Test Article Considerations
Effects: Sharing as much information as you can with your contract research organization (CRO) about your test article and its known or potential effects is a critical component of the study design process. Have in-depth discussions about the structure, class, intended use, mechanism of action, previous findings, and anything else that may affect the animals exposed to your test article. If there isn’t any existing information about test article-related toxicity, discussions on the pharmacology of the test article can help with understanding possible toxicities that could result from exposure to your test article.
Logistics: Planning ahead in the manufacturing and delivery of your test article is critical to avoiding delays. It is not uncommon for a test article to be manufactured at a contract manufacturing organization (CMO) in a different country, which will require planning for importing/exporting the test article. Most of the delays in importing material are due to requests from Customs officials for specific information on the material being imported. Be sure to investigate the details of the process as it applies to your situation to understand what information is needed and which paperwork is required for the countries involved to prevent unnecessary delays.
Issues can arise during the manufacturing of your test article, leading to delays in availability. Many manufacturing processes have key steps in the synthetic route that can be used to gauge whether the process is on track or delayed. These processes can be used to help mitigate the risk of delaying a study. You should calculate an estimate of the quantity of test article needed for the nonclinical studies prior to the synthesis of the material. This can be a challenge particularly if you do not have much information on your test article and therefore may not be sure what the dose levels will be or even which species might be appropriate for your test article. When calculating the amount of test article needed for the nonclinical studies, be sure to use realistic dose levels, accurate animal body weights, frequency of preparation, inclusion of any correction factors for salt form/purity, as well as an overage to account for the loss of test article during the preparation procedure. While manufacturing costs can be significant, it is advisable to over calculate test article needs rather than under calculate to ensure proper quantities to complete the study.
Formulation: Another common issue involves the formulation being used to deliver the test article to the test system(s). In the early phases of drug development, the assays/studies involved use fairly low levels of test article to determine pharmacology, efficacy, etc. This is in contrast to the nonclinical safety toxicology studies where the doses for small molecules may need to be much higher to adequately explore the toxicity of your test article; sometimes using doses of 1000 mg/kg or higher. When working on your formulation, it is best to explore higher concentrations as a means to determine if there will be issues should you need to dose at these higher concentrations.
Quality: For your clinical trials, you will need GMP material as it ensures the quality and reproducibility of your test article from lot to lot. For nonclinical studies, using GMP material is fine but not required. You could use non-GMP material as long as it is characterized according to the Good Laboratory Practice (GLP) regulations (identity, composition, strength/purity, and stability information) and it should be comparable to the GMP material to be used in the clinical trial. Comparability is based on an evaluation of the characteristics of the material used for the nonclinical studies and that to be used in the clinical trials. There are a series of guidance documents to describe the regulatory expectations for the manufacturing of material to be administered in nonclinical and clinical studies (ICH Q1, Q2, and Q3 guidelines).
Vehicle/Solubility: The ability to formulate a drug so that it can be administered to animals or humans can be taken for granted early in the development process. The vehicle or carrier to be used in the nonclinical studies will depend to a large extent on the chemical properties of the drug, as well as the desired pharmacokinetic profile. The selection of a vehicle should consider factors such as solubility and stability, the dose volume to be used, the route of administration, and tolerability of the vehicle in the nonclinical species to be used.