CT SOP version no 1.0.

Main changes from LM SOP No. 2.07: Adapted to the wording of the clinical trial regulation no 536/2014.

Sponsor

The sponsor has overall responsibility for ensuring that the CRF and PRO forms are prepared and managed in compliance with this SOP.

The sponsor’s responsibilities shall be described in the quality system of the sponsor institution. Tasks are delegated according to SOP Roles and Responsibilities in clinical trials implemented in the institution.

The sponsor may transfer any or all of the sponsor's trial-related duties and functions to a third-party vendor such as a Contract Research Organisation (CRO), but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf. Transfer of duties shall be specified in a written agreement.

Coordinating Investigator

The coordinating investigator has the responsibility for ensuring that assigned tasks are carried out according to the requirements of this SOP.

The coordinating investigator will ensure that:

• The appropriate CRF and any required PRO forms (paper or electronic) for the collection of trial-related data are prepared.
• The correct versions are available and used by each centre.
• CRF and PRO forms are or have been tested or validated before use.

The coordinating investigator must approve the CRF and any PRO forms before use, and approve any amended versions.

Principal Investigator

The principal investigator is responsible for correctly completing all required fields in the CRF. This task may be delegated to other suitably qualified persons. The names and roles of people who have been assigned the task will be entered into the site specific Delegation Log - Template.

Data Managers

Data managers will:

• Prepare and test CRFs and PRO forms.
• Review data in trial databases.
• Manage auto and manual query process.

Statistician

It is recommended that a statistician checks that the variables necessary for evaluation of at least primary endpoint are included in the CRF.

Monitors

It is recommended that the lead monitor checks the CRF for variables that should be source data verified, and that check boxes are placed accordingly (if possible). Monitors will verify the accuracy and completeness of CRF entries by reviewing source documents and other trial-related records, including PRO data, according to the agreed monitoring plan.

General Principles

The CRF and PRO forms should be designed and completed to ensure accurate recording, interpretation, verification and reporting of data from the trial, and shall be in accordance with the approved protocol.

Data recorded in the CRF and PRO forms should be pseudonymised, unless otherwise specifically authorised by the IEC, and a unique identification code (subject number/randomisation number) should be used for each subject.

Full identification of the trial subject (Identification & Enrollment Log - Template) should not be stored together with the trial data.

In general, only data required for the study objectives should be collected. To comply with data protection principles as few personal data (e.g. demographics) as possible should be collected (data minimizing).

To ensure uniformity in the collection of data, it is recommended that CRF completion guidelines are prepared, as necessary. If a new version of the CRF is issued, then the completion guidelines should be revised, and if necessary, an explanation of what has changed should be included.

Completion instructions for PRO forms are usually part of the collection instrument and separate instructions are not required.

A blank original (not completed) CRF and PRO forms are essential documents according to ICH GCP, and copies must be kept in trial file. See Study Files – SOP 1.6.a.

There will be additional requirements specific to e-CRF/e-PRO and other electronic systems used in data collection. See Data Management - SOP 1.12.b.

CRF Construction

The data manager will start work on the design of the CRF before the protocol is finalised. The CRF will be finalised when the protocol is final and approved by the relevant authorities.

If the protocol is amended during the trial and this has an impact on the data to be collected, the data manager will ensure that the CRF is updated and given a new version number and version date. The new version must be approved by the coordinating investigator before it is made available for the trial centres.

The data manager will ensure that CRFs are easy to use, logically constructed and divided into the separate trial visits described in the protocol.

The data manager will prepare CRFs which consist mostly of multiple forms for each trial visit (treatment and follow-up visit, if applicable), continuous forms and final trial completion forms. In some trials it is also appropriate to include follow-up visit forms. A treatment visit is a visit which occurs while the subject is being administered trial drug, as opposed to follow-up visits, which are intended to evaluate long term safety and/or efficacy of the treatment.

Adverse events and concomitant medication are usually collected in modules that are independent of trial visits (continuous forms).

When using a paper CRF, the data manager will ensure that all pages are numbered with the page number and the total number of pages. Each page shall be clearly marked with the visit identifier or name (for a continuous form).

CRF Outline

The data manager will ensure that all required modules for a trial and the trial-specific data are included in the CRF. The required modules will usually include, but not be limited to the following:

Selection criteria

• Inclusion criteria.
• Exclusion criteria.
• Date of consent.

Treatment visits

• Demography (first visit).
• Medical history (first visit).
• Trial Procedures (tests/examinations).
• Response to treatment (laboratory results, CT scans etc.).
• Safety variables (laboratory results, etc.).
• Handling and administration of trial drug (this can also be a continuous form).
• If necessary, a signature module for the principal investigator or authorised trial personnel to confirm that the data is complete and correct.

Continuous forms

• Documentation of adverse events (Adverse Events, Serious Adverse Events).
• Concomitant Medication.
• Handling and administration of trial drug (depending on the trial setup).

Follow-up visits

• Trial Procedures (tests/examinations).
• Response to treatment (laboratory results, CT etc.).
• Safety variables (adverse events incl. laboratory results etc.).

End of trial form

• Date and reasons for trial termination.
• Signature module where principal investigator or sub-investigator confirms that all data are complete and correct.

