Clinical Research and Pharmacovigilance

2. Introduction
Proper documentation is critical to the success of
a clinical study. Every aspect of the study must be
documented in order to obtain useful data and
demonstrate compliance with Good Clinical
Practice (GCP) guidelines and with all applicable
regulations.
Documentation Requirements in GCP and Federal Regulations
GCP guidelines list the essential documents (ICH GCP E6 Section 8)
that, at a minimum, must be maintained for every clinical study.
These documents are to be maintained by the site and the
sponsor, and are classified according to the stage of a study at
which they are normally created. These documents may be
maintained in multiple locations, depending on whether they are
stored with regulatory files or as participant documents.
The sponsor and the investigator/institution should maintain a record of the
location(s) of their respective essential documents, including source documents.
Additional documents may be developed and maintained by the sponsor or the
sponsor(s) representatives.
Documentation Requirements in Good Clinical Practice
Guidelines

3. Before a Study Begins
The following essential documents must be created and kept on file at study sites before a study
begins:

4. While a Study is in Progress
The following are essential documents that should be added to the file while a study is in
progress:

5. After a Study is Completed or Terminated
The following are essential documents that should be added to the file after a study is
completed or terminated:
Documentation Requirements in Federal Regulations
21 CFR 312.62 requires investigators to:

6. Examples of Other Sponsor-Required Documents
In addition to the essential documents
included in the GCP guideline, the sponsor
may require other documentation. The
following lists examples of other
documentation that may apply to clinical trials.
Certificate of Confidentiality
A Certificate of Confidentiality provides an
additional level of protection for the privacy
of participants in alcohol and drug abuse
research studies.
Quality Assurance Documents
Quality assurance documents may include the following:
• Research site Initiation Activation Form, which indicates that a site is ready to start study
enrollement.
• Site visit logs, to record visits to the research site by quality assurance monitors and other
personnel
Training Documents
A training plan and verification of compliance with the training plan, including:
• All training documentation form for each staff person
• Documentation of required assessments training per the study training plan.
• Documentation of study–specific training.
• Pertinent certifications for clinical staff implementing a study intervention.

7. Behavioural Therapy Documents
Many CTN studies involve behavioural interventions. Behavioural studies may require essential
documents different from, or in addition to, those required by GCP guidelines. These documents
may include therapy manuals and materials, audio and videotapes of treatment sessions, and
other documents specific to the behavioural intervention that is being studied.
Source Documents
Source documents are original documents, data, or
records that are created during a clinical study, that
relates to the medical treatment and the history of
the participant, and from which study data are
obtained. Source documents are one type of
essential document that is required by GCP
guidelines.
The purpose of source documents (GCP 8.3.13) is to:
• Document the existence of study participants.
• Substantiate the integrity of the study data collected.
Any document in which information, an observation, or data generated relevant to a study
is recorded for the first time is a source document. Thus, a scrap of paper, a note, or an
electronic mail message may be a source document if it is the original form on which
information relevant to a study is recorded.

8. Examples of Source Documents
The following are examples of source documents:
• Adverse event and concomitant medication logs
• Reports of diagnostic test results
• Signed and dated Informed Consent Forms
• Participant diaries
• Appointment calendars
• Progress notes
• Paper case report forms (CRFs) on which data are entered directly onto the CRF, rather than
extracted from another source document.
Progress Notes
These source materials must be readily available and
retrievable for quality assurance monitoring and for
auditing, for example, by the study sponsor (NIDA) or
for inspection by the U.S. Food and Drug
Administration (FDA). The purpose of progress notes
is to document participants’ involvement in the study
and the study–related care they receive. Both
research and clinical staff may complete progress
notes.
Progress notes are source documents; and may not be recorded in the study database or sent to
the sponsor. Often, progress notes are used on–site to monitor the progress of the study.
Another important purpose of progress notes is to substantiate the data recorded in the case
report forms (CRFs)

9. Progress notes should be concise but should provide enough information that the participant’s
study– related activities, and the order in which events occurred, can be easily understood.
Progress notes are of two types, both considered to be essential study documents:
• Clinical notes record information related to the experimental treatment that the participant
received during the clinical phases of the study.
• Research notes record information related to the participant's involvement in the research
phases (e.g., follow-up assessment visits) of the clinical study.
CTN–Specific Essential Documents
CTN investigators are required to maintain a Certificate of Confidentiality, QA, Training,
Behavioural Therapy, Source, Progress Note, and CRF documents for CTN studies. Additionally,
contact information should be maintained for the following CTN study personnel:
• Key personnel at the Lead Node.
• Key personnel at the Participating Node.
• Key personnel at the NIDA Center for the Clinical Trials Network (CCTN).
• The NIDA Study Medical Officer and other parties who must be contacted when expedited
reporting of an adverse event is necessary.

