Study Close-Out Procedures and Final Reporting

Part of Good Clinical Practice (GCP) — ICH E6(R3): Clinical Trial Closure and Archiving.

About 8 minutes. Free, in your language, no account needed.

Why this matters

A trial that recruits well and monitors well can still fail at the end. Data locked before queries were resolved cannot be reopened cleanly. Investigational product destroyed without documented sponsor authorization cannot be reconciled. Participants who are never told the results learn that research took something and gave nothing back.

Ending a trial early

Not every trial reaches its planned end. ICH E6(R3), the current revision of the Good Clinical Practice (GCP) guideline, sets duties on both sides. On the sponsor side, section 3.17.1 applies. If a trial is prematurely terminated or suspended, the sponsor should promptly inform the investigators, institutions and regulatory authorities, and give the reasons. The IRB/IEC is also informed promptly and given the reasons, by the sponsor or by the investigator or institution. Where appropriate, the sponsor gives the investigator information about potential subsequent therapies and follow-up for participants.

On the investigator side, section 2.6.1 is the one to memorize. If the trial is prematurely terminated or suspended for any reason, the investigator or institution "should promptly inform the trial participants and should ensure appropriate therapy and follow-up for the participants." Participants come first, before the paperwork.

Section 2.6.2 covers the investigator stopping without the sponsor's prior agreement: they promptly inform the institution, the sponsor, the IRB/IEC and the regulatory authorities, with a detailed explanation.

Section 2.6.3 covers the mirror case, and it is the one sites most often assume is somebody else's problem. Where the sponsor terminates or suspends the trial, the investigator or institution, or the sponsor — in accordance with applicable regulatory requirements — should promptly inform the IRB/IEC and the regulatory authorities, and should provide an appropriate explanation. The section cross-refers to the sponsor's duty in 3.17.1, and the point of reading them together is that the notification must reach the IRB/IEC and the authorities, not that it must come from a particular party. Agree before the day arrives which of you is making it.

Under section 2.6.4, if the IRB/IEC terminates or suspends its approval or favorable opinion, the investigator informs the institution where applicable, and the investigator or institution promptly notifies the sponsor.

Locking the database

Database lock is the point after which trial data may no longer be changed by routine means. E6(R3) does not use that phrase, but section 4.2.6, Finalization of Data Sets Prior to Analysis, describes the process.

Section 4.2.6(a) requires that data of sufficient quality for analysis are defined, and achieved by timely and reliable processes for data capture, verification, validation, review and rectification of errors and omissions that meaningfully affect participant safety or the reliability of results.

Section 4.2.6(b) requires the activities that finalize the data sets to be confirmed and documented in accordance with pre-specified procedures. They may include:

Section 4.2.6(c) requires data extraction and the determination of data analysis sets to take place in accordance with the planned statistical analysis, and to be documented.

Two consequences follow for sites. Outstanding queries sit on the critical path to lock, so late query closure delays the whole trial. And protocol deviations must be compiled and their impact addressed before lock, so a deviation reported after lock is a serious problem.

Section 4.1.4 also requires any unblinding, planned or unplanned, to be documented and assessed for its impact on the results.

Close-out at the site

Section 3.11.4.5.2(j) states what monitoring confirms at site close-out: "the arrangement for the retention of the essential records and the final accountability of the investigational product". A practical close-out visit covers four tasks:

Reporting duties

The investigator has reporting duties of their own. Section 2.13, Reports, states that upon completion of the trial the investigator, where applicable, should inform the institution. The investigator or institution should give the IRB/IEC a summary of the trial's outcome and, if applicable, give the regulatory authorities any required reports.

The sponsor's duties are in section 3.17.2. Under 3.17.2(a), whether the trial is completed or prematurely terminated, or an interim analysis is undertaken for regulatory submission, the sponsor should ensure clinical trial reports, including interim reports, are prepared and provided to the regulatory authorities as required. Reports in marketing applications should meet the standards of ICH E3, or otherwise accord with applicable regulatory requirements. Under 3.17.2(b), consideration should be given to a coordinating investigator being a signatory on that report.

Transparency and the participant summary

Section 3.17.2(c) applies once the trial is unblinded and the relevant analyses and conclusions are finalized. The sponsor should generally, in accordance with applicable regulatory requirements:

  1. Make trial results publicly available.
  2. Provide the investigator with information about the treatment taken by their participants, for blinded trials.
  3. Provide investigators with the trial results.

On the participant summary the guideline is explicit. Where a summary of trial results is provided to participants, this "should have language that is non-technical, understandable to a layperson and non-promotional." Non-promotional means you may not present a negative or inconclusive result as a success.

Principle 9.6 sets the wider expectation: "timely registration on publicly accessible and recognized databases and the public posting of clinical trial results. Communicating trial results to participants should be considered. Such communication should be objective and non-promotional."

In practice

ABC Pharmaceuticals suspends the hypertension trial after an interim safety review. Dr. Sarah's site has eleven participants still on the investigational product.

Her first action is not the file. Under section 2.6.1 she promptly informs the eleven participants and arranges appropriate therapy and follow-up for each. The sponsor, under section 3.17.1, gives information about potential subsequent therapy and notifies the investigators, institutions and regulatory authorities. Section 2.6.3 and section 3.17.1 both allow the IRB/IEC notification to come from either side, so Dr. Sarah confirms in writing with the sponsor which of them is making it before assuming it is done.

The site still has nineteen open queries. Under section 4.2.6 these must be resolved and the deviation list compiled and assessed before the data sets are finalized. Amina, the coordinator, closes them in nine days.

At the close-out visit the monitor confirms the essential record retention arrangement and the final investigational product accountability, as section 3.11.4.5.2(j) requires. Under section 2.13 Dr. Sarah gives the IRB/IEC a summary of the trial's outcome and informs her institution.

Nine months later ABC Pharmaceuticals sends a two-page participant summary. Amina reads it before distributing it. One sentence calls the suspended trial "an important step forward for our product". That is promotional, and section 3.17.2(c) says the summary must be non-promotional. She asks the sponsor to rewrite it.

A trial is not finished when the last participant leaves. It is finished when the record is closed, the results are public, and the participants have been told in words they can read.

Key takeaways