Overview

Nowadays the majority of Clinical Trials are multi-national involving various countries, so the main (“master”, typically English) versions of Study Materials should be adapted as per country-specific requirements in order for Sponsor to obtain trial authorisation from Regulatory Authorities and Ethics Committees.

Study Materials are covered in our article Study Materials Development and Review Service

Aim

This article aims to briefly introduce the process of Study Materials’ adaptation to satisfy country-specific requirements.

Process

In most of cases the following Study documentation requires country-specific adaptation:

• Informed Consent Forms for subjects to document their agreement to participate in a given Clinical Trial
• Subject Emergency Cards (if used) containing essential Clinical Trial information (Sponsor name, protocol title, general information on the Investigational Medicinal Product etc.) along with contact details of Investigator and Sponsor in case of emergency situations
• Scales and Questionnaires (if used) aiming at collection of information necessary to analyse various aspects of subjects’ participation in a given Clinical Trial
• Subjects’ Recruitment materials, if used (including advertisements)
• Investigational Medicinal Product Labels which will be affixed to the Study Drug in a given Clinical Trial
• Clinical Trial Insurance documentation for participating subjects
• Study Plans (e.g., Project Management Plan, Study Start-up Plan, Clinical Monitoring Plan, Recruitment Plan etc.).

All Study documentation being provided to subjects should always be in language understandable to clinical trial participants , therefore it should be appropriately translated to all official languages in the particular country and included into the submission dossier for Regulatory Authorities and Ethics Committees review before they can grant Clinical Trial Authorisation.

Investigational Medicinal Product Labels are always submitted for Regulatory Authority’s review and used in official language of the country in which a given Clinical Trial is planned to be conducted.

Other documentation mentioned in the above list can be used in English or be bi-lingual (English + official language of the country in which Clinical Trial is to be conducted).

Below is a non-exhaustive list of applicable actions which are performed in order to ensure that Study documentation is compliant with country-specific requirements:

1. Check that documentation is in line with country-specific legislation and regulations governing the conduct of Clinical Trials (both with respect to content and document availability)
2. Check that documentation is accurately identifying the study Sponsor (e.g., name and address, contact details etc.)
3. Check that the Study title is in accordance with the Clinical Study Protocol, and its identification number
4. Check if Investigator’s and Institution’s name and address are accurately specified or there are allocated fields to enter this information (e.g., during Informed Consent Process)
5. Check that Regulatory Authority, Ethics Committee names and approval status are accurately specified
6. Check that Clinical Trial Insurance information (e.g., company name, insurance agreement/policy number, contact details or responsible person) is accurately specified
7. Check that emergency contact details of Clinical Trial Site are specified
8. Check that documentation (e.g., Informed Consent Form) has appropriate signature fields for subject, his/her legally authorised representative (if applicable), impartial witness (if applicable); and for responsible Investigator obtaining Informed Consent Form
9. Check that all document’s headers and footers contain accurate Clinical Trial specific information, type of the document itself, as well as appropriate versioning, dating and pagination
10. Check that country-specific requirements for Data Privacy protection are clearly specified in applicable documentation
11. Check that country-specific requirements for handling of biological samples (e.g., blood, urine, tissue samples etc.), including their exportation abroad with further analysing in Central Laboratory are clearly specified in applicable documentation
12. Check that country-specific requirements for managing subject’s complaints and appeals with regards to Clinical Trial participation are clearly specified in applicable documentation
13. Check that Investigational Medicinal Product Labels clearly specify manufacturer, Clinical Trial specific information, pharmaceutical dosage form, route of administration, quantity of dosage units, strength/potency, batch and/or code number to identify the contents and packaging operation, directions for use, specification “For clinical trial use only” etc.

During the adaptation process the clear and proactive communication between Contract Research Organisation and Sponsor ensures that the process is executed smoothly and reduces the amount of potential deficiency letters received from Regulatory Authorities and Ethics Committees.

Only approved by Sponsor English country-specific versions of Study documentation are sent for corresponding translation for subsequent use in a given Clinical Trial.

Carpathian Research Group capabilities

CRG as a CRO has a proven track record of country-specific adaptations of Study documentation leading to Clinical Trial authorisations and having no documentation-related findings during audits & inspections.

Information on all other Clinical Trial services that we provide could be found at www.crg.global

You can contact us at info@crg.global

Overview

As per Good Clinical Practice (GCP) guideline “the purposes of trial monitoring are to verify that:

• a) The rights and well-being of human subjects are protected.
• b) The reported trial data are accurate, complete, and verifiable from source documents.
• c) The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).”.

Clinical Trial monitoring is achieved via conducting the monitoring visits to Clinical Trial Sites (hereinafter referred to as “Sites”) either face-to-face or remotely.

The visits are performed by monitors (Clinical Research Associates, CRAs).

According to GCP guideline:

• “a) Monitors should be appointed by the sponsor.
• b) Monitors should be appropriately trained and should have the scientific and/or clinical knowledge needed to monitor the trial adequately. A monitor’s qualifications should be documented.
• c) Monitors should be thoroughly familiar with the investigational product(s), the protocol, written informed consent form and any other written information to be provided to subjects, the sponsor’s SOPs, GCP, and the applicable regulatory requirement(s).”.

