Among the four phases of clinical trials, phase 1 is particularly crucial as it marks the first time a new drug is tested in humans. This phase is meticulously designed to gather preliminary data on safety, pharmacokinetics, and pharmacodynamics.

However, the success of your phase 1 study hinges on a strategic approach to trial design – a precise blueprint guiding every step of the journey. In this blog, we reveal the core components of phase 1 clinical trial design. From the strategic role of medical writers to the critical timing of SAD and MAD cohort designs, and inclusion of patient cohorts, each aspect is meticulously crafted to maximize insights, and minimize risks.

The role of medical writers in phase 1 clinical trial design

At the intersection of science and communication lies the indispensable role of medical writers in phase 1 clinical trial design. These professionals wield a unique skill set, translating complex scientific concepts and existing pre-clinical data into comprehensible language for various stakeholders, including regulatory bodies and ethics committees. Most importantly, medical writers work with sponsors, statisticians, investigators, and operations staff to design trials that are practical, and answer the required questions to take next steps in product development.

We spoke with one of Southern Star Research’s senior medical writers, Janet Hillary, to learn more about her role in phase 1 clinical trial design.

“When writing a study protocol, our goal is to produce a document with clearly stated objectives and measurable endpoints, which is easy for study sites to follow,” said Janet.

“Sponsors will usually provide a synopsis or draft protocol document as a starting point. This could include an outline of the study design, objectives, eligibility requirements, and schedule of assessment, however, we will also assist with fleshing these out if required.”

“It’s also important that we understand the context in which the investigational product is being tested, and the regulatory aims of the study. This means reviewing any correspondence or advice from regulatory agencies to ensure we are on the right track with study design.”

“Once we have this information, we can start producing the full document using our tried and tested templates.”

Single Ascending Dose (SAD) vs. Multiple Ascending Dose (MAD)

Dose escalation or ascending dose studies are commonly used in early phase 1 studies. Two key designs are Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) studies. Both play a vital role in understanding a drug's safety and pharmacokinetics.

Single Ascending Dose (SAD) studies aim to determine the safety and tolerability of a single dose of the investigational product. In these studies, participants receive a single dose of the investigational product, and the dosage may be increased in subsequent groups until a predefined safety threshold is reached. The primary outcome of SAD studies is establishing the maximum tolerated dose (MTD), and generating initial pharmacokinetic (PK) data.

On the other hand, Multiple Ascending Dose (MAD) studies are designed to evaluate the safety, and tolerability of repeat doses of the investigational drug over a specified period. In MAD studies, participants receive multiple doses, with the dosage increasing in subsequent cohorts. This study design helps researchers understand the drug's behavior under steady-state conditions. The outcomes of MAD studies provide early insights into the drug's safety profile, pharmacokinetics (PK), and pharmacodynamic (PD) properties.

Unlike other therapeutic areas that largely use simple SAD and MAD studies, phase 1 oncology trials follow a different study design while still increasing the dose sequentially. Instead of testing in healthy volunteers, cancer patient populations are targeted. These studies typically involve fewer participants, lack comparator groups, and have clearly defined dose-limiting toxicities.

Phase 1 clinical trial design and safety

Whichever trial design is chosen, the primary objective in phase 1 is typically safety, and the study protocol should clearly define how safety of trial participants by the investigator, and study staff will be assessed.

“This can include checking vital signs, ECGs, clinical laboratory testing, and physical examinations, to name a few. The protocol should also provide information on how to document, report, and follow-up adverse events,” explained Janet.

“Phase 1 trials will typically have a safety review committee, who reviews the safety data from participants in order to monitor any emerging safety signals or concerns,” she added.

“This committee will review an ascending dose study at defined timepoints in each SAD or MAD cohort to assess if the next dose level should commence. They have the authority to stop dose escalation if they identify concerning safety signals or protocol-defined stopping rules are triggered.”

As the landscape of drug development continues to evolve, a nuanced understanding of phase 1 clinical trial design remains paramount to unlocking the potential of novel therapeutics and advancing patient care. If you want to learn more about running a clinical trial, download our clinical trial study start-up checklist.

Southern Star Research is a full-service Australian Contract Research Organization. We help sponsors run safe and efficient trials that meet regulatory requirements, ensure scientific excellence, and demonstrate the commercial viability of your product. If you're looking for an agile and dedicated team to help you run a successful trial, contact us today.