Essential Documents for Clinical Trials

In this article we wish to present a brief review of study essential documents that most often require translation during the course of a clinical study. We hope this article will be useful to those who, due to their activities, deal with translation of materials for clinical studies.

The essential documents for clinical trials are the following:

  • Investigator's Brochure
  • Clinical Study Protocol
  • Subject Information and Informed Consent Form
  • Clinical Study Reports
  • Case Report Form (CRF)

Now, let us consider in more detail these documents:

INVESTIGATOR'S BROCHURE (IB):

Contains pre-clinical and clinical information related to an investigational drug. The information should be presented in a concise, simple, objective, balanced form that should be taken into account during translation.

The Investigator's Brochure includes Title Page, which provides the Sponsor's name, the identity of investigational product (products), an edition number and date, and the number and date of the edition it supersedes as well. The Sponsor may wish to include a Confidentiality Statement instructing to treat the IB as a confidential document. A standard Investigator's Brochure usually includes the following sections:

  • List of Abbreviations
  • Contents
  • Summary – a brief description of significant physical, chemical and pharmaceutical properties of the investigational product, and also pharmacological, toxicological, pharmacokinetic, metabolic and therapeutic information that is relevant to the appropriate stage of clinical trial.
  • Introduction provides the chemical name (and generic and trade names, if approved) of the investigational product, all active components, pharmacological class, the rationale for performing further research with the investigational product and anticipated indications for its use. This section should provide the general approach to be followed in evaluating the investigational product.
  • Physical, chemical and pharmaceutical properties and formulation of the medicinal product.
  • Non-clinical studies - this section provides the data from animal studies regarding non-clinical pharmacological, pharmacokinetic, metabolic and toxicological characteristics of the investigational drug.
  • Clinical studies – this section provides information on pharmacokinetics, biotransformation, safety and efficacy in humans; data on post-marketing experience if the product under investigation has been already approved for use for other indications.
  • Conclusions and Guidance for the Investigator
  • References (the references should be provided at the end of each section)

The Investigator's Brochure should be reviewed at least annually and revised as necessary in compliance with a standard procedures established by drug development company.

CLINICAL STUDY PROTOCOL

After the objectives and design of a clinical study have been determined, these issues should be documented in the Study Protocol. The Study Protocol is a document containing instructions for all the parties involved in the clinical trial that establish specific objectives for each participant and provide guidelines for their performing.
The Study Protocol should ensure adequate conduction of the clinical trials and collection and analysis of data that are further submitted to the regulatory authorities for review and consideration.

The following sections should be included in the Study Protocol:

  • Introduction (brief description of the problem and treatment regimen(s))
  • Objectives and purposes of the study
  • Study duration
  • Number of subjects
  • Informed Consent
  • Opinion of the Ethics Committee
  • Subject selection criteria:
    • Inclusion criteria
    • Exclusion criteria
  • Methodology:
    • Study Plan
    • Study schedule
    • Study Visits
    • Study Assessments / Procedures
    • Definition of efficacy endpoints
    • Treatment cycles
  • Safety Reporting
    • Adverse events (AEs)
    • Serious adverse events (SAEs)
    • Abnormal laboratory test values
    • Abnormal values of other safety parameters
    • Withdrawal from the Study
  • Clinical laboratory parameters
  • Other safety parameters
  • Concomitant medications
  • Data analysis
  • Appendixes

The following appendixes may be included in the Study Protocol: Patient Information Sheet/Written information and/or Informed consent form (ICF). Instruction sheet (e.g. for study subjects or study site staff).

The terms, which may be difficult for understanding by study subjects (both medical and law terms) should be avoided in translation of the abovementioned documents containing patient information. If special terms are used in the documents, they should be clarified or explained.

PROTOCOL AMENDMENT

Protocol amendment describes major changes to the initial Study Protocol. Protocol amendment must be again approved by the Ethics Committee.

INFORMED CONSENT

Informed consent is one of the most important elements of system ensuring the ethics of medical experiments and protection of the rights of the study subjects.

