Masterstudiengang "Drug Regulatory Affairs"


Nonclinical and Clinical Requirements for the Development of an Anticancer Drug Intended for Treatment of Advanced or Late-Stage Disease - The European Perspective ***

Dr. Birgitta Sauer (Abschlußjahr: 2009)

Language: English
Malignant tumours represent seriously life-threatening disorders. Tumour progression and its prognosis are strongly dependent on the type of neoplastic disease and the time point of diagnosis. Often, the tumour is diagnosed when the lesion is in an advanced stage of malignancy or had proceeded to metastatic disease. Prognosis then is very poor; surgery or irradiation, respectively are no options and cure is not achievable any more. The only possibility left is a treatment applying cytotoxic or cytostatic drugs with the aim to stabilise the disease and to prolong survival at increased quality of life.

Even if diagnosed and treated early, tumours often progress to an advanced stage or become metastatic and spread to the body. Typically, the patient undergoes multiple treatments until no further treatment option is left, which is largely due to drug resistance. Despite much progress in understanding the molecular factors underlying cancer development, to date most drugs which have been approved for treatment of advanced or late-stage solid tumours, have limited effectiveness. Overall, there remains a high medical need for novel effective late-stage anticancer drugs providing alternative therapeutic options. Such products need to be made available more rapidly since only a narrow time span is left for medical intervention.

Drug development encompasses three major steps: chemical-pharmaceutical, nonclinical and clinical research. The nonclinical evaluation should demonstrate drug safety and efficacy and aims to protect clinical trial subjects from possible adverse effects. The clinical programme generates data in man about adequate dosing regimen, administration route and potential side effects of the drug. For marketing of a novel late-stage anticancer product in the EU, its safety and efficacy need to be studied in line with Regulation (EC) 726/2004 and in consistency with cancer-specific international ICH and European guidelines. Currently, guidance for development of anticancer drugs does not consider the grade of tumour malignancy. Regarding severity and life-threatening nature of late-stage cancer, a higher risk would be acceptable in favour of a life-prolonging benefit compared to a type of cancer where cure is possible. A specific development strategy for a late-stage anticancer drug regarding the European regulatory requirements is evaluated in this thesis.

Nonclinical evaluation of a late-stage drug could be significantly facilitated by: (1) Evaluation of acute toxic drug effects, safety pharmacology and immunotoxicity parameters within repeat-dose toxicity studies instead of stand-alone studies. (2) Shortening of toxicity studies from 6 months, actually requested in Europe to support treatment until progression in phase III trials and for marketing of an anticancer drug, to 3 months. This should suffice justified by limited life expectancy of late-stage patients and an ethically acceptable higher risk. (3) Minor impact to demonstrate NOAEL/NOEL levels in toxicology studies in order to support clinical use of such drugs. This is arguable since MTD/DLT is assessed as primary objective in clinical phase I/II trials. Beside others these measures may accelerate nonclinical development and allow earlier entry into clinical trials at acceptable safety evaluation.

For clinical programmes, the conduct of a single well-designed pivotal trial beside phase I/II and supportive phase II data is regarded to suffice for successful approval of a late-stage drug. OS and/or PFS, however, must be statistically significantly increased and a clear clinical benefit compared to current standard of care must be demonstrated. OS as the most reliable primary endpoint in combination with PFS as secondary endpoint should be favoured for the pivotal study. Useful information e.g. for pivotal study design (adequate comparator, endpoints, patient numbers, etc.) can be derived from published EPARs and CHMP discussions of centrally approved late-stage anticancer drugs. These documents are reflecting current regulatory views and expectations of the CHMP for successful drug development and centralised approval. Since consolidated guidance is missing scientific advice should be requested, especially for clinical development issues and in case of an orphan tumour indication.

Late-stage anticancer drugs need to be approved by the centralised procedure. Beside the regular procedure, other approval options (accelerated assessment, authorisation under exceptional circumstances or conditional marketing authorisation) should be considered. They may be opportune for faster approval of the drug and clinical practise.

It would be desirable that consolidated guidance for nonclinical and clinical development of anticancer drugs intended to treat advanced or late-stage cancer would be available at international level. This would ensure consistency and accelerate development.

Pages: 99
Annexes: 4, pages: 5