Free scoping read. A written assessment of your manuscript in two business days, at no cost.

Start one
Contents

On this page

  1. Efficiency of the crossover design and its core requirement
  2. Consequences of an inadequate washout period
  3. Appropriate and inappropriate uses of a run-in period

Academy · Research Data, Analytics & AI · Crossover, run-in and washout design

Crossover, Run-In and Washout Periods in Clinical Trial Design: Purposes and Requirements

In a crossover trial each patient serves as their own control. The design is efficient, but only when carryover effects between treatment periods are eliminated by an adequate washout rather than assumed to be absent.

Pubrica AcademyWritten by a clinical trial methodologist Reviewed bya biostatistician Published10 October 2026 Last checked10 October 2026 Reading time7 minutes Sources1 peer-reviewed

A crossover trial has each participant receive two or more treatments in sequence, often separated by a washout period intended to eliminate carryover effects from the prior treatment. A run-in period is a preliminary phase before randomisation, often used to confirm adherence or establish a stable baseline. Each addresses a distinct design concern.

Learning objectives

  • Why crossover design increases statistical efficiency, and what it requires to remain valid.
  • Why an inadequate washout period undermines the fundamental premise of a crossover trial.
  • What a run-in period is and is not an appropriate tool for.

Common misconceptions

  • “A crossover design is just a more efficient way to run any trial.” Mills and colleagues note that crossover designs are appropriate only for stable, chronic conditions in which the treatment is not expected to cure or permanently alter the condition; they are unsuitable for acute, curable or rapidly progressing conditions, in which a patient’s state in the second period is not comparable to that in the first, irrespective of treatment.
  • “A fixed, standard washout period length is adequate for any drug.” Mills and colleagues emphasise that the washout period must be sufficiently long, relative to the pharmacokinetics of the treatments involved, to eliminate carryover effects; a washout adequate for a drug with a short half-life may be wholly inadequate for one with a long half-life or active metabolites, and the duration should therefore be justified individually rather than assumed from convention.

Efficiency of the crossover design and its core requirement

Mills and colleagues describe the central advantage of a crossover design: because each participant serves as their own control, between-participant variability is removed from the treatment comparison, which can substantially reduce the sample size required for the same statistical power compared with a parallel-group design1. This advantage depends entirely on the condition being sufficiently stable for a participant’s state in one treatment period to be comparable to that in another, which makes the design appropriate chiefly for chronic, stable conditions.

Consequences of an inadequate washout period

The washout period between treatment periods exists specifically to eliminate carryover, that is, any residual effect of the first treatment that could contaminate measurement of the second. Mills and colleagues stress that the required length of the washout depends on the specific pharmacokinetics of the treatments under study, including the half-life of the drug and any active metabolites, and that an inadequately justified washout period, or one fixed by convention, is a frequently underappreciated source of bias in published crossover trials1. Statistical tests for carryover effects exist and should be reported, although they often have insufficient power to detect carryover reliably on their own.

Appropriate and inappropriate uses of a run-in period

A run-in period, which precedes randomisation, is typically used to establish a stable baseline measurement, to confirm participant adherence to study procedures, or to allow washout from a prior non-study treatment. It is a design tool for improving data quality and participant suitability before randomisation, not a treatment period, and outcomes observed during run-in do not form part of the trial’s treatment comparison1. A run-in used before randomisation to exclude participants who do not respond or adhere can itself affect the generalisability of the subsequently randomised population, and should be reported transparently.

Key points

Key points

Crossover design increases statistical efficiency for stable, chronic conditions, but remains valid only if the washout period is sufficiently long, as justified by the pharmacokinetics of the specific drugs, to eliminate carryover; a run-in period serves a distinct purpose, establishing baseline and adherence before randomisation, not treatment comparison.

