1. The Clinical Trial Protocol: Writing Considerations AMWA Northern California Chapter 04 Oct 2014 10/4/20141

2. Topics Relevant definitions, background Protocol audiences Purposes of protocols Protocol components – Per ICH E6 – Additional (synopsis, glossary, appendices) IRB (or equivalent) review Uses for protocols Resources Writing tips 10/4/20142

3. What is a Clinical Trial? A clinical trial is any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. The terms clinical trial and clinical study are synonymous (ICH Guideline for Good Clinical Practice E6[R1] 10 June 1996). 10/4/20143

4. What is a Protocol? A protocol is a document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial.... [It] usually also gives the background and rationale for the trial, but these could be provided in other protocol referenced documents (ICH E6). 10/4/20144

5. Protocol Amendment A protocol amendment is a written description of a change(s) to or formal clarification of a protocol (ICH E6) A protocol amendment is – Required for any change that significantly affects the safety of subjects or the investigation’s scope or scientific quality, eg, increase in drug dosage or duration of exposure, any significant increase in the number of subjects under study (21 CFR 312.30) A protocol can only be amended by the Sponsor Usually a new (amended) protocol is prepared that includes or is accompanied by a list of descriptions of the change(s) and the rationales for the changes 10/4/20145

6. Protocol Audiences (I) Sponsor (and Clinical Research Organization) personnel (who are sometimes also contributors) – Medical monitors – Regulatory professionals – Those responsible for interacting with persons at vendors and clinical research sites and for monitoring the conduct of the trial (eg, Clinical Research Associates) – Writers of sample informed consent form (ICF), clinical study report (CSR), and manuscript(s) Persons at regulatory agencies (multiple times, eg, at initial review, when amended, when incorporated into the CSR) 10/4/20146

7. Protocol Audiences (II) IRB (or equivalent) members Site personnel – Investigators – Clinical Research Coordinators – Those preparing site-specific ICFs – Physicians and those implementing trial assessments and interventions – Subjects (indirectly, through the ICFs) 10/4/20147

8. Purposes of Protocols Communicate the details of the clinical trial to all audiences Contribute to the scientific soundness of the trial by helping to insure uniformity in its conduct Determine, in some instances, aspects of a patients’ medical care 10/4/20148

9. Protocol Components (I) Per ICH E6: – General information (title, sponsor [medical expert, signatories], monitor, Investigator[s]) – Background information (investigational product, previous nonclinical and clinical studies, risks, benefits, rationale, population) 10/4/20149

10. Protocol Components (II) – Objectives and purposes – Design (scientific integrity and data credibility, endpoints, type of trial, minimization of bias [randomization, blinding], treatment[s], duration, discontinuation criteria, study drug accountability procedures, treatment randomization codes, procedures for breaking codes, data recording) 10/4/201410

11. Protocol Components (III) – Selection and withdrawal of subjects (inclusion, exclusion, withdrawal criteria) – Subject treatment (screening through follow-up) – Prior and concomitant treatments (sometimes this includes food and activities) permitted – Compliance measurement – Efficacy assessment (parameters, assessment methods) – Safety assessment (parameters, assessment methods, follow-up) 10/4/201411

12. Protocol Components (IV) Statistics (methods; interim analyses; # of subjects; level of significance; trial termination criteria; handling of missing, unused, and spurious data and deviations from the Statistical Analysis Plan; subjects included in analyses) Direct access to source data/documents Quality control and quality assurance Ethical considerations Data handling, recordkeeping Financing, insurance, publication policy (if not in a separate agreement) 10/4/201412

13. Additional Protocol Components Protocol Synopsis Not mentioned in ICH E6 but usually is the first part of a protocol Should not have anything in it that is not in the protocol itself (though it may have statements that summarize what is in the protocol) Often in table format 10/4/201413

14. Additional Protocol Components Protocol Synopsis Content (I) Sponsor Product name Protocol title Planned study center(s) Objectives Study design Number of subjects 10/4/201414

15. Additional Protocol Components Protocol Synopsis Content (II) Test product information Duration of treatment Inclusion and exclusion criteria Assessments Endpoints Statistical methods Schedule(s) of Assessments and Procedures (SOA[s]) (may be here, within the protocol itself, or in an appendix to the protocol) 10/4/201415