The Sponsor of each Clinical Trial is responsible to develop a systematic, prioritized, risk-based approach to monitoring Clinical Trials. The Sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or, where justified, centralized monitoring. The Sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan).

Centralized monitoring is a remote evaluation of accumulating data, performed in a timely manner, supported by appropriately qualified and trained persons (e.g., data managers, biostatisticians). Centralized monitoring processes provide additional monitoring capabilities that can complement and reduce the extent and/or frequency of on-site monitoring and help distinguish between reliable data and potentially unreliable data.

Aim

This article aims to briefly introduce the monitoring, describe the types of monitoring visits of Sites in Clinical Trials, and focus on a Pre-Study Site Selection Visit as a starting point in the monitoring process.

Process

Depending on the timeframe (phase) in which each particular Clinical Trial Project is the following visits types are identified:

• Pre-Study Site Selection Visit (also known as Pre-Study Visit, Site Selection Visit, Site Qualification Visit)
• Site Initiation Visit
• Interim Monitoring Visit (also known as Routine Monitoring Visit)
• Close-out Visit.

Additionally, Co-Monitoring Visit(s) may be performed with the aim of either supporting the CRAs in their visit activities or assessing Site’s/CRAs’ adherence to Clinical Trial Protocol, GCP and other clinical research regulations. Co-Monitoring Visits are out of scope of this article.

Monitoring visits have typically one business day in duration, but depending on Clinical Trial complexity, amount of data to be reviewed and other factors their duration can be increased.

The main written documentation of each monitoring visit (irrespectively of its type) includes:

• Confirmation letter – a letter/e-mail sent to Site well in advance of planned monitoring visit and which includes the details and activities to be done during the visit
• Visit report – detailed description of all activities performed during the visit as well as all identified deficiencies, deviations, and action item(s)
• Follow-up letter – a letter/e-mail sent to Site after the visit has been conducted and which includes the details of all activities performed during the visit as well as all identified deficiencies, deviations, and action item(s).

All confirmation, follow-up letters and Site Initiation Visit Report (per GCP requirements) are to be properly stored in Investigator Site File located at Sites.

Pre-Study Site Selection Visit (PSSV)

This is the starting point of interactions between Sponsor/CRO and Clinical Trial Site. It is performed after the Site Identification & Feasibility process has been completed.

The PSSV is performed to ensure that:

1. A potential Principal Investigator (PI) is qualified and interested in conducting the clinical study
2. The PI’s Site has adequate facilities, and resources to properly complete all required study activities
3. Site has required pool of patients to complete enrollment.

Items to be reviewed/discussed may include, but are not limited to:

• Feasibility Questionnaire completed by Site
• Clinical Study Protocol/Synopsis and Clinical Study timelines
• Enrollment (recruitment) target, strategy, expectations, and availability of subject population
• Qualifications/ training, experience, interest and availability of the PI and Site Staff performing study related duties
• PI and Site Staff obligations, ICH-GCP / ISO 14155 guidelines (if applicable) and regulatory requirements
• Therapeutic area being investigated (including applicable standard of care)
• The PI’s/Site Staff’s regulatory inspection/audit experience, if any, and the outcome of the inspection/audit(s)
• IRB/IEC requirements, documentation, and approval timelines
• Site budget and execution of Clinical Trial Agreements
• Informed Consent Process and documentation requirements
• Source document and study record requirements, as well as Source Data definitions and Good Documentation Practice
• Monitoring visit process/schedule, PI and Site Staff availability, other competitive clinical trials with the same pathology run by Site
• The monitoring strategy including remote monitoring and remote Source Data Verification capacity and acceptance (if applicable)
• Electronic Data Capture (EDC) requirements, including vendor-specific experience, internet connectivity, and computer availability, if applicable
• Turn-around time for data entry and data query resolution
• Local country / Site-specific requirements for clinical study conduct (e.g., Site SOPs)
• Reporting and documenting safety events (e.g., Adverse Events, Serious Adverse Events, Adverse Events of Special Interest, SUSARs, pregnancy, study drug overdose etc.)
• Medical management of study subjects remotely, if appropriate
• Assessment of storage area and conditions for Investigational Medical Product (IMP) (includes Investigational Medical Device (IMD) and/or other study supplies/materials)
• IMP/IMD Accountability procedures (receipt, storage, dispensing, and record keeping)
• Laboratory sample handling procedures, including supplies, collection, and shipment.

During PSSV CRA ensures the adequacy of facilities where study subjects will be seen by visiting (touring) them (e.g., exam rooms for subject evaluation and treatment, laboratory and any special testing area, pharmacy (if applicable), any satellite sites (if applicable), working area for Site staff, data entry area etc.) CRA also ensures the adequacy of available equipment to be used in clinical study (including validity check for calibration/maintenance documentation).

