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Parts of a clinical trial protocol and Clinical Data Management (CDM) prospective to review

This blog talks about Protocol parts and key information needed for any Data Manager to design CRF. Protocols are quite specific to studies but share some common information and that is included in this blog to develop a general understanding about protocol. As per ICH, followings are the parts of any protocol.

  1. Protocol components:
  2. Study title
  3. Introduction/Background
  4. Objectives and End Points
  5. Study design and its rationale
  6. Population (Inclusion/exclusion criteria)
  7. Treatment
  8. Informed Consent Procedure
  9. Visit Schedule and Assessment
  10. Efficacy assessment
  11. Safety Assessment
  12. Discontinuation of the Study
  13. Data collection and its management
  14. Statistical methods
  15. Ethics
  16. Quality Control and Assurance
  17. Publication Policy
  18. Reference

1. Study title:  Protocol first page always has the title and Sponsor name. Example: “An Open label Phase III study to evaluate effectiveness of ATC-XX in treatment of Triple Negative Breast Cancer” The data Manager can easy interpret about Phase, Design and Target indication by just reading the study title.

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2. Table of content: It is same as any book’s table of content. Protocol is a big document so it is easiest way to navigate in the protocol.

3. Introduction: It gives the overview of the disease, epidemiology and current treatments. It tells about investigational drug candidates and purpose of the study. Not important for designing CRF but quite useful while preparing study related presentations.

4. Objectives and End Points:  Primary objective and secondary objectives and their associated end points are described in this segment. All study specific assessments are done considering primary and secondary points. All studies do not have secondary objectives.    

5. Study design and its rationale: This segment provides the key information for the data manager. In case of blinded study, Clinical Data manager has to provide restriction based data base access. The site generally has Clinical research co-ordinator and Investigator access to add data into database.  If it is adoptive design, then one has to be ready for many post production data base changes. This part gives the insight about rationale for the study design. If any particular combination of drugs is used or risk/benefit associated with any combination then this segment provide the rationale behind that.

 For example, it is needed to blind prolactin for many antipsychotic interventional studies. It is well known that Antipsychotic drugs increase the level of prolactin and by knowing its level one can learn about subject’s randomized status. This segment gives information about number of participants, cohorts and randomization method. It describes the study arms and One CRF is dedicated for study arms in eDC. Many CRF pages can be dependent on particular study arm. Just note down the study arms and read all the protocol with respect to each arm because many data point including inclusion/exclusion criteria may differ in each study arm. It is one of the most important segments of a protocol from a data manager point of view.

6. Population (Inclusion/exclusion criteria):  It is key information which determines which subjects meet the all set criteria to participate in a study. Inclusion criteria/exclusion criteria may be as simple as age/sex/Demography/Race and it may be as complicated as looking for a particular mutation in a tumor. Any subject, which does not meet all inclusion criteria but continue in study, may be the case of protocol deviations. Rescreening criteria should be checked in this section carefully. Sometimes Protocol allows rescreening after a particular time window eg one month. Rescreened subject may have a different subject number. Inclusion criteria/exclusion criteria numbers need to be captured in CRF.   It is confusing sometime for <= or >= signs commonly used for laboratory values.  Some protocol allows performing retest if initial laboratory results do not meet the inclusion criteria. Data Manager has to note these minute details.

7. Treatment: Description of all investigational drugs with their dosage form, route of administration, dosages, duration and frequency of administration and supply type (bulk, vials etc) can be seen here. Prohibited medication, concomitant therapy, infusion reaction therapy and prophylaxis regimens are described in this section. Prior and Concomitant therapy CRF, Dose administration record CRF are the two CRFs which gets 90 percents information from here. This part can be further divided into these parts. A) Subject numbering, treatment assignment and randomization (if study has this). B) Guidelines for dose reductions/modification, determination of Maximum tolerated dose (If it is Phase I study). C) Determination of dose limiting toxicities. D) Handling of study treatment and additional treatment E) Instruction on how to administer the drugs. F) Additional guidance if any applicable.

8. Informed Consent Procedure: It suggests about things which are needed to convey to subjects such as study related risk, any pregnancy related restrictions, common side effect which are known about investigational drugs. IRB/IEC approved informed consent form need to be signed by Subject prior participating in a study. Informed consent CRF is commonest CRF among all study related CRFs.

9. Visit Schedule and Assessment: This segment provide a description about visits, cycle in each visit, time window between each visits and assessment to be carried out at each visit and cycle. Data Manager must read the table given in protocol in this section. Vital sign, physical examination, laboratory assessment, imagine assessment, ECG, PK evaluation; RECIST evaluation (oncology studies), study drug administration time, post treatment evaluation, baseline assessments and study specific assessments are the common points. 70 percents CRF pages can be prepared by just this table.

10. Efficacy assessment: The procedure or check which can clearly tells whether investigational drug works or not.  iRECIST and RECIST assessments are the common for oncology assessments and CRF for this is included in the database design. Measuring glucose level and Hba1c is done for diabetic studies quite commonly. It depends generally on primary and secondary end points in study.

11. Safety Assessment: It describes the definition of adverse events, serious adverse event and reporting requirements.  Duration, start date, end date, Outcome of adverse event, relationship to study drug, CTCAE Grades, are the common information required to report an adverse event. Protocol can provide study specific guidance for reporting the adverse event. CTCAE version is mentioned in the protocol.  Protocol says about timing for SAE reporting, In general, 24 hours it should be reported to sponsor after learning of its occurrence. Data Manager read this section carefully as there is one dedicated CRF for this crucial information.  Generally, AE is noted once subject signs the informed consent form and may be recorded even till follow up visit as per study requirement.

12. Discontinuation of the Study:  Protocol defines the circumstances under which study drug can be withdrawn. Generally they are; Subject or guardian decision, adverse event including death or major protocol deviation and early termination of study by sponsor. Data manger has to understand under which circumstance study treatment is discontinued and under which circumstance subject is discontinued from the study. Even after discontinuation of study treatment, subject can be in study. Protocol may suggest assessment before or after discontinuation of study treatment.

13. Data collection and its management:  It explains the process of data recording, format (electronic or paper), site monitoring, and review and query management.  It also mentions the names of dictionary for coding of concomitant medications, Medical history and adverse event. Recording keeping is done by sponsor designated portal which is matching regulatory stanadard.

14. Statistical methods: Protocol describes the statistical method to analyse the date. It talks about analysis of primary end point, secondary end point, handling of missing values, assessment of subject dosing, identification of recommended dose (Phase I), and PK data. It can include additional information based on study.

15. Ethics: Protocol mentions the statement about its commitment to follow ICH GCP and local guideline of particular country and other related information such role of IRB and Investigator. It is not important for CRF designing (Data Manager prospective)

16. Quality Control and Assurance: It contains the information about sponsor’s internal process of audit, standard operating procedure, all activities to meet GCP compliance. This segment does not have any particular information to be added directly into CRF. 

17. Publication Policy : It says where the protocol will be registered (eg, website of mode of publication of study results. Every sponsor may have different policy for publication.

18. Reference: List of all reference used in protocol to gather information.


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