Cancer clinical trial phases and design
Introduction to cancer clinical trials
Although the percentage of patients with cancer who are enrolled in clinical trials is estimated to be <5% (with some analyses suggesting ~7% to 16%, depending on setting), such trials represent an important link between cancer research and clinical practice.1,2 Clinical trials serve as the foundation for evidence-based medicine by addressing specific clinical questions that may lead to improvements in current clinical practice.3
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.4-6
Clinical trials by Phase5-7
|I||Initial trial of a drug in humans for dosing, safety, and early efficacy information (20-80 patients*)|
|II||Subsequent trial of a drug's safety and efficacy in a particular disease setting (100-300 patients*)|
|III||Larger trial comparing a drug with best available therapy to confirm efficacy and safety; often used for drug approval (100-3000 patients*)|
|IV||Trial conducted after US Food and Drug Administration (FDA) approval to gain additional information about the drug's risks and benefits. Phase IV studies can range in study size, from a few hundred to a few thousand participants.|
*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 include5:
- Patient population to be studied
- Treatment(s) to be investigated
- How the trial will be conducted (eg, randomized vs nonrandomized)
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.8 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.9
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).9
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.10,11
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.8
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.12 Secondary endpoints are other outcomes that provide additional and potentially valuable information about the treatment being tested.8 The trial protocol should prespecify secondary endpoints to increase the likelihood that statistical analysis of those endpoints will be valid.8
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 results13
- Can a sufficient number of patients be recruited to complete
- Some endpoints necessitate larger trials in order to demonstrate statistically significant differences between arms, potentially creating difficulties in recruitment13
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.8
Components of clinical trial design9
|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
|Allows investigators to examine the effects of the treatment in patient subgroups|
Efficacy endpoints in oncology clinical trials
The following table shows a number of efficacy endpoints. Each of these endpoints is associated with certain advantages and limitations. Although the endpoint definitions provided here are from FDA guidance, please note that individual clinical trials may use different definitions.
Commonly used efficacy endpoints in oncology clinical trials: advantages and limitations14
Overall survival (OS)
|Time from randomization* until death from any cause|| || |
|Progression-free survival (PFS) ||Time from randomization* until disease progression or death||
|Time to progression (TTP) ||Time from randomization* until objective tumor progression; does not include deaths|
|Time to treatment failure (TTF ||Time from
randomization* to discontinuation of treatment for any reason,
including disease progression, treatment toxicity, and
death || || |
|Event-free survival (EFS) ||Time from
randomization* to disease progression, death, or discontinuation
of treatment for any reason (eg, toxicity, patient preference,
or initiation of a new treatment without documented
progression) || || |
|Time to next treatment (TTNT) ||Time from end of
primary treatment to institution of next therapy
|| || |
|Objective response rate (ORR) ||Proportion of
patients with reduction in tumor burden of a predefined
amount || || |
*Not all trials are randomized. In nonrandomized trials, time from study enrollment is commonly used.
Safety endpoints in cancer clinical trials
Toxicity criteria in oncology/hematology clinical trials
To standardize the reporting of adverse events in clinical trials, the National Cancer Institute (NCI) has developed Common Terminology Criteria for Adverse Events (NCI CTCAE). The NCI CTCAE was most recently updated in November 2017 (version 5.0). Clinical trials that began earlier than this date may use earlier versions of the NCI CTCAE when reporting adverse events. According to the NCI CTCAE, adverse events are reported by grade (level of severity) on a scale of 1 to 5. Generally, the descriptions follow the guidelines below.15,16
NCI CTCAE definitions of severity for adverse events16
Degree of severity
|1||Mild, with mild or no symptoms; no interventions required|
|2||Moderate; minimal intervention indicated; some limitation of activities|
|3||Severe but not life threatening; hospitalization required; limitation of patient's ability to care for him/herself|
|4||Life threatening; urgent intervention required|
|5||Death related to adverse event|
Common adverse events by grade16
The following table shows NCI CTCAE grades for some adverse events commonly observed in clinical trials in oncology/hematology. This list is not all-inclusive; please consult the NCI CTCAE for a full list of adverse event criteria.
|Anemia||Hgb <LLN to 10.0 g/dL||Hgb <10.0 g/dL to 8.0 g/dL||Hgb <8.0 g/dL; transfusion indicated||Life-threatening consequences; urgent intervention indicated||Death|
|Neutropenia||Neutrophils <LLN to 1500/mm3||<1500/mm3 to 1000/mm3||<1000/mm3 to 500/mm3||<500/mm3||N/A|
|Thrombocytopenia||Platelets <LLN to 75,000/mm3||<75,000/mm3 to 50,000/mm3||<50,000/mm3 to 25,000/mm3||<25,000/mm3||N/A|
|Hepatic failure||N/A||N/A||Asterixis; mild encephalopathy; limitation of self-care||Moderate to severe encephalopathy; coma; life-threatening consequences||Death|
|Creatinine increase||>ULN to 1.5 × ULN||>1.5 to 3.0 × baseline; >1.5 to 3.0 × ULN||>3.0 × baseline; >3.0 to 6.0 × ULN||>6.0 × ULN||N/A|
|Fatigue||Relieved by rest||Not relieved by rest; limitation of instrumental ADL||Not relieved by rest; limitation of self-care ADL||N/A||N/A|
|Febrile neutropenia||N/A||N/A||ANC <1000/mm3 with single temperature reading >38.3°C (101.0°F) or sustained temperature ≥38.0°C (100.4°F) for >1 hour||Life-threatening consequences; urgent intervention indicated||Death|
|Fever||38.0°C to 39.0°C (100.4°F to 102.2°F)||>39.0°C to 40.0°C (102.3°F to 104.0°F)||>40.0°C (>104.0°F), lasting ≤24 hours||>40.0°C (>104.0°F), lasting >24 hours||Death|
|Infections and infestations||Asymptomatic or mild symptoms; observations only; intervention not indicated||Moderate symptoms; minimal intervention indicated; limitation of instrumental ADL||Severe or medically significant but not immediately life threatening; hospitalization indicated; limitation of self-care ADL||Life-threatening consequences; urgent intervention indicated||Death|
|Infusion reactions||Mild, transient reaction; interruption/intervention not indicated||Interruption indicated, but responds promptly to symptomatic treatment; prophylactic medications indicated for ≤24 hours||Prolonged (not rapidly responsive to treatment and/or infusion interruption); recurrence of symptoms following initial improvement; hospitalization indicated||Life-threatening consequences; urