematic review and meta-analysis. Clin Exp Allerg 41:482–489

    Article  CAS  Google Scholar 

  • Feinberg SM, Feinberg AR, Moran CF (1953) Penicillin anaphylaxis, nonfatal and fatal reactions. J Am Med Assoc 152:114–119

    Article  PubMed  CAS  Google Scholar 

  • Forni L, Coutinho A, Köhler G, Jerne NK (1980) IgM antibodies induce the production of antibodies of the same specificity. Proc Natl Acad Sci USA 77:1125–1128

    Article  PubMed  CAS  Google Scholar 

  • Gelinck LBS, Van der Bijl AE, Visser LG, Huizinga TWJ, Van Hogezand RA, Rijkers GT, Kroon FP (2008) Synergistic immunosuppressive effect of anti-TNF combined with methotrexate on antibody responses to the 23 valent pneumococcal polysaccharide vaccine. Vaccine 26:3528–3533

    Article  PubMed  CAS  Google Scholar 

  • Gerberick FG, Ryan CA, Kern PS, Schlatter H, Dearman RJ, Kimber I, Patlewicz GY, Basketter DA (2005) Compilation of historical local lymph node data for evaluation of skin sensitization alternative methods. Dermatitis 16:157–202

    Article  PubMed  Google Scholar 

  • Gourley I, Descotes J (2008) Bridging immunotoxicology to clinical drug development. In: Herzyk DJ, Bussiere JL (eds) Immunotoxicology strategies for pharmaceutical safety assessment. Wiley, Hoboken, NJ, pp 375–384

    Google Scholar 

  • Grainger DJ (2004) Immunomics: principles and practice. IRTL Rev 2:1–6

    Google Scholar 

  • Grandjean P, Andersen EW, Budtz-Jørgensen E, Nielsen F, Mølbak K, Weihe P, Heilmann C (2012) Serum vaccine antibody concentrations in children exposed to perfluorinated compounds. J Am Med Assoc 307:391–397

    Article  CAS  Google Scholar 

  • Gulmez SE, Holm A, Frederiksen H, Jensen TG, Pedersen C, Hallas J (2007) Use of proton pump inhibitors and the risk of community-acquired pneumonia. Arch Intern Med 167:950–955

    Article  PubMed  CAS  Google Scholar 

  • Haley P, Perry R, Ennulat D, Frame S, Johnson C, Lapointe J-M, Nyska A, Snyder PW, Walker D, Walter G (2005) STP position paper: best practices guideline for the routine pathology evaluation of the immune system. Toxicol Pathol 33:404–407

    Article  PubMed  CAS  Google Scholar 

  • Hastings KL (1996) Regulatory issues of importance to developing anti-HIV therapeutics. Toxicol Pathol 24:278–280

    Article  PubMed  CAS  Google Scholar 

  • Hastings KL (2002) Implications of the new FDA/CDER immunotoxicology guidance for drugs. Int Immunopharmacol 2:1613–1618

    Article  PubMed  CAS  Google Scholar 

  • Hinton DM (2000) US FDA “Redbook II” immunotoxicity testing guidelines and research in immunotoxicity evaluations of food chemicals and new food proteins. Toxicol Pathol 28:467–478

    Article  PubMed  CAS  Google Scholar 

  • Holsapple MP, Burns-Naas LA, Hastings KL, Ladics GS, Lavin AL, Makris SL, Yang Y, Luster MI (2005) A proposed testing framework for developmental immunotoxicology. Toxicol Sci 83:18–24

    Article  PubMed  CAS  Google Scholar 

  • Horvath CJ, Milton MN (2009) The TeGenero incident and the Duff report conclusions: a series of unfortunate events or an avoidable event? Toxicol Pathol 37:372–383

    Article  PubMed  Google Scholar 

  • House RV, Luebke RW (2007) Immunotoxicology: thirty years and counting. In: Luebke R, House R, Kimber I (eds) Immunotoxicology and immunopharmacology. CRC, Boca Raton, FL, pp 3–20

    Google Scholar 

  • Irey NS (1978) Drug adverse reaction reports related to immunotoxicity. In: Asher IM (ed) Inadvertent modification of the immune response: the effects of foods, drugs, and environmental contaminants. US Food and Drug Administration, Washington, DC, pp 140–143

    Google Scholar 

  • Jerne NK, Nordin AA (1963) Plaque formation in agar by single antibody-producing cells. Science 140:405

    Article  Google Scholar 

  • Kuper CF, Harleman JH, Richter-Reichelm HB, Vos JG (2000) Histopathologic approaches to detect changes indicative of immunotoxicity. Toxicol Pathol 28:454–466

    Article  PubMed  CAS  Google Scholar 

  • Landsteiner K (1945) The specificity of serological reactions. Harvard University Press, Cambridge, MA

