clinical-trial-protocol-skill: создание протоколов исследований

--- name: clinical-trial-protocol-skill description: Generate clinical trial protocols for medical devices or drugs. This skill should be used when users say "Create a clinical trial protocol", "Generate protocol for [device/drug]", "Help me design a clinical study", "Research similar trials for [intervention]", or when developing FDA submission documentation for investigational products. --- # Clinical Trial Protocol Skill ## ⚠️ EXECUTION CONTROL - READ THIS FIRST **CRITICAL: This orchestrator follows a SIMPLE START approach:** 1. **Display the welcome message FIRST** (shown in "Startup: Welcome and Confirmation" section below) 2. **Ask user to confirm they're ready to proceed** - Wait for confirmation (yes/no) 3. **Jump directly into Full Workflow Logic** - Automatically run subskills sequentially 4. **Do NOT pre-read subskill files** - Subskills are loaded on-demand only when their step executes **Why this matters:** - Pre-reading all subskills wastes context and memory - Subskills should only load when actually needed during execution - Workflow automatically handles resuming from existing waypoints ## Overview This skill generates clinical trial protocols for **medical devices or drugs** using a **modular, waypoint-based architecture** ## What This Skill Does Starting with an intervention idea (device or drug), this orchestrated workflow offers two modes: **🔬 Research Only Mode (Steps 0-1):** 0. **Initialize Intervention** - Collect device or drug information 1. **Research Similar Protocols** - Find similar trials, FDA guidance, and published protocols - **Deliverable:** Comprehensive research summary as formatted .md artifact **📄 Full Protocol Mode (Steps 0-5):** 0. **Initialize Intervention** - Collect device or drug information 1. **Research Similar Protocols** - Find similar trials, FDA guidance, and published protocols 2. **Protocol Foundation** - Generate protocol sections 1-6 (foundation, design, population) 3. **Protocol Intervention** - Generate protocol sections 7-8 (intervention details) 4. **Protocol Operations** - Generate protocol sections 9-12 (assessments, statistics, operations) 5. **Generate Protocol** - Create professional file ready for stakeholder review ## Architecture ### Waypoint-Based Design All analysis data is stored in `waypoints/` directory as JSON/markdown files: ``` waypoints/ ├── intervention_metadata.json # Intervention info, status, initial context ├── 01_clinical_research_summary.json # Similar trials, FDA guidance, recommendations ├── 02_protocol_foundation.md # Protocol sections 1-6 (Step 2) ├── 03_protocol_intervention.md # Protocol sections 7-8 (Step 3) ├── 04_protocol_operations.md # Protocol sections 9-12 (Step 4) ├── 02_protocol_draft.md # Complete protocol (concatenated in Step 4) ├── 02_protocol_metadata.json # Protocol metadata └── 02_sample_size_calculation.json # Statistical sample size calculation ``` **Rich Initial Context Support:** Users can provide substantial documentation, technical specifications, or research data when initializing the intervention (Step 0). This is preserved in `intervention_metadata.json` under the `initial_context` field. Later steps reference this context for more informed protocol development. ### Modular Subskill Steps Each step is an independent skill in `references/` directory: ``` references/ ├── 00-initialize-intervention.md # Collect device or drug information ├── 01-research-protocols.md # Clinical trials research and FDA guidance ├── 02-protocol-foundation.md # Protocol sections 1-6 (foundation, design, population) ├── 03-protocol-intervention.md # Protocol sections 7-8 (intervention details) ├── 04-protocol-operations.md # Protocol sections 9-12 (assessments, statistics, operations) └── 05-generate-document.md # NIH Protocol generation ``` ### Utility Scripts ``` scripts/ └── sample_size_calculator.py # Statistical power analysis (validated) ``` ## Prerequisites ### 1. clinical trials MCP Server (Required) **Installation:** - Install via drag-and-drop `.mcpb` file into Claude Desktop - Or configure manually in Claude Desktop settings **Available Tools:** `search_clinical_trials` - Search by: condition - Disease or condition (e.g., "pancreatic cancer") intervention - Drug, device, or treatment (e.g., "pembrolizumab", "CAR-T") sponsor - Sponsor or collaborator name (e.g., "Pfizer", "NIH") location - City, state, or country (e.g., "California", "Boston") status - "recruiting" (default), "active", "completed", "all" phase - Trial phase: "1", "2", "3", "4", "early_phase1" max_results - Default 25, max 100 `get_trial_details` - Get comprehensive details for a specific trial using its nct_id (e.g., "NCT04267848"). Returns eligibility criteria, outcomes, study design, and contact information. **Verification:** Step 1 will automatically test MCP connectivity at startup. ### 2. FDA Database Access (Built-in) **Purpose:** FDA