Writing Clinical Research Protocols Part 1 Preparation and

Writing Clinical Research Protocols Part 1: Preparation and Process Jonathan Mc. Call, BA Editor DCRI Communications

The Protocol-writing Process

The Protocol-writing Process ■ Clinical Protocols: an Overview ■ Preparatory Steps ■ Assembling a Protocol Team ■ Managing the Process ■ Resources and Guidance

Protocol Writing “The validity, accuracy, and coherency of the [protocol] document can have a huge influence on the treatment administration and on the interpretability of the results. If we wish to improve the quality of clinical trial protocols, we should improve the…writing process. ” Gennari JH, Medinfo, 2004

Protocol Writing: a Collaborative Process Clinical research protocols often (always? ) require the input of many knowledgeable people, including physicians, nurses, CRAs, regulatory experts, statisticians, information technology experts, and even sometimes editors…

Protocol Writing: a Collaborative Process “[protocol writing] is an intellectual and creative group task…” Weng C, Medinfo, 2004

Protocol Writing: an Iterative Process ■ Protocols are in constant flux*: ■ Content changes due to multiple contributors ■ Content changes in response to review or critique ■ Content changes necessitated by new clinical information ■ Content changes dictated by an evolving regulatory and ethical landscape *van der Lei J, What’s in a Protocol (position paper), 2000

The Protocol-writing Process ■ Clinical Protocols: an Overview ■ Preparatory Steps ■ Assembling a Protocol Team ■ Managing the Process ■ Resources and Guidance

Passing Muster You probably thought having an earthshaking idea that could advance scientific knowledge and change clinical practice was the hard part.

Passing Muster ■ Between the bright idea and successfully completed study, your protocol will have to pass muster with the following people: ■ Other physicians ■ Nurses ■ Patients ■ Reviewers (including IRBs)

Passing Muster ■ Thinking ahead about challenges—scientific, regulatory, cultural, and logistical—may mean the difference between a successful protocol and one that never makes it out of the preliminary review committee.

Some Questions to Ask Before Beginning ■ Basic Feasibility: ■ Are there enough potential subjects to meet my accrual goal? ■ Are there competing trials? (Remember: a trial may compete not only for patients but for access to drugs and devices. ) ■ Is there (note: NOT “should there be”) clinical equipoise regarding this research question?

Some Questions to Ask Before Beginning ■ Physicians and institutions: ■ Are other physicians likely to be receptive to this study idea? ■ Would participating in this study require special resources or entail financial drains on a practice? ■ Are other institutions likely to have the technology/expertise/support infrastructure/levels of training needed?

Some Questions to Ask Before Beginning ■ Patients: ■ Are patients likely to find this study interesting or acceptable? ■ How will patients learn about this study? ■ What risk or costs might patients have to bear in participating in this study?

Some Questions to Ask Before Beginning ■ Logistics ■ How will we accomplish randomization, drug shipments, unblinding, etc? ■ How will specimens be collected, stored, shipped, banked, read? ■ How will we audit for performance? ■ How will data be collected, transferred, stored analyzed? ■ How will we respond to “help desk” issues?

The Protocol-writing Process ■ Clinical Protocols: an Overview ■ Preparatory Steps ■ Assembling a Protocol Team ■ Managing the Process ■ Resources and Guidance

Representing the Relevant Areas of Knowledge ■ Principal Investigators ■ Statistics ■ Specialists (Imaging, Nuclear Med, Surgery) ■ Data management ■ Nursing/CRA ■ Regulatory ■ Safety ■ Patient advocacy ■ Study coordinator ■ Protocol editor

Creating a Realistic Timetable ■ The typical process: 1. “Submit an initial proposal, 2. Generate the first complete draft, 3. Iteratively review and revise the drafts, 4. Submit final draft to the [reviewing body] for approval. However, the details within step #3 are quite complex. ” Gennari JH, Medinfo, 2004

Creating a Realistic Timetable “However, the details within step #3 are quite complex. ” NB: UNDERSTATEMENT Gennari JH, Medinfo, 2004

Creating a Realistic Timetable ■ However long you think it will take, it will take longer. ■ Be aware of the intersection of: ■ Your own and others’ schedules ■ Project benchmarks and timetables ■ Review cycles

Clear Channels ■ Establish the lines of communications: ■ Who’s in charge? ■ Who has final responsibility for a given task? ■ How are consensus decisions made? ■ How is information communicated a) among the protocol group, b) between the protocol group and outside entities?