    Google Scholar 

  • Linsky A, Gupta K, Lawler EV, Fonda JR, Hermos JA (2010) Proton pump inhibitors and risk for recurrent Clostridium difficile infection. Arch Intern Med 170:772–778

    Article  PubMed  Google Scholar 

  • Luebke RW, Holsapple MP, Ladics GS, Luster MI, Selgrade MJ, Smialowicz RJ, Woolhiser MR, Germolec DR (2006) Immunotoxicogenomics: the potential of genomics technology in the immunotoxicity risk assessment process. Toxicol Sci 94:22–27

    Article  PubMed  CAS  Google Scholar 

  • Luster MI, Munson AE, Thomas PT, Holsapple MP, Fenters JD, White KL Jr, Lauer LD, Germolec DR, Rosenthal GJ, Dean JH (1988) Development of a testing battery to assess chemical-induced immunotoxicity: National Toxicology Program’s guidelines for immunotoxicity evaluation in mice. Fundam Appl Toxicol 10:2–19

    Article  PubMed  CAS  Google Scholar 

  • Luster MI, Rosenthal GJ, Cao W, Thompson MB, Munson AE, Prejean JD, Shopp G, Fuchs BA, Germolec DR, Tomaszewski JE (1991) Experimental studies of the hematologic and immune system toxicity of nucleoside derivatives used against HIV infection. Int J Immunopharmacol 13(S1):99–107

    Article  PubMed  CAS  Google Scholar 

  • Luster MI, Portier C, Pait DG, White KL Jr, Gennings C, Munson AE, Rosenthal GJ (1992) Risk assessment in immunotoxicology I: sensitivity and predictability of immune tests. Fundam Appl Toxicol 18:200–210

    Article  PubMed  CAS  Google Scholar 

  • Luster MI, Portier C, Pait DG, Rosenthal GJ, Germolec DR, Corsini E, Blaylock BL, Pollock P, Kouchi Y, Craig W, White DL, Munson AE, Comment CE (1993) Risk assessment in immunotoxicology II: relationships between immune and host resistance tests. Fundam Appl Toxicol 21:71–82

    Article  PubMed  CAS  Google Scholar 

  • Maronpot RR (2006) A monograph of histomorphologic evaluation of lymphoid organs. Toxicol Pathol 34:409–696

    Article  Google Scholar 

  • Organisation of Economic Cooperation and Development (1995) Guideline for testing chemicals. Method No. 407: Repeated dose oral toxicity – rodents: 28-day or 14-day study. OECD, Paris (Updated 2008)

    Google Scholar 

  • Ovary Z (1958) Immediate reactions in the skin of experimental animals provoked by antibody-antigen interaction. Prog Allerg 5:459–508

    CAS  Google Scholar 

  • Pharmaceutical Manufacturers Association (1988) Immunotoxicology Task Force, Report to the Drug Safety Subsection Steering Committee on Immunotoxicology and the Pharmaceutical Industry. PMA, Washington, DC

    Google Scholar 

  • Phillips KE, McCay JA, Brown RD, Musgrove DL, Meade BJ, Butterworth LF, Wilson S, White KL Jr, Munson AE (1997) Immunotoxicity of 2′,3′-dideoxyinosine in female B6C3F1 mice. Drug Chem Toxicol 20:189–228

    Article  PubMed  CAS  Google Scholar 

  • Piccotti JR, Lebrec HN, Evans E, Herzyk DJ, Hastings KL, Burns-Naas LA, Gourley IS, Wierda D, Kawabata TT (2009) Summary of a workshop on nonclinical and clinical immunotoxicity assessment of immunomodulatory drugs. J Immunotoxicol 6:1–10

    Article  PubMed  CAS  Google Scholar 

  • Pieters R (2008) Systemic hypersensitivity. In: Herzyk DJ, Bussiere JL (eds) Immunotoxicology strategies for pharmaceutical safety assessment. Wiley, Hoboken, NJ, pp 241–256

    Google Scholar 

  • Portier P, Richet C (1902) De l’action anaphylactique de certain venins. C R Soc Biol 54:170–172

    Google Scholar 

  • Putman E, Van Loveren H, Bode G, Dean J, Hastings K, Nakamura K, Verdier F, Van der Laan J-W (2002) Assessment of immunotoxic potential of human pharmaceuticals, a workshop report. Drug Info J 36:417–427

    Google Scholar 

  • Putman E, Van der Laan J-W, Van Loveren H (2003) Assessing immunotoxicity: guidelines. Fundam Clin Pharmacol 17:615–626

    Article  PubMed  CAS  Google Scholar 

  • Rock KL, Latz E, Ontiveros F, Kono H (2010) The sterile inflammatory response. Annu Rev Immunol 28:321–342

    Article  PubMed  CAS  Google Scholar 

  • Shubin H, Lambert RE, Heiken CA, Sokmensuer A, Glaskin A (1959) Steroid therapy and tuberculosis. J Am Med Assoc 170:1885–1890

