Trial Documents in Clinical Research

Documents play an important role as they individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents provide to exhibit the compliance of the investigator, sponsor and monitor with the norms of Good Clinical Practice and with all applicable regulatory requirements.

Various other important purposes are also served by these documents. Timely filing of essential documents at the investigator/institution and sponsor sites provides assistance in the successful conduct of a trial by the investigator, sponsor, and monitor. The sponsor’s independent audit function scrutinizes these documents and is also being inspected by the regulatory authority(ies) as part of the process to confirm the validity of the trial conduct and the integrity of data collected.

Trial documents required are as follow:

• Consent Document
• Case report for Protocol
• Investigator Brochure
• Informed rms
• Clinical study reports and summaries
• Contracts and agreements

Before moving into the next section, let us first know about the first and foremost important document “Protocol”.

A protocol can be understood with a simple quote “The beginning is the most important part of the work.”

What is Protocol?

• The context and structure for the planned study and how it will be implemented can be described by the Protocol document.
• These documents are written by trial sponsor personnel, individual investigators, clinicians, scientists, or any combination of these individuals.
• In the United States, the final protocol is submitted by the trial sponsor to the U.S. Food and Drug Administration (FDA) as part of an Investigational New Drug (IND) application or Investigational Device Exemption (IDE) application.
• The FDA must approve the protocol before the sponsor can start off the clinical trial at the investigative sites. However, not all protocols, require FDA review and approval.
• Protocols that are exempted from FDA approval before starting the trial are clinical investigations of marketed drugs, protocols that are post-marketing (phase 4), and observational protocols (that is, there is no investigational product understudy).

Components of Protocol:

• Introduction
• Background
• Rationale
• Previous Animal/Human Studies
• Objectives
• Endpoints
• Trial Design
• Subject Selection
• Randomization
• Treatment Plan
• Schedule of Assessments
• Test Article
• Preparation, Packaging, and Labeling
• Dosing Schedule
• Storage, Dispensing, and Disposal/Return
• Accountability Records
• Data Collection
• Adverse Event Reporting
• Statistical Analysis
• Ethical Considerations
• Informed Consent
• Confidentiality
• Benefits/Risk of Harm
• Inclusion of Women, Children, and Minorities
• Monitoring
• Subject Compensation
• Publication of Results

Background and rationale for the study:

• The background section of the protocol includes results from pre-clinical studies and previous clinical trials with a description of the disorder and Safety & Efficacy information from previous studies.
• The rationale for the study should clearly state the reason the trial is being conducted and should be consistent with the background information provided.

Study Organisation:
The organizational structure of the study is based on protocol needs, financial considerations, and logistical issues presented by the study design.

End Points:
• Endpoints are measures believed to appraise the potent effect of a treatment or therapy under study. In addition to clinical endpoints, the standard of living and economic factors may also be identified as endpoints.
• A clinical endpoint should be relevant and easy to interpret; clinically apparent and easy to identify; and sensitive to treatment differences.

Background Information:

• Literature review
• Safety assessment
• Therapeutic need
• New drug delivery system
• New dosage schedule
• Exploring new indications
• Therapeutic drug monitoring for safety/efficacy
• Regulatory filing

Aim of the study:

• Avoid multiple aims in a single study
• Comparison of efficacy of 2 antihypertensive drugs
• Effect on diurnal blood variation
• Efficacy with respect to Age, Sex, Associated conditions
• Makes the study design complex and often difficult to execute
• Advisable to consider not more than 2 aims at a time

Patient Selection: Inclusion Criteria:

• Systolic BP >140 mm Hg in sitting position
• Glycosylated Hb > 7.5%
• Acute myocardial infarction: ECG changes of AMI: q waves, ST elevation
• Age limits (lower and upper)
• Sex
• Associated disorders
• Concomitant treatments
• Effect of nondrug therapy

Patient Selection: Exclusion Criteria:

• Pregnancy, lactation
• Associated conditions, treatments
• Contraindications to study treatment
• Consider relative contraindications as well
• Patients not likely to attend follow up or comply with treatment

Criteria for evaluation of Efficacy:

• Necessary for efficacy comparison
• Definition of endpoint

1. Mortality
2. Completion of study treatment duration
3. Achieving target values

• Blood pressure, glycemia parameters
• Techniques/methods/conditions

1. Sitting and standing blood pressure
2. Analytical method for lipid estimation: Central laboratory
3. 24-hour urine output for protein estimation

• Calibration of equipment

1. Weighing machine, BP instruments

Data Collection:

1. Crucial information with impact on outcome measurement
2. Information to check the comparability of groups

• Physiological characteristics
• Demographic characteristics
• The onset of signs and symptoms
• Prognostic factors
• Concomitant illness
• Concomitant therapy
• Logical order for data collection
• Advantages and disadvantages of the order of data collection

Clinical Tolerability:

• Open-ended questions

1. Description of the event occurred in detail
2. The treatment administered for the AE
3. Outcome

• Close-ended questions

1. Demographic details
2. Date, time, manufacturing details of medication
3. Severity, duration
4. Laboratory investigations performed

Measuring Compliance:

• Questionnaire- Diet recall
• Tablet count- During follow up visit, collect used strips/blister/containers, unused medication
• Presence of markers - Colour markers for urine, stools, saliva
• Measurement of drug/metabolite in biological fluids
• Recording device incorporated in packaging
• Memory aids in packaging - Printing day/dates, illustrations

Golden rules of Good Clinical Practice:

• Let us conclude with a quote saying the importance of documentation as well as GCP
• If something is not written down, probably it was not done!

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