The MHRA Review and Clinical Trials in Cancer

James McBlane, Preclinical Assessor in the Clinical Trials Unit, Medicines & Healthcare products Regulatory Agency (MHRA), joins Pharma IQ to discuss clinical trials in patients with advanced cancer, ahead of the 2nd Annual Optimising Clinical Development in Oncology conference, taking place the 15th - 16th March, 2011, ETC Venues, London, UK.

Pharma IQ: Please can you give an overview of ICHS9 guidance and how it is applied in the UK?

J McBlane: ICHS9 is a document agreed between regulators in Europe, Japan and the US which addresses the studies needed to support the development of anti-cancer drugs inpatients with cancer whose disease is advanced disease and who have limited therapeutic options. It is a statement of what data are needed in order to conduct trials in this patient group. I emphasise this patient group because medicines under development which have not been fully characterised as to their safety or efficacy may be the only chance these patients have for some therapeutic benefit. At the same time, development needs to be appropriately cautious to make sure that as much as can reasonably be done to protect patients from adverse events is done. By refining the amount and nature of preclinical data needed prior to conducting such trials, ICHS9 should make it easier to get such trials underway. Implementation in the UK should not be different to that in other countries, but I’d hope to give a feel for how we at the MHRA approach the assessment of applications for trials like this.

Pharma IQ: What preclinical data are essential to support initial clinical exposure?

J McBlane: We are focused primarily on safety – provided the applicant establishes the reasons for believing the clinical trial protocol should be safe, then we can approve the trial. Of course, we also need to understand the potential benefits too, as safety needs to be considered in the context of the potential for benefit. As regards the preclinical data needed, we need to understand the basic mechanism of action and how the anti-tumour effect is brought about and we must have evidence supporting the specific proposed dosing regime – schedule dependency – for instance, what evidence is there to support daily dosing versus a dosing strategy that includes a break from dosing? If combination treatment is proposed, it needs to be understood as to why the combination is reasonable to try – two different mechanisms for instance. For safety pharmacology, that is, assessment of possible adverse effects to vital systems – the heart, lungs and brain – these studies can be dropped if general toxicity data indicate no particular reasons for concern, whereas in conventional development, this would likely not be the case. Limited kinetic data are needed – basic exposure data and estimates for half life may be all that is needed to start clinical trials. And, in general toxicity testing, it is not appropriate to define no effect level doses (NOEL) – as these drugs act by killing cells, they will likely have toxicity at active doses.  

Pharma IQ: What is different regarding the approach to trials in patients with advanced cancer?

J McBlane: There are many differences, but perhaps the most stark is the approach for selecting the first dose and related issues like achieving therapeutic benefit and accepting some degree of toxicity in patients. In conventional developments, we are keen to see doses for first human dosing that have no activity – because these should be safe. Cautious dose escalation then follows until some degree of activity or minor toxicity is evident. These studies are usually short term, usually in healthy subjects who do not personally derive any medical benefit. In contrast, studies in advanced cancer patients may need to offer possible therapeutic benefit to that individual and this could be life-extending, and if a patient responds, they may keep taking the drug for as long as they derive overall benefit. This means getting to an active dose very quickly –it is not straightforward to estimate this accurately before there is human dosing. To gain the possible benefit, some degree of toxicity would be quite acceptable for this patient population, whereas this would not be true in conventional developments. And, in this regard, whereas for a conventional development, we would be reluctant to let human exposure exceed that in animals, for advanced cancer patients, the highest clinical dose need not be limited by this.

Pharma IQ: Can you give some examples, based on MHRA experience?

J McBlane: You know, when you give a talk like this, the audience is always very keen to hear other people’s experiences, yet there is an equal degree of reticence in the other direction – of offering one’s own experience as an example. So, I will be giving some examples, but these have to be altered to ensure they can’t be identified. The point to convey may not really be what specifically happened with this particular drug, but rather to say that this approach is acceptable; it has worked for this drug; and if it is suitable for your drug, do consider it.

Pharma IQ: What do you think will be the key discussion points to come out of the conference and what do you hope to gain personally from taking part?

J McBlane: On the latter point, I hope that the audience will appreciate more the perspective that staff at MHRA have when looking at their applications and in particular that there is flexibility, but still clarity, within the scope of ICH S9. We are keen for these trials to be conducted in the UK, so hopefully, the MHRA review should not be seen as too much of a hurdle. From the wider perspective, taking time to plan a development programme in some detail at the beginning is really worth doing.

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