Clinical Trial Design: A New Level of Scientific Rigor

Before a drug can be approved for use, it must pass through several phases of clinical testing, each designed to answer a specific set of questions.

Phase 1 trials are the first time a new therapeutic is tested in humans. Typically involving 40 to 60 healthy volunteers, these studies focus on safety, pharmacokinetics (what the body does to a drug), and determining a safe dosage range. In cases where drugs are expected to have serious side effects—such as oncology drugs—or require specialized delivery methods, Phase 1 studies may instead enroll patients with the target condition.

Once safety is established, Phase 2 trials shift attention to the drug’s intended population. These studies identify therapeutic dose levels and dosing frequencies and look for preliminary signs of efficacy. Phase 3 trials are large-scale studies that confirm safety and efficacy in hundreds or thousands of participants, often using endpoints defined by regulatory agencies such as the US FDA. While two Phase 3 studies are the standard path to approval, exceptions exist for rare or life-threatening conditions.

After approval, Phase 4 post-marketing studies continue to collect data on long-term safety, efficacy, and real-world use.

Before launching into trial design, researchers must determine whether a study is even feasible. Clinical trials are expensive, time-consuming, and logistically complex.

A practical approach (and a SPARK NS mantra) is to start with the end in mind. Identify the intended commercial indication and imagine what a successful Phase 3 program would need to demonstrate for regulators, clinicians, and payors. From that endpoint, work backwards to outline what Phase 2 and Phase 1 studies must achieve to build a credible development path.

Key considerations include the target population, availability of biomarkers for patient selection, trial duration and size, cost, and the competitive landscape for patient enrollment.

Every trial design is shaped by its phase, therapeutic type, and patient population. Before any clinical testing can begin in the US, investigators must file an Investigational New Drug (IND) application with the FDA. Included in the application is the clinical protocol and overall development plan.

A strong clinical plan should clearly define the patient population, inclusion and exclusion criteria, outcome measures, and statistical considerations. Randomized controlled trials remain the gold standard because they minimize bias and balance confounding factors, but uncontrolled or open-label studies may be appropriate when efficacy is not the primary endpoint—such as in early dose-finding work.

Researchers must also specify how efficacy and safety will be measured, identify primary, secondary, and surrogate endpoints, and ensure the study has enough statistical power to detect meaningful differences.

“The importance of a well-written clinical trial protocol is underscored by the wide range of individuals who read it,” said Dr. Lyn Frumkin, MD, PhD, a biotechnology consultant and SPARK NS industry expert advisor.

From investigators and clinical trial research assistants to regulatory scientists and even potential investors, the protocol is the blueprint that keeps everyone aligned.

It may seem premature to think about clinical trials when preclinical work is still early in development, but planning early helps ensure a smooth path to translation. A well-structured clinical plan is not only required for an IND submission—it also informs the design of the preclinical studies that will be used to support moving the drug into clinical testing, such as toxicology studies conducted under Good Laboratory Practice (GLP) standards.

“When designing your clinical development plan, consult with clinicians and business development advisors to ensure you’re on the right path and have considered all required details,” advised Kevin Grimes, MD, MBA, Chief Clinical and Education Advisor at SPARK NS. Engaging statisticians and key opinion leaders early, and referencing your Target Product Profile (TPP), can help optimize the design and improve the likelihood that your discovery will move successfully from bench to bedside.