Description
This guidance is intended to assist applicants in choosing a control group for clinical trials intended to demonstrate the efficacy of a treatment. The guidance also discusses related trial design and conduct issues and describes what trials using each design can demonstrate. This guidance does not address the regulatory requirements of any region.
Key Topics
Terms and concepts identified from this document
Scope & Applicability
Product Classes
2Commonly studied using add-on designs
Commonly studied using add-on or replacement designs
Stakeholders
8Selection of subjects for an active control trial can affect outcome.
useful to have an independent set of reviewers reassess endpoints
Body that may propose protocol amendments or maintain trial integrity
Responsible for submission and communication oversight; Safeguard the rights, safety and well-being of trial participants; Reviewing trial conduct and records
Governs top dose in clinical studies
Entities submitting supplements to BLAs
Entity responsible for submitting applications under section 524B
Responsible for qualifications, training, and trial conduct; Individual responsible for trial conduct and data governance at a site.; May delegate tasks but retains overall responsibility; Person responsible for the conduct of the clinical trial at a trial site; Responsible for trial conduct and participant safety; Responsible for trial conduct, data integrity, and investigational product management.; Individual responsible for trial conduct at a site and informing the institution.; maintaining
Regulatory Context
Regulatory Activities
6The regulatory activity where inclusion of specific populations is discussed; The primary vehicle for generating robust clinical data for these populations.; Trials including pregnant participants for non-obstetric or obstetric indications; Inclusion of breastfeeding women in clinical trials; Research studies where breastfeeding women may be included.; The context in which these outcome parameters are collected.
Dose-Response Information to Support Drug Registration
may provide adequate support for a marketing approval
Clinical trials designed to demonstrate efficacy of a new drug by showing that it is not less effective than the control by more than a defined amount.; intended to show non-inferiority of the test drug to a standard agent; a non-inferiority or equivalence trial can be used and can be persuasive; Design used when proven treatment is life-saving or prevents irreversible morbidity.
Clinical trials designed to demonstrate efficacy of a new drug by showing that it is similar in efficacy to a standard agent.; intended to show equivalence between two treatments; a non-inferiority or equivalence trial can be used
Potential option to evaluate antibacterial drugs
Document Types
1Defines the standard of veterinary practice and limits for anesthetic regimens
Attributes
6Systematic errors introduced due to sampling or measurement.
confidence that the active control provides the expected extent of analgesic effect
Measured by placebo-controlled trials
Measured by placebo-controlled trials
Experience used to identify an appropriate margin and support efficacy findings
It is important to choose an appropriate dose and dose regimen of the control and test drugs.
Technical Details
Substances
7Accountability procedures for the investigational product including placebo; used as a reference in a clinical trial
Used in post-infarction treatments
investigate the benefits of streptokinase in the treatment of acute myocardial infarction
Example of a product achieving purpose through chemical action
Used in patients with acute myocardial infarction.
Blacks usually respond poorly to the blood pressure effects of beta blockers.
Blacks usually respond poorly to ACE inhibitors.
Testing Methods
5Clinical trial design comparing test drug with an inactive preparation
Types of controls; Option when no proven effective treatment exists.
Types of controls; can include one or more doses of an active control treatment; potential usefulness of the principal types of control (placebo, active, and dose-response); Option for demonstrating efficacy across various scenarios.
Types of controls; investigational drug is compared with a known active drug; potential usefulness of the principal types of control (placebo, active, and dose-response); Used to show superiority or non-inferiority to a proven treatment.
Including historical control; control group consists of patients who are not part of the same randomized study; potential persuasiveness of findings from externally controlled trials
Processes
10Process of assigning trial participants to treatment or control groups using an element of chance; Process of assigning participants to treatment groups.; Process of assigning participants to groups using chance to reduce bias.
Randomized control similar to placebo but cannot be fully blinded
Subjects randomly assigned to two or more dosage groups
A study design used to evaluate the persistence of effects over time.
Design where new drug is added and conventional treatment is withdrawn; Design modification for clinical trial control groups.
Placebo-controlled trial of a new agent conducted in people receiving standard treatment; may be more appropriate if conditions allow; Design modification for placebo-controlled trials in the presence of effective treatment.
Trial design where subjects receive a sequence of different treatments
Used to explore several doses of investigational drug as monotherapy and in combination
Trial design using a known effective treatment as a comparator
Trial in which treatment with a placebo is compared with treatment with a test drug
Clinical Concepts
10Unsatisfactory response regarding efficacy as a reason for withdrawal.
condition where it is generally inappropriate to use a placebo control
Potential disease exacerbation upon stopping a drug
Trial intended to show that the effect of a new drug is not worse than an active control
Treatment provided when a patient's disease is poorly controlled or clinical status worsens
Prompt removal of subjects whose clinical status worsens or fails to improve; often with early escape provisions; Design modification to minimize exposure to placebo or ineffective treatment.
comorbidity associated with obesity; Common weight-related comorbidity; Weight-related comorbidity
Potential risks like low blood pressure or irregular heartbeat from ingredient interactions.
surgical treatment of stable patients with angina
Software providing a prioritized list of FDA-authorized depression treatment options.
Identified Hazards
Hazards
1Serious harm that makes placebo control generally inappropriate
Standards & References
Specifications
1The margin of difference (delta) specified before conducting a study
ICH References (7)
Choice of Control Group in Clinical Trials.
document remedial actions in the clinical trial report; Structure and Content of Clinical Study Reports standards.
Dose-Response Information to Support Drug Registration
Ethnic Factors in the Accessibility of Foreign Clinical Data.
Referenced for safety data collection and adverse event reporting plans.
General Considerations for Clinical Studies
Statistical Principles for Clinical Trials; Discourages deterministic procedures due to high risk of bias; Notes that the use of Bayesian methods in clinical trials may be considered.
Related MFDS Guidelines
Korean regulatory guidelines covering similar topics
See Also (8)
- E11A Pediatric Extrapolation
- M15 General Principles for Model-Informed Drug Development
- Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product
- Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances
- Rare Diseases: Considerations for the Development of Drugs and Biological Products
- Q3C Impurities: Residual Solvents_2011
- Providing Regulatory Submissions in Electronic Format --Content of the Risk Evaluation and Mitigation Strategies Document Using Structured Product Labeling: Guidance for Industry
- Q4B Annex 5: Disintegration Test General Chapter