Guidelines for the preparation of protocol and documents in clnical trials
Download as PPTX, PDF50 likes9,719 views
The document discusses documentation requirements for clinical studies, including Good Clinical Practice (GCP) guidelines and federal regulations. It provides examples of essential documents that must be maintained at different stages of a study, such as documents created before, during, and after a study. It also discusses source documents, progress notes, documentation of investigational drugs, and other sponsor-required documents like quality assurance and training records. Proper documentation is necessary to obtain useful study data and demonstrate compliance with regulations.
Guidelines for the preparation of protocol and documents in clnical trials
- 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.