The FDA has produced some draft guidance aimed at establishing an internationally accepted objectives and / or recommendations on the design and conduct of nonclinical studies to support the development of anticancer pharmaceuticals in patients with advanced disease and limited therapeutic options.

Because malignant tumours are life-threatening, the death rate from these diseases is high, and existing therapies have limited effectiveness, it is desired to provide new effective anticancer drugs to patients more expeditiously. Nonclinical evaluations are intended to 1)identify the pharmacological properties of a pharmaceutical, 2) establish a safe initial dose and 3) understand the toxicological profile.

These new guidlines only apply to pharmaceuticals intended to treat cancer in patients with late stage or advanced disease regardless of the route of administration, including both small molecule and biotechnology-derived pharmaceuticals.

Studies to support nonclinical evaluation

Pharmacology – prior to phase I studies, preliminary characterization of the mechanism(s) of action, resistance, and schedule dependencies as well as anti-tumour activity should have been made. appropriate models should be selected based on the target and mechanism of action but need not be studied using the same tumour types intended for clinical evaluation. these studies can provide proof of principle, guide schedules and dose escalation schemes, provide information for selected test species, and aid starting dose selection.

Safety Pharmacology – as assessment of vital organ function should be available before initiation of clinical studies. Stand alone safety pharmacology studies need not be conducted to support studies in pateiutne with late stage cancer or advanced disease.

Pharmacokinetics – the evaluation of limited kinetic parameters, e.g. peak plasma levels, AUC and half life in the animal species used for non-clinical studies can facilitate dose escalation during phase I.

General Toxicology – The primary objective of Phase I clinical trials in patients with cancer is to assess the safety of the pharmaceutical. This can include dosing to a maximum tolerated dose (MTD) and dose limiting toxicity (DLT). Therefore, determination of a no observed adverse effect level (NOAEL) or no effect level (NOEL) in the toxicology studies is not considered essential to support clinical use of an anticancer pharmaceutical. To support Phase I clinical trials at least one nonclinical study should incorporate a recovery period at the end of the study to assess for reversibility of toxicity findings or the potential that toxicity continues to progress after cessation of drug treatment. Toxicokinetic evaluation should be conducted as appropriate.

Reproduction Toxicology – These studies are not considered essential to support clinical trials intended for the treatment of patients with late stage or advanced cancer. These studies are also not considered essential for pharmaceuticals which target rapidly dividing cells in general toxicity studies or belong to a class which has been well characterized in causing developmental toxicity. Generally no fertility study is warranted to support the treatment of patients with late stage or advanced cancer. A peri- and postnatal toxicology study is generally not warranted to support the treatment of patients with late stage or advanced cancer.

Genotoxicity – Genotoxicity studies are not considered essential to support clinical trials for therapeutics intended to treat patients with late stage or advanced cancer.

Immunotoxcity – For anticancer pharmaceuticals the design components of the general toxicology studies are considered sufficient to evaluate immunotoxic potential and support marketing.

The guidelines go on to describe how you can use the pre-clinical data in designing you clinical trial: start dose for first administration in man, dose escalation and the highest dose in clinical trials. the guidelines also provide guidance on duration and schedule of toxicology studies to support initial clinical trials, the duration of toxicology studies to support continued clinical development and marketing, how to manage combination pharmaceuticals and Finlay the non clinical studies to support trials in pediatric populations. Other considerations addressed in the guidelines include conjugated agents, liposomal products, evaluation of drug metabolites, and evaluation of impurities.

Table – Example schedules for anticancer pharmaceuticals to support initial clinical trials. (reproduced from FDA guidelines S9)

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch