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Visit window deviations are the earliest sign of trial delay

A Phase III protocol averages more than 100 protocol deviations, and about a third of its patients experience at least one. Leading sponsors and sites are starting to read each missed or out-of-window visit as an early warning of site strain and timeline risk, and to act on it within days.

Clinical researchSegeta Insights
Clinical research
The number14x

more protocol deviations in Phase III than Phase I

What is at stake

Tufts CSDD estimates that a Phase III trial costs about $$55,700 a day to run, and that a launched drug earns about $$800,000 a day in sales.

Where days are lost
  1. From visit schedule to patient
  2. From patient to site on the day
  3. From site record to sponsor and CRA

Clinical research has long treated protocol deviations as a record of what went wrong. Deviations are logged at the site, reconciled by the clinical research associate (CRA) at the next monitoring visit and summarized for the clinical study report, often months later. That cycle serves compliance well, yet it files as history a signal that is most useful as a forecast. A visit that drifts outside its protocol window usually reflects a patient struggling with the schedule, a coordinator stretched across too many studies or a site falling behind, and each of these conditions tends to repeat.

At industry scale, the volume of that signal is large. Tufts Center for the Study of Drug Development (Tufts CSDD) found that Phase III protocols averaged 118.5 protocol deviations each, and that 32.8 percent of enrolled patients experienced at least one.1 The study covered 187 protocols approved between 2013 and 2018 at 20 large and mid-sized pharmaceutical companies and contract research organizations.2 Read daily across the visit schedule, the site and the sponsor, visit window compliance gives clinical operations the earliest warning of clinical trial delays available to them, and the gap between detecting it and acting on it carries a measurable daily cost.

Protocol complexity and new GCP rules raise the stakes of every visit

Protocols have become heavier for patients and sites to carry. Tufts CSDD reported in 2021 that a Phase III protocol averaged about 263 procedures per patient and about 3.6 million data points, and that total procedures per patient in Phase II and III protocols rose 69 percent from the 2009 to 2012 period to the 2017 to 2020 period.3 A later Tufts CSDD study with TransCelerate found that Phase III protocols averaged 5.96 million data points, and that non-core and non-essential procedures accounted for up to 32.5 percent of Phase III data collected per patient.4 Every added procedure lengthens the visit and adds another way for it to deviate.

Regulators now expect sponsors to manage that burden in proportion to risk. The International Council for Harmonisation published the final E6(R3) guideline on good clinical practice on January 6, 2025, and the European Medicines Agency's adoption took effect on July 23, 2025.5 The FDA published its final E6(R3) guidance on September 9, 2025, asking sponsors to identify critical to quality factors at design and to match oversight to risk through risk-based quality management and centralized monitoring.6 Deviation counts reviewed after each monitoring visit fit poorly with that expectation, because the risk has usually materialized by then.

Protocol deviations begin at three handoffs around each visit

In the Tufts CSDD analysis, higher numbers of distinct procedures, endpoints, eligibility criteria, countries and investigative sites each raised the odds that a protocol fell into the high-deviation group.1 At the site level, a 2026 audit of 526 protocol deviations across 21 regulatory trials at a tertiary referral center in Mumbai found that follow-up beyond the allowed visit window made up about 42 percent of the total, the largest single category, although many occurred during the pandemic.7 Most of the days lost to these deviations are lost at three handoffs.

Phase III protocols averaged about 14 times as many protocol deviations as Phase I protocols.

Exhibit 1Phase III protocols average about 14 times the deviations of Phase IMean protocol deviations per protocol, 187 protocols approved 2013 to 2018
Phase I8.7
Phase II75.3
Phase III118.5
Phase II/III oncology108.8
Phase II/III non-oncology91.9

Source: Getz et al., Therapeutic Innovation & Regulatory Science (Tufts CSDD), 2022

01From visit schedule to patient

The protocol defines each visit window in days relative to randomization or the previous dose, but the patient experiences it as a date that must fit around work, travel and caregiving. Coordinators typically calculate due dates in a spreadsheet or the site's scheduling system and confirm by phone or text, so a rescheduled appointment can push a visit outside its window before anyone outside the site knows. The cost appears later as a missing timepoint.

02From patient to site on the day

A visit inside its window can still deviate when a procedure is skipped, a sample is processed late or a fasting requirement is missed. The coordinator works from the schedule of assessments, the laboratory manual and the electronic data capture (EDC) system at once, and an incomplete visit often surfaces only at data entry.

03From site record to sponsor and CRA

The sponsor sees a deviation when it reaches the EDC system, the clinical trial management system (CTMS) or the CRA's monitoring visit report, and each of those runs on its own clock. A CRA covering several sites may learn of a pattern of late visits at the next on-site or remote review. Escalation then travels by email between the CRA, the study manager and the site, and corrective action reaches patients long after the first missed window.

A connected operating model treats each visit window as an obligation

Leading sponsors, contract research organizations and site networks are starting to manage each visit window as an obligation with an owner, a deadline and a cost for every day it stays open. A connected layer reads the systems already in use, including the CTMS, EDC, interactive response technology (IRT), site scheduling tools, email and patient messaging, and holds one live view of every upcoming window across sites. It runs the same four-step loop described in earlier articles in this series:

  1. Detect

    a visit approaching the end of its window without a confirmed appointment, or a site whose share of late visits is rising, on the day the pattern appears.

  2. Explain

    the likely cause, such as a coordinator vacancy, a patient's transport barrier or a procedure the site's laboratory cannot schedule, with the source record for each.

  3. Recommend

    a specific action, such as a reminder and a ride offer to the patient, a call from the CRA to the site or a protocol clarification, each with an owner and a date.

  4. Execute and track

    each action until the visit is completed in window, and report the deviations avoided by site and by study.

