The adage “begin with the end in mind” is particularly appropriate for pre-clinical development, as the resulting IND must support the planned clinical trial design. Pre-clinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Pre-clinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design.²  Pre-clinical studies involve defining safety characteristics, pre-formulation studies, drug product evaluation, CMC planning, and clinical trial design.

Define safety characteristics

Industry experts cite the most important element of the pre-clinical process is selecting the best new molecular entities to enter into the clinical trials and to limit failure in full development. Thus, the priority during the preclinical selection process lies in the safety and efficacy testing of a new molecular entity.

According to Regulatory Professionals consultants, the first step in evaluating a new chemical entity (NCE) or new molecular entity is conducting in vitro and in vivo preclinical studies that define relevant safety characteristics.³

These include:

• Safety pharmacology studies to assess how the drug affects the respiratory, cardiovascular, and central nervous systems, among others
• Pharmacodynamics studies to establish the drug’s mechanism of action and contribute to dose selection for clinical studies
• Toxicology studies to determine much drug can be safely administered and how frequently, including the maximum tolerated dose; the no-observed-adverse-effect level, which determines the first-in-human dosage; and whether repeat doses are toxic
• Pharmacokinetics assays to characterize how the drug is absorbed, distributed, metabolized, and excreted

Pre-formulation Studies
Life science leaders describe pre-formulation studies as the process of “learning before doing.” These laboratory studies determine the characteristics of an active pharmaceutical ingredient (API) and excipients that may influence formulation and process design and performance.

These studies include:

• Solubility
• API Stability
• pH Stability
• Physicochemical properties of the API
• Excipient Compatibility
• Component Compatibility (for generics not NCEs)
• Particle Size Testing

Drug Product Evaluations

During pre-clinical drug development, the drug’s toxic and pharmacological effects need to be evaluated through in vitro and in vivo laboratory animal testing. The Food and Drug Administration (FDA) requires sponsoring companies to develop a pharmacological profile, determine toxicity in at least two species of animals and conduct short-term toxicity studies.4 The following steps will be taken during drug production evaluation:

• Solubility studies for improving dissolution, bioavailability and concentration of API in toxicology dosage form;
• Preparation of simple concentrated dosage forms for animal toxicology dose ranging studies (API in bottle, powder in bottle, solutions, suspensions);
• IND enabling pre-clinical dosage form development-minimizing API use;
• Phase-appropriate method development/verification for formulated drug product;
• Formulation and prototype screening and testing;
• Stability of formulation/dosage form;
• Lyophilization cycle development/optimization if needed
• Cleaning method development/validation.

Clinical Trial Design

Clinical trial design is the final step of the pre-clinical phase. Scientists determine the appropriate amount of the drug to achieve both safety and efficacy through microdose, single ascending dose, or multiple ascending dose trials. For randomized trials, decisions must be made on the type of blinding. Will the new entity be tested against an approved comparator or placebo? Supplemental safety studies may also be required at one or more phases.³

When the trial design has been finalized, an investigational new drug (IND) or analogous clinical trial application, must be filed with the FDA, the European Medicines Agency, and/or the regulatory bodies of any other countries where you are planning to conduct the study. This application requests authorization to administer the biopharmaceutical to humans. Requesting a pre-IND meeting with the agency prior to submission may be useful for resolving questions, addressing concerns, and preventing surprises right before your trial is set to start. The FDA requires a briefing package with relevant materials and data at least a month before a requested meeting.³