regulatory pathway research via explicit database URLs **Sources:** - Step 1: FDA device/drug databases (510(k), PMA, De Novo, Drugs@FDA, Orange Book, Purple Book) - All sources use direct FDA database URLs - no generic web searches ### 3. Clinical Protocol Template **Template Files:** Any `.md` files in the `assets/` directory **Purpose:** Reference template for protocol structure and content guidance. The system automatically detects available templates and uses them dynamically. ### 4. Python Dependencies (Required for Step 2) **Installation:** ```bash pip install -r requirements.txt ``` **Dependencies:** - scipy >= 1.11.0 (statistical calculations) - numpy >= 1.24.0 (numerical operations) **Purpose:** Accurate statistical sample size calculations for clinical protocols ## How to Use Simply invoke the skill and select your desired mode: **🔬 Research Only Mode:** 1. Select "Research Only" from the main menu 2. Provide intervention information 3. Receive comprehensive research summary as formatted .md artifact 4. Option to continue with full protocol generation or exit **📄 Full Protocol Mode:** 1. Select "Full Protocol" from the main menu 2. Guide you through all steps sequentially (Steps 0-5) 3. Pause after Step 4 to review the draft protocol 4. Generate the final protocol document when ready **Resume Capability:** If interrupted, simply restart the skill and it will automatically resume from your last completed step. ## Execution Flow ### Startup: Welcome and Mode Selection When skill is invoked, display the following message: ``` 🧬 CLINICAL TRIAL PROTOCOL Welcome! This skill generates clinical trial protocols for medical devices or drugs. [If waypoints/intervention_metadata.json exists:] ✓ Found existing protocol in progress: [Intervention Name] Type: [Device/Drug] Completed: [List of completed steps] Next: [Next step to execute] 📋 SELECT MODE: 1. 🔬 Research Only - Run clinical research analysis (Steps 0-1) • Collect intervention information • Research similar clinical trials • Find FDA guidance and regulatory pathways • Generate comprehensive research summary as .md artifact 2. 📄 Full Protocol - Generate complete clinical trial protocol (Steps 0-5) • Everything in Research Only, plus: • Generate all protocol sections • Create professional protocol document 3. ❌ Exit Please select an option (1, 2, or 3): ``` **🛑 STOP and WAIT for user selection (1, 2, or 3)** - If **1 (Research Only)**: Set `execution_mode = "research_only"` and proceed to Research Only Workflow Logic - If **2 (Full Protocol)**: Set `execution_mode = "full_protocol"` and proceed to Full Workflow Logic - If **3 (Exit)**: Exit gracefully with "No problem! Restart the skill anytime to continue." --- ### Research Only Workflow Logic **This workflow executes only Steps 0 and 1, then generates a formatted research summary artifact.** **Step 1: Check for Existing Waypoints** - If `waypoints/intervention_metadata.json` exists: Load metadata, check if steps 0 and 1 are already complete - If no metadata exists: Start from Step 0 **Step 2: Execute Research Steps (0 and 1)** For each step (0, 1): 1. **Check completion status:** If step already completed in metadata, skip with "✓ Step [X] already complete" 2. **Execute step:** - Display "▶ Executing Step [X]..." - Read and follow the corresponding subskill file instructions - Wait for completion - Display "✓ Step [X] complete" - **Step execution method (ON-DEMAND LOADING):** When a step is ready to execute (NOT before), read the subskill markdown file and execute ALL instructions within it - **Step-to-file mapping:** - Step 0: `references/00-initialize-intervention.md` (collect intervention info) - Step 1: `references/01-research-protocols.md` (clinical research and FDA guidance) 3. **Handle errors:** If step fails, ask user to retry or exit. Save current state for resume capability. **Step 3: Generate Research Summary Artifact** After Step 1 completes successfully: 1. **Read waypoint files:** - `waypoints/intervention_metadata.json` (intervention details) - `waypoints/01_clinical_research_summary.json` (research findings) 2. **Create formatted markdown summary:** Generate a comprehensive, well-formatted research summary as a markdown artifact with the following structure: ```markdown # Clinical Research Summary: [Intervention Name] ## Intervention Overview - **Type:** [Device/Drug] - **Indication:** [Target condition/disease] - **Description:** [Brief intervention description] - **Mechanism of Action:** [How it works] ## Similar Clinical Trials [List top 5-10 similar trials with NCT ID, title, phase, status, key findings] ## FDA Regulatory Pathway - **Recommended Pathway:** [510(k), PMA, De Novo, IND, NDA, BLA, etc.] - **Regulatory Basis:** [Rationale for pathway selection] - **Key Requirements:** [Major regulatory considerations] ## FDA Guidance Documents [List relevant FDA guidance documents with links and key excerpts] ## Study Design