As part of PSSV CRA requests/collects any required Site documentation which may include, but is not limited to:

• Confidentiality (Non-Disclosure) Agreement, if applicable
• Medical licenses (Institution and Site staff) and dated/signed Curriculum Vitae (CVs)
• Current GCP and ISO 14155 (if applicable) training certificates or certificates of relevant training(s) as listed on the corresponding CVs
• IRB/IEC membership list (roster), SOPs (if applicable) and statement of compliance
• Electronic Health Records related documentation, if used
• Completed dated/signed Project-specific forms and questionnaires required to qualify the Site, as applicable
• Local laboratory reference ranges, accreditation certificates and CV of Head of local laboratory if it will be used
• Dated/signed attendees log, Clinical Study Protocol, and Investigator Brochure acceptance pages.

The above documents may be collected as originals or copies, depending on Sponsor’s/country specific requirements.

On the basis of conducted PSSV and the review of all applicable documentation the Sponsor either approves Site’s participation in the given Clinical Trial or declines it.

If Site is approved CRA sends an appropriate Site Selection Letter and in case of disapproval – the appropriate Site Non-Selection Letter.

The above letters will thank PI and Site Staff for completion of Selection activities and will state the further actions to be completed (if Site is approved) or will explain the reason(s) for non-selection decision.

Carpathian Research Group capabilities

CRG as a CRO has extensive experience in conducting Pre-Study Site Selection Visits and choosing the most suitable Sites for successful Clinical Trial execution.

Information on all other Clinical Trial services that we provide could be found at www.crg.global

You can contact us at info@crg.global

Overview

The majority of Clinical Trials are international and run in multiple countries, so in order to make their conduct successful many trial-related documentation needs to be translated, reviewed, and delivered on time.

The key outcome of each translation project is that the translated documents/materials are accurate and completely convey the content and meaning of the source documents.

Prior to initiating the translation process of any documentations, the Translation Project Manager analyzes and confirms the Customer`s specifications for the translation and CRG’s capability to meet them, determining whether all the necessary human, technical, and technological resources are available.

Aim

The aim of this article is to describe the process of managing translation projects at CRG from the moment they are awarded by a Customer to the agreed completion of the project. At CRG all translation processes are organized and running as per ISO 17100:2015 “Translation services — Requirements for translation services”.

Definitions used in this article

Computer-Assisted Translation (CAT) Tool – a software used by human translators, revisers, reviewers, and others to facilitate their work.

Certificate of Translation Accuracy (usually abbreviated as CoT) – a written statement certifying that the translation has been completed by an experienced, qualified, and competent professional translation team and that the translated text truly reflects the content, meaning and the style of the original text and constitutes in every respect a complete and accurate translation of the original documents.

Domain – a subject field, sphere of knowledge or activity having its own specialized culture, social context, and linguistic characteristics.

Subject Matter Experts (SMEs) – are those individuals with specific expertise and responsibility in a particular area or field.

Source language – a language of the content to be translated.

Target language – a language into which source language content is translated.

Term base – a database containing single words or expressions related to a specific subject. Terms in term bases are often bilingual or even multilingual.

Translation memory – a database in CAT tool that stores sentences, paragraphs or segments of text that have been translated before. Each entry, or segment, in the translation memory includes the original source language and its translation, known as the “target”.

Translation project (process) lifecycle

The process lifecycle is a sequence of the process stages (key and supporting tasks) which illustrates the whole process from the beginning to its closure (see below). The SME review stage is not mandatory and could be requested by the Customer.

Perform the Translation

The Translator performs the translation of the source document(s) in accordance with the purpose of the translation project, including the linguistic conventions of the target language and relevant project specifications. To complete the translation, the Translator makes use of translation glossaries and translation memories, when available, to make sure that standardized and agreed translation terms are used.

Review the Translation

The Reviewer performs the review of the translation, as per the timelines communicated by the Translation Project Manager.

To complete the verification, the Reviewer examines the translation against the appropriate source document(s) (i.e., the original English source document) for any errors and other issues, and its suitability for purpose. The review is performed for the language flow, the edibility of the translated document(s), in order to confirm that the translation is accurate and completely conveys the content and meaning of the source document(s).

Perform the SME Review

The Subject Matter Expert carries out a translation validation to assess the suitability of the target language content for the agreed upon purpose and domain.

Errors identified during translation review process

All errors could be divided into such categories: Accuracy, Language, Terminology, Style, Country and Functional.

They are also further classified as Minor, Medium and Major as per corresponding CRG criteria.

Perform a Final Verification

The Translation Project Manager performs a final verification of the translation against the project specifications indicated in the Customer-CRG agreement concerning the document(s) formatting. If the final verification indicates any deficiencies in meeting these specifications, the Translation Project Manager makes corrections in the target document formatting.

Issue a CoT

The Translation Project Manager issues and signs a CoT and adds it to the package with the translated document(s).

Deliver the Translation

The Translation Project Manager delivers the translated document(s) to a Customer by means and in the format indicated.

CRG in-house translation services

Carpathian Research Group capabilities

Carpathian Research Group as a Clinical Research Organization provides professional translation services and helps our Customers to successfully achieve Clinical Trial goals and objectives. Information on translation services could be found at https://translate.crg.global/