Cancer Clinical Trial Phases and Design

Introduction to cancer clinical trials

Although less than 5% of patients with cancer are enrolled in clinical trials, such trials represent an important link between basic cancer research and clinical practice.1 Clinical trials serve as the foundation for evidence-based medicine by addressing specific clinical questions that may lead to improvements in current clinical practice.

Phases of clinical development

Investigating the efficacy and safety of an agent or combination of agents through clinical trials involves multiple Phases of development, beginning with smaller Phase I trials and culminating in larger, randomized Phase III trials. Phase IV trials may also be conducted to gather additional information.2,3

Clinical trials by Phase2-4

Trial Phase



Initial trial of a drug in humans for dosing, safety, and early efficacy information (20-80 patients*)


Subsequent trial of a drug's safety and efficacy in a particular disease setting (100-300 patients*)


Larger trial comparing a drug with best available therapy to confirm efficacy and safety; often used for drug approval (1000-3000 patients*)


Trial conducted after US Food and Drug Administration (FDA) approval to gain additional information about the drug's risks and benefits (thousands of patients*)

*The patient numbers cited here apply to clinical trials in general.

Design of clinical trials

When designing a clinical trial, it is important to define a number of parameters in order to generate meaningful results. These parameters include the patient population to be studied, treatment(s) to be investigated, endpoints, and how the trial will be conducted (eg, randomized vs nonrandomized).

The patient population

When selecting the patient population to be studied in a clinical trial, investigators should include patients who are likely to benefit from the intervention being tested.5 The population should also be selected such that the results of the trial can be generalized to patients in clinical practice. Overall, the more diverse the patient population, the more generalizable the results may be to the wider patient population.6

In order to study a patient population of the appropriate disease state and level of diversity, investigators define criteria that determine whether or not a patient is eligible for a trial. Inclusion and exclusion criteria can include patient characteristics (eg, age) as well as disease- and treatment-specific characteristics (eg, number and type of prior therapies).6

Use of controls in a clinical trial

In controlled trials—most Phase III and some Phase II trials—the agent or regimen being investigated is compared to a control. The control may be either a placebo (if no effective therapies are available for the disease being studied) or a standard treatment—one in wide use and considered effective at the time the trial is designed.2,3 Although placebo is sometimes used as a control in clinical trials, it is rarely used in oncology trials, where there may be ethical issues with this approach. It is important to note that because some clinical trials take months or even years to complete, the standard treatment may no longer be in wide use by the time results from the trial are reported.

Selecting primary and secondary endpoints

Efficacy and safety in clinical trials are measured by means of certain predetermined endpoints, or outcomes, that the trial is designed to evaluate.2 These may include clinical endpoints, such as survival, as well as surrogate endpoints, which are expected to predict for a clinical outcome.7

The primary endpoint is the key measure from which clinical benefit is assessed. The primary endpoint selected by the investigators impacts the number of patients needed for the trial and must be determined before the trial is initiated.8 Secondary endpoints are other outcomes that provide additional and potentially valuable information about the treatment being tested.5 The trial protocol should prespecify secondary endpoints to increase the likelihood that statistical analysis of those endpoints will be valid.5

Selection of the primary endpoint in a clinical trial requires consideration of several factors.

  • What is the most clinically meaningful measure of benefit that could guide treatment decision making in this disease state and patient population?
  • Can the trial be conducted in a reasonable time frame?
    • Some endpoints require longer follow-up than others, lengthening the time required to complete trials and obtain meaningful results9
  • Can a sufficient number of patients be recruited to complete the trial?
    • Some endpoints necessitate larger trials in order to demonstrate statistically significant differences between arms, potentially creating difficulties in recruitment9

Conducting the trial

When the trial population, treatment, and endpoints have been identified and defined, the trial design is not yet complete. In Phase III and some Phase II trials, the patient population may be randomized and stratified. The gold standard in clinical research is a scientifically rigorous, randomized, and well-controlled trial.5

Components of clinical trial design6




Randomization Patients are randomly assigned to one of the trial arms (experimental or control) Reduces investigator and sample bias

Patients are sorted by characteristics (eg, extent of disease) that could influence the outcome of the trial 


  • Creates randomized groups that are comparable in prognosis


Allows investigators to examine the effects of the treatment in patient subgroups


  1. Keller JK, Bowman J, Lee JA, et al. Poor access to clinical trials among newly diagnosed adult cancer patients in the community—1999–2004. Comm Oncol. 2007;4:695-700.
  2. Learn about clinical studies. Accessed June 4, 2018.
  3. US Food and Drug Administration. The FDA's drug review process: ensuring drugs are safe and effective. Accessed June 4, 2018.
  4. protocol registration data element definitions for interventional and observational studies. Updated June 29, 2017. Accessed June 4, 2018.
  5. Chin R, Lee BY. Principles and Practice of Clinical Trial Medicine. Amsterdam, The Netherlands: Academic Press; 2008:3-16.
  6. National Cancer Institute. Cancer Clinical Trials: The In-Depth Program. Reprinted September 2002. Accessed June 4, 2018.
  7. Brenner DE. Cancer prevention: chemoprevention. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, eds. Cancer Principles & Practice of Oncology. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:609-635.
  8. Stanley K. Design of randomized controlled trials. Circulation. 2007;115:1164-1169. PMID: 17339574
  9. Lebwohl D, Kay A, Berg W, Baladi JF, Zheng J. Progression-free survival: gaining on overall survival as a gold standard and accelerating drug development. Cancer J. 2009;15:386-394. PMID: 19826358