Practical application

Practical application

  1. The crossover design should be justified on the basis of the stability of the condition, not efficiency alone. The protocol should state explicitly why the condition under study is suitable for a within-participant comparison across periods.
  2. The washout duration should be justified against the pharmacokinetics of the specific drugs. The half-life and active-metabolite profile of each treatment should be cited to justify the chosen washout duration, rather than a generic convention being applied.
  3. Any run-in-based exclusions and their effect on the randomised population should be reported. The number of participants excluded during run-in, and the reasons, should be stated, since this affects the generalisability of the subsequently randomised sample.

Frequently asked questions

Yes, although Mills and colleagues note that such tests often have insufficient power in crossover trials of typical size; a washout period adequately justified at the design stage therefore remains more reliable than reliance on a statistical test to detect an inadequate one retrospectively.

Generally not, because the condition may resolve or change between periods irrespective of treatment, rendering the two periods non-comparable; crossover designs are best reserved for stable, chronic conditions.

It can, if it is used to exclude non-adherent or non-responding participants before randomisation, which restricts the trial population to those more likely to show benefit; this should be reported transparently as part of the trial’s eligibility criteria and participant flow.

References

  1. Mills EJ, Chan AW, Wu P, Vail A, Guyatt GH, Altman DG. Design, analysis, and presentation of crossover trials. Trials. 2009;10:27. read 10 October 2026. View on PubMed Central

Every source above is a peer-reviewed article, a publisher’s record of one, or a standard issued by the body that owns it. Each carries the date it was last read. Where a standard moves, this article is revised rather than left up with a note.

How to cite this article

Pick your referencing style and copy it. Your university or target journal may vary the punctuation — check its guide if it has one.

Pubrica Academy. (2026, October 10). Crossover, Run-In and Washout Periods in Clinical Trial Design: Purposes and Requirements. Pubrica. https://pubrica.com/academy/concepts-definitions/crossover-run-in-washout-design/

This article is written to be learned from. Cite it if you are referring to what it says; if you are using the evidence behind it, cite the sources listed above instead.

Crossover-design reporting check

For use when designing or reporting a crossover trial.

[ ] Condition's suitability for crossover design justified explicitly
[ ] Washout period length justified against treatment pharmacokinetics
[ ] Statistical test for carryover effect reported, with its power acknowledged
[ ] Run-in period's purpose stated, and any resulting exclusions reported
[ ] Period and sequence effects reported alongside the treatment effect

Pubrica AcademyWritten and maintained by Pubrica’s subject matter experts. Articles are revised when the underlying standards change, and each article states the date on which it was last reviewed.

How Pubrica can help

Pubrica assists in justifying crossover, washout and run-in design choices against the specific treatments and condition involved, so that the design withstands reviewer scrutiny.

Submit an enquiry Get your crossover trial design reviewed

Explore

Related Academy articles

Selected from the same topic and category, with the most recent first.

Article

The Impact of Electronic Health Records on Research

What electronic health records change about research data, the five quality dimensions reviewers check, and what FDA real-world-data guidance expects…

10 October 2026 · 10 min read

Article

Adverse Drug Effects: Definition and Classification

The precise difference between an adverse event and an adverse drug reaction, the standard mechanistic classification, and why causality has to be…

10 October 2026 · 8 min read

Article

What Post-Marketing Surveillance Is

What post-marketing surveillance is, why pre-approval trials cannot detect every safety signal, the ICH E2E pharmacovigilance planning framework, and…

10 October 2026 · 8 min read

Find something else

Search the Pubrica Academy

Access is free and requires no account. Enter a topic, or open the full library to filter by category, sub-topic or resource type.

Review of washout and run-in design before protocol finalisation

A scoping assessment is free and takes two business days. It provides a written assessment of what the work requires and which specialist would undertake it.

Get a free quote Ask about your own case
Get a free quote

Regulations

Check your project against this rule

  1. 1Your work
  2. 2Your details
  3. 3Send
What do you need?

Material you send is held under signed confidentiality, with access limited to the assigned team and encrypted transfer. It is not used to train anything and is not passed to third-party tools. Ask for the agreement before you send anything you would rather cover first.