4.1 Site Feasibility Assessment, Capability Analysis & Investigator Selection

Site Feasibility Assessment, Capability Analysis & Investigator Selection

Exam scope note: This section cites national regulations (for example US Code of Federal Regulations provisions) because they shape day-to-day practice. ACRP states the ACRP-CP exam is referenced only to ICH Guidelines and that no country-specific framework is tested. Treat those citations as professional context; the provision examined here is ICH E6(R3) Annex 1 sections 2.1 (Qualifications and Training), 2.2 (Resources) and 3.7 (Investigator Selection), with Principle 5 on qualified individuals.

Quick Reference: Site feasibility and investigator selection represent the foundational stage of clinical trial execution. Under ICH E6(R3) Annex 1 section 2.2 and Section 5.6, the sponsor must ensure that selected investigators are qualified by education, training, and experience, and have adequate resources—including time, qualified staff, suitable facilities, and access to an adequate population of eligible subjects—to conduct the study to completion.

Selecting high-performing, compliant clinical research sites is critical to the operational and financial success of any clinical trial. Poor site feasibility assessment leads to protocol amendments, enrollment delays, budget overruns, and compromised data integrity. For candidates preparing for the ACRP-CP (ACRP Certified Professional) exam, mastering the metrics, regulatory requirements, and practical processes governing site feasibility, capability analysis, and investigator selection is essential.

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The Site Feasibility Lifecycle

The site selection and feasibility process follows a structured, sequential workflow designed to protect intellectual property, assess operational capabilities, and ensure regulatory compliance before protocol finalization and site contract execution.

┌───────────────────────────────────────────────────────────────────────────┐
│                     THE SITE FEASIBILITY LIFECYCLE                         │
├───────────────────────────────────────────────────────────────────────────┤
│  1. Confidential Disclosure Agreement (CDA / NDA)                         │
│     • Mutual confidentiality execution prior to protocol disclosure       │
├───────────────────────────────────────────────────────────────────────────┤
│  2. Protocol Synopsis & Site Feasibility Questionnaire (SFQ)              │
│     • Site evaluates scientific alignment, patient access & capabilities   │
├───────────────────────────────────────────────────────────────────────────┤
│  3. Patient Population & Competitive Pipeline Analysis                    │
│     • EHR querying, inclusion/exclusion pressure testing & trial clash    │
├───────────────────────────────────────────────────────────────────────────┤
│  4. Facility & Technical Infrastructure Assessment                        │
│     • Lab certifications (CLIA/CAP), storage (-80°C/2-8°C), pharmacy      │
├───────────────────────────────────────────────────────────────────────────┤
│  5. Investigator & Staff Qualification Review                             │
│     • Medical licenses, CVs, GCP certifications, FTE resource mapping     │
├───────────────────────────────────────────────────────────────────────────┤
│  6. Pre-Study Qualification / Site Selection Visit (PSV / SSV)            │
│     • On-site or virtual validation of physical capabilities and staff    │
├───────────────────────────────────────────────────────────────────────────┤
│  7. Formal Site Selection & Greenlight Initiation                         │
│     • Sponsor / CRO selection committee approval and start-up handoff     │
└───────────────────────────────────────────────────────────────────────────┘

1. Confidential Disclosure Agreements (CDA / NDA)

Before a sponsor or Contract Research Organization (CRO) can share an investigational protocol, detailed study synopsis, or Investigator's Brochure (IB) with a prospective site, both parties must execute a Confidential Disclosure Agreement (CDA), also termed a Non-Disclosure Agreement (NDA). The CDA protects proprietary preclinical findings, chemical structures, mechanism of action data, and commercial patent strategies from unauthorized public disclosure.

2. The Site Feasibility Questionnaire (SFQ)

The Site Feasibility Questionnaire (SFQ) is a standardized evaluation instrument sent by the sponsor or CRO to assess a prospective site's operational, clinical, and logistical readiness. Key domains evaluated in an SFQ include:

• Patient Volume & Demographics: Annual incidence and prevalence of the target disease entity treated at the institution.
• Recruitment Track Record: Historical enrollment performance in similar Phase I–IV clinical trials within the same therapeutic indication.
• Staffing Capacity: Dedicated Full-Time Equivalents (FTEs) of Clinical Research Coordinators (CRCs), research nurses, sub-investigators, and data managers.
• Facility Capabilities: Diagnostic imaging modalities (e.g., 3T MRI, PET-CT, DEXA), local and specialized laboratory equipment, and specialized clinic spaces.
• Regulatory Timelines: Institutional Review Board (IRB) review type (Central vs. Local/Institutional), Scientific Review Committee (SRC) requirements, and standard contract negotiation cycle times.

