For many years, early‑phase development followed a rigid sequence. Early-phase clinical development started with single‑ascending dose studies, moved into multiple‑ascending dose studies in healthy volunteers, and only much later introduced the first patient cohorts. Regulators encouraged this separation, believing that the safest path was to keep healthy volunteer studies entirely distinct from patient studies. It was a conservative model that made early‑phase development slow, expensive, and often disconnected from the biological reality of the disease being treated.
Today, that model is being replaced.
Across cardiometabolic and metabolic liver disease, obesity, and other multi‑mechanism conditions, combination protocols—integrated studies that include SAD, MAD in healthy volunteers, and the first patient cohorts—are becoming central approach to modern drug development. The shift is driven by a shared priority: sponsors and regulators both want early clarity. They want to generate data for proof of concept or proof of failure for a new drug early in the clinical development process. This helps to make early reasoned decisions and avoid time consuming and expensive phase 2 and 3 studies in unpromising candidates.
Mechanistic Clarity. Early.
Sponsors, especially small biotechs, depend on investor confidence. Investors depend on evidence. And no one wants to wait until late phase 2 results to learn whether a mechanism is viable. Combination protocols compress timelines by allowing healthy volunteer studies and first patient cohorts to run within a single integrated programme, giving sponsors early signals—positive or negative—before they commit to larger Phase II trials.
Regulators have evolved in the same direction. Ethics boards that once insisted on long sequences of healthy volunteer studies now recognise that early patient data can be safer, more informative, and more efficient. They want early proof of mechanism just as much as sponsors do. Minds have changed on both sides of the table, and combination protocols are the natural result.
Biosignals – Making Combination Protocols Possible
The success of combination protocols depends on the ability to measure meaningful biological signals within a very short window. In early‑phase studies, we cannot track long‑term outcomes such as cardiovascular outcomes or long lasting organ damage. We need to implement meaningful endpoints that respond quickly and reliably.
This is where biomarkers—and increasingly, what I prefer to call “biosignals”—become essential. Biosignals include laboratory markers, composite scores, imaging‑based measures, and functional assessments that can demonstrate whether a drug is a promising candidate to proceed to late-stage development.
In metabolic liver disease, for example, changes in liver health can be detected within a short time frame using scores like the FIB-4 score or tissue investigations using MRI or FibroScan. In obesity programmes, shifts in nutrition uptake and changes in energy expenditure appear powerful signals long before changes in weight or body composition can be detected. Assessment of insulin resistance, inflammation markers or endothelial, renal or cardiac function can provide reliable predictive information about cardio-renal protective effects of a new drug candidate. These types of biosignals allow us to provide efficacy signals for new drugs very early in the clinical development process.
The Operational Reality: Why Only a Few CROs Can Deliver These Studies
Combination protocols are operationally complex, and only a small number of CROs can execute them well. They require deep Phase I expertise, access to the right patient populations, large and well‑characterised databases, and the ability to integrate biomarker strategy, imaging, and scientific consultancy into a single coherent programme. They also require experience—real experience—in designing and running studies that combine healthy volunteers and patients in a controlled, safe, and scientifically rigorous way.
Patient selection is one of the most challenging aspects. Many combination protocols require patients who are already on background therapy, and identifying the right individuals demands precision recruitment and access to large, diverse patient databases. It also requires a clear understanding of the disease biology and the biosignals that matter most for early proof of concept.
Where Combination Protocols Are Making the Biggest Impact
Combination protocols are becoming particularly important in obesity, insulin resistance, metabolic liver disease, and cardiometabolic conditions. In these areas, sponsors increasingly need to demonstrate more than weight loss or a single metabolic effect. They need to show improvements in liver fat, insulin resistance, cardiac function, and other interconnected mechanisms. Combination protocols allow sponsors to evaluate these effects early, in a controlled environment, and with the scientific clarity needed to make confident decisions.
For biotechs, the value is obvious. These protocols provide early go/no‑go decisions, reduce capital burn, strengthen partnering discussions, and give investors the evidence they need to support continued development. They also help larger pharmaceutical companies identify promising assets earlier in the development cycle.
Regulators are now fully supportive of this approach. They expect early mechanism clarity, early patient data, and early biosignal evidence. Meeting early and often with regulators remains essential, but the pathway is now well‑established and increasingly encouraged.
This alignment between sponsor and regulator is one of the reasons why combination protocols are accelerating development across multiple therapeutic areas.
Why hVIVO Has Become a Leader in Combination Protocols
At hVIVO, we have become a leader in combination protocols because we bring together all the elements required to execute them well: Phase I capability, patient access, biomarker and biosignal strategy, imaging partnerships, scientific consultancy, and decades of early‑phase operational experience. These studies are complex and require precision, but they are exactly the kind of work we are built to deliver.
Combination protocols represent the future of early‑phase development. They offer speed, clarity, and scientific depth at a moment when sponsors need all three. And with the right expertise and infrastructure, they can transform the way new therapies are evaluated and advanced.