10. Documenting the Use of Investigational Drugs
21 CFR 312.62 requires investigators to maintain adequate records of the disposition of
investigational drugs, including dates, quantities, and use by participants. The investigator must
also maintain records of receipt.
The following equation may help in understanding the process of accountability for drug
disposition:
Although this equation may look simple, in practice accounting accurately for the disposition of
an investigational drug can be quite complicated. The investigator must account for every unit of
the investigational product (e.g., tablet, capsule, inhaler).
Let’s take a closer look at what is involved in accounting for every unit of an investigational
product.

11. Documentation of the "Amount of Drug Received"
Documentation of the "amount of drug received" must account for:
• The total number of capsules, tablets, etc. in every dosage (e.g., 5 mg, 10 mg).
• Multiple lot numbers.
• The type of packaging in which the medication is delivered (e.g., bulk supply, individual kits).
Documentation of the "Amount of Drug Used"
Documentation of the "amount of drug used" must account for:
• The amount of medication that each study participant is individually exposed to.
• The total amount of medication consumed by all study participants.
• The amount of medication that is returned by participants (i.e. unused).
• The amount of medication that is wasted (e.g., lost, dropped down the kitchen sink).
Verification of the "Amount of Drug on Hand"
Inventory must be taken at regular intervals to verify the "amount of drug on hand." Any
discrepancies must be documented.
To ensure proper accountability, a carefully designed plan (or standard operating procedure)
must be in place at the beginning of the study to document the disposition of the investigational
product at each site. This plan must be adhered to throughout the study and, if necessary,
modified to ensure 100% accountability. The investigator’s records of drug disposition must
agree with the data submitted to the sponsor.

12. Summary of Key Points

13. Guidelines for the Preparation of Protocol
Introduction
The trial documents are both a resource and an outcome; they are the outcome of the study
and a resource for the regulators.
• The regulators cannot observe each trial but would depend on the trial documents and results
to decide whether the new drug or device has an acceptable risk benefit ratio or not.
Trial master file
• Guideline E6 states that trial master file should be established at the beginning of the trial,
both at the investigator/institution site and at the sponsor’s office.
• A final close-out of a trial only be done when the monitor has reviewed both the
investigator/institution and sponsor files and confirm that all necessary documents are in the
appropriate files .
• The file maintained at the site is often called the site master file.
• The file is generally the responsibility of a designated member of the investigating team at the
site of the monitor at the sponsors office.

14. Protocols and their Amendments
• The master document of the trial is the protocol.
• The Guideline ICH E6 defines the protocol as the document that describes the objectives,
design, methodology, statistical considerations, an organisation 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 also.
• In case, if there is an amendment to the protocol, the same should be put up before the IRB
for approval before it is implemented.
• Appendix II (6) of schedule Y to Drugs and Cosmetic rules(2005) implies that all clinical trials to
be carried out as per the conditions laid down in the Declaration of Helsinki(DOH).
Contents of protocol
• The contents of a trial protocol should generally include the following topics. However, site
specific information may be provided on separate protocol page(s), or addressed in a separate
agreement, and some of the information listed below may be contained in other protocol
referenced documents, such as an Investigator’s Brochure.
General Information:
• Protocol title, protocol identifying number, and date. Any amendment(s) should also bear the
amendment number(s) and date(s).
• Name and address of the sponsor and monitor (if other than the sponsor).
• Name and title of the person(s) authorized to sign the protocol and the protocol
amendment(s) for the sponsor.