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Target Patient Population Modeling & Lasagna's Law

A critical failure mode in clinical research feasibility is the overestimation of available trial subjects. In clinical research lore and operations, this phenomenon is formalized as Lasagna's Law (named after clinical pharmacologist Louis Lasagna): the moment a clinical trial begins, the supply of available patients plummets to a fraction of the number estimated prior to trial initiation, only to return to normal levels once the trial closes.

                     PATIENT ATTRITION FUNNEL
┌─────────────────────────────────────────────────────────────┐
│  Total Clinic Patient Population with Target Diagnosis     │  1,000 pts (100%)
├─────────────────────────────────────────────────────────────┤
│  Meets Stage / Biomarker Inclusion Criteria                 │    420 pts (42%)
├─────────────────────────────────────────────────────────────┤
│  Passes Organ Function & Lab Exclusionary Filters           │    180 pts (18%)
├─────────────────────────────────────────────────────────────┤
│  Free from Competing Trial Enrollment & Prior Therapy Bans  │     85 pts (8.5%)
├─────────────────────────────────────────────────────────────┤
│  Willing to Provide Informed Consent & Complete Visits       │     25 pts (2.5%)
└─────────────────────────────────────────────────────────────┘

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Competitive Trial Analysis & Pipeline Conflict

A clinical site cannot be evaluated in isolation. A thorough capability analysis requires examining competing clinical trials within the site's portfolio and broader institutional ecosystem.

Types of Trial Competition

1. Direct Intra-Site Competition: Another trial actively recruiting at the same investigative site targeting the identical disease stage, biomarker, or patient demographic.
2. Indirect Inter-Departmental Competition: Studies conducted in adjacent departments (e.g., Interventional Radiology vs. Surgical Oncology) competing for the same subject referral base.
3. Regional Market Competition: Other academic medical centers or commercial sites within the same metropolitan area competing for the same regional patient pool.

Mitigation Strategies

• Pre-Selection Disclosure: The Principal Investigator must transparently disclose all active and pipeline studies to the sponsor in the SFQ.
• Patient Allocation Algorithms: Establishing objective, institutional triage systems (e.g., alternating enrollment, prioritized biomarker allocation, or patient preference protocols) to ensure ethical and unbiased subject allocation.

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Facility, Equipment & Laboratory Capability Analysis

Under ICH E6(R3) Annex 1 section 2.2, the investigator must have available adequate facilities and equipment to conduct the trial properly and safely. The feasibility audit must evaluate physical, technical, and environmental infrastructure.

┌───────────────────────────────────────────────────────────────────────────┐
│                    SITE INFRASTRUCTURE AUDIT DOMAINS                      │
├───────────────────────────────────────────────────────────────────────────┤
│  1. Diagnostic & Specialty Equipment                                      │
│     • Calibrated 12-lead ECGs with standardized interval algorithms       │
│     • Certified imaging modalities: CT, 1.5T/3T MRI, PET, DEXA scanners   │
│     • Specialty ophthalmic, spirometric, or neurological testing tools    │
├───────────────────────────────────────────────────────────────────────────┤
│  2. Specimen Processing & Analytical Laboratory                           │
│     • CLIA Certificate of Compliance / Accreditation & CAP certification │
│     • Calibrated refrigerated centrifuges (verified RPM & temperature)    │
│     • Biosafety cabinets (Class II Type A2/B2) for biohazardous specimens │
├───────────────────────────────────────────────────────────────────────────┤
│  3. Investigational Product Storage & Cold-Chain Governance               │
│     • Ultra-low freezers (-80°C ± 10°C) with continuous data loggers      │
│     • Standard freezers (-20°C ± 5°C) & dedicated refrigerators (2°C–8°C) │
│     • Dual backup emergency generator circuits & automated call-out alerts│
├───────────────────────────────────────────────────────────────────────────┤
│  4. Pharmacy & Investigational Product Security                           │
│     • Double-locked, badge-restricted access investigational pharmacy     │
│     • Controlled Substances Registration (DEA Schedule II-V if applicable)│
│     • Cleanroom / laminar flow hoods for aseptic drug compounding (USP 797)│
└───────────────────────────────────────────────────────────────────────────┘

Local Laboratory Standards: CLIA & CAP

When local clinical laboratories are utilized for screening, safety, or endpoint analysis, the site must provide:

• CLIA Certification: Valid Clinical Laboratory Improvement Amendments (CLIA) Certificate of Compliance, Accreditation, or Waiver.
• CAP Accreditation: College of American Pathologists (CAP) accreditation documentation (preferred in high-complexity clinical trials).
• Laboratory Reference Ranges: Current, dated, and signed laboratory normal reference ranges for all clinical chemistry, hematology, and urinalysis assays covering gender and age stratifications.
• Laboratory Director Credentials: Current Curriculum Vitae and medical/scientific license of the laboratory director.

