Phases of Clinical Trials in Drug Development

Phases of Clinical Trials in Drug Development

1. Definition & overview

• A clinical trial is a prospective, ethically designed investigation in human subjects to objectively discover, verify or compare the results of two or more therapeutic measures (KDT 8e Ch.5, pp.83–4).
• Clinical trials acquire information about the pharmacokinetic and pharmacodynamic properties of a candidate drug in humans and establish its efficacy and safety before marketing (G&G 14e Ch.1, pp.14–15).
• Human drug evaluation is conventionally divided into four temporal phases (Phase I → IV), sequenced so that results of earlier studies inform decisions about later ones — "the basis for rational drug development is to ask and answer important questions with appropriate studies in a sequence" (MethodsCT Ch.58, p.700; KDT 8e Ch.5, p.90).
• The four phases are divisions of convenience in a single continuously expanding process: it begins with a few closely observed subjects in a laboratory setting, proceeds through hundreds of patients, to thousands, before a national/international regulatory authority agrees the drug is a medicine (Bennett & Brown 11e Ch.4, pp.41–2).
• Phases I–III are pre-marketing (establish safety + efficacy → support the marketing application); Phase IV is post-marketing (surveillance + additional data gathering after approval) (G&G 14e Ch.1, p.14; NDCT Rules 2019, 2nd Sch. p.86).
• The phased structure embodies a risk-minimisation logic: initially few subjects receive the drug under close supervision; later, larger numbers are treated with only relevant monitoring (KDT 8e Ch.5, p.90).
• Attrition is steep at each successive stage: of ~5,000–10,000 screened compounds, ~250 enter preclinical testing, ~5 enter clinical trials, and only ~1 is ultimately approved (Bennett & Brown 11e Ch.4, Fig.4.1, p.41; G&G 14e Ch.1, Fig.1–6, p.15).
• Overall timeline from synthesis to approval is ~10–15 years; estimated cost to bring one new molecular entity (NME) from laboratory to FDA approval is US $1–4 billion (G&G 14e Ch.1, Table 1–1, p.14; KDT 8e Ch.5, p.88).

Position of the phases within new-drug development (KDT 8e Ch.5, p.90; G&G 14e Ch.1, pp.13–14)

• Synthesis / isolation of the compound (1–2 years).
• Preclinical studies — screening, pharmacological evaluation, pharmacokinetics, acute/subacute/chronic toxicity, mutagenicity, carcinogenicity, reproductive/teratogenicity testing in ≥2 species (one rodent + one non-rodent), under Good Laboratory Practice (GLP) (2–4 years) (KDT 8e Ch.5, pp.89–90).
• Investigational New Drug (IND) application — filed before any human administration; the sponsor requests permission to give the drug to humans, supplying the rationale, preclinical pharmacology/toxicology, chemistry/manufacturing data and the human-study protocol. The FDA has 30 days to review and may approve, ask for more data, or disapprove (G&G 14e Ch.1, p.13).
• Clinical studies — Phase I, II, III (+ long-term animal toxicity in parallel) (3–10 years) (KDT 8e Ch.5, p.90).
• New Drug Application (NDA) / Biologics License Application (BLA) → review and grant of marketing permission (0.5–2 years) (G&G 14e Ch.1, p.14; KDT 8e Ch.5, p.90).
• Phase IV — post-marketing surveillance (continues for the drug's market life) (KDT 8e Ch.5, p.90).