5.3.5.1 — Controlled Clinical Studies (Efficacy)

Full study reports for controlled clinical efficacy and safety trials (pivotal studies)

Requirements by Phase

IND Phase 2: protocol IND Phase 3: report NDA: required

Content Requirements

• Study reports of controlled clinical studies pertinent to claimed indication
• Pivotal trials with full CSR per ICH E3
• Statistical analysis per ICH E9
• Primary and secondary efficacy endpoints
• Safety data integrated in CSR

Expected Deliverables

• Full CSR per ICH E3 format for each pivotal trial
• Statistical analysis plan (SAP)
• Tables, figures, and listings (TFLs)

ICH Guidelines: E3, E9(R1), M4E(R2)

Regulatory Requirements (ICH E1)

• [Clinical Drug Development] The safety evaluation during clinical drug development is not expected to characterise rare adverse events.

Regulatory Requirements (ICH E2A)

• [Clinical Development] The provisions of this guideline should be used in conjunction with other ICH Good Clinical Practice guidelines.
• [Pre-approval] All noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions (in pre-approval clinical experience).
• [All] The term "side effect" should no longer be used and should not be regarded as synonymous with adverse event or adverse reaction.
• [Clinical Investigations] Reactions that threaten life or function should be reported promptly to regulators.
• [Clinical Investigations] Medical and scientific judgement should be exercised in deciding whether expedited reporting is appropriate for important medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardise the patient or require intervention to prevent other serious outcomes.
• [Clinical Investigations] Expedited reporting is required for additional occurrences of an unexpected adverse reaction until source documents are amended.
• [Pre-approval] For unapproved medicinal products, the Investigator's Brochure will serve as the source document to determine expectedness.
• [All] Reports adding significant information on specificity or severity of a known, already documented serious ADR constitute unexpected events.
• [All] All adverse drug reactions (ADRs) that are both serious and unexpected are subject to expedited reporting.
• [All] The source of a report (investigation, spontaneous, other) should always be specified.
• [All] Expedited reporting of reactions which are serious but expected will ordinarily be inappropriate.
• [Clinical Investigations] Expedited reporting is inappropriate for serious events from clinical investigations that are considered not related to study product.
• [All] Non-serious adverse reactions, whether expected or not, will ordinarily not be subject to expedited reporting.
• [All] Information obtained by a sponsor or manufacturer on serious, unexpected reports from any source should be submitted on an expedited basis to appropriate regulatory authorities if the minimum criteria for expedited reporting can be met.
• [Clinical Investigations] Causality assessment is required for clinical investigation cases.

Regulatory Requirements (ICH M3R2)

• Serious adverse clinical or nonclinical findings should be evaluated to determine the appropriateness and design of additional nonclinical and/or clinical studies.
• [before Phase 1] All relevant nonclinical data (pharmacological dose response, pharmacological/toxicological profile, pharmacokinetics) should be considered when determining the recommended starting dose in humans.

Regulatory Requirements (ICH Q1AR2)

• [Pre-approval] Stability studies should include testing of those attributes of the drug substance that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy.
• [Pre-approval] Stability studies for drug product should include testing of those attributes that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy.

Regulatory Requirements (ICH Q6A)

• [Marketing Approval] Specifications should focus on those characteristics found to be useful in ensuring the safety and efficacy of the drug substance and drug product.
• [Marketing Approval, Post-approval] Initially approved tests and acceptance criteria should be reviewed and potentially modified as more information is collected post-approval, focusing on safety and efficacy at filing.

Regulatory Requirements (ICH Q6B)

• [Development, Approval] Specifications are chosen to confirm the quality of the drug substance and drug product rather than to establish full characterization and should focus on those molecular and biological characteristics found to be useful in ensuring the safety and efficacy of the product.
• [Development] If a consistent pattern of product heterogeneity is demonstrated, an evaluation of the activity, efficacy and safety (including immunogenicity) of individual forms may not be necessary.

Regulatory Requirements (ICH S7A)

• [Non-clinical] Safety pharmacology studies should be designed to define the dose-response relationship and time course of the adverse effect observed. Doses should include and exceed the primary pharmacodynamic or therapeutic range.

Regulatory Requirements (ICH S9)

• [Nonclinical] Assessment of the potential to recover from toxicity should be provided to understand whether serious adverse effects are reversible or irreversible.

Note: P2: protocol. P3: P2 reports + P3 protocol. NDA: all pivotal reports

Source: ICH E3; ICH E9(R1)