Recommendations - **Suggested Study Type:** [RCT, single-arm, etc.] - **Phase Recommendation:** [Phase 1, 2, 3, etc.] - **Primary Endpoint Suggestions:** [Based on similar trials] - **Sample Size Considerations:** [Preliminary thoughts] ## Key Insights and Recommendations [Synthesized recommendations for protocol development] ## Next Steps [If user wants to proceed with full protocol development] --- *Generated by Clinical Trial Protocol Skill* *Date: [Current date]* ``` 3. **Save artifact:** Write the formatted summary to `waypoints/research_summary.md` 4. **Display completion message:** ``` ✅ RESEARCH COMPLETE Research Summary Generated: waypoints/research_summary.md 📊 Key Findings: • Similar Trials Found: [X trials] • Recommended Pathway: [Pathway name] • FDA Guidance Documents: [X documents identified] • Study Design: [Recommended design] 📄 The research summary has been saved as a formatted markdown artifact. Would you like to: 1. Continue with full protocol generation (steps 2-5) 2. Exit and review research summary ``` **Option 1 Logic (Continue to Full Protocol):** - Set `execution_mode = "full_protocol"` - Continue to Full Workflow Logic starting from Step 2 (since 0 and 1 are complete) **Option 2 Logic (Exit):** - Display: "✓ Research summary saved. Restart the skill anytime to continue with protocol generation." - Exit orchestrator gracefully --- ### Full Workflow Logic **Step 1: Check for Existing Waypoints** - If `waypoints/intervention_metadata.json` exists: Load metadata, check `completed_steps` array, resume from next incomplete step - If no metadata exists: Start from Step 0 **Step 2: Execute Steps in Order** For each step (0, 1, 2, 3, 4, 5): 1. **Check completion status:** If step already completed in metadata, skip with "✓ Step [X] already complete" 2. **Execute step:** Display "▶ Executing Step [X]...", read and follow the corresponding subskill file instructions, wait for completion, display "✓ Step [X] complete" - **Step execution method (ON-DEMAND LOADING):** When a step is ready to execute (NOT before), read the subskill markdown file and execute ALL instructions within it - **IMPORTANT:** Do NOT read subskill files in advance. Only read them at the moment of execution. - **Step-to-file mapping:** - Step 0: `references/00-initialize-intervention.md` (read when Step 0 executes) - Step 1: `references/01-research-protocols.md` (read when Step 1 executes) - Step 2: `references/02-protocol-foundation.md` (read when Step 2 executes - sections 1-6) - Step 3: `references/03-protocol-intervention.md` (read when Step 3 executes - sections 7-8) - Step 4: `references/04-protocol-operations.md` (read when Step 4 executes - sections 9-12) - Step 5: `references/05-concatenate-protocol.md` (read when Step 5 executes - final concatenation) 3. **Handle errors:** If step fails, ask user to retry or exit. Save current state for resume capability. 4. **Display progress:** "Progress: [X/6] steps complete", show estimated remaining time 5. **Step 4 Completion Pause:** After Step 4 completes, pause and display the Protocol Completion Menu (see below). Wait for user selection before proceeding. **Step 2.5: Protocol Completion Menu** After Step 4 completes successfully, display the EXACT menu below (do not improvise or create alternative options): ``` ✅ PROTOCOL COMPLETE: Protocol Draft Generated Protocol Details: • Study Design: [Design from metadata] • Sample Size: [N subjects from metadata] • Primary Endpoint: [Endpoint from metadata] • Study Duration: [Duration from metadata] Protocol file: waypoints/02_protocol_draft.md File size: [Size in KB] 📋 WHAT WOULD YOU LIKE TO DO NEXT? 1. 📄 Review Protocol in Artifact - click on the .md file above 2. 📄 Concatenate Final Protocol (Step 5) 3. ⏸️ Exit and Review Later ``` **Option 1 Logic (Review in Artifact):** Pause, let user open the section files, wait for further instruction **Option 2 Logic (Concatenate Protocol):** 1. Execute Step 5 by reading and following `references/05-concatenate-protocol.md` 2. Step 5 will concatenate all section files into final protocol document 3. Continue to Step 3 (Final Summary) after Step 5 completes **Option 3 Logic (Exit):** 1. Display: "✓ Protocol sections saved. You can resume with Step 5 anytime to concatenate." 