Clinical Trials: How They Work and How to Enroll

Clinical trials are the structured research process through which new cancer treatments, diagnostic tools, and prevention strategies earn evidence-based validation before entering standard care. This page covers how trials are designed and regulated, what happens at each phase, the types of trials most relevant to oncology patients, and what determines whether enrollment is appropriate for a given situation. Understanding this process is relevant to any patient weighing options beyond first-line treatment or seeking access to investigational therapies.

Definition and scope

A clinical trial is a prospective research study conducted in human participants to evaluate the safety, efficacy, or optimal dosing of a medical intervention. In oncology, interventions under study include cytotoxic drugs, immunotherapies, targeted agents, radiation protocols, surgical techniques, combination regimens, and supportive care strategies.

The U.S. Food and Drug Administration (FDA) governs clinical trial conduct under 21 CFR Parts 312 and 314, which establish Investigational New Drug (IND) requirements. The National Institutes of Health (NIH) maintains ClinicalTrials.gov, the federal registry where all U.S. trials must be registered under the Food and Drug Administration Amendments Act of 2007 (FDAAA 801). As of published NIH data, ClinicalTrials.gov lists more than 480,000 registered studies globally, with oncology representing the largest single disease category.

For a broader view of how federal regulatory structures shape oncology care, see the Regulatory Context for Oncology resource on this site.

How it works

Clinical trials in oncology proceed through four defined phases, each with a distinct scientific objective and participant population size.

Phase I — Evaluates safety, tolerability, and dosing in a small cohort, typically 20–80 participants. The primary endpoint is identification of dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD). Most Phase I oncology trials enroll patients who have exhausted standard treatment options.
Phase II — Assesses preliminary efficacy and continues safety monitoring, generally enrolling 100–300 participants. Endpoints include objective response rate (ORR), progression-free survival (PFS), and tolerability in a disease-specific population.
Phase III — Compares the investigational intervention against the current standard of care in a randomized, controlled format. Phase III trials enroll hundreds to thousands of participants and generate the evidence base required for FDA approval. Randomization is a defining feature: participants are assigned by chance to the experimental arm or the control arm, reducing selection bias.
Phase IV — Post-market surveillance conducted after regulatory approval to identify long-term effects and real-world effectiveness across broader populations.

The trial protocol, which specifies eligibility criteria, treatment schedules, and safety monitoring procedures, must be reviewed and approved by an Institutional Review Board (IRB) before enrollment begins. IRB oversight is mandated under 45 CFR Part 46 (the Common Rule), which protects human subjects in federally funded research. Every participant must provide written informed consent prior to enrollment, a requirement codified in both FDA and Department of Health and Human Services (HHS) regulations.

Sponsor-investigators must also comply with Good Clinical Practice (GCP) standards as defined by the International Council for Harmonisation (ICH) guideline E6(R2), which governs data integrity, participant safety monitoring, and adverse event reporting.

Common scenarios

Three trial types account for the majority of enrollment decisions in oncology:

Treatment trials test new drugs, drug combinations, or novel delivery methods. These are the most prevalent type on ClinicalTrials.gov within the oncology category and include trials studying immunotherapy, targeted therapy, and CAR-T cell therapy approaches.

Prevention trials evaluate agents or interventions designed to reduce cancer incidence in high-risk populations. The NSABP Breast Cancer Prevention Trial, which studied tamoxifen, is a historically documented example reviewed in National Cancer Institute (NCI) publications.

Biomarker and genomic trials focus on identifying molecular predictors of treatment response. These trials often incorporate molecular profiling and biomarker analysis as a primary or co-primary endpoint rather than a secondary measure.

Basket trials and umbrella trials represent more recent structural designs. A basket trial enrolls participants across multiple cancer types sharing a common genetic alteration. An umbrella trial tests multiple agents within a single cancer type, stratified by biomarker subgroup. Both designs allow more efficient testing across smaller, molecularly defined populations.

Decision boundaries

Eligibility for enrollment is governed by protocol-specific inclusion and exclusion criteria. Standard oncology trial criteria commonly address:

Diagnosis specificity — Histologic confirmation and, increasingly, molecular subtype (e.g., KRAS mutation status, PD-L1 expression level)
Prior treatment history — The number and type of prior lines of therapy, including whether a patient has received specific drug classes
Performance status — Most trials require an ECOG performance status of 0 or 1, indicating full or near-full functional capacity
Organ function thresholds — Defined acceptable ranges for hepatic, renal, and hematologic function
Concurrent medication restrictions — Prohibitions on certain concomitant drugs that could confound results or create safety interactions

Patients considering enrollment should discuss trial options with their treating oncologist and consult ClinicalTrials.gov directly using its disease and location filters. The NCI also operates a Cancer Information Service at 1-800-4-CANCER, which can assist with trial identification at no cost.

Phase III randomization is a boundary condition that some patients find difficult to accept — specifically the possibility of assignment to the control arm. Understanding that the control arm receives the current standard of care, not a placebo (in most oncology contexts), is critical to informed decision-making. For an orientation to the full landscape of cancer care from diagnosis through treatment and follow-up, the oncologyauthority.com home resource provides a structured entry point across all major topic areas.

Financial and logistical factors — including travel to trial sites and insurance coverage of trial-associated costs — are addressed in the separate Financial Considerations for Cancer Treatment resource.

References

The law belongs to the people. Georgia v. Public.Resource.Org, 590 U.S. (2020)