PhD PGDip (Law)
Fund for the Replacement of Animals in Medical Experiments
The EU Clinical Trials Directive 2001/20/EC, governing the conduct of clinical trials for investigational medicinal products (IMPs, defined by Article 1 Directive 2001/83/EC), embraces provisions of the Helsinki Declaration and operates alongside guidelines, including the International Conference on Harmonization (ICH) Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95), to protect the rights, safety and wellbeing of trials volunteers. In reality, however, adverse reactions to IMPs are not always anticipated because of inherent problems with extrapolating to the clinic information from animal and in vitro studies. Indeed, one survey suggests that only around 11% of IMPs that progress to clinical trials are ever registered, with around half of all drug failures due to safety, toxicity or efficacy problems.(1)
A new drug development paradigm for humanised therapeutics
Applying traditional preclinical and clinical drug development strategies to biological products is particularly problematic, in that such products are generally human-specific – a view that has been expressed repeatedly over the years in documents, including the ICH M3 (CPMP/ICH/286/95) guidance on nonclinical safety studies. Yet it took the events of March 2006 – when a new superagonistic humanised monoclonal antibody, TGN1412, caused severe adverse reactions in six otherwise healthy men – to bring this issue into the foreground. Since this incident occurred, several reports – including that of the Expert Scientific Group set up by the UK Department of Health – have suggested ways in which the safety of human volunteers might be better protected during early clinical trials.(2)
CHMP draft guideline for testing a high-risk medicinal product
More recently, the EMEA’s Committee for Medicinal Products for Human Use (CHMP) issued a draft guideline for developing high-risk medicinal products.(3) The guideline defines a high-risk medicinal product as one where there are concerns about or gaps in knowledge about, for instance, its mode and/or target(s) of action, or the relevance of preclinical animal models.
TGN1412, with its potential to override the usual biological control mechanisms, target numerous cell types, initiate a cascade of events and modulate the function of the complex immune system, falls within the high-risk IMP criteria. The draft guideline also extends the criteria for selecting suitable preclinical animal models (as listed within ICH s6 CPMP/ICH/302/95) for assessing biotechnological products, from those that simply express the desired epitope and demonstrate a similar tissue cross-reactivity profile, to that which allows for structural homology, similarity of pharmacological effects and downstream signal transduction.
However, there are several important points that have not been addressed in the draft guideline.
The first is how equivocal results from different preclinical studies can be resolved. In the case of TGN1412, two closely related species of macaque were used in preclinical evaluation, but data from studies on only one species of macaque were preferred. The reason for this is unclear, except that TGN1412 appeared less active in the other species.
Secondly, a comprehensive assessment of how studies in transgenic rodents expressing human proteins in clinical study design or studies on species-specific surrogates of an IMP translate in terms of clinical-trial design is required. The importance of the latter is highlighted by the fact that, had data from rat studies on the TGN1412 rat surrogate, JJ316, been afforded more significance, phase I single doses would have been substantially smaller than they were.
Clinical design in the face of uncertainty
Should the maximum recommended safe starting dose (MRSD) for phase I single-dose clinical trials be based on the “no observed adverse effect level” (NOAEL) or the minimum active biological effect level (MABEL) estimated from preclinical studies? The answer to this will almost certainly depend on the subject group. However, since NOAEL-based approaches rely on knowing which species gives the most relevant values, whereas the MABEL approach is able to take into account the lowest active dose from any preclinical studies, including those on surrogate molecules, the MABEL approach has been advocated for estimating starting doses for phase I studies on healthy volunteers.(4,5)
Since one of the proposed uses of TGN1412 was for the management of B-type chronic lymphotic leukaemia, in the case of TGN1412 should phase I clinical trials have been conducted on patients rather than on healthy volunteers? How then should starting doses have been estimated? Since TGN1412 bolsters the dysfunctional immune systems of certain patient groups, patient studies may have avoided what appears to be overstimulation of the immune systems of otherwise healthy adults.
However, selecting a suitable patient group requires careful consideration, since late- or end-stage patients unresponsive to other treatments may respond differently, if at all, to TGN1412 compared with patients who are responsive to existing treatment, such that the former may respond atypically while risk-benefit analysis may not justify use of the latter group.
It is clear, however, that whereas phase I trials on healthy volunteers are conducted at doses that are predicted to have no pharmacological activity, patients are generally given starting doses in the pharmacologically active range. Thus, a decision has to be made as to what would be a sufficient pharmacological activity, and this requires at least a basic grasp of differences in target density and function in healthy individuals and patients.
Such studies generally require dose-response relationships for specific surrogate endpoints, determined by in vitro studies on human cells and tissues and which are also of value to estimate the dose-response profile and assist with selection of suitable animal models and data extrapolation to humans. Hence, assessment of the merits of these systems and formal scientific validation of in-vitro methodologies are warranted, especially where animal studies are of limited relevance.
In any case, administration of a high-risk IMP to individual subjects must take into account the duration and onset of clinical or biochemical changes seen during animal studies, particularly since biopharmaceuticals may be anticipated to have relatively long plasma half-lives. For TGN1412, cytokine changes were only evident two hours after TGN1412 administration to macaques, such that TGN1412 should only have been given to a single volunteer at a time and dosing of individual volunteers should have been staggered by at least two hours.
A recent survey suggests that the biotherapeutics market has matured. Such biological products represent around 20% of the marketed therapeutics and around 40% of drugs in the developmental pipeline.6,7 In light of this, one can only hope that the failed TGN1412 phase I trial acts as the trigger for the development of state-of-the-art guidance documents for testing humanised medicines.
1. Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 2004;3(8):711-5.
2. Expert Group on Phase One Clinical Trials. Final report. London: HMSO; 2006. Available from:
3. EMEA Committee for Medicinal Products for Human Use. Draft guideline on requirements for first-in-man clinical trials for potential high risk medicinal products. EMEA CHMP/SWP/28367/2007. London: EMEA; 2007. Available from: http://www.emea.europa.eu/pdfs/human/swp/2836707en.pdf
4. Early Stage Clinical Trial Taskforce. Joint ABPI/BIA report. London: ABPI; 2006. Available from: http://www.abpi.org.uk/information/pdfs/BIAABPI_taskforce2.pdf
5. Food and Drug Administration. Guidance for industry on estimating the maximum safe dose in initial clinical trials for therapeutics in adult healthy volunteers. Rockville MD: FDA; 2005. Available from: www.fda.gov/cder/guidance/guidance.htm
6. Lawrence S. Biotech drug market steadily expands. Nature Biotechnol 2005;23:1466.
7. Overington JP, et al. How many drug targets are there? Nat Rev Drug Discov 2006;5(12):993-6.