Why the site keeps calling, what a missed visit does to the dataset, and why nobody is angry with you. Written for trial participants, and for the coordinators making those calls.

In this file:

·        What a visit window is, and why no regulation defines one

·        The phone calls, and why they are not nagging

·        What a missed visit actually does to the data

·        The 3 different things people mean by leaving a study

Walter's ride fell through on a Monday. His daughter's car was in the shop, the visit was Wednesday, and the window closed Friday.

Coordinator Nani spent 40 minutes on the phone. She called the daughter, then the study's travel reimbursement contact, then the clinic to move an appointment that was not part of the study at all. None of that is technically her job. It’s also the whole job, and every experienced coordinator knows it.

What she didn’t do, at any point, was tell Walter he was in trouble, because he wasn’t. Nobody in this system is angry with you for missing a visit, and the reasons why are worth understanding from both sides of that phone call.

A visit window is the range of days around a scheduled study visit in which that visit can still happen and still count. Day 28 plus or minus 3 days, or Week 12 minus 5 or plus 7.

Here’s the thing most people assume and get wrong. No FDA regulation defines a visit window, and no regulation sets one. Windows are written into the protocol, study by study, by the people designing it, and they are set by what the science needs. A pharmacokinetic sample has a narrow window because the drug level changes by the hour. A quality of life questionnaire has a wide one because how you felt this month does not swing on a Tuesday.

What makes the schedule binding is not a rule about windows. It’s 21 CFR 312.60, which makes the investigator responsible for conducting the study according to the investigational plan, and ICH GCP, which says the investigator should conduct the trial in compliance with the protocol. The protocol says day 28 plus or minus 3. So day 28 plus or minus 3 is the rule, for this study, and a different study 2 doors down has a different one.

That’s also why a site can’t simply grant you an extra week. It isn’t being rigid. The site doesn’t own the number, and a visit done outside the window becomes a protocol deviation that has to be documented and explained.

From the participant's side a string of voicemails can feel like pressure. From the site's side, those calls are usually about 3 things, and only one of them is the calendar.

The assessment that has a clock on it. Some visits carry a safety assessment tied to a rule, a lab that determines whether the next dose is safe, an ECG, a symptom check that feeds a stopping boundary. Those are the calls that sound urgent because they are.

The logistics nobody put in the protocol. Rides, parking, a shift that cannot be moved, a caregiver who’s also sick. Sites solve these constantly and almost none of it is written down anywhere. Worth knowing as a participant: the FDA has said in its own information sheet on payment and reimbursement that it does not consider reimbursement for travel to and from the trial site, and associated costs such as airfare, parking and lodging, to raise concerns about undue influence. Reimbursing your parking is not a bribe, and it’s not a favor either. So ask.

The data. Which is the part that is genuinely at stake, and which almost nobody explains to the person being called.

Start with the principle that governs the whole analysis. ICH E9, the guideline on statistical principles for clinical trials, says the intention to treat principle "implies that the primary analysis should include all randomized subjects." Everyone who was randomized is in the analysis. You do not get dropped for missing a visit, and you do not get dropped for stopping the drug.

That’s a protection, and it creates a problem the same guideline names. If you are still in the analysis but your data is missing, something has to be assumed about you.

The National Research Council put it plainly in a 2010 report on missing data in clinical trials, produced at FDA's request: missingness "reduces the benefit provided by the randomization and introduces potential biases in the comparison of the treatment groups." Randomization works by making the 2 groups comparable. Missing data can quietly unbalance them, because the reasons people miss visits are not random. People who feel worse miss more visits. People who feel entirely better sometimes stop coming too.

The scale is real but not catastrophic. A 2012 systematic review in the BMJ found a median 6 percent of participants lost to follow up across the trials it examined, with an interquartile range of 2 to 14 percent. Read that as a description of that sample, from a search that ended over a decade ago, not as today's universal rate.

The modern framing for all of this is the estimand. ICH E9(R1), adopted at Step 4 on 20 November 2019 and issued by FDA as guidance in May 2021, introduced the idea of intercurrent events, defined as "events occurring after treatment initiation that affect either the interpretation or the existence of the measurements associated with the clinical question of interest." Stopping the drug is an intercurrent event. So is starting a rescue medication. The addendum's whole point is that a trial should decide in advance how it will handle those, rather than discovering them at the end and improvising.

One missed visit rarely changes an answer. The pattern of missed visits can change what the trial is able to conclude, which is why the phone rings.

This is the section to send to someone who is thinking about stopping, because these get collapsed into one and they are not one.

Stopping the study drug. You stop taking it. You can still come to visits, still be assessed, still be counted. This happens constantly and is completely normal.

Stopping the visits. You stop coming in but have not withdrawn your consent. The site will usually ask whether you would accept a shorter version, a phone call, or permission to check your medical records. Every one of those is a real option, and saying yes to the smallest one is worth more to the trial than most people realize.

Withdrawing consent. You end your participation. Your consent form says you can, and it says so because federal regulation requires it to. 21 CFR 50.25(a)(8) requires a statement that participation is voluntary, that refusing involves no penalty or loss of benefits you are otherwise entitled to, and that you may discontinue at any time without penalty or loss of benefits.