Informed consent is a process by which a subject voluntary confirms his/her willingness to participate in one or another clinical trial, after having been informed of all aspects of the study. Informed consent should be documented by means of a written, signed and dated Informed Consent Form (ICF).

Potential subjects should be informed of the objectives and methods of the study, the drug product and treatment regimen, the available alternative treatments, potential risks and benefits, and of possible complications and discomforts, which may arise from participation in the study.

Based on information that he/she had received and understood, the potential subject freely gives consent to participate in a study. The informed consent should not be obtained through inducement or coercion. The subject should be aware that he/she may withdraw from the study at any time, and this will not affect his/her future medical care in any way.

The main principles of Informed consent

The subject should be informed of the following:

  • the purposes of the trial;
  • the methods of the trial;
  • the study drug(s) and treatment regimens;
  • available alternative treatment(s);
  • the potential risks and benefits, and possible discomforts.

The subject should understand:

  • that informed consent should be given freely;
  • that consent should not be obtained through inducement or coercion;
  • that he/she may withdraw from the study at any time;
  • that withdrawal from the study will not affect his/her future medical care.

STUDY PROGRESS REPORTS

The Investigator should provide written reports on study progress to the Ethics Committee. These may be the Interim report on the interim results of the study and their assessment based on the analysis conducted in the course of the study, or the Final report - full, comprehensive description of the study including description of investigational materials, study design, and presentation and assessment of results of statistical analysis. Additionally, the Investigator should prepare the written reports on all major changes that might affect study conduction and/or increase risk to study subjects. These are the following: Adverse Event Report or Adverse Drug Reaction Report, Patient Entry Form(Patient Entry Card/Patient Notification Form) and Patient Withdrawal Form, Protocol Deviation/Violation Report, Study Termination Report etc.

Reporting on study progress is not only responsibility of the Investigator, but also the Study Monitor should provide the written reports on each Study Monitoring Visit (Monitor Report). The Expert Report is prepared for the regulatory authorities by an expert in the appropriate field (company officer or independent person) and covers different aspects of drug development.

CASE RECORD FORM (CRF)

Case record form is a paper or electronic document designed to record all the information for an individual study subject required by the Study protocol.

The Case record form is used for several purposes:

  • to ensure data collection in accordance with the Study protocol;
  • to ensure fulfilling of the regulatory authorities' requirements for data collection;
  • to facilitate the effective, comprehensive data processing and analysis, results reporting, and to promote the safety data sharing between the study team and other departments of the institution.

The data collected in the study site during the course of a study should be comprehensive and provide true and fair information on what happened to each study subject. Only if the above criteria are met, the study will reliably answer the questions concerning the efficacy and safety of the investigational drug.

All CRF's should include the following data:

  • study title and number;
  • Investigator's name;
  • study subject/patient ID (number and initials);
  • inclusion / exclusion criteria;
  • demographic data;
  • detailed description of dosage regimens of investigational drug;
  • concomitant treatment;
  • adverse events (side effects and intercurrent diseases);
  • conclusion on subject's health;
  • Investigator's signature and date.

Additionally, the CRF's should include special pages to record the following information:

  • past medical history;
  • results of physical examination;
  • primary and secondary diagnoses;
  • relevant previous treatment;
  • baseline characteristics, results of interim assessments, evaluation of efficacy endpoints, laboratory tests, description of study procedures etc.

All CRF's should be legible and suitable for duplication and possible additional sharing.

References:

  • Cochrane Collaboration Glossary
  • A. Yu. Mel'kov, English-Russian Glossary of terms used in clinical studies of pharmaceutical products, CRO “InnoPharm”
  • Rules of Clinical Practice in the Russian Federation Ministry of Health of the Russian Federation.
  • M.V. Leonova, I.L. Asetskaya, Development of Study Protocol and Case Record Form Russian State Medical University, Moscow. Article in Russian language.
  • T.K. Efimtseva, A.L. Spasokukotsky, O.V. Mironova. Good Clinical Practice. English-Russian glossary. Ukrainian medical Journal - № 2 (28) - III / IV 2002.

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