The process of filling out the application:
- Develop the investigational plan.
An investigational plan is a document created at the start of an investigation that identifies: the goal of an investigation, limitations of the investigation, the potential sources of evidence and information, what evidence is required to reach the goals, what investigational drugs and devices are being used, and all required supplies.
- Preclinical testing.
Preclinical researches consist of animal pharmacology and toxicology studies to find out if a drug, procedure, or treatment is likely to be useful. All preclinical studies take place before any testing in humans is done.
- Manufacturing information
Manufacturing Information includes composition, manufacturer, stability, and the controls used for, manufacturing the drug. Used to ensure that the company can properly produce and supply consistent batches of drugs.
- Investigator information.
The investigator information is a comprehensive compilation of clinical and non-clinical data on the investigational product maintained by the drug developer or investigator that contains the body of information about the investigational product obtained before and during a drug trial.
- Clinical trial protocols.
Clinical trial protocols are the main part of IND. Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose the subjects to unnecessary risks.
Key ind-enabling studies:
The main purpose of the IND-enabling studies is to ensure that the new drug is effective and safe to administer to humans. To understand the safety and effectiveness, the new drug should go through key IND-enabling testing as pharmacology, pharmacokinetics, and toxicology assessments.
Pharmacology
Safety pharmacology studies evaluate how a new drug affects the biological systems of animals (specifically: respiratory, central nervous systems, and cardiovascular systems). The therapeutical effect of a new drug and its relationship to its concentration in body fluids is assessed by pharmacodynamic studies.
Pharmacokinetics (PK)
IND-enabling PK analysis usually includes in vitro metabolism and the drug concentration in plasma assay together with systemic exposure studies to evaluate repeated-dose toxicity. These studies are normally sufficient to initiate human trials. However, additional studies such as characterization of ADME, metabolic profile, and drug-drug interaction are often needed before conducting clinical studies.
Toxicology studies
The IND-enabling toxicology studies are accomplished using appropriate animal models and consist of both single-dose (acute) and repeated-dose toxicity studies. The final goal is to understand the animal model responses to predict the risk for human subjects. The acute toxicity studies are done in two animal species (one is non-rodent) when a drug is administered in a single dose, or in several doses for 24 hours using the clinical and parenteral route. The information obtained from the acute toxicity studies allows for determining a maximum tolerated dose (MTD) and the highest dose for the no-observed-adverse-effect level (NOAEL). These studies provide evidence of the poisoning level of a drug and possible target organs.
Acute toxicity studies are often complemented with repeated-dose toxicity studies. The repeat-dose toxicity study allows long-term assessment of the physiological effect of accumulation of a new drug or its metabolites within the body. The duration of these studies depends on the period of the therapeutic use of a new drug in human clinical trials. Detailed and accurate information about dose levels and dose regimens derived from animal models will maximize the safety in clinical trials.
The potential of an investigational drug to cause any DNA damage directly or indirectly is assessed through genotoxicity studies. The Ames is the most basic test used to determine the mutagenic ability of a new drug and support single-dose clinical studies. Additional cytogenic tests that evaluate chromosomal damage are integrated into repeated dose toxicity studies. Complete genotoxicity testing should be performed before Phase 2 starts.
A complete list of all types of investigations enough to submit the IND application can be pretty extensive. This may also include studies such as reproductive toxicity tests, immunotoxicity, phototoxicity studies, and assessment of the abuse potential of a new drug. However, even then, this is no guarantee that a new drug will prove completely safe in clinical trials. Therefore, long-term studies such as carcinogenicity studies are typically conducted after the initial submission of the IND application.