Overview

In order to run a successful clinical trial of pharmaceutical or medical device a large number of supporting trial materials (documentation) need to be created, reviewed, and implemented.

Aim

This article aims to briefly describe the types of documentation used in clinical trial and the service for their development and review. Within the article the words “Trial” and “Study”, “Subject” and “Patient” have the same meaning and are used interchangeably.

Grouping of Clinical Trial Documentation

Some of the trial materials could be regarded as “core” documentation (e.g., Clinical Study Protocol, Investigator’s Brochure etc.), others as materials created to support clinical trial (e.g., Project Management Plan, Project Communication Plan, Clinical Monitoring Plan, Newsletters, Study Logs and various study-specific Forms etc.). Large and essential group of trial materials are called “subject facing materials” meaning they are supposed to be directly distributed to subjects participating in a clinical trial – those include, but are not limited to Informed Consent Forms, Emergency Cards, various scales, and questionnaires.

Types and purpose of Clinical Trial Documentation

Below is a non-exhaustive list of the most common trial material types and their purpose:

Clinical Study Protocol (CSP) – as per Good Clinical Practice guideline it is “A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial. The protocol usually also gives the background and rationale for the trial, but these could be provided in other protocol referenced documents.”. This essential document is a cornerstone of a clinical trial and should be mandatorily followed by all involved parties. Clinical trial investigational Sites could find all necessary information in it, e.g., subjects’ inclusion/exclusion criteria, study procedures flowchart, information about Investigational Medicinal Product (study drug) or Medical Device, safety events reporting requirements & considerations etc. The above information helps them to effectively run clinical trial from the moment their Site is initiated in the study until the closure of the study.

Investigator’s Brochure (IB) – as per Good Clinical Practice guideline it is a “compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects. Its purpose is to provide the investigators and others involved in the trial with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose frequency/interval, methods of administration: and safety monitoring procedures. The IB also provides insight to support the clinical management of the study subjects during the course of the clinical trial.”.

Project Management Plan (PMP) – main document describing the planning, execution, and oversight of the clinical study project. This document should be in place and agreed between the Sponsor and Clinical Research Organization (CRO) the latest prior to initiating the first clinical trial Site in the study. Professionally written PMP makes it easy to run clinical trial and to promptly make any changes to it if needed.

Project Communication Plan – documents the process of project communications (including escalations, if applicable) between CRO, Sponsor, Regulatory Authorities, and any involved Third Party Vendors (Suppliers). This document, when followed ensures the smooth communication and execution of the clinical trial.

Clinical Monitoring Plan – Documents the process of clinical study Sites monitoring from the moment of their initiation and until their closure. Good Clinical Practice defines monitoring as the process “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).”.

Project Risk Management Plan – documents the process of project-related risk identification, assessment, monitoring, and control (including risk mitigation actions). It is of vital importance that any risks in running clinical trial are identified, documented, and mitigated as applicable.

Trial Master File Management (TMF) Plan – documents how records for the clinical study will be managed and stored during and after the study. Handling of all trial records as per TMF Plan ensures the trial data accuracy, integrity and completeness and allows for reproduction of clinical trial events well after the clinical trial closure (according to GCP and other local country-specific requirements the trial records should be retained for prolonged periods of times and should be destroyed only upon Sponsor’s approval).

Protocol Deviation Management Plan – documents the process for identification, reporting and management of Protocol Deviations in clinical study. We all are humans and during our day to day activities we are prone to mistakes/errors. Those could however be either non-intentional or intentional. All departures from the requirements stipulated in the Clinical Study Protocol and related trial documentation are considered as protocol deviations and should be promptly identified, documented, reported to applicable authorities and all efforts should be performed in order to prevent their reoccurrence in the future.

Safety Management Plan (SMP) – documents the roles and responsibilities involved in the collection and processing of Safety Events (e.g., Serious Adverse Events, Adverse Events of Special Interest etc.) in a particular clinical trial. SMP make sure that all Safety Events are managed in a unified manner and as per GCP and country-specific requirements.

