1. Caution Flags, Roadblocks & Pitfalls of Protocol Writing Brigitte Robertson, MD Sr. Medical Director March 2009

2. Page 2 Caution Flags: pay close attention or vigilance to minimize risk Over harmonization and use of templates with built-in language current approaches require a delicate balance between “standardizing” and addressing the specific needs of a project When entering new therapeutic areas, need to assure the key experts are involved early in design process – can’t be too early or too often.

3. Page 3 Caution Flags: pay close attention or vigilance to minimize risk Beware of the differences between Industry standard verses FDA guidance verses FDA international regulations in the treatment of patients. e.g. suicidality, abuse liability and comparators Need to consider corporate culture in projecting timelines for protocol completion and study execution When can third party vendors be contacted for study involvement, and is their review of the protocol necessary? What are the timelines around delivering a final protocol? Need to consider the whole audience Internal stakeholders FDA IRB Sites

4. Page 4 Roadblocks - any condition that makes it difficult to make progress or to achieve an objective; "intolerance is a barrier to understanding Ineffective and iterative reviewing and revising Poor version control for evolving protocol drafts Challenging integration of heterogeneous input: Functional area experts that recommend/insist on changes outside of their area

5. Page 5 Roadblocks roadblock - any condition that makes it difficult to make progress or to achieve an objective; intolerance is a barrier to understanding Insufficient feedback and awareness of group activities: Revisiting resolved issues by late-comers to the project or program Inefficient group coordination Need to anticipate functional lines ability to respond and integrate changes to each version of protocol

6. Page 6 Pitfalls: An unapparent source of trouble or danger; a hidden hazard A concealed hole in the ground that serves as a trap. Assumptions Protocol not fitting into the greater program and field e.g. clinical standard of care verses what is in the protocol i.e. placebo/active control, demographic and geographic influences may vary dramatically IRB changing membership/idiosyncratic Logistics: patient participation, recruitment of physicians and sites: run through from each disciplines perspective, and very important to journey through the study as a patient Percieved verses actual understanding of proposed objective, metric or activity CRA/CRF capture of data

7. Page 7 High quality important, perfection impossible

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9. Page 9 TIP SHEET Writing a Research Protocol Last updated August 2008 1 CTEO TIP SHEET | Writing a Research Protocol First Steps  Have a good idea!  Know the difference between a grant proposal and a research protocol. Grant Proposal Research Protocol Purpose Obtain funding Regulatory document describing single study in detail Focus Describes aims, methods, hypotheses Organized around objectives of study Feasibility Costs, staffing, equipment Specifics of enrolling, implementation details Tone Persuasive Informative; focused on details  Determine your study objectives. These should be clearly defined and attainable. Start Work  Review the latest literature.  Generate measures of exposure and outcome. Consider how others have defined/measured the exposure and/or outcome.  Consult with your DF/HCC biostatistician. The statistical power of a study should be an early consideration, and investigators should draw on professional statistical advice to avoid unnecessary or unproductive studies.  Draft a concept first and ask others to review it. Start Writing  Use the DF/HCC Biomedical Protocol Template or guidance document most appropriate to your study. These are located on the DF/HCC website in the Clinical Investigator Toolkit. The toolkit is accessible through the Clinical Trials Portal.  Assign writing tasks to others when appropriate.  Be specific about data requirements. Outline what data is needed, when it needs to be collected, how often it needs to be collected, and how it will be analyzed. TIP SHEET Writing a Research Protocol Last updated August 2008 2  Use checkpoints to maintain design consistency. The research question(s) must be measurable by the response variables and recorded on the data collection forms in a format suitable for statistical analysis. As each section of the protocol is written, cross-check it with other segments for agreement.  Minimize the likelihood of protocol amendments, where possible. Consider the strictness of the eligibility criteria and consider whether any flexibility can be incorporated into the protocol to minimize the need for substantial protocol amendments. For example, changing the age range in a study from, say, 18-70 to 18-75 in order to increase the rate of accrual is less likely to affect the safety of a study than a change in age range from, say 18-70 to 14-70.  Spell out abbreviations and acronyms at first use. Even the most well known acronyms.  Utilize version numbers and version dates during the drafting process. The final protocol that is submitted to the SRC/IRB should ideally be numbered version 1.0 with the date of finalization of the protocol.  Apply the CATS standard to your title. Keep it Concise, Accurate, To the Point, and Short.  Proofread the document. Correct any typographical errors, misspellings, or sloppy formatting.  Don’t panic or give up if your protocol isn’t approved the first time. The SRC/IRB review critiques can be used to improve the protocol so that it does better the next time it is reviewed.