Preclinical toxicity studies, completion

By the time Phase III testing is completed, some additional preclinical safety tests must also generally be in hand. These include the three separate reproductive and developmental toxicity studies (Segments I and III in the rat, and Segment II in the rat and rabbit) and carcinogenicity studies in both rats and mice (unless the period of therapeutic usage is intended to be very short). Some assessment of genetic toxicity will also be expected. 

The MTD was 27.3 mg/m2, with the principal DLT being neutropenia (four of 14 patients experienced Grade 4 toxicity), which was consistent with preclinical toxicology studies. The other principal toxicides consisted of mild-to-moderate transaminitis, alopecia, fatigue, and nausea. One patient with melanoma metastatic to liver and bone who was treated at 15.4 mg/m2 experienced a complete response and received 20 courses of tasidotin. Two other patients with melanoma had mixed responses of cutaneous metastases at 27.3 mg/m2 per day associated with either stable or progressive visceral disease. In addition, nine patients with various other malignancies had stable disease. 

Once preclinical toxicology studies have been completed, an application is submitted to the FDA for approval to perform clinical trials for efficacy and toxicity in human subjects. Finally, if efficacy and toxicology warrant it, another application is submitted to the FDA for drug marketing approval. As we can see from the brief description, the pharmacologist plays a pivotal role in every aspect of the drug discovery and development process. A thorough discussion of this process can be found in Chapter 15 of this textbook. 

It is therefore essential that before pivotal (repeat dose) preclinical studies are initiated, bioanalytical assay development must be completed. This has to cover potential test species, normal and diseased humans. The assays must be validated in the sampling matrix of the toxicity test species, and one should also develop suitable assays for antibodies to the test article. 

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