How to Write a Clinical Protocol Rebecca Torguson, MPH Director, Cardiovascular Research Operations MedStar Cardiovascular Research network MedStar Heart Institute

I/we have no real or apparent conflicts of interest to report. Rebecca Torguson I/we have no real or apparent conflicts of interest to report.

What is research? Research is the systematic collection, analysis and interpretation of data to answer a certain question or solve a problem Formation of the topicHypothesis Conceptual definitions Operational definition Gathering of data Analysis of data Test, revising of hypothesis Conclusion, iteration if necessary

The Research Question However, usually too general ! ‘Research’ usually begins with a general question of interest to you, which may arise from an observation within your area of work or interest a prompt or issue in your field of study prior research of relevance However, usually too general ! Needs to be formulated into a specific question that can be investigated Once the question is defined, a systematic approach to the investigation must follow (research)

First Steps Gather your thoughts so you can clearly formulate them in the form of questions, aims, and hypotheses Perform a literature research make sure your ideas were not studied and published already Establish your investigational team Design a research approach strategy Secure budget and seek help for grant application writing

Research Protocol What is a Research Protocol? A formal document specifying what the study hopes to achieve and how it is to be conducted When should you write a Research Protocol? For every research project, no matter how small or seemingly insignificant

Why Writing a Research protocol? To clarify the research question To compile existing knowledge To formulate a hypothesis and objectives To decide about a study design To clarify ethical considerations (need for FDA approval, etc.) To apply for funding To have a guideline and tool for the research team Study design – causal relationship between exposure and outcome is relevant Ethical considerations - in new TB drugs I still need to cure the patients Order is not relevant

The Research Team… Ensure expertise in scientific, clinical, and methodological areas Expertise in statistics, health economics behavioral sciences, qualitative research, trialists (for RCTs) Add as Co-applicants / Collaborators Partner Organizations, e.g. academic, health service providers, government agencies

Prinicpal Components of the Protocol Adequate title Introduction/rationale of the study Objectives/hypothesis/endpoints Methodology/ Intended Populations Plan of analysis/ Statistical Approach Timeline Ethical considerations Bibliography Budget

Title of a research project Accurate, short, concise Descriptive: should make the main objective clear, should mention the target population Key words: should contain key words for referencing

Specific Aims Objectives

Research Objectives Define a GENERAL OBJECTIVE and derive SPECIFIC OBJECTIVES The formulation of objectives will help to: Focus the study (narrowing it down to essentials) Avoid the collection of data which are not strictly necessary for understanding and solving the problem you have identified Organize the study in clearly defined parts or phases

Research Hypothesis Intervention, Observation, Control variable Independent variable Dependent variable Make clear statements! Describes the relationship between INDEPENDENT variables (risk factors, predisposing factors) and DEPENDENT variables (outcome) Determines the type of data to be collected and the type of analysis to be conducted

Outcome of Interest Primary Endpoint Secondary Endpoints – What is it? – Can it be defined precisely? – Can it be measured? – How do you plan to measure / document it? Secondary Endpoints – Are there any? – If yes, how many? (too many?) – If no, should there be?

Study Design /Methods

Eligibility Criteria (Inclusion/ Exclusion)

Sample Size Estimation For almost every type of study Different inputs depending on study design Well laid out in statistical texts Trade off between power and practicality Be prepared to abandon study if necessary Get help!

Objective of Sample Size Estimation

Methodology Data quality control Describe measures of data quality control: Double data entry Consistancy checking Data monitor Verfication procedures of source data Interrater variability measurements (definition interpritiation)

Ethical considerations One of the most important aspects of biomedical research! Ask local IRB for advice as needed! Important aspects to consider: Data safety / confidentiality (need for CEC‘s and DSMB‘s) Any possibly harm/ side effects/ consequences Right of discontinuation at any time Role of data safety and monitoring board (in trials) Alternative treatments/ approaches (in trials) Risk versus Benefits

Ethical considerations Informed consent Outline how, when and where the patient will be consented! Information form should contain: Justification for research Responsibilities (Who) Outline of study Risks Insurance Confidentiality (legal framework) Volontary particpation A separate consent form is required! Simple language!

References/Bibliography Use of standard referencing system: Harvard style Name and publication year in text Alphabetical bibliography Vancouver style Numbered references Continous referencing in text Make use of software Reference Manager Endnote software See also „A Pratical Guide for Health Researchers“

Budget The budget should be broken down by: Items Budget justification Personnel Consumables, equipment, supplies, communication, funds for patients, data processing Budget justification Jusitify the use of each item, considering the workplan of the study

Appendicies Case Record Forms (CRFs) Questionaires Patient information form (in required languages) Consent form (in required languages) Core Lab requirements (as applicable) CV of investigators Statistical analysis plan Timelines: enrollment projections, follow up completion, manuscript submission Clinicaltrials.gov registration

Practical hints for funding proposals Discuss research proposal with your collaborators well in advance Strictly follow guidelines for applicants Application deadlines are strict Demonstrate your expertise Be realistic about the time things take Ask your colleagues to read your proposal prior to submission No typographical or other errors!

Consider the job of the reviewer … has an interest in ranking the applications in an unbiased, fair, scientifically rigorous way, giving the best scores to those grants that are most likely to contribute to our body of knowledge. may not be extremely familiar with all techniques. All parts of the grant must be clear and written in such a way that a non-expert can understand them. may not know the applicant personally. It is the job of the applicant to convince the reviewer. may not fully understand the significance of the research area without a clear, compelling argument presented in the application. is capable of understanding and interpreting preliminary data if well-presented.  must read 10 to 15 applications in great detail and form an opinion about all of them. The successful proposal is clear and precise, is easy to read, has a detailed experimental design section, and is free of typographical and other errors.

Good Luck!