Cinical trial protocol writing
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This document provides guidance on writing clinical trial protocols and investigators brochures. It discusses that a protocol is a complete description of a clinical trial that includes objectives, design, methodology, and other key elements. It emphasizes writing clear and unambiguous eligibility criteria. It also reviews important sections of a protocol including study design, safety reporting, statistics, and informed consent. An investigators brochure is a comprehensive document summarizing safety information about an investigational product from preclinical and clinical trials to guide its use in humans.
Cinical trial protocol writing
- 1. CLINICAL TRIAL PROTOCOL DEVELOPMENT AND INVESTIGATORS BROCHURE Dr Urmila M. Aswar, Sinhgad Institute of Pharmacy, Narhe, Pune -41
- 2. Protocol writing It is a complete written description and scientific rationale for a research activity involving human subjects. o Objectives o Design o Methodology
- 3. Writing a Protocol – First steps  The PI must know the answers for  Is it reasonable? Do we have the resources?  What are the significant risks?  Do we have the patient population?  Associate Investigator/ outside investigators may be included.  Should be able to write the whole CT in few lines
- 4. Who Reads Protocols? • The protocol language/ content should be understood by – Other physicians – Nurses/CRAs – IRB members – Scientific reviewers – IC for a lay person
- 5. Templates availability • Many NIH programs encourage to use the protocol templates available eg. – http://ctep.cancer.gov/guidelines/templates.html • Following template guidelines can help guide authors with proper modifications.
- 6. Parts of the Protocol 1. 2. 3. 4. 5. 6. 7. 8. Introduction/Abstract Objectives Background/Rationale Eligibility criteria Study design/methods (including drug/device info) Safety/adverse events Regulatory guidance Statistical section (including analysis and monitoring) 9. Human subjects protection/informed consent
- 7. 1. Objectives • Objectives should be stated clearly as hypotheses to be tested. • Each objective should have a corresponding discussion in the statistical section.
- 8. 2. Background and Rationale • All protocols require a section detailing the scientific rationale for a protocol and the justification in medical and scientific literature for the hypothesis being proposed. • Introductory section should be organized in a logical, sequential flow.
- 9. Background and Rationale • Double check all citations • Common mistakes • Name misspellings (including wrong initials), wrong journal names, wrong years of publication, and wrong volume numbers
- 10. 3. Eligibility criteria- defn. • Inclusion and exclusion criteria are the conditions that must be met in order to participate in a clinical trial. • The most important criteria used to determine appropriateness for clinical trial participation include age, sex, the type and stage of a disease, treatment history, and other medical conditions.
- 11. Writing Eligibility Criteria for Patient • Eligibility criteria are the largest barrier to clinical trials. • There is no guideline for writing these criteria • Poorly written or poorly conceived criteria may affect the scientific validity of CT. • Reasons for imposing eligibility criteria includes scientific rationales, safety concerns, regulatory issues, and practical considerations
- 12. The points to be considered to write a good eligibility criteria 1. The number of eligibility criteria should be kept to a minimum. 2. Criteria should include only those absolutely necessary to ensure scientific validity and patient safety. 3. Eligibility criteria should be clearly defined and verifiable by an external auditor.
- 13. 4. Eligibility criteria should be straightforward and unambiguous. Which of these criteria is better understood? 1. Pregnant and/or nursing women are not eligible. 2. All women of childbearing age are required to have a negative serum pregnancy test. 3. Nursing women are not eligible for this study. All women of childbearing potential must have a negative serum pregnancy test within 2 weeks of study enrollment.
- 14. Failure to write eligibility criteria properly • Leads to Failure to mimic clinical practice Increased study complexity Increased costs Less number of patient getting recruited
- 15. Example • Eligibility criteria given by National Institute of Neurological Disorders and Stroke’s for recruiting participants for a clinical trial titled Study of Brain Activity During Speech Production and Speech Perception. • The inclusion criteria specified for the experimental group were (a) right-handed children and adolescents, (b) native speakers of American English, and (c) stuttering or phonological disorders. • The comparison (control) group consisted of normally developing right-handed children and adolescents who were native speakers of American English. • Exclusion criteria were (a) language use in the home other than American English, (b) speech reception thresholds greater than 25 dB, and (c) contraindications to magnetic resonance scanning.
- 16. 4. Study Design • The study design section of the protocol should contain a stepwise description of all procedures required by the study. • A good study design section includes sufficient information for the participating site.
- 17. Study Design • Parts of the study design section may include:  Initial evaluations  Screening tests  Required lab tests  Details of treatment or procedures  Device specifications  Dose scheduling and modification  Calendars
- 18. 5. Safety • Adverse effect and side effect are terms commonly associated with drugs. They are used by nurses and doctors, to refer to undesirable effects of a medication on a patient. • The Safety (or Adverse Events) section should include: • Detailed information for reporting adverse including reporting to the FDA and/or the sponsor • Unblinding processes (if applicable) • Lists of expected adverse events events,
- 19. 6. The Statistical Section • The study objectives and study design elements in the statistical section should be described in the Objectives section • The descriptions and definitions of toxicities in the statistical section match those in the Safety/AE section.
- 20. 7.Human Subjects Protection • This section includes discussion of: – Subject selection and exclusion – Proposed methods of patient recruitment – Minority representation – Recruitment (or exclusion) of special subjects, including vulnerable subjects – Lists of potential risks and benefits, including justification for risks
- 21. Informed Consent o Disclosure of relevant information to prospective research subjects o Comprehension of the information provided to the subject o Voluntary agreement of the subject. The protocol’s informed consent must • Be thorough and complete • Be written in simple, nontechnical language • Be carefully worded to avoid complexity.
- 22. The protocol’s informed consent must provide • Statement that the study involves research • Purpose of the research and the length of the study • Description of risks and benefits • Discussion of alternative therapies • Confidentiality policy • Compensation for injury • Contact for further questions/information • Statement of voluntary participation
- 23. Tools for Better Writing: Proofreading Working too long on a protocol may habituate eyes and brains to mistakes, simply because they’ve been there all along. Spell-checkers, etc. – A document should be checked by automatic software – The document should be proofread.
- 24. • Aoccdrnig to a rscheearch at Cmabrigde Uinervtisy, it deosn't mttaer in waht oredr the ltteers in a wrod are, the olny iprmoetnt tihng is taht the frist and lsat ltteer be at the rghit pclae.
- 25. NIH Guidance on Protocol Writing • Protomechanics: http://www.cc.nih.gov/ccc/protomechanics/ • The Office of Human Subjects Research: http://ohsr.od.nih.gov/info/info.html • The NCI Investigators’ Handbook: http://ctep.cancer.gov/handbook/index.html
- 27. IB • It is a comprehensive document summarizing information about an investigational product obtained during a drug trial. • The IB is updated with new information as it becomes available. • Compile data relevant to studies of the investigational drug in human subjects gathered during preclinical and other clinical trials.
- 28. • It sd provide the information for management of CT and safety during CT • • • • Dose (of the study drug) Frequency of dosing interval Methods of administration Safety monitoring procedures
- 29. IB contains Summary of Data and Guidance for the Investigator • Provide the investigator with a clear understanding of the possible risks and adverse reactions, details of tests, observations, and precautions that may be needed for a clinical trial
- 30. • The information should be based on the available physical, chemical, pharmaceutical, pharmacological, toxicological, and clinical information on the investigational product. • Should also provide treatment of possible overdose and adverse drug reactions. • The IB should be reviewed annually
- 31. IB • Detail guideline is provided in GCP and ICH