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Dedicated Staffing, FTE Mapping & Investigator Qualifications

Full-Time Equivalent (FTE) Resource Allocation

One of the most frequent findings during FDA bioresearch monitoring (BIMO) inspections is inadequate investigator supervision stemming from overcommitted staff. A comprehensive capability analysis maps the required time commitment across all study team roles.

$\text{Total Required Study FTE} = \sum \left( \frac{\text{Expected Visits per Subject} \times \text{Hours per Visit} \times \text{Enrolled Subjects}}{\text{Annual Working Hours per FTE (approx. 2080 hrs)}} \right) + \text{Admin/Regulatory Hours}$

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Investigator Credentialing & Regulatory Sanctions Review

Before selecting an investigator, sponsors and CROs must conduct formal background screening to confirm regulatory standing and good clinical practice history:

• FDA Debarment List: Verification that the investigator is not listed on the FDA Debarment List (under Section 306(a) or (b) of the Federal Food, Drug, and Cosmetic Act).
• FDA Warning Letters & Form 483s: Review of prior FDA inspectional observations and resolution status.
• Disqualified/Restricted/Assurance List: Checking the FDA Clinical Investigators Disqualified and Restricted Information Page.
• State Medical Board Sanctions: Verification of an active, unrestricted medical license without disciplinary actions, probation, or malpractice sanctions.
• Office of Inspector General (OIG) Exclusions: Verification on the HHS-OIG List of Excluded Individuals/Entities (LEIE) regarding participation in federal healthcare programs.

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The Pre-Study Qualification Visit (PSV / SSV)

The Pre-Study Qualification Visit (PSV), also called the Site Selection Visit (SSV), is conducted by a Clinical Research Associate (CRA/Monitor) or sponsor medical representative. It serves as the final on-site or virtual validation gate.

┌───────────────────────────────────────────────────────────────────────────┐
│                     PRE-STUDY SELECTION VISIT AGENDA                      │
├───────────────────────────────────────────────────────────────────────────┤
│  1. Investigator & Staff Interview                                        │
│     • Discuss protocol complexity, visit schedules & investigator oversight│
│     • Evaluate PI availability and understanding of safety obligations    │
├───────────────────────────────────────────────────────────────────────────┤
│  2. Facility & Storage Physical Tour                                      │
│     • Inspect pharmacy, infusion suite, clinic exam rooms & lab processing│
│     • Check temperature logs, freezer calibration tags & backup power     │
├───────────────────────────────────────────────────────────────────────────┤
│  3. Patient Recruitment & Data Management Evaluation                      │
│     • Review EHR capability, screening logs from prior trials & pipeline  │
│     • Assess electronic source capabilities & internet bandwidth for EDC  │
├───────────────────────────────────────────────────────────────────────────┤
│  4. Regulatory & IRB Workflow Review                                      │
│     • Confirm local vs central IRB pathways and expected approval timelines│
│     • Identify institutional sub-committees (Radiation, IBC, Pharmacy)    │
└───────────────────────────────────────────────────────────────────────────┘

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Realistic Clinical Scenario: Site Feasibility & Patient Attrition

Scenario: A regional academic medical center is approached to participate in a Phase III randomized, double-blind trial evaluating an investigational monoclonal antibody for severe eosinophilic asthma. The protocol mandates:

• Baseline blood eosinophil count $\ge 400\text{ cells}/\mu\text{L}$.
• At least 3 documented asthma exacerbations requiring systemic corticosteroids in the preceding 12 months.
• Pre-bronchodilator $\text{FEV}_1 < 60%$ predicted.
• Maintenance high-dose inhaled corticosteroids (ICS) plus long-acting beta-agonists (LABA).
• Exclusion: Any history of smoking within the past 10 years or $>10\text{ pack-years}$.

The site's lead pulmonologist completes the SFQ and claims the clinic treats 500 severe asthma patients annually and promises to enroll 25 patients within 6 months.

Feasibility Assessment & Analysis:

1. Data Query Realities: During the Pre-Study Selection Visit, the CRA and research coordinator perform a targeted EHR query. Of the 500 diagnosed asthma patients:
   • Only 120 patients have documented baseline eosinophils $\ge 400\text{ cells}/\mu\text{L}$.
   • Of those 120, only 45 have $\ge 3$ documented systemic corticosteroid exacerbations in the past year.
   • Of those 45, 18 have a significant smoking history ($>10\text{ pack-years}$) and are excluded.
   • Of the remaining 27 eligible candidates, 12 are already enrolled in a competing commercial biologic trial managed by another investigator at the same center.
2. Realistic Yield: Only 15 truly eligible candidates exist across the entire practice. Assuming an industry-standard 35% consent rate, the site can realistically expect to randomize 5 to 6 subjects over the 6-month period—not the 25 claimed on the initial questionnaire.
3. Operational Recommendation: The sponsor approves the site but sets the contractual enrollment target at 6 subjects with milestone-based screening allocations, avoiding over-allocation of expensive investigational product supplies.