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Term of the Day

Natural history study

A natural history study is a preplanned observational study intended to track the course of a disease over time, identifying demographic, genetic, environmental and other variables that correlate with its development and outcomes in the absence of intervention, or under standard of care. Designs may be retrospective (chart review of existing records) or prospective (longitudinal follow-up of a cohort or registry).

Natural history data is particularly important in rare and paediatric diseases, where randomised placebo-controlled trials may be infeasible or unethical. The FDA (guidance on rare disease natural history studies, 2019) and the EMA accept well-designed natural history studies to define endpoints and biomarkers, identify patient subgroups, estimate sample sizes and, in some cases, serve as external or historical control arms for single-arm trials supporting orphan products.

Because they are non-interventional, natural history studies fall outside the CTR and are governed by national law (for example France's MR-003 or MR-004 reference methodologies) and by the GDPR. They typically involve secondary use of medical records, long-term follow-up, genetic data and small populations in which anonymisation is rarely achievable, so pseudonymisation, a DPIA and a robust research legal basis under Art. 9(2)(j) are essential. Registries maintained by patient organisations or academic consortia raise additional questions of joint controllership and data access governance.

P

Pharmacokinetics (PK)

Pharmacokinetics (PK) is the study of how a drug moves through the body over time: its absorption from the site of administration, distribution into tissues and fluids, metabolism (mainly hepatic, through enzymes such as the cytochrome P450 family) and excretion (mainly renal and biliary), collectively known as ADME. Key parameters include bioavailability, maximum concentration (Cmax), time to maximum concentration (Tmax), area under the concentration-time curve (AUC), half-life, clearance and volume of distribution. Pharmacokinetics is paired with pharmacodynamics, the study of the drug's effect, in PK/PD modelling.

PK studies are central to Phase I and to the clinical pharmacology package of a marketing application: first-in-human dose escalation, food-effect, drug-drug interaction, renal and hepatic impairment, bioequivalence for generics and biosimilars, and paediatric extrapolation all rest on PK data. Sparse sampling in later phases is analysed using population PK methods, and regulators accept model-informed approaches under ICH M15 and EMA/FDA guidance.

PK datasets consist of timed drug concentrations for each subject, linked to dosing records, demographics, body weight, organ function and often pharmacogenomic genotypes. They are pseudonymised health data processed by bioanalytical laboratories and pharmacometrics vendors acting as processors, frequently located outside the EEA. Sample shipment, residual sample retention and any future exploratory assays should be covered in the informed consent form, the DPIA and the relevant data processing agreements.

How is pharmacokinetics different from pharmacodynamics?

Pharmacokinetics describes how the body handles a drug over time, including absorption, distribution, metabolism and elimination. Pharmacodynamics concerns the drug’s effects on the body. In a study, distinguish concentration measurements from response measurements so that sampling times, endpoints and the analysis address the intended PK or PD question.