    Article  PubMed  CAS  Google Scholar 

  • Stebbings R, Findlay L, Edwards C, Eastwood D, Bird C, North D, Mistry Y, Dilger P, Liefooghe E, Cludts I, Fox B, Tarrant G, Robinson J, Meager T, Dolman C, Thorpe SJ, Bristow A, Wadhwa M, Thorpe R, Poole S (2007) “Cytokine storm” in the phase I trial of monoclonal antibody TGN1412: better understanding the causes to improve preclinical testing of immunotherapeutics. J Immunol 179:3325–3331

    PubMed  CAS  Google Scholar 

  • Taylor LD, Binienda Z, Schmued L, Slikker W Jr (1994) The effect of dideoxycytidine on lymphocyte subpopulations in nonhuman primates. Fundam Appl Toxicol 23:434–438

    Article  PubMed  CAS  Google Scholar 

  • Thaxton JP, Tung HT, Hamilton PB (1974) Immunosuppression in chickens by aflatoxin. Poult Sci 53:721–725

    Article  PubMed  CAS  Google Scholar 

  • Udaka K (1992) Cellular and humoral mechanisms of immunotoxicological tissue manifestations induced by immunotoxic drugs. Toxicol Lett 64/65:93–100

    Article  Google Scholar 

  • US Environmental Protection Agency (1998) Health effects test guidelines: OPPTS 870.7800 Immunotoxicity (revised 2006). US EPA, Washington, DC

    Google Scholar 

  • US Food and Drug Administration (1993) Points to consider in the immunotoxicology evaluation of new drugs intended for the treatment of HIV infection and related disorders. Division of Antiviral Drug Products, Center for Drug Evaluation and Research, US FDA, Washington, DC

    Google Scholar 

  • US Food and Drug Administration (2002) Guidance for industry: immunotoxicology evaluation of investigational new drugs. US FDA, Washington, DC

    Google Scholar 

  • Van der Laan J-W, Krajnc EI, Krajnc-Franken MAM, Van Loveren H (1995) Immunotoxicological screening of morphine and methadone in an extended 28 day study in rats. Int J Immunopharmacol 17:535–543

    Article  PubMed  Google Scholar 

  • Van der Laan J-W, Timmerman H, Van Loveren H (1996) Comparison of the in vivo effects of morphine and methadone on natural killer cell activity in spleen, peritoneal cavity, and lungs in rats. Int J Immunopharmacol 18:401–407

    Article  PubMed  Google Scholar 

  • Van der Laan J-W, Van Loveren H, Vos JG, Dean JH, Hastings K (1997) Immunotoxicity of pharmaceuticals: current knowledge, testing strategies, risk evaluation & consequences for human health. Drug Info J 31:1301–1306

    Article  Google Scholar 

  • Vos JG (1977) Immune suppression as related to toxicology. CRC Crit R Toxicol 5:67–101

    Article  CAS  Google Scholar 

  • Vos JG, Van Loveren H (1998) Experimental studies on immunosuppression: how do they predict for man? Toxicology 129:13–26

    Article  PubMed  CAS  Google Scholar 

  • Weaver JL, Tsutsui N, Hisada S, Vidal J-M, Spanhaak S, Sawada J, Hastings KL, Van der Laan J-W, Van Loveren H, Kawabata T, Sims J, Durham SK, Fueki O, Matula TI, Kusunoki H, Ulrich P, Nakamura K (2005) Development of the ICH guidelines for immunotoxicology evaluation of pharmaceuticals using a survey of industry practices. J Immunotoxicol 2:171–180

    Article  PubMed  CAS  Google Scholar 

  • Yang L, Moses HL (2008) Transforming growth factor β: tumor suppressor or promoter? Are host immune cells the answer? Cancer Res 68:9107–9111

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Sanofi SA, Bethesda, MD, USA

    Kenneth L. Hastings

Authors
  1. Kenneth L. Hastings
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kenneth L. Hastings .

Editor information

Editors and Affiliations

  1. , Section on Pharmacology, Toxicology, and, Medicines Evaluation Board, Graadt van Roggenweg 500, Utrecht, 3531 AH, Netherlands

    Jan Willem van der Laan

  2. , Drug Safety Testing, Merck Research Laboratories, Sumneytown Pike 770, West Point, 19486, Pennsylvania, USA

    Joseph J. DeGeorge

Rights and permissions

Reprints and permissions

Copyright information

© 2013 American Association of Pharmaceutical Scientists

About this chapter

Cite this chapter

Hastings, K.L. (2013). ICH S8: History and Perspectives. In: van der Laan, J., DeGeorge, J. (eds) Global Approach in Safety Testing. AAPS Advances in the Pharmaceutical Sciences Series, vol 5. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5950-7_12

Download citation

Publish with us

Policies and ethics

Search

Navigation