2. Exit orchestrator gracefully **Step 3: Final Summary** Display completion message with: - Intervention name, type (device/drug), indication - Protocol details (design, sample size, endpoints, duration) - All completed steps list - Final deliverable: Complete protocol markdown file location (waypoints/protocol_complete.md) - Waypoint files list for reference - Important disclaimers (FDA Pre-Sub, biostatistician review, IRB approval required) - Thank you message ## Technical Details ### Waypoint File Formats **JSON Waypoints** (Steps 0, 1): - Structured data for programmatic access - Small file sizes (1-15KB) - Easy to parse and reference **Markdown Waypoints** (Steps 2, 3, 4): - Step 2: `02_protocol_foundation.md` (Sections 1-6) - Step 3: `03_protocol_intervention.md` (Sections 7-8) - Step 4: `04_protocol_operations.md` (Sections 9-12) - Step 4: `02_protocol_draft.md` (concatenated complete protocol) - Human-readable protocol documents - Can be directly edited by users - Individual section files preserved for easier regeneration ### Data Minimization Strategy Each step implements aggressive summarization: - **Keep:** Top-N results (5-10 max) - **Keep:** Key facts and IDs (NCT numbers, endpoint types) - **Keep:** Concise rationale (2-3 sentences) - **Discard:** Raw MCP query results (not needed after analysis) - **Discard:** Full FDA guidance text (only excerpts/citations kept) - **Discard:** Lower-ranked search results ### Step Independence Each subskill is designed to: - Read only from waypoint files (not conversation history) - Produce complete output in single execution - Not depend on conversation context from previous steps - Be runnable standalone ## Error Handling ### MCP Server Unavailable - Detected in: Step 1 - Action: Display error with installation instructions - Allow user to retry after installing MCP server - No fallback available - MCP server is required for protocol research ### Step Fails or Returns Error - Action: Display error message from subskill - Ask user: "Retry step? (Yes/No)" - Yes: Re-run step - No: Save current state, exit orchestrator ### User Interruption - All progress saved in waypoint files - User can resume anytime by restarting the skill - Workflow automatically detects completed steps and resumes from next step - No data loss ## Disclaimers ⚠️ **IMPORTANT:** This protocol generation tool provides preliminary clinical study protocol based on NIH/FDA guidelines and similar trials. It does NOT constitute: - Official FDA or IRB determination or approval - Medical, legal, or regulatory advice - Substitute for professional biostatistician review - Substitute for FDA Pre-Submission meeting - Guarantee of regulatory or clinical success **REQUIRED before proceeding with clinical study:** - Biostatistician review and sample size validation - FDA Pre-Submission meeting (Q-Submission for devices, Pre-IND for drugs) - IRB review and approval - Clinical expert and regulatory consultant engagement - Legal review of protocol and informed consent - Site investigator review and input - Sponsor completion of all [TBD] items in protocol **PROFESSIONAL CONSULTATION STRONGLY RECOMMENDED** Clinical trial protocols are complex, high-stakes documents requiring expertise across multiple disciplines. Professional consultation with clinical trial experts, biostatisticians, and regulatory affairs specialists is essential before proceeding with clinical study planning. ## Implementation Requirements When this skill is invoked: 1. **Display the welcome message with mode selection** (shown in "Startup: Welcome and Mode Selection" section) 2. **Wait for user mode selection** (1: Research Only, 2: Full Protocol, 3: Exit) 3. **Execute based on selected mode:** - **Research Only Mode (Option 1):** - Execute Research Only Workflow Logic (Steps 0-1 only) - Generate formatted research summary as .md artifact - Offer option to continue with full protocol or exit - **Full Protocol Mode (Option 2):** - Execute Full Workflow Logic (Steps 0-5) - Check for existing waypoints and resume from last completed step - OR start from Step 0 if no waypoints exist - Execute all steps sequentially until complete 4. **For each step execution (LAZY LOADING - On-Demand Only):** - **ONLY when a step is ready to execute**, read the corresponding subskill file - Do NOT read subskill files in advance or "to prepare" - Example: When Step 1 needs to run, THEN read `references/01-research-protocols.md` and follow its instructions - **For protocol development:** Execute Steps 2, 3, 4 sequentially in order - Do NOT try to execute multiple steps in parallel - run sequentially - Read each step's subskill file only when that specific step is about to execute 5. **Research summary artifact generation (Research Only Mode):** - After Step 1 completes, read waypoint files - Generate comprehensive, well-formatted markdown summary - Save to `waypoints/research_summary.md` - Display completion message with key findings 6. **Handle errors gracefully:** - If a step fails, give user option to retry or exit - If MCP server unavailable, explain how to install - All progress is saved automatically in waypoints 7. **Track progress:** - Update `waypoints/intervention_metadata.json` after each step - Show progress indicators to user (e.g., "Progress: 3/6 steps complete" or "Progress: 2/2 research steps complete") - Provide clear feedback on what's happening 8. **Final output:** - **Research Only:** Display research summary location and offer to continue with full protocol - **Full Protocol:** Congratulate user, display protocol location and next steps - Remind user of disclaimers