On 1 April 2018, a new Guideline on the evaluation of anticancer medicinal products in man by the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) is coming into effect. This guideline replaces EMA/CHMP/205/95 Rev 4, Guideline on the evaluation of anticancer medicinal products in man. In the Executive summary, it’s stated that the purpose of this guideline is to provide guidance on all stages of clinical drug development for the treatment of malignancies, including drug resistance modifiers or normal tissue protective compounds. Supportive measures such as anti-emetics and haematopoietic growth factors, however, are covered by separate guidelines.
Alongside conventional aims such as defining the proper dose(s) and schedule(s), the importance of identifying a target population with optimised benefit risk is emphasised in Section 6 entitled Exploratory Studies. Guidance is also provided on combination studies. Combinations of drugs with minimal activity as monotherapy, but synergistic effects when combined, as well as combinations of conventional cytotoxics, are also discussed.
Convincingly demonstrated favourable effects on overall survival (OS) are from both a clinical and methodological perspective the most persuasive outcome of a clinical trial. Prolonged progression-free or disease-free survival (PFS/DFS), however, are in most cases as such considered relevant measures of patients benefit, but the magnitude of the treatment effect should be sufficiently large to outbalance toxicity and tolerability problems. In order to capture possible negative effects on the activity of next-line therapies and also treatment related fatalities, informative data on OS compatible with a trend towards favourable outcome are normally expected at time of submission. This has consequences with respect to interim analyses, other than for futility, and cross-over, which thus should be undertaken only when available survival data provide the information needed for a proper evaluation of benefit/risk.
An assessment of benefit/risk should encompass all relevant data on efficacy and safety, also taking into account uncertainties as well as external data of relevance in relation to the experimental compound and the disease to be treated. Therefore, no precise definition of “trend towards favourable effects on survival” or “reasonably excluding negative effects on OS” is given in this document. If a major increase in toxicity is foreseeable (section 7), it is recommended that confirmatory studies are undertaken with the aim to show an OS benefit. It is also acknowledged that improved safety without loss in efficacy may constitute tangible aims and the design of non-inferiority efficacy studies are discussed in 7.6.4.
The requirements of the characterisation of the safety profile have changed with the emergence of molecularly targeted agents, immunomodulating drugs and other non-cytotoxic agents. These types of agents may have other types of toxicity and are often dosed differently compared to conventional chemotherapy. The dose-finding process and concepts such as dose limiting toxicity may therefore need to be addressed differently than for standard cytotoxic agents. This is discussed in section 6.2.1. Furthermore, cumulative incidences of adverse events by toxicity grade alone are not sufficient to characterise the toxicity profile. The impact of an adverse drug reaction (ADR) on the benefit-risk balance may for example differ importantly depending on how the incidence, prevalence and severity change with time on treatment, and on the possibility to alleviate the ADR by dose reduction or interruption. This is addressed in section 8.
In section 9, definitions and abbreviations used in this guideline are summarised. Appendix 1 provides methodological guidance on the use of PFS as endpoint in confirmatory studies. Appendix 2 focuses on the use of patient reported outcome measures and health-related quality of life from a regulatory perspective. A revised paediatric guideline is also foreseen as Appendix 3 and Appendix 4 is dedicated to condition-specific guidance.
The text of full Guideline is available here.