Clinical studies in human volunteers are an essential part of drug development. These studies are designed to account for possible differences between the effects of pharmaceutical products in pre-clinical studies and in humans. However, the tragic outcome of the recent Phase 1 clinical trial on TGN1412 casts considerable doubt over the relevance of this traditional drug development paradigm to the testing of therapeutic agents for human use. The role of alternatives to animal testing is considered, and a series of recommendations are made, which could ensure that clinical trials are well informed and based on the most relevant scientific information.
Anon. (2001). Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. Website http://eudract.emea.eu.int/docs/Dir2001-20_en.pdf (Accessed 18.04.06).
KolaI., & LandisJ. (2004). Can the pharmaceutical industry reduce attrition rates?Nature Reviews: Drug Discovery3, 711–715.
13.
Anon. (2006). Parexel clinical Trial Protocol: A Phase-1 single-centre, double-blind, randomised, placebo-controlled, single escalating-dose study to assess the safety, pharmacokinetics, pharmacodynamics and immunogenicity of TGN1412 administered to healthy volunteers. Website http://www.mhra.gov.uk/home/groups/comms-po/documents/websiteresources/con2023517.pdf (Accessed 12.02.06).
LinC-H., KerkauT., GuntermannC., TrischlerM., BeyersdorfN., ScheuringY., TonyH-P., KneitzC., WilhelmM., MuellerP., HünigT., & HankeT. (2004). Superagonistic Anti-CD28 Antibody TGN1412 as a Potential Immunotherapeutic for the Treatment of B Cell Chronic Lymphocytic Leukemia. Blood104 (ASH Annual meeting), abstract 2519.
18.
HofstetterH., FranzC., GronenF., ButtmannM., RuprechtK., HankeT., HünigT., ToykaK.V., & RieckmannP. (2005). The superagonistic monoclonal anti-CD28 antibody modulates cytokine expression in mononuclear blood cells of multiple sclerosis patients and healthy controls.21st Congress of the European Committee for the Treatment and Research in Multiple Sclerosis. 10th Annual Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis. 28.09.2005–01.10.2005.
AbramowiczD., SchandeneL., GoldmanM., CrusiauxA., VereerstraetenP., De PauwL., WybranJ., KinnaertP., DupontE., & ToussaintC. (1989). Release of tumor necrosis factor, interleukin-2 and gamma interferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients. Transplantation47, 606–608.
21.
TackeM., HankeG., HankeT., & HünigT. (1997). CD28-mediated induction of proliferation in resting cells in vitro and in vivo without engagement of the T cell receptor: evidence for functionally distinct forms of CD28. European Journal of Immunology27, 239–247.
22.
BeyersdorfN., HankeT., KerkauT., & HünigT. (2005). Superagonistic anti-CD28 antibodies: potent activators of regulatory T cells for the therapy of autoimmune diseases. Annals of Rheumatic Diseases64, 91–95.
23.
BeyersdorfN., HankeT., KerkauT., & HünigT. (2006). CD28 superagonists put a break on autoimmunity by preferentially activating CD4+ CD25+ regulatory T cells. Autoimmunity Reviews5, 40–45.
24.
BeyersdorfN., GauppS., BalbachK., SchmidtJ., ToykaK.V., LinC.H., HankeT., HünigT., KerkauT., & GoldR. (2005). Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis. Journal of Experimental Medicine202, 445–455.
25.
SchmidtJ., ElfeinK., StienekemeierM., Rodriguez-PalmeroM., SchneiderC., ToykaK.V., GoldR., & HünigT. (2003). Treatment and prevention of experimental autoimmune neuritis with superagonistic CD28-specific monoclonal antibodies. Journal of Neuroimmunology140, 143–152.
26.
DingS.H., InglebyL., AhernC.A., & HornR. (2005). Investigating the putative glycine hinge in shaker potassium channel. Journal of General Physiology126, 213–226.
27.
MarguliesD.H. (2003). CD28, costimulator or agonist receptor?Journal of Experimental Medicine197, 949–953.
28.
VillingerF., BrarS.S., MayneA., ChikkalaN., & AnsariA.A. (1995). Comparative sequence analysis of cytokine genes from human and nonhuman primates. Journal of Immunology155, 3946–3954.
29.
HopkinM. (2006). Can Super-antibody drugs be tamed?Nature440, 855–856.
30.
HoganS.P., KoskinenA., & FosterP.S. (1997). Interleukin-5 and eosinophils induce airway damage and bronchial hyperreactivity during allergic airway inflammation in BALB/c mice. Immunology & Cell Biology75, 284–288.
Anon. (2006). Guidance for Industry, Investigators, and Reviewers Exploratory IND Studies U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) January 2006.
33.
CombesR.D., BerridgeT., ConnellyJ., EveM.D., GarnerR.C., ToonS., & WilcoxP. (2003). Early microdose drug studies in human volunteers can minimise animal testing — proceedings of a workshop organised by Volunteers in Research and Testing. European Journal of Pharmaceutical Sciences19, 1–11.
34.
SillimanC.C., & WangM. (2005). The merits of in vitro versus in vivo modelling in investigation of the immune system. Environmental Toxicology and Pharmacology21, 123–134.
35.
GogginM.J. (2005). Introduction to the work of the research ethics committees in the United Kingdom. What is involved in being on a research ethics committee. Website www.abpi.org.uk (Accessed 12.04.06).
FDA (2006). FDA and the Critical Path Institute Announce Predictive Safety Testing Consortium Will Share Tests to Understand Safety of Potential New Drugs Earlier. Website http://www.fda.gov/bbs/topics/news/2006/NEW01337.html (Accessed 18.04.06).
39.
KramerB.S., WilentzJ., AlexanderD., BurklowJ., FriedmanL.M., HodesR., KirschsteinR., PattersonA., RodgersG., & StrausS.E. (2006). Getting it right: Being smarter about clinical trials: A major NIH meeing led to recommendations for conducting better clinical trials. PLoS Medicine3, 144.