15. • Name, title, address, and telephone number(s) of the sponsor's medical expert (or dentist
when appropriate) for the trial.
• Name and title of the investigator(s) who is (are) responsible for conducting the trial, and the
address and telephone number(s) of the trial site(s).
• Name, title, address, and telephone number(s) of the qualified physician (or dentist, if
applicable), who is responsible for all trial-site related medical (or dental) decisions (if other
than investigator).
• Name(s) and address(es) of the clinical laboratory(ies) and other medical and/or technical
department(s) and/or institutions involved in the trial.
Background Information
• Name and description of the investigational product(s).
• A summary of findings from nonclinical studies that potentially have clinical significance and
from clinical trials that are relevant to the trial.
• Summary of the known and potential risks and benefits, if any, to human subjects.
• Description of and justification for the route of administration, dosage, dosage regimen, and
treatment period(s).
• A statement that the trial will be conducted in compliance with the protocol, GCP and the
applicable regulatory requirement(s).
• Description of the population to be studied.
• References to literature and data that are relevant to the trial, and that provide background for
the trial.

16. Objectives/Rationale/Research Question
• Include a detailed description of the primary and secondary objectives and the purpose of the
study and clearly state your research hypothesis or your question.
• Discuss the project’s feasibility
• Give details of resources, skills and experience to complete the study.
• Include any pilot study information
Clinical Study Design
• Primary and secondary endpoints, if any, to be measured during the study.
• Include the information that is needed to answer the research question.
• Include the study design e.g. single, double-blind, observational, randomized, retrospective
etc. A schematic diagram of the study design would be helpful.
• Include the amount of dosage, dosing regimen of the drug, packaging and labelling of the
experimental drug.
• Identify possible benefits of the study.
Inclusion and Exclusion criteria of the Subjects
• Include subjects inclusion criteria.
• Include subjects exclusion criteria. Women of childbearing potential may not be routinely
excluded from participating in research, however, pregnant women should be excluded unless
there is a clear justification to include them.
• Include enrolment of persons of diverse racial and ethnic back grounds to ensure that the
benefits of the research study are distributed in an equitable manner.

17. Informed consent form process
• Provide information about the regulatory requirements of the consent form and which
languages will be used.
• Include a discussion of additional safeguards taken if potentially vulnerable subjects will be
enrolled in the study e.g., children, prisoners, cognitively impaired and critically ill subjects.
• Specify Code of Ethics under which consent will be obtained.
• Include a copy of the proposed informed consent along with the protocol.
Adverse Event Reporting
• Describe your plan to report any adverse event.
• Anticipated adverse events should be clearly documented.
• Identify the type and duration of follow up and treatment for subjects that experience an
adverse event.
Assessment of Safety and Efficacy
• Be specific about the efficacy parameters.
• Include the methods and timing for assessing, recording, and analyzing efficacy parameters.
• Specify the safety parameters.
• Record and report properly all the adverse events and inter current illnesses.

18. Treatment of Subjects
• List all the treatments to be administered including product’s name, dose, route of
administration, and the treatment period for subjects.
• Include all medication permitted before and during the clinical trial.
• Include the procedures for monitoring subject compliance.
Data Collection Plan
• Define the type of data collection instrument that will be used and list all the variables.
• Specify if computerized databases will be used.
• Identify what software will be used.
• Explain precautionary steps taken to secure the data.
Data Access
• Inform who will have access to the data and how the data will be used. If data with subject
identifiers will be released, specify the person(s) or agency to whom the information will be
released and the purpose of the release.
• Address all study related monitoring, audits, and regulatory inspections.
Statistical Methods
• Describe the statistical methods in detail.
• Include the number of subjects you are planning to enrol. For multi-center studies, include the
total number of sites expected and the total number of subjects to be enrolled across all sites.
• Provide the rationale for the sample size , the calculations on the power of the trial and the
clinical justification.
• Procedure of accounting for missing, unused and spurious data.
• Procedures for reporting deviations from the original statistical plan.

19. Publication and Presentation Plans
List any meetings or conference you will be presenting the data and the results of your study.
Timeline
• A short paragraph stating when you plan to start and complete the study.
• Include a description e.g. subjects enrolment within a month, data collection within 6 months
etc.
References
List all the references used in the back ground section at the end of the protocol.