Clinical trial design

Clinical trial design defines how a study will test hypotheses and generate credible, regulator-ready evidence while protecting participants and keeping development on track. At KLIFO, trial design is handled within a strategic decision framework that links scientific intent, statistical considerations, regulatory expectations, and operational reality from protocol to execution.

We design studies that comprehensively and efficiently answer the right questions, in the right population, with defensible endpoints and a structure that holds up under regulatory and ethical scrutiny.

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What KLIFO delivers

Clinical trial design is never a standalone academic exercise. Understanding the client’s development end goal and current clinical position, KLIFO delivers a thought through framework that becomes the backbone
of the clinical protocol,
the statistical analysis plan, and downstream clinical execution.

In practical terms, KLIFO takes responsibility for defining and aligning:

The clinical trial design is the very core of the clinical protocol development providing a robust and defensible backbone for the clinical trial that matches the development objectives and accommodates regulatory expectations.

Trial design as a risk-management tool

A well-constructed clinical trial design is one of the most effective ways to reduce regulatory, scientific, and operational risk.

Design decisions determine whether a study can be authorized, whether it will recruit as planned, and whether the resulting data unequivocally answer the clinical development questions and ultimately support the chosen regulatory strategy. Weak and incoherent designs are common root causes of regulatory pushback, clinical holds, protocol amendments, delayed timelines, and inconclusive outcomes.

Clinical trial design as a control framework

KLIFO sees clinical trial design as a key component in the control mechanism that ensures:

Risks to participants are proportionate to condition and objectives and actively mitigated
Bias and confounding are minimised through appropriate controls, randomisation, and blinding strategies
Study is adequately powered to address primary the objective
Endpoints and assessments are aligned with the study objectives and statistical analysis plan
Data will be interpretable in the context of other data generated in the development program and will be seen as sufficient and robust in future regulatory submissions

This mindset ensures a drug development pathway, where right early design decisions pave the way for cost efficient solutions in the following phases of the drug development program.

**Choosing the right clinical trial design**

KLIFO sees clinical trial design as a key component in the conChoosing the appropriate clinical trial design rests on strategic decisions driven by the development end goal, the current scientific and clinical questions, the characteristics of the target population, and the regulatory context in which the study will be evaluated. Designs for each of the classical development phases are well known but should always be customized to ensure feasibility, minimize risk, and make sure that the trial objectives can be adressed.

In practice, design selection is guided by factors such as:

Clinical development phase i.e. First-in-Human, Proof of Concept, Dose Finding, Confirmatory
Treatment effects which may be temporary or persistent, influencing the use of parallel group versus crossover designs
Standard of care for the condition/disease in question
Recruitment constraints, limited patient populations or orphan indications
Clinical, ethical and regulatory considerations around use of placebo control
The timing and reliability of endpoints, including how quickly meaningful outcomes can be observed

Why design is the first strategic decision

At KLIFO, clinical trial design is considered the most important first step in the clinical protocol development, statistical planning, and downstream execution of the clinical trial. The right design ensures that robust data can be delivered and defended throughout the development program and that the objectives are addressed.

Core clinical trial design archetypes

KLIFO works across the full spectrum of recognized clinical trial designs and selects structures based on the scientific question, feasibility constraints, and regulatory context of each program.

SAD MAD FiH design

A Phase 1 dose-escalation study used to evaluate a new drug in humans for the first time. SAD assesses safety and pharmacokinetics after a single dose, while MAD evaluates safety, tolerability, and PK/PD after multiple doses. Designed to establish safe dose ranges and inform further development.

Oncology 3+3 Design

A traditional Phase 1 oncology dose-escalation design used to identify the maximum tolerated dose (MTD). Small patient cohorts are treated sequentially, with dose escalation guided by observed dose-limiting toxicities (DLTs). Simple, rule-based, and widely accepted in early oncology development.

Parallel-group designs

Parallel-group designs remain the default choice for many confirmatory and comparative studies. Participants are randomized to one of two or more arms and remain in that allocation for the duration of the trial.

