| The FDA has produced some draft guidance aimed | | | | considered essential to support clinical use of an |
| at establishing an internationally accepted objectives | | | | anticancer pharmaceutical. To support Phase I clinical |
| and / or recommendations on the design and conduct | | | | trials at least one nonclinical study should incorporate |
| of nonclinical studies to support the development of | | | | a recovery period at the end of the study to assess |
| anticancer pharmaceuticals in patients with advanced | | | | for reversibility of toxicity findings or the potential |
| disease and limited therapeutic options. | | | | that toxicity continues to progress after cessation of |
| Because malignant tumors are life-threatening, the | | | | drug treatment. Toxicokinetic evaluation should be |
| death rate from these diseases is high, and existing | | | | conducted as appropriate. |
| therapies have limited effectiveness, it is desired to | | | | Reproduction Toxicology - These studies are not |
| provide new effective anticancer drugs to patients | | | | considered essential to support clinical trials intended |
| more expeditiously. Nonclinical evaluations are | | | | for the treatment of patients with late stage or |
| intended to 1) identify the pharmacological properties | | | | advanced cancer. These studies are also not |
| of a pharmaceutical, 2) establish a safe initial dose | | | | considered essential for pharmaceuticals which target |
| and 3) understand the toxicological profile. | | | | rapidly dividing cells in general toxicity studies or |
| These new guidelines only apply to pharmaceuticals | | | | belong to a class which has been well characterized in |
| intended to treat cancer in patients with late stage or | | | | causing developmental toxicity. Generally no fertility |
| advanced disease regardless of the route of | | | | study is warranted to support the treatment of |
| administration, including both small molecule and | | | | patients with late stage or advanced cancer. A peri- |
| biotechnology-derived pharmaceuticals. | | | | and postnatal toxicology study is generally not |
| Studies to support nonclinical evaluation | | | | warranted to support the treatment of patients with |
| Pharmacology - prior to phase I studies, preliminary | | | | late stage or advanced cancer. |
| characterization of the mechanism(s) of action, | | | | Genotoxicity - Genotoxicity studies are not |
| resistance, and schedule dependencies as well as | | | | considered essential to support clinical trials for |
| anti-tumour activity should have been made. | | | | therapeutics intended to treat patients with late |
| appropriate models should be selected based on the | | | | stage or advanced cancer. |
| target and mechanism of action but need not be | | | | Immunotoxcity - For anticancer pharmaceuticals the |
| studied using the same tumour types intended for | | | | design components of the general toxicology studies |
| clinical evaluation. these studies can provide proof of | | | | are considered sufficient to evaluate immunotoxic |
| principle, guide schedules and dose escalation | | | | potential and support marketing. |
| schemes, provide information for selected test | | | | The guidelines go on to describe how you can use |
| species, and aid starting dose selection. | | | | the pre-clinical data in designing you clinical trial: start |
| Safety Pharmacology - as assessment of vital organ | | | | dose for first administration in man, dose escalation |
| function should be available before initiation of clinical | | | | and the highest dose in clinical trials. the guidelines also |
| studies. Stand alone safety pharmacology studies | | | | provide guidance on duration and schedule of |
| need not be conducted to support studies in | | | | toxicology studies to support initial clinical trials, the |
| pateiutne with late stage cancer or advanced disease. | | | | duration of toxicology studies to support continued |
| Pharmacokinetics - the evaluation of limited kinetic | | | | clinical development and marketing, how to manage |
| parameters, e.g. peak plasma levels, AUC and half life | | | | combination pharmaceuticals and Finlay the non clinical |
| in the animal species used for non-clinical studies can | | | | studies to support trials in pediatric populations. Other |
| facilitate dose escalation during phase I. | | | | considerations addressed in the guidelines include |
| General Toxicology - The primary objective of Phase | | | | conjugated agents, liposomal products, evaluation of |
| I clinical trials in patients with cancer is to assess the | | | | drug metabolites, and evaluation of impurities. |
| safety of the pharmaceutical. This can include dosing | | | | Table - Example schedules for anticancer |
| to a maximum tolerated dose (MTD) and dose limiting | | | | pharmaceuticals to support initial clinical trials. |
| toxicity (DLT). Therefore, determination of a no | | | | (reproduced from FDA guidelines S9) |
| observed adverse effect level (NOAEL) or no effect | | | | If you would like more detail in this area please get in |
| level (NOEL) in the toxicology studies is not | | | | touch with Damien Bové damien. |