Regulatory Rites

Published

May 5, 2025

Regulatory documents are generally filled with walls of text, and much is up for interpretation.

This is why a clear yes/no answer from regulatory agencies are not possible until the final asssessment, when an assessment and interpretation of the totality of evidence has been made.

Good Clinical Practice (GCP)

GCP is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials involving human subjects’ participation. Compliance with this standard provides public assurance that trial subjects’ rights, safety, and well-being are protected, consistent with the principles in the Declaration of Helsinki, and that the clinical trial data are credible.

ICH E6 provides a unified global standard for ethics, data quality, and subject safety. Other ICH guidelines relevant to the conduct of clinical trials are:

  • E2A (clinical safety data management)
  • E3 (clinical study reporting)
  • E7 (geriatric populations)
  • E8 (general considerations for clinical trials)
  • E9 (statistical principles)
  • E11 (pediatric populations)
Table 1: Clinical study abbreviations
Abbreviation Name
ADR Adverse drug reaction
AE Adverse event
CRF Case report form
CRO Contract research organization
IB Investigator’s Brochure
IDCM Independent Data-Monitoring Committee
IEC Independent Ethics Committee
IRB Institutional Review Board
SAE Serious Adverse Event
Table 2: Principles
Principle from ICH E6 Relevance to pharmacometrics
2.4 Adequate prior data Dose‑setting PK modeling must rest on solid non‑clinical & early clinical results.
2.5 Scientific soundness Protocol must pre‑define sampling times, bioanalytical methods, population‑PK or NCA strategy.
2.10 Accurate recording/storage Raw concentration data ⇒ audit‑trails, ALCOA (Attributable‑Legible‑Contemporaneous‑Original‑Accurate).
2.13 Quality systems Risk‑based checks on data pipelines, LIMS, PK analysis scripts.

Take‑home checklist for pharmacometricians

Table 3: Checklist
Task GCP Hook
Build a sampling‑time QC script §5.0 Risk control; §4.9 Source data integrity
Store raw, cleaned, and analysis datasets with hashes §2.10 Data verifiability; §5.5.3 Audit‑trail
Validate NONMEM/R scripts (unit tests) §5.5.3 Computerised‑system validation
Document model decisions in a contemporaneous log §4.9 ALCOA; §5.18 Monitoring evidence
Archive assays, datasets, reports ≥ 2 years post‑marketing §4.9.5 & §5.5.11 Record retention

Submission workflow at the EMA

Finding your way through and assessing pharmacometric modeling in a submission dossier:

  • Cover letter (1.0)
    • Who is the applicant?
  • SmPC, Summary of product characteristics (1.3.1)
    • 5.2 Pharmacokinetics
    • What is the modeling used for? (goals and conclusions)
      • PK-bridging, dose selection, parameters in the SmPC?
    • What is the impact of modeling?
      • Low: Descriptive only
      • Medium: Supports clinical evidence
      • High: Replacing clinical evidence
  • Clinical overview (2.5)
  • Summary of clinical pharmacology studies (2.7.2)
  • popPK study reports (5.3.3.5)
    • Focus on the data and the model results, not so much the methods
    • What does the structural model look like?
    • Are the parameter estimates and associated RSE’s reasonable?
    • Is the graphical evaluation (focus on VPCs) reasonable?
    • Is the covariate evaluation reasonable?
  • Finally, does you conclusion align with the one in the dossier?

SmPC, Summary of product characteristics

The SmPC is a legal document approved as part of the marketing authorisation of each medicine. It is the basis of information for healthcare professional on how to use the medicine. Its information is updated throughout the life-cycle of the product as new data emerge.

Information is presented according to a predefined structure:

    1. Name of the medicinal product
    1. Qualitative and quantitative composition
    1. Pharmaceutical form
    1. Clinical particulars
    • 4.1 Therapeutic indications
    • Defines the target disease and the population to benefit from the medicine.
    • 4.2 Posology and method of administration
      • Specifies the dose for each indication(s) and each relevant subpopulation (e.g. depending on age, concomitant disease):
        • With information on frequency of intake, influence of food, duration of treatment,
        • Advice on dose adjustment (e.g. to optimise the benefits according to patient’s response or to limit the risk e.g. in relation to drug interactions),
        • Additional information on dosing as necessary (e.g. need for dose titration or tapering off, maximum recommended dose, action to be taken if an intake is missed)
      • Also informs on the method of administration, which information can be complemented with special instructions for handling the medicine in section 6.6.
      • Possible dose adjustments due to e.g. hepatic/renal impairment or concomitant diseases
    • 4.3 Contraindications
    • 4.4 Special warnings and precautions for use
    • 4.5 Interactions with other medicinal procucts and other forms of interaction
    • 4.6 Fertility, pregnancy and lactation
    • 4.7 Effects on ability to drive and use machines
    • 4.8 Undesirable effects
    • 4.9 Overdose
    1. Pharmacological properties
    • 5.1 Pharmacodynamic properties
      • Summarises the benefits of the medicine in presenting:
        • Its mechanism of action
        • The main results of the clinical trials supporting the marketing authorisation
          • In giving the main characteristics of the patient population studied
          • And presenting the effects qualitatively and quantitatively
        • Additional clinically relevant information in special populations:
          • In a balanced way (i.e., informing on uncertainties as appropriate)
          • Including study results in the paediatric population, even if the product is not (yet) indicated, to improve the information available on the use of medicine in the various paediatric populations
    • 5.2 Pharmacokinetic properties
      • Desciptive information on general PK
      • Differences in PK due to e.g. hepatic/renal impairment or concomitant diseases
    • 5.3 Preclinical safety data
    1. Pharmaceutical particulars
    • 6.1 List of excipients
    • 6.2 Incompatibilities
    • 6.3 Shelf life
    • 6.4 Special precautions for storage
    • 6.5 Nature and contents of container
    • 6.6 Special precautions for cisposal and other handling of the product

Certain information is suitable in different sections but cross-references are made to avoid repetitive information.

References