These designs are particularly robust when contamination between arms must be avoided and when outcomes are not reversible. KLIFO focuses on allocation methods, balance across arms, and operational feasibility in multi-site settings.

Crossover and within-subject designs

Crossover designs allow participants to receive multiple interventions sequentially, enabling within-subject comparisons thus minimizing variation. Such designs are efficient in terms of sample size but specific risks related to carryover effects, washout periods, and period effects should be considered.

Crossover designs should be used selectively, only when treatment effects are reversible and stability assumptions can be justified.

Factorial designs

Factorial designs, such as 2×2 structures, allow multiple interventions to be evaluated simultaneously. While efficient, they require careful consideration of interaction effects, power assumptions, and interpretability.

We assess whether the added complexity is justified by the development question and whether the design can be supported operationally.

Seamless adaptive designs

Seamless adaptive clinical trial designs usually combine Phase 2 dose-finding/efficacy exploration and Phase 3 confirmatory testing into one continuous trial, using pre-planned interim analyses to adapt e.g., selecting dose, dropping arms or adjusting sample size without stopping the trial.

Seamless adaptive clinical trial designs are attracting increasing attention since they provide a mechanism for speeding up the development process, saving time and diminish the number of regulatory interactions.

Control strategy, randomisation, and blinding

Design credibility depends heavily on how comparisons are constructed and protected.

KLIFO advises on:

Selection of placebo, active, or concurrent controls based on ethical and scientific considerations
Randomisation timing and methods, including simple, blocked, and stratified approaches
Allocation concealment to prevent selection bias
Blinding strategies, including assessor blinding or double-dummy approaches when full blinding is not feasible

These elements are prespecified and aligned with the statistical analysis plan to avoid post-hoc decision-making.

Endpoints, estimands, and data integrity

DeEndpoints sit at the intersection of clinical relevance, feasibility, and regulatory expectation. Poorly chosen endpoints are a frequent source of regulatory challenge.

KLIFO ensures that:

Primary and secondary endpoints are clearly defined and measurable
Assessment schedules are symmetric across arms to avoid systematic bias
Estimands are aligned with the clinical question and handling of intercurrent events
Measurement instruments and definitions are consistent across sites

This discipline supports robust interpretation and reduces the risk of inconclusive or disputed results.

Sample size and statistical foundations

Sample size planning is driven by the clinical question, not negotiation or convenience. Assumptions about effect size, variability, power, and acceptable error rates are made explicit and tested for sensitivity.

We integrate statistical considerations early, ensuring that:

Sample size rationale is consistent with the endpoint and analysis method
Interim analyses and monitoring plans are prespecified where relevant
Intent-to-treat principles and handling of deviations are clearly defined

This alignment between design and analysis is critical for regulatory defensibility.on and reduces the risk of inconclusive or disputed results.

Adaptive elements and interim decision logic

Adaptive features, including response-adaptive randomisation or interim decision points, can increase efficiency but also increase complexity and regulatory scrutiny.

KLIFO applies adaptive elements only when:

Decision rules can be fully prespecified
Data integrity and operational execution can be protected
The adaptive approach clearly reduces development risk or timelines

Adaptive design is treated as a governed strategy, not an experimental add-on.duces the risk of inconclusive or disputed results.

When organisations typically engage KLIFO

Sponsors often involve KLIFO when:

In these situations, trial design becomes a strategic lever rather than a procedural task.

How KLIFO reduces regulatory and scientific risk

KLIFO combines strategic advisory and operational execution, allowing design decisions to be tested against real-world constraints before they become fixed.

Our teams bring highly experienced profiles across clinical, regulatory, statistical, and operational disciplines. This enables us to challenge assumptions early, align design with regulatory expectations, and ensure that what is written can actually be executed.

Design is never treated in isolation, but as an integrated part of the wider drug development programme.

Embedded within drug development

Clinical trial design is tightly connected to upstream strategy and downstream delivery. At KLIFO, design work is performed in the context of the full development journey, ensuring continuity from early planning through protocol development, analysis planning, and execution.