Safety First

A pharmaceutical plant may seem a long way from the clinic, but everything that happens there is — or should be — guided by considerations of patient safety. In March 2006, six healthy volunteers dosed with the monoclonal antibody TGN1412 at a clinical trials unit at Northwick Park Hospital (London, UK) suffered sudden and extreme adverse reactions — an unprecedented event in a Phase I trial. The resulting headlines did the biotech industry no favours at all, and TeGenero, the German company that manufactured the drug, folded last July.

MHRA accordingly set up an enquiry, which showed that no manufacturing issues were involved in the TGN1412 incident. So this differed from the viral contamination of blood products that infected thousands with HIV or hepatitis C. This scandal led, eventually, to requirements for biologics manufacturers to insert purification steps that assure viral decontamination into their processes; it also started a move away from the use of animal-derived components in manufacturing (a trend accelerated by the BSE crisis). Had some overlooked aspect of manufacture or purification put patients at risk again? No, as it turned out. Instead, the TeGenero problem derived from the novel mode of action of TGN1412, which was designed to 'superactivate' T cells in a way that was hoped would prove useful as a therapy for rheumatoid arthritis and leukaemia. The result in this case, however, was a so-called 'cytokine storm'. I'm no immunology expert, but I'm told this phenomenon is as unpleasant and dangerous as it sounds, involving an uncontrolled release of inflammatory molecules (cytokines) into the bloodstream, which leads to pain, vomiting, burning fever, massive swelling and multiple organ failure.

MHRA's investigation has led to 22 recommendations on what more should be done in the transition from preclinical to clinical for certain biologic drugs. These have now been largely translated into the EMEA Committee on Medicinal Products for Human Use 'Guidelines on requirements for first-in-man clinical trials for potential high-risk medicinal products'. These are intended to provide a common approach across EU Member States for the design and conduct of such trials, although they are not binding. High risk refers to molecules with a novel mode of action, such as TGN1412, and also to those involving novel targets, as well as those for which there is (as yet) no relevant animal model for preclinical work.

It is likely that the biotech industry will produce many more potential drugs in the first two categories; many companies are developing therapies that work on T cells and the Human Genome Project has generated thousands of new targets, many of which are regarded as 'novel'. We have also moved away from the traditional monoclonal antibody towards more novel, engineered molecules. The guidelines mention, for instance, bispecific antibodies and novel fusion proteins as being categories which may be regarded as 'high risk'. In short, the number of 'high risk' molecules in the biotech industry pipeline is sure to increase, with implications for both clinical trials and manufacturing.

Many of the recommendations in the guidelines concern preclinical work and the design of clinical trials with high risk biologics. But manufacturers could also be affected if they are producing these molecules — especially in two of these areas we have touched on here before, namely, characterization and comparability. A high degree of quality characterization is now being called for at an early stage of development. In particular, characterization of product-related variants, including heterogeneity and degradation products, should be performed if these might have an impact on the molecule's pharmacological profile. The guidelines also ask for 'special consideration for the suitability and qualification of methods to sufficiently characterize the active substance and drug product'. More work for the analytical team, in other words.

On comparability, the EMEA recognises how modifications to manufacturing processes can result in subtle changes to molecular structure that are not readily detectable by characterization studies — but may still affect biological properties and, therefore, have clinical consequences. This may lead to a requirement for more preclinical testing to try to prove comparability between batches made by different processes. Yet it is not clear how valid preclinical work actually is for some of these novel biologics; tests in monkeys gave no hint of the problems to come with TGN1412.

The guidelines were published in March after which there has been a two-month consultation period, followed by a stakeholder workshop in June. At the time of writing, it is not clear what kind of agreement will be reached. If they remain as guidelines, then EU Member States will interpret them as they see fit. At a recent conference, Professor Gordon Duff of the University of Sheffield, who chaired the MHRA investigation into the TGN1412, said they were determined not to inhibit biotech innovation. I wonder.

In February, MHRA announced new rules for clinical trial applications involving novel biologics; these must now first be checked by a specialist advisory group. This is likely to slow down entry of such compounds into trials and make the UK less competitive as a place to perform clinical developments. Companies may move this work to other EU Member States, India or the Far East. And there's likely to be a shortage of healthy young volunteers for Phase I — they may think twice before going down this road to earn a bit of extra cash. The impact on manufacturing remains to be seen, but requirements for better characterization and more comparability data are likely to add to timelines and costs. It would be a pity if these constraints put a block on the development and manufacture of what could be important new therapies.

Back to the patients. Prompt action by medical staff at Northwick Park thankfully saved the lives of the six young men affected by TGN1412's cytokine storm. But two have been left with long-term disabilities and all have ongoing damage to their immune systems, which is likely to have consequences to their future health. It is up to biotech companies and the regulatory authorities to make sure that this human tragedy never happens again.