Assessing immunotoxicity: guidelines

Abstract

Over the last couple of years the assessment of immunotoxic potential of human pharmaceuticals has drawn considerable attention worldwide. Regulatory agencies entrusted with the registration of pharmaceuticals (or other compounds) found an increased need for guidance on this issue. This has resulted in the release of guidance documents on immunotoxicity in Europe, USA and Japan in close succession. In Europe the CPMP has released their immunotoxicity guidance documents that are now in force. The FDA and the Japanese Authorities are in the process of doing so, and will shortly enforce them. Immune suppression and stimulation, hypersensitivity, photosensitivity, drug-induced autoimmunity and developmental immunotoxicity are the focus of regulatory testing. This review discusses these kinds of immunotoxicity and their clinical implications. The three regional guidelines and screening tools for detection are discussed. Additionally, the scientific background on which these guidelines are based is briefly highlighted.

Regulatory immunotoxicology: does the published evidence support mandatory nonclinical immune function screening in drug development?

“…The most important considerations leading to the adoption of EU immunotoxicity guideline have been reported by Putman et al (2002) and are summarised below. Collectively, these factors are thought to demonstrate a Ôstrong scientific basis for European requirements.Õ In addition, it is claimed that, Ôsuch testing has been very instrumental in identifying immunotoxicantsÕ (Putman et al, 2003).…”

“…Detailed assessments have been undertaken on those drugs proposed (e.g., by Putman et al, 2002Putman et al, , 2003 to support the concept underpinning the EU guidance on immunotoxicity (i.e., ability of IFTs to identify unexpected immunotoxic potential that would otherwise have been undetected using conventional approaches). The outcome of these assessments is summarised in Table 9, and it can be seen that there are good reasons to doubt the validity of all of the examples.…”

Immunotoxicology

“…The regulations administered by government agencies are greatly influenced by the history,culture and legislations of the countries concerned.This still accounts for many national differences [83,84]. However, worldwide harmonization of regulatory requirements is ongoing.…”

Profiling Adverse Immune Effects

“…In 2000 the European Medicines Agency/Committee for Medicinal Products for Human Use (EMEA/CHMP) incorporated the TDAR assay (or the nonfunctional immunotyping of leucocytes) as a routine test in the Note for Guidance on Repeated Dose Toxicity for human pharmaceuticals [7,21]. Germolec et al [35,36] evaluated past National Toxicology Program (NTP) studies performed in the mouse using ten chemicals and three positive controls.…”

“…The induction of cellular proliferation in draining lymph nodes is measured by determining the tritium-thymidine incorporation in the DNA as an indicator for immune stimulation. This assay has replaced almost entirely the previously used guinea pigs assays (Buehler assay, guinea pig maximization test) after extensive validation and evaluation [7,[52][53][54]. The cellular proliferation after treatment is compared to that of control (vehicle) treated animals, and a so-called stimulation index (treated vs control) is calculated.…”