The patient is an external party in this model, and patient-facing reminders in the patient's own channel, followed up by the right coordinator, can close the first handoff before it fails. CRAs and RBQM teams receive the same signals as key risk indicators for central monitoring, ranked by their effect on critical to quality data. Artificial intelligence does the reading, linking and drafting of reminders, site notes and escalations, while investigators, coordinators, CRAs and study managers remain accountable for every clinical and protocol decision.

A day of Phase III delay can cost about $$856,000

Cost of delay in clinical research is the daily trial operating cost and forgone revenue created when a study's database lock, submission or launch moves out by one day.

Tufts CSDD estimates that a Phase III trial costs about $$55,700 a day to run, and that a launched drug earns about $$800,000 a day in sales.

Exhibit 2. Estimated daily exposure when a Phase III trial on the critical path slips

ComponentBasisEstimate per day
Direct cost of running a Phase III trialTufts CSDD analysis of 447 protocol budgets, $$55,716 a day in 2023 dollars 8About $$55,700
Forgone prescription drug salesTufts CSDD average daily sales across 645 drugs launched since 2000; assumes the trial sits on the critical path to approval and launch 8About $$800,000
Total daily exposureSum of the two componentsAbout $$856,000

Source: Segeta estimate based on Tufts CSDD data; assumptions are illustrative.

On these assumptions, a 30-day slip in database lock on a Phase III program could expose about $$25.7 million, and a 60-day slip about $$51.4 million, most of it in deferred sales. The direct trial cost alone reaches about $$1.7 million over 30 days and $$3.3 million over 60 days. Two factors offset the total: sales are more often deferred than lost, and the Tufts CSDD sales figure varies widely by therapeutic area, from a median of about $$840,000 a day in oncology to $$1.4 million for cardiovascular drugs.8

What clinical operations and RBQM leaders can do now

  1. 01Treat visit window compliance as a leading indicator

    Report the share of visits completed in window by site and by study every week, alongside the deviation counts already sent to quality.

  2. 02Map every visit window to an owner

    Assign each upcoming window to a named coordinator, with the target date, the latest permissible date and the procedures required.

  3. 03Reach patients in their own channel

    Send reminders, travel support and rescheduling options through the patient's preferred channel, with a coordinator following up when a patient does not confirm.

  4. 04Feed visit signals into risk-based monitoring

    Add late and incomplete visits to the key risk indicators used in central monitoring, weighted by their effect on critical to quality data.

  5. 05Price each open window in dollars per day

    Attach the daily cost of the study to visits at risk on the critical path, so a site's staffing gap is discussed with the urgency it carries.

ICH E6(R3) gives sponsors and sites a regulatory reason to manage risk in proportion to its effect on patients and data, and visit windows are among the most direct measures of that risk. Organizations that read each window as a live obligation are likely to record fewer protocol deviations, cleaner endpoints and steadier timelines, and their sites and patients may come to regard their studies as easier to run.

Questions leaders ask

How many protocol deviations does a typical clinical trial have?

Tufts CSDD benchmarked 187 protocols approved between 2013 and 2018 and found that Phase III protocols averaged 118.5 protocol deviations, Phase II protocols 75.3 and Phase I protocols 8.7. About 32.8 percent of Phase III patients experienced at least one deviation, and oncology protocols in Phase II and III affected 46.6 percent of patients.

Why do missed or out-of-window visits matter in clinical trials?

An out-of-window visit can cost a data point at a scheduled timepoint, add queries for data management and signal that a patient or a site is under strain. Because these conditions tend to repeat, visit window compliance tracked daily by site gives clinical operations teams an early warning of deviations, data loss and timeline risk.

What does ICH E6(R3) change for risk-based monitoring?

ICH published the final E6(R3) guideline in January 2025, the European Medicines Agency's adoption took effect in July 2025 and the FDA published its final guidance in September 2025. It asks sponsors to identify critical to quality factors at design and to match oversight to risk through risk-based quality management and centralized monitoring.

How much does a day of clinical trial delay cost?

Tufts CSDD estimates that a Phase III trial costs about $$55,716 a day to run, in 2023 dollars, and that launched drugs earn about $$800,000 a day in sales on average. For a Phase III trial on the critical path to launch, the combined daily exposure can approach $$856,000, although deferred sales are often recovered later.

Notes and sources
  1. Kenneth Getz, Zachary Smith, Ananya Jain and Randy Krauss, "Benchmarking Protocol Deviations and Their Variation by Major Disease Categories," Therapeutic Innovation & Regulatory Science, April 2022, pmc.ncbi.nlm.nih.gov.
  2. Kenneth Getz, "Quantifying Protocol Deviation Experience by Clinical Phase," Applied Clinical Trials, June 2022, appliedclinicaltrialsonline.com.
  3. Tufts Center for the Study of Drug Development, "Impact Report," Volume 23, Number 1, January/February 2021, files.constantcontact.com.
  4. Drug Discovery News, "TransCelerate and Tufts CSDD uncover opportunities to rethink data collection and optimize protocol design," September 2025, drugdiscoverynews.com.
  5. Julie Kim and Deborah L. Livornese, "The ICH E6(R3) Guideline: A Major Update to Good Clinical Practice," FDA Law Blog, Hyman, Phelps & McNamara, February 2025, thefdalawblog.com.
  6. Association of Clinical Research Professionals, "FDA Publishes ICH E6(R3): What it Means for U.S. Clinical Trials," September 2025, acrpnet.org.
  7. R. Parida et al., "A retrospective audit to analyze protocol deviations that occurred in regulatory clinical trials at a tertiary referral center in India," Perspectives in Clinical Research, February 2026, kem.edu.
  8. Tufts Center for the Study of Drug Development, "Day of Delay" white paper, August 2024, csdd.tufts.edu.