16. Other Additional Protocol Components Glossary or List of Terms/Abbreviations – Abbreviations/acronyms used in text and, for some sponsors, tables (although also defined in table footnotes) – When to use abbreviations/acronyms and include in list varies by sponsor Reference list Appendices – Examples Schedules of Assessments and Procedures Sample ICF Instruments used to measure efficacy Specific laboratory tests to be performed Sponsor and Investigator signature pages 10/4/201416

17. Protocols Inform the IRB (or Equivalent Review Committee) An IRB – An independent body constituted of medical, scientific, and non-scientific members, whose responsibility is to ensure the protection of the rights, safety, and well-being of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of the trial protocol and amendments and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects (ICH E6) – Has authority to approve, require modifications in (to secure approval), or disapprove all research activities (21 CFR 56.109) at its associated institution – Performs continuing review of ongoing research at least once per year (21 CFR 56.109) 10/4/201417

18. Protocols Form the Basis for Information Provided to Potential Subjects and to Subjects Subject recruitment materials ICF Calendars and other instructions for subjects 10/4/201418

19. Protocols Inform Those Conducting the Clinical Trial Investigators and research site personnel use protocols to find out about why the trial is being conducted, what is to be learned, who is eligible to participate, and when and how clinical trial procedures are to be performed. 10/4/201419

20. Protocols Form CSR Content A CSR is a written description of a trial/study of any therapeutic, prophylactic, or diagnostic agent conducted in human subjects, in which the clinical and statistical description, presentations, and analyses are fully integrated into a single report (see ICH Structure and Content of Clinical Study Reports E3, 30 November 1995) (ICH E6) Sections of the protocol are often copied into the CSR (eg, introduction, objectives, investigational plan sections) and then the future tense (used in the protocol) is changed to past tense 10/4/201420

21. Protocols (Not Just Study Data) Are Described in the Investigator’s Brochure An Investigator’s Brochure is a compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the investigational product(s) in human subjects (ICH E6) 10/4/201421

22. Resources (I) Guidances – ICH Guideline for Good Clinical Practice E6(R1) 10 June 1996 – Disease-specific (eg, Guidance for Industry Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment [describes endpoints]) – Evaluation-specific (eg, Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs) 10/4/201422

23. Resources (II) Published style manuals (eg, AMA Manual of Style) Investigator’s Brochures Sponsors’ style guides, templates, and other protocols Package inserts for commercially available drugs Web sites of indication-specific organizations, eg, Infectious Diseases Society of America References obtained using search engines such as PubMed 10/4/201423

24. Writing Tips (I) Clarity and accuracy (to reduce error by those interpreting and implementing protocols) are of the highest priority; protocol deviations, which affect the scientific integrity of the results, should not occur because of a lack of writing clarity or accuracy – Write for understanding by all audiences – Be particular about internal consistency; those interpreting and implementing a protocol may not study the entire document – Make sure the SOA is complete as it may be the primary source of what is to be done when 10/4/201424

25. Writing Tips (II) If possible, include additional elements that can reduce protocol deviations: – Windows around time points, eg, ± 10 minutes around the time a sample is to be drawn – Specification that no eligibility criteria waivers (which are considered deviations) are permitted 10/4/201425

26. Writing Tips (III) Reduce redundancy (there is opportunity for error each time something is described); if possible write it once: – Write the synopsis after writing the body of protocol and excerpt sections from the body of the protocol for the synopsis or write the synopsis and then expand the synopsis text as necessary for the body of the protocol; writing them simultaneously can mean a matching nightmare – If assessments are repeated on multiple days, copy and past their first mentions to the sections for the subsequent time points that they are to be done – Unless it reduces clarity, combine sections that are identical that describe assessments at the various time points (eg, if assessments for Day 3, 7, and 9 are the same, combine all into 1 section for Days 3, 7, and 9) – Write it the same way every time so there is no confusion about what is meant; use search function to find all instances and paste in decided-upon text wherever needed – Unless it reduces clarity, use cross references whenever possible instead of repeating large blocks of text; eg, if a questionnaire is used, describe it once and reference this description elsewhere in the protocol 10/4/201426

27. Writing Tips (IV) – If possible, save most of the work on the abbreviation list and abbreviations in the text for the final draft and let the reviewers know that you have done this – Ditto for the reference list – List procedures in the procedure section of the protocol in the same order as in the SOA Complete the SOA, print it, and proceed from top to bottom, line by line, to write the assessment and procedures sections in the body of the protocol – Write keeping in mind the CSR and the New Drug Application (or similar) (eg, use the same definitions across the protocols for a particular study drug) 10/4/201427