Examples
Worked examples
- Is an instance
A randomized, double-blind, three-arm clinical investigation assessing a new molecular entity against both an established active comparator and a concurrent placebo arm to establish assay sensitivity while demonstrating therapeutic superiority or non-inferiority under ICH E10 Section 1.4.
- Is an instance
A randomized, parallel-group, fixed-dose trial evaluating three pre-specified dose levels of an investigational compound against an active control to define exposure-response relationships under ICH E10 Section 1.3.3.
Counter-examples
Looks similar, but isn't
- Not an instance
A single-arm, unblinded observational registry cohort evaluated post-marketing without prospectively defined concurrent or historically matched comparator standards meeting the formal bias-control criteria of ICH E10.
Editorial commentary
ICH E10 (Choice of Control Group and Related Issues in Clinical Trials) is the ICH harmonised tripartite guideline that describes the general principles for choosing a control group in clinical trials meant to demonstrate the efficacy of a treatment, and the design and conduct issues that follow from that choice. Its Step 4 version is dated 20 July 2000, when it was recommended for adoption to the regulatory bodies of the European Union, Japan and the USA.
The guideline states that it does not address the regulatory requirements of any region; it describes what trials using each design can demonstrate. It sits beside other ICH texts that it names as particularly relevant, including E6 (Good Clinical Practice, see ICH E6(R2)), E8 (see ICH E6 vs ICH E8) and E9 (statistical principles).
What does ICH E10 say control groups are for?
Section 1.2 states that a control group has one major purpose: to allow discrimination of patient outcomes caused by the test treatment from outcomes caused by other factors, such as the natural progression of the disease, observer or patient expectations, or other treatment. In most situations a concurrent control group is needed because outcome cannot be predicted with adequate accuracy. The test and control groups should be similar in all baseline and on-treatment variables that could influence outcome, except for the study treatment. Two techniques are usually used to protect that similarity:
- Randomization (1.2.1): randomly dividing one sample population into groups avoids systematic differences between groups in known or unknown baseline variables.
- Blinding (1.2.2): treating and observing the groups similarly during the trial, so that knowledge of assignment does not bias management, assessment or interpretation.
What are the five control group types in ICH E10?
Section 1.3 classifies control groups by the type of control treatment and by how the control group is chosen. The first four types are concurrently controlled, usually with random assignment; the fifth is external.
1. Placebo concurrent control (1.3.1)
Subjects are randomly assigned to the test treatment or to an identical-appearing treatment that does not contain the test drug. Such trials are almost always double-blind. The guideline notes that the benefit is not only control of the placebo effect: with blinding and randomization it controls for influences on the course of disease other than the pharmacologic action of the test drug, including natural history, regression to the mean and expectations. Using a placebo does not imply the control group is untreated, because in many trials both arms are added to a common standard therapy (add-on studies). See also placebo-controlled study design.
2. No-treatment concurrent control (1.3.2)
Subjects are randomly assigned to the test treatment or to no study treatment. Subjects and investigators are not blind to assignment. The guideline says this design is likely to be needed and suitable only when double-blinding is difficult or impossible and when there is reasonable confidence that endpoints are objective. A blinded evaluator for endpoint assessment should always be considered in such trials.
3. Dose-response concurrent control (1.3.3)
Subjects are randomized to one of several fixed-dose groups, and the intended comparison is between groups at their final dose. These trials are usually double-blind and may include a placebo (zero dose) or active control. Concentration-controlled and regimen-controlled variants are also described. Section 2.3.7 notes that it is not uncommon to show no difference between doses, which is usually uninformative if there is no placebo group.
4. Active (positive) concurrent control (1.3.4)
Subjects are randomly assigned to the test treatment or to an active control. Such trials can aim to show efficacy by showing the test treatment is as good as a known effective treatment, or by showing superiority to the active control. Whichever the aim, the guideline says the question of whether the trial could distinguish effective from less effective or ineffective treatments is critical.
5. External control, including historical control (1.3.5)
An externally controlled trial compares treated subjects with a group external to the study, for example patients treated at an earlier time. Because of serious concerns about comparability and bias, the guideline describes this design as usable only in unusual circumstances. Section 2.5 restricts it to situations where the effect of treatment is dramatic and the usual course of the disease highly predictable, with objective endpoints.
What is assay sensitivity in ICH E10?
Section 1.5 covers assay sensitivity: the ability of a trial to distinguish effective from less effective or ineffective treatments. In a placebo-controlled trial, a difference from placebo shows the trial could detect an effect. In an active-control non-inferiority or equivalence trial there is no such internal demonstration, so a finding of no difference can mean both treatments worked or that neither did in that trial.
Section 1.5.1 lists the steps for using a non-inferiority design to show efficacy: determine that historical evidence of sensitivity to drug effects exists (without it, demonstrating efficacy from non-inferiority is not possible and should not be attempted), design and conduct the trial to adhere closely to the trials that provided that evidence, and define an acceptable non-inferiority margin. The margin cannot be greater than the smallest effect size the active drug would reliably be expected to have compared with placebo in the planned setting.
How do ethics and hybrid designs fit in?
Section 2.4.3 notes that where the active control therapy is known to improve survival or decrease irreversible morbidity, a placebo or no-treatment control would be unacceptable. More generally, whether a placebo-controlled trial is acceptable is a matter of investigator, patient and IRB/IEC judgment, and may differ among ICH regions. The guideline describes modifications that can resolve ethical, practical or inferential issues, including:
- Three-arm trials (2.1.5.1.1): placebo and active control alongside the test treatment in one trial.
- Add-on studies (2.1.5.2.1): the test treatment or placebo added to a common standard therapy.
- Early-escape designs: defining failure so that patients not responding on an assigned treatment are identified rapidly.
- Factorial designs (2.1.5.1.3) and randomized withdrawal designs.
For protocol-level application, see clinical trial protocol design, and for the wider regulatory context regulatory affairs in the pharmaceutical industry.
FAQ
What is ICH E10?
The ICH guideline on choice of control group and related issues in clinical trials, Step 4 version dated 20 July 2000.
Is ICH E10 a regulation?
It is a guideline. It states that it does not address regulatory requirements in any region. The FDA and EMA each publish it (see Sources).
Which control types does it describe?
Placebo, no-treatment, dose-response, active, and external (including historical) control.
Why does it stress assay sensitivity?
Because without it a non-inferiority result cannot be read as evidence of efficacy.
Sources
Checked 2026-11-07.
- ICH. Choice of Control Group and Related Issues in Clinical Trials (E10), Step 4 version dated 20 July 2000. https://database.ich.org/sites/default/files/E10_Guideline.pdf
- U.S. FDA. E10 Choice of Control Group and Related Issues in Clinical Trials (guidance, May 2001). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e10-choice-control-group-and-related-issues-clinical-trials
- European Medicines Agency. ICH E10 Choice of control group in clinical trials, scientific guideline. https://www.ema.europa.eu/en/ich-e10-choice-control-group-clinical-trials-scientific-guideline
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