Broadly, the process of drug development can be divided into preclinical and clinical work.
Pre-clinical New chemical entities (NCEs, also known as new molecular entities or NMEs) are compounds that emerge from the process of
drug discovery. These have promising activity against a particular biological target that is important in disease. However, little is known about the safety,
toxicity,
pharmacokinetics, and
metabolism of this NCE in humans. It is the function of drug development to assess all of these parameters prior to human clinical trials. A further major objective of drug development is to recommend the dose and schedule for the first use in a human clinical trial ("
first-in-human" [FIH] or First Human Dose [FHD], previously also known as "first-in-man" [FIM]). In addition, drug development must establish the physicochemical properties of the NCE: its chemical makeup, stability, and solubility. Manufacturers must optimize the process they use to make the chemical so they can scale up from a
medicinal chemist producing milligrams, to manufacturing on the kilogram and
ton scale. They further examine the product for suitability to package as
capsules,
tablets, aerosol, intramuscular injectable, subcutaneous injectable, or
intravenous formulations. Together, these processes are known in preclinical and clinical development as
chemistry, manufacturing, and control (CMC). Many aspects of drug development focus on satisfying the regulatory requirements for a
new drug application. These generally constitute a number of tests designed to determine the major toxicities of a novel compound prior to first use in humans. It is a legal requirement that an assessment of major organ toxicity be performed (effects on the heart and lungs, brain, kidney, liver and digestive system), as well as effects on other parts of the body that might be affected by the drug (e.g., the skin if the new drug is to be delivered on or through the skin). Such preliminary tests are made using
in vitro methods (e.g., with isolated cells), but many tests can only use experimental animals to demonstrate the complex interplay of metabolism and drug exposure on toxicity. However, aside from regulatory requirements, there is a broad range of other factors, such as patient requirements, that are considered during development and testing. The information gathered from this preclinical testing, as well as information on CMC, and submitted to regulatory authorities (in the US, to the
FDA), as an
Investigational New Drug (IND) application. If the IND is approved, development moves to the clinical phase.
Clinical phase Clinical trials involve four steps: • Phase I trials, usually in healthy volunteers, determine safety and dosing. • Phase II trials are used to get an initial reading of efficacy and further explore safety in small numbers of patients having the disease targeted by the NCE. • Phase III trials are large, pivotal trials to determine safety and efficacy in sufficiently large numbers of patients with the targeted disease. If safety and efficacy are adequately proved, clinical testing may stop at this step and the NCE advances to the
new drug application (NDA) stage. • Phase IV trials are post-approval trials that are sometimes a condition attached by the FDA, also called post-market surveillance studies. The process of defining characteristics of the drug does not stop once an NCE is advanced into human clinical trials. In addition to the tests required to move a novel vaccine or antiviral drug into the clinic for the first time, manufacturers must ensure that any long-term or chronic toxicities are well-defined, including effects on systems not previously monitored (fertility, reproduction, immune system, among others). If a vaccine candidate or antiviral compound emerges from these tests with an acceptable toxicity and safety profile, and the manufacturer can further show it has the desired effect in clinical trials, then the NCE portfolio of evidence can be submitted for marketing approval in the various countries where the manufacturer plans to sell it. A study covering clinical research in the 1980–1990s found that only 21.5% of drug candidates that started Phase I trials were eventually approved for marketing. During 2006–2015, the success rate of obtaining approval from Phase I to successful Phase III trials was under 10% on average, and 16% specifically for vaccines. The high failure rates associated with pharmaceutical development are referred to as an "attrition rate", requiring decisions during the early stages of drug development to "kill" projects early to avoid costly failures. == Cost ==