Protocol Development and Feasibility

Part of Good Clinical Practice (GCP) — ICH E6(R3): Clinical Trial Protocol and Design.

About 6 minutes. Free, in your language, no account needed.

Why this matters

A protocol that cannot be run at a real site produces deviations, not data. Sites that accept trials they cannot deliver enroll slowly, lose staff and fail inspections. The International Council for Harmonisation (ICH) guideline ICH E6(R3) treats operational feasibility as a requirement, not a preference. Feasibility work done before the first participant is enrolled is the cheapest quality activity in the whole trial.

What the sponsor must get right before the protocol is final

ICH E6(R3) section 3.1 sets out the sponsor's duties in trial design. Four of them shape the protocol directly.

• Adequate supporting evidence (3.1.1) — the sponsor should ensure sufficient safety and efficacy data are available to support human exposure by the intended route, dose, duration and population. The data may come from nonclinical studies, earlier clinical trials or real-world sources.
• Quality built in (3.1.2) — the sponsor should incorporate quality into the design by identifying factors that are critical to the quality of the trial and by managing risks to those factors.
• Input from interested parties (3.1.3) — the sponsor should consider inputs from a wide variety of interested parties, for example healthcare professionals and patients, when developing the protocol and the informed consent materials.
• Operational feasibility (3.1.4) — the sponsor should ensure all aspects of the trial are operationally feasible and should avoid unnecessary complexity, procedures and data collection.

Section 3.1.4 ends with a sentence worth memorizing: "The sponsor should not place unnecessary burden on participants and investigators."

Principle 4 sits behind all of this. Trials should be scientifically sound for their intended purpose and based on adequate and current scientific knowledge. Principle 4.3 asks for periodic review of current scientific knowledge to see whether the trial needs modifying. Feasibility is therefore not a single event at start-up. It is revisited as the trial runs.

Designing for the population the product is meant to help

Principle 1.4 changed the tone of eligibility criteria. It states that the scientific goal and purpose should be considered carefully so as not to unnecessarily exclude particular participant populations. Participant selection should be representative of the population groups the investigational product is intended to benefit once authorized, so results can be generalized across the broader population.

Principle 1.4 also gives a limit. Certain trials, for example early phase, proof of concept and bioequivalence studies, may not require such a heterogeneous population.

For protocol writers this has practical consequences. An exclusion criterion needs a scientific reason, not habit. Blanket exclusions for age, comorbidity, renal function or background therapy narrow the evidence base and slow recruitment. For a global audience there is a second consequence. If the protocol requires a test or device that is unavailable in most of the world, the trial excludes those regions by design.

Site feasibility: what a site must be able to show

Two short sections in E6(R3) set the standard for the site side.

Section 2.2.1 states that the investigator should be able to demonstrate a potential for recruiting the proposed number of eligible participants within the agreed recruitment period. The guideline names the evidence: retrospective or currently available data. An estimate from memory is not evidence.

Section 2.2.2 requires sufficient time, an adequate number of available and qualified staff, and adequate facilities for the foreseen duration of the trial.

Section 3.7.1 places the selection decision with the sponsor. Each investigator should be qualified by education, training and experience, and should demonstrate adequate resources and facilities. Section 3.7.2 requires the sponsor to provide the protocol and an up-to-date Investigator's Brochure, plus sufficient time to review them.

Reading a feasibility questionnaire critically

A feasibility questionnaire collects the patient population, staff experience, facilities, recruitment potential, competing trials and any specialized capability the protocol needs, such as imaging, biopsy or infusion.

Validate the answers rather than accepting them. Useful checks:

• Volume against prevalence — does the claimed patient number match the local disease burden?
• Procedures on site — are the required scans, laboratory tests or biopsies genuinely available?
• Investigator time — does the investigator have protected time, or a full clinical service?
• Competing trials — can the same staff support all the studies already open?
• Technology — can the site use the electronic data capture, randomization and outcome tools reliably?

Common warning signs are high claimed volumes with no supporting data, an investigator with heavy clinical duties and no protected time, and feasibility answers that contradict past enrollment performance. Sites with weak recruitment history rarely improve on their own.

In practice

ABC Pharmaceuticals is designing a Phase III heart failure trial. The draft protocol requires a cardiac magnetic resonance scan at four visits and excludes anyone with an estimated glomerular filtration rate below 45.

Dr. Sarah is a potential investigator at a district hospital. Her feasibility answer is honest. The hospital has one scanner shared with oncology, and she can reasonably obtain two research slots a month. Her clinic sees a large number of eligible patients, but roughly a third have reduced renal function.

Two things follow. First, the site is feasible only if the scan schedule is reduced or slots are booked in advance, so the sponsor and Dr. Sarah agree a written recruitment and scanning plan before selection. Second, the medical team revisits the renal exclusion. It was copied from an earlier protocol and no longer has a clear scientific justification at that threshold. Removing it widens the eligible population and improves how well the results represent the patients who will receive the product.

Refusing a trial you cannot deliver is a mark of a strong site, not a weak one.

Key takeaways

• ICH E6(R3) section 3.1.4 requires the sponsor to ensure the trial is operationally feasible, to avoid unnecessary complexity, procedures and data collection, and not to place unnecessary burden on participants and investigators.
• Section 3.1.2 requires quality to be built into the design by identifying critical to quality factors and managing the risks to them.
• Section 3.1.3 asks the sponsor to consider input from interested parties, including healthcare professionals and patients, when developing the protocol and consent materials.
• Principle 1.4 requires participant selection to be representative of the population the investigational product is intended to benefit, while allowing narrower populations for early phase, proof of concept and bioequivalence studies.
• Section 2.2.1 requires the investigator to demonstrate recruitment potential using retrospective or currently available data, not an unsupported estimate.
• Section 3.7.1 makes the sponsor responsible for selecting investigators who are qualified and who demonstrate adequate resources and facilities.