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The principles of safety evaluation of medicinal drugs

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Step 1: Discovery and Development

Drug discovery and development pipeline is a long and complex process. The initial research is starting with the identification of a target of disease, which may require further validation. Once a target has been chosen an intensive search ensues to find a drug-like small molecule or biological therapeutic, which marks a transition to the drug discovery and development phase. These R&D phase may include high throughput screening or knowledge-based screening approaches for hit identification, where in silico, in vitro and in vivo models can be used. The development phase begins when the most promising compounds are determined, and considers aspects related to the effectivity and safety, including dosage amount of a drug should be, how effective it is, and potential side-effects etc.

Step 2: Non-clinical Research

Non-clinical studies are conducted using different protocols including animal studies, which mostly follow the Good Laboratory Practice (GLP) regulations. During the early pre-clinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics), absorption, distribution, metabolism and elimination (ADME) and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. These preliminary studies generally do not need to comply with GLP regulations. These studies aim at investigating the drug safety to obtain the first information about its tolerability in different systems that are relevant for further decisions. There are, however, other studies that should be performed according to GLP standards and are mandatory for the safe exposure to humans, such as repeated dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted before the Investigational New Drug (IND) application. The package of non-clinical studies should cover all information needed for the safe transposition of drugs from animals to humans, generally based on the non-observed adverse effect level (NOAEL) obtained from general toxicity studies. After IND approval, other GLP experiments for the evaluation of chronic toxicity, reproductive and developmental toxicity, carcinogenicity and genotoxicity, are carried out during the clinical phase of development. However, the necessity of performing such studies depends on the new drug clinical application purpose (reference).

Step 3: Clinical Research

Clinical research refers to studies, that are done in people. As the developers design the clinical study, they will consider what they want to accomplish for each of the different Clinical Research Phases and begin the Investigational New Drug Process (IND), a process they must go through before clinical research begins. Researchers design clinical trials to answer specific research questions related to a medical product. These trials follow a specific study plan, called a protocol, that is developed by the researcher or manufacturer. Before beginning clinical research drug developers must submit an Investigational New Drug (IND) application including animal study data and toxicity data, manufacturing information, clinical protocols (study plans) for studies to be conducted, data from any prior human research, information about the investigator. Clinical trials follow a typical series from early, small-scale, Phase 1 studies to late-stage, large scale, Phase 3 studies (reference). 

Step 4: FDA Review

The FDA review team has 30 days to review the original IND submission with further approval to begin clinical trials or clinical hold to delay or stop the investigation. This process continues until the developer decides to end clinical trials or files a marketing application. Before filing a marketing application, a developer must have adequate data from two large, controlled clinical trials (reference).

Step 5: Post-Market Safety Monitoring

Even though clinical trials provide important information on a drug’s efficacy and safety, it is impossible to have complete information about the safety of a drug at the time of approval. Despite the rigorous steps in the process of drug development, limitations exist. Therefore, the true picture of a product’s safety actually evolves over the months and even years that make up a product’s lifetime in the marketplace. FDA reviews reports of problems with prescription and over-the-counter drugs, and can decide to add cautions to the dosage or usage information, as well as other measures for more serious issues (reference).

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