Clear Channels “…participants involved in protocol development have different levels of status…. the clinician researcher is usually treated as the highest-level authority. Thus, it is often hard or impossible for others (eg, the protocol editors) to make demands on these researchers. ” Gennari JH, Medinfo, 2004

The Protocol-writing Process ■ Clinical Protocols: an Overview ■ Preparatory Steps ■ Assembling a Protocol Team ■ Managing the Writing Process ■ Resources and Guidance

Some Problems that Plague the Process… ■ Ineffective or excessive review and revision ■ Poor version control ■ Integrating input from other contributors ■ Poor coordination Weng C, Medinfo, 2004

…and Some Possible Solutions: ■ Identify the person responsible for the content. ■ Identify the person responsible for integrating the content into the protocol. ■ Establish a process for deciding on accepting or rejecting critiques or suggestions. ■ Keep detailed minutes/records of all meetings or project discussions; mandate acknowledgment of receipt of important communications

Technological Solutions ■ Researchers with the available resources may be interested in exploring technological solutions, including software packages for multi-contributor projects, or develop an “inhouse” system. ■ These solutions may offer particular help in managing communication flow.

Be Mindful of Constraints ■ Protocols have a way of growing into “fishing expeditions. ” ■ “Mission creep” should be sharply constrained—don’t succumb to “kitchen sink” data collection. ■ Keep the protocol lean.

Maintaining Control ■ The “single-scriber” approach*: ■ A single person (usually the protocol editor) is charged with integrating contributions, maintaining a master file, and controlling file access during the draft process. ■ This person also usually takes responsibility for draft circulation and dissemination. *Gennari JH, Medinfo, 2004

Maintaining Control ■ A procedure for collecting sign-off on a draft document should be established. ■ A protocol checklist enumerating required items can be useful. * ■ Remember: regardless of procedures, final responsibility rests with the PI. † *CTEP Investigators’ Handbook, 2002 (Appendix VII) †Protomechanics, Chapter 1, 2005 (www. cc. nih. gov. protomechanics )

Iterations ■ The cyclical process of drafting the protocol extends through the protocol submission and review process. ■ The PI, protocol editor, and study coordinator are usually responsible for most duties relating to submission and critique.

A Typical Review Cycle 2: Final draft created by team; submitted for higherlevel review 1: Draft study approved by local research committee Phase II/III Study 4: Draft modified per reviewer comments; reply drafted 3: Protocol returned with comments requiring response or modification

The Protocol-writing Process ■ Clinical Protocols: an Overview ■ Preparatory Steps ■ Assembling a Protocol Team ■ Managing the Process ■ Resources and Guidance

NIH (Protomechanics) http: //www. cc. nih. gov/ccc/protomechanics/ These are the NIH’s guidance documents for protocols proposed for the Warren Grant Magnuson Clinical Center. Subjects include: ■ Protocol content ■ Roles and responsibilities ■ Regulatory compliance ■ Scientific and statistical design ■ Compensation and reimbursement issues

Cancer Therapy Evaluation Program (CTEP) http: //ctep. cancer. gov/guidelines/ Contains guidelines and resources for clinical cancer trials conducted under NCI auspices, including: ■ Investigators’ Handbook ■ Protocol templates (phase I, II, & III) ■ Regulatory and process guidance

NIH Roadmap Funding http: //nihroadmap. nih. gov/grants/index. asp Contains listing of NIH Roadmap funding opportunities for basic/correlative sciences.

Office of Human Research Protection (OHRP) http: //www. hhs. gov/ohrp/policy/index. html This is a DHHS site that houses regulatory guidance documents for conducting clinical trials in human subjects.

Office of Human Subjects Research (OHSR) http: //ohsr. od. nih. gov/info. html List of OHSR guidance documents, including: http: //ohsr. od. nih. gov/info/sheet 5. html Guidelines for writing research protocols http: //ohsr. od. nih. gov/info/sheet 6. html Guidelines for writing informed consent documents

Summary ■ Proper preparation can make the difference between success and failure in protocol development. ■ Protocols are the work of many hands—and as such, require some care to ensure coordination and cooperation among contributors.

Questions?