ABSTRACT
This review summarizes scientific, ethical and regulatory aspects of Phase I clinical trials with monoclonal antibodies. The current standard requirements for pre-clinical testing and for clinical study design are presented. The scientific considerations discussed herein are generally applicable, the view on legal requirements for clinical trials refer to the German jurisdiction only. The adverse effects associated with the TGN1412 Phase I trial indicate that the predictive value of pre-clinical animal models requires reevaluation and that, in certain cases, some issues of clinical trial protocols such as dose fixing may need refinement or redesign. Concrete safety measures, which have been proposed as a consequence of the TGN1412 event include introduction of criteria for high-risk antibodies, sequential inclusion of trial participants and implementation of pre-Phase I studies where dose calculation is based on the pre-clinical No Effect Level instead of the No Observed Adverse Effect Level. The recently established European clinical trials database (EUDRACT Database) is a further safety tool to expedite the sharing of relevant information between scientific authorities.
Subject(s)
Antibodies, Monoclonal/adverse effects , Antineoplastic Agents/adverse effects , Clinical Trials, Phase I as Topic/legislation & jurisprudence , Drug Approval/legislation & jurisprudence , Human Experimentation/legislation & jurisprudence , Legislation, Drug , Research Design , Adverse Drug Reaction Reporting Systems , Animals , Antibodies, Monoclonal/toxicity , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/toxicity , Clinical Trials, Phase I as Topic/ethics , Clinical Trials, Phase I as Topic/methods , Drug Evaluation, Preclinical/methods , Ethical Review , Germany , Guidelines as Topic , Human Experimentation/ethics , Humans , No-Observed-Adverse-Effect Level , Reference Values , Risk Assessment , Toxicity TestsABSTRACT
The prevalence of migraine in Germany is up to 14% in the female and up to 8% in the male population and peaks between the age of 35 and 45. Few studies have investigated the productivity loss and resulting costs attributable to migraine in Germany or addressed the question whether these costs can be reduced by optimal treatment. In recent years, 5-HT(1B/D) agonists (so-called triptans), a generation of drugs highly specific for migraine treatment, have been introduced. Seven 5-HT(1B/D) agonists have been approved in Germany with more than 20 dosage forms. We present a model that enables employers to estimate the annual cost of migraine and the annual cost that could be saved by treatment of migraine with rizatriptan compared with the use of non-specific antimigraine medication. A representative German company with 10,000 employees is used for the reference case analysis. This company is predicted to have 580 female and 284 male employees with migraine. These employees are estimated to lose 6992 workdays or 31.8 person years of productive effort annually due to migraine, valued approximately 1,431,719 euros. The value of work loss that could be avoided by treating migraine with rizatriptan is estimated at 619,094 euros annually. These data indicate that costs arising from lost productivity can be reduced by treating migraine headaches with a triptan.
Subject(s)
Efficiency , Migraine Disorders/drug therapy , Serotonin Receptor Agonists/therapeutic use , Triazoles/therapeutic use , Tryptamines/therapeutic use , Absenteeism , Adult , Aged , Cost of Illness , Female , Germany/epidemiology , Humans , Male , Middle Aged , Migraine Disorders/economics , Migraine Disorders/epidemiology , Prevalence , Serotonin Receptor Agonists/economics , Triazoles/economics , Tryptamines/economicsABSTRACT
Calcitonin gene related peptide (CGRP) released from the C-fibers projecting from the trigeminal ganglion to the meninges has been suggested to play a crucial role in the pathophysiology of headache, particularly migraine. In humans it has been shown that CGRP is released during migraine-attacks, and this is attenuated by the administration of typical anti-migraine drugs such as dihydroergotamine or sumatriptan. We describe a new rat model which allows the study of CGRP release from the meninges into venous blood following activation of the trigeminal vascular system. The effects of classical and new anti-migraine drugs such as acetylsalicylic acid (ASA), sumatriptan and the new high efficacy 5-HT1B/1D agonist donitriptan (4-[4-[2-(2-aminoethyl)-1H-indol-5-yloxyl]acetyl]piperazinyl-1-yl]benzonitrile) were evaluated in comparison with the established model of neurogenic inflammation in the meninges. Sumatriptan and donitriptan inhibited CGRP release as well as neurogenic inflammation. ASA, however, attenuated neurogenic inflammation, but not CGRP release, confirming the concept of prejunctional inhibition of CGRP release by 5-HT1B/1D receptors. This new model allows the further study of prejunctional pharmacology and mechanisms of neuropeptide release in the trigeminal vascular system, which might be crucial for the further development of potent, more effective anti-migraine drugs.
