Flow of a BE trial.
The lifecycle is short relative to a Phase 3 (typically 12–24 months from protocol to dossier) but unforgiving: every step must hold under regulator inspection years later.
Flow of a BE trial.
Operational pipeline · protocol → submissionThe lifecycle is short relative to a Phase 3 (typically 12–24 months from protocol to dossier) but unforgiving: every step must hold under regulator inspection years later.
Protocol design & statistical plan.
Study design selection (2×2 crossover, replicate, parallel), sample-size calculation under Schuirmann TOST, washout, fed/fasted scheme. SAP locked before unblinding. Choice anchors the entire submission.
Site qualification & regulator notification.
Phase I unit selection (volunteer recruitment capacity, bioanalytical proximity, inspection history). FDA IND-exempt or ANVISA notification, EU CTR submission via CTIS where applicable. Local ethics committee approval.
Bioanalytical method validation.
ICH M10 full validation: selectivity, accuracy & precision, calibration curve, matrix effect, stability, dilution integrity. Method must be production-ready before first sample.
Healthy volunteer enrolment.
Screening (PE, ECG, labs, drug-of-abuse). Informed consent. ANVISA volunteer registry check (Brazil). Replacement strategy defined if dropouts occur.
Dosing & sample collection.
Period 1 dosing, washout, Period 2 dosing (crossover) or replicate. Dense PK sampling around Cmax; tail sampling to support AUC0–t and lambda-z estimation. Chain of custody from cannula to freezer.
Bioanalytical sample analysis.
LC-MS/MS quantification under validated method. Run acceptance criteria (calibration, QC), incurred sample reanalysis (ISR) on ≥7% of samples. Out-of-trend investigation documented.
PK parameter derivation.
Non-compartmental analysis: Cmax (observed), AUC0–t (linear-up/log-down), AUC∞ (extrapolated), tmax, t½, lambda-z. Outlier handling per pre-specified rules. No post-hoc parameter substitution.
Statistical analysis.
Log-transformed ANOVA with sequence, period, subject(sequence), treatment terms. 90% CI of T/R geometric mean ratio for AUC and Cmax. RSABE scaling if HV (FDA) or Cmax-only widening (EMA/ANVISA). NTI tightening if applicable.
Clinical study report.
ICH E3-structured CSR. Bioanalytical report appendix (ICH M10 compliant). Statistical analysis appendix. Volunteer narratives for dropouts, adverse events, protocol deviations.
Module 5 compilation.
CTD Module 5.3.1 BE study reports. Cross-reference Module 3 (CMC, dissolution f2, formulation), Module 2.7 (clinical summary). Reference-product source documentation per jurisdiction.
Submission & regulator dialogue.
ANDA (FDA) / EMA generic / ANVISA generic / WHO PQ submission. Deficiency letters typically within 6–14 months. BE-specific questions: bioanalytical robustness, reference sourcing, statistical assumptions, NTI/HV designation.
Inspection readiness.
Pre-approval clinical and bioanalytical inspection (FDA BIMO, EMA national authority, ANVISA). Source documents, raw chromatograms, freezer logs, audit trail. The dossier is only as defensible as the binders behind it.