Construction guidelines

The CRF designer should prepare CRFs which are clear, concise and consistent, by ensuring that:

• All CRF pages contain fields for recording the trial subject's identification code (subject number/randomisation number). It is also recommended to have a field for the centre number.
• The data which is to be recorded and measuring scale/unit to be used, must be clearly and unambiguously identified.
• Electronic CRFs include logical checks or minimum/maximum values for the data, if possible.
• Free text fields are not recommended, as textual data is difficult to analyse. If text fields are necessary, the designer should ensure that there is enough space.
• Features exist to facilitate coding (drug use, diagnoses and/or adverse events).
• Check that the CRF contains exactly, and only, the data required by the protocol.
• There are fields where one can check if procedures are not carried out and/or are not relevant. If not carried out, this should be explained in a separate field.
• Familiar terminology is used, including established abbreviations, for the relevant discipline.
• There is no duplication of information.
• The CRF is dated and version controlled.
• The person entering data does not need to perform calculations, unless this is absolutely essential. It is more efficient to perform calculations in the analysis phase of the project.
• Standardised font size, colours, headers, etc. are used throughout the CRF.

To ensure accurate recording and interpretation of data, it is recommended that the project leader, a data manager, a statistician and monitor review the CRF prior to its use.

The data manager and statistician and the project leader should approve the CRF. An email from each person stating that the CRF is approved can be used to document approval.

Testing

Data manager must ensure that the CRF and PRO are tested before use. This should be done by entering some representative test data (including errors) to the eCRF/DEA.

Testing/validation should be documented, and the documentation should include the test data, printouts/listings of data and for eCRFs a PDF of the resulting eCRFs.

Updating of CRFs

If any deficiencies in any parts of a CRF are observed during the trial, the project leader should ensure that the developers are requested to make the necessary modifications, while at the same time informing all centres about the changes. Every effort should be made to schedule CRF development to avoid the need for design changes once data entry has started.

Data monitoring

Monitors will check the accuracy and completeness of CRF entries according to the monitoring plan, see Monitoring - SOP 1.14.a.

Data managers will review data recorded in the database for missing data, inconsistent data, data outliers. This will be done using automatic and manual queries as defined in the data management plan for the trial.

Use of PROs

It is recommended that only validated Quality of Life Forms and other validated instruments or questionnaires forms are used. These often belong to an organisation who owns the copyright, and some organisations charge for use of instruments which they own. The project leader must ensure that requirements for licenses and copyrights are satisfied.

If it is necessary to use a PRO other than validated quality life questions, the project leader should ensure that the instrument is self-explanatory, or if necessary, simple instructions should be provided.

Free text fields should be avoided/minimised in PROs, including diary cards. Free text fields are difficult to analyse and patients may report adverse events etc that are not picked up.

Useful links

• European Organisation for Research and Treatment of Cancer: Cancer-specific quality of life questionnaires and multiple diagnosis specific questionnaire modules for use with different cancer diagnoses.
• RAND Medical Outcomes Trial Measures of Quality of Life Core Survey from RAND Health Use of the SF-12 is governed by Quality Metric, which has no affiliation with RAND (payment is required).

• WHO-5 Well-Being Index 

Instructions can be included in the eCRF or specified in a separate document.

Data managers and CRF designers should consider including the following in the CRF instructions:

Electronic CRF and paper CRF (all CRF types)

• Never leave any fields blank. If data is unavailable, enter UN (unknown), NK (not known), MD (missing data), ND (not done) or other agreed notation. NA (not applicable) should be used only if the data is not relevant.
• Be accurate, data should match the source data. If data is subject to interpretation, obtain expert advice.
• Only use standard clinical abbreviations.
• Never write the name or social security number of a subject in the CRF.

Paper CRF

• Always use a black or blue ball point pen.
• If CRF is made of NCR paper, always use an appropriate separator (cardboard/thick paper) prior to writing on the CRF.
• Use the fields that are provided, do not write in the margins.
• Each trial visit should be signed and dated by the principal investigator or professionally qualified person who has been delegated the task, to confirm that all the data reported in the CRF for a subject is complete and correct.

Electronic CRF (eCRF)

• Never share your user ID and password.
• Never store user ID and password in unsecured locations. Try to memorise them so that they do not need to be kept on paper.

Electronic CRF and paper CRF (all CRF types)

Any change or correction to a CRF should be dated, initialled, and explained (if necessary) and should not obscure the original entry (i.e. an audit trial should be maintained); this applies to both handwritten and electronic changes or corrections.

Procedures for making corrections to CRF data, or for answering queries (including custom correction forms) shall be agreed in advance with the project leader.

Paper CRFs

Corrections to the sponsor’s copy of the CRF (before the original is sent to the sponsor) will be carried out as follows:

• Delete the incorrect data by drawing one straight line through the incorrect data, so that the original data can still be read.
• Write the correct data in close proximity to the original field.
• Corrections shall be dated and signed with initials and an explanation of the correction should be provided if it is not obvious why the correction was made
  For example: 2009 2010NBL.

Corrections made to CRF data after the original page has been sent to the data manager will be done using query forms. Query forms are also used to verify data that is outside defined quality standards and specified limits, or where data are unclear or difficult to read.

The data managers will send queries to the principal investigator who will ensure that the query is answered. A copy of the completed and signed query form with be attached to the CRF and the original will be sent to the data manager.

• Delegation Log - Template
• Identification & Enrollment Log - Template