Third Party Vendor (TPV) Management Plan – documents deliverables, milestones, oversight, escalation, and clinical study project related procedures applicable to TPVs contracted to perform various services. TPVs are essential in clinical trial management and could perform a range of services e.g., laboratory samples management, storage and distribution of study drug(s), organizing subject travel to and from clinical trial Sites etc. Carefully selected and managed TPVs are essential to clinical trial execution.

Project Blinding Plans – document the Project and Site level processes for maintaining clinical study blind, managing intentional and unintentional unblinding incidents in the clinical study. Some of the clinical studies as per design are blinded. Most typical example is a double-blind study in which neither the study subject nor the most of CRO, Sponsor or clinical study Site staff, involved in the treatment or clinical evaluation of the study subjects, are aware of the treatment received (either an active study drug or placebo or comparator).

Informed Consent Form (ICF) – also is usually called “Patient Information Sheet and Informed Consent Form” (for adult subjects) or Assent Form (for adolescents). This is a written document which has all necessary clinical trial information in order for the subject to make an informative voluntary decision to participate or not to participate in a proposed clinical trial. Before being handed to subjects for signature each ICF template is thoroughly reviewed and approved by Regulatory Authorities and applicable Ethics Committee.

Subject Emergency Card – the small, usually “pocket size” format document having 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. This document is discussed and distributed to subjects as soon as they sign the corresponding ICF to take part in the clinical trial. Subjects are recommended to keep this card with them at all times during the participation in the clinical trial, so they can demonstrate it to medical personnel not involved in the clinical trial in which the subject participates.

Scales and Questionnaires – a set of documents aiming at collection of information necessary to analyze various aspects of subjects’ participation in a given clinical trial (e.g., changes in subjects’ quality of life, changes in health status and vital signs etc.). Depending on their aims such documents could be either completed by Investigators (by interviewing subjects) or by subjects themselves. In the latter case it is essential that Investigators do not adversely influence the subjects responses/completion, so that unbiased data can be obtained and analyzed. Usually if subjects are completing scales and questionnaires this is done before any clinical trial procedures are performed at the day of completion.

Study Logs and study-specific Forms – documents that are developed with the aim to ease the collection of study-specific information at Clinical Trial Sites and make it readily available for clinical monitoring and audits. Various clinical trials have various logs and forms, but the typical examples of such documents are: Subject Screening and Enrollment (Randomization) Logs, Investigational Medicinal Product Accountability Logs, Serious Adverse Event Report Forms, Temperature Monitoring Logs for storage of study drug and other trial materials etc.

Study Newsletters – a compilations of important study information (e.g., subject recruitment status, study news and updates, safety information, instructions on elimination of issues leading to protocol deviations etc.) which are provided on a regular basis to participating Clinical Trial Sites.

Regulatory considerations for Clinical Trial Documentation

Some of the above clinical trial documentation (e.g., Clinical Study Protocol, Investigator’s Brochure, subject facing materials etc.) are a part of regulatory submission dossier and should be mandatorily approved by Regulatory Authorities (usually Ministries of Health of participating countries) and Ethics Committees (could be Central and/or Local ones) prior to their use in the clinical trial.

Adaptation of Clinical Trial Documentation and translation considerations

In international clinical trials the typical language of the documentation is English, so in order for such documentation to be used in different counties an adaptation to country-specific requirements and corresponding translations have to be performed.

Initial versions of the created trial documentation are usually called “master” versions; after their adaptation they become “country-specific” and sometimes “site-specific” (if Clinical Trial Sites have their own requirements). If talking about clinical trial documentation the terms “draft” and “final” are also being used to identify the status of the document.

Amendments to Clinical Trial Documentation

Clinical trials can be of various duration and there might be a necessity to implement changes. In such cases amendments to the trial documents are being issued.

CRO-Sponsor cooperation with regards to Clinical Trial Documentation

Services that are provided by Clinical Research Organization to Sponsors with regards to study materials include, but are not limited to:

• Development of the documentation
• Review of Sponsor-provided documentation and providing feedback with suggestions and recommendations
• Adaptation of documentation to Country and/or Site-specific requirements
• Translations of Country and/or Site-specific documentation.

Carpathian Research Group capabilities

Carpathian Research Group as a Clinical Research Organization provides the service of study materials development/review and helps our Customers to successfully achieve Clinical Trial goals and objectives. 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

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