Before you withdraw completely, talk with your study coordinator about exactly what you want to stop. You can often stop the visits and still agree to a later check in, like a phone call, to see how you’re doing. In a trial asking whether a drug helps people live longer, that check in can be the most important data point there is. The main result depends on knowing how long every participant lived, and even a small number of people whose status is unknown can make that answer less certain.

Now the part people are rarely told. Data already collected stays. FDA's October 2008 guidance on data retention when subjects withdraw is explicit that it is critical for data already collected to be retained, because removing it would jeopardize the scientific validity of the findings. What withdrawing stops is future collection about you, not the erasure of what has already happened. If that matters to you, it is a fair question to ask before you sign, not after.

And ICH GCP asks the investigator to do something specific here, which is worth knowing because it can be misread as pressure. A participant is not obliged to give a reason for withdrawing, and the investigator "should make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights." The coordinator asking why is following a guideline, and you are allowed to decline to answer.

Note to File. For coordinators. The retention conversation belongs at the visit before the one somebody misses, not after. When a participant starts describing their week in a certain way, the ride that keeps falling through, the shift that changed, the caregiver who got sick, that is the moment to sort out the logistics, not the day of the visit. Almost every lost to follow up in a real site file was visible 2 visits earlier to somebody who was listening. And write the retention effort down. A note saying you called 3 times, offered a phone visit and arranged a ride is the difference between a missing data point and a documented one.

A visit window is the range of days in which a study visit still counts, and it comes from the protocol rather than from any FDA regulation, which is why a site cannot extend it for you. Missing a visit is a protocol deviation, which is logged and explained, and FDA's own draft guidance on deviations lists a missed scheduled visit as an ordinary example. It’s not a violation of your agreement and it carries no penalty for you. What it costs is data, and because everyone randomized stays in the analysis under the intention to treat principle, a missing measurement has to be handled with an assumption rather than a fact, which is why a pattern of missed visits matters more than any single one. Stopping the drug, stopping the visits and withdrawing consent are 3 different decisions with 3 different consequences, and data already collected is retained in all of them. Walter made his visit on Thursday. Nani wrote down what it took.

Reply to this email or leave a comment on the newsletter: have you ever had to miss or move a study visit, as a participant or on the site side? What made it easy, or hard, to get back on track? Every query gets read, and the best ones get answered in a future issue.

Know someone training for their first coordinator job, or thinking about one? Send them this issue with your own referral link below, so the share counts. The Open Site File is written for exactly that person.

The Open Site File is one part of Root to Rx, and we all work toward the same thing: making clinical research easier to understand and harder to misrepresent. Monday, The Root Room shows a real health claim trying to work on someone. Wednesday, Plain Talk takes one topic from the news apart in plain language, with the receipts. Sunday, The Roots, on LinkedIn and Substack, is a letter for the people whose family treats them as the medical desk. And twice a week, The Open Site File shows you the inside of the site, where the people who make trials run actually work. Different doors, one mission: more people who understand how medicine gets made, and fewer people misled about it.

·        Previous issue: Issue 15, clinical research careers for foreign trained doctors

·        Next issue: Issue 17, Version History, why consent is a document

·        Related: Issue 14, what counts as a protocol deviation

·        For the people whose family treats them as the medical desk: The Roots, our weekly letter.

·        Why the rules read the way they do, and the history behind them: Version History.

·        Helping a patient or family member look for a study? A walkthrough of the public trial registries.

·        Patient materials, including a free Medication and Supplement Log modeled on the conmed logs used in trials, and a Symptom Log.

·        21 CFR 50.25, Elements of informed consent (eCFR)

·        21 CFR 312.60, General responsibilities of investigators (eCFR)

·        ICH E9, Statistical Principles for Clinical Trials, section 5.2.1

·        ICH E9(R1), Addendum on Estimands and Sensitivity Analysis, ICH Step 4, 20 November 2019

·        National Research Council. The Prevention and Treatment of Missing Data in Clinical Trials. 2010, produced at FDA's request

·        Akl EA, Briel M, You JJ, et al. Potential impact on estimated treatment effects of information lost to follow-up in randomised controlled trials (LOST-IT): systematic review. BMJ. 2012;344:e2809

·        FDA, Data Retention When Subjects Withdraw from FDA-Regulated Clinical Trials. Guidance, October 2008, announced in the Federal Register 1 December 2008

·        FDA, Payment and Reimbursement to Research Subjects. Information sheet guidance, January 2018

·        FDA, Protocol Deviations for Clinical Investigations of Drugs, Biological Products, and Devices. Draft guidance, December 2024

·        ICH E6(R3) Good Clinical Practice, section 2.9 on participants who discontinue or withdraw

•  •  •

The Open Site File is general education about how clinical research sites work. It is not regulatory, legal, or medical advice, and it is not tied to any specific study, sponsor, or employer. If you are in a trial, your study team and your own doctor are the right people to ask about your situation. Always follow your own site’s SOPs, your protocol, and your PI and QA team. Names and characters are invented composites.

Disclosure: The Open Site File is part of Root to Rx, published independently by Open Label Media LLC. Views expressed are personal views of Justin Yamashita and do not represent his employer or any affiliated organization. No employer resources or proprietary information are used. Every claim is sourced from publicly available materials.

Filed by Justin Yamashita, MSc., Open Label Media

Next in the file: Issue 17, Version History. Why consent is a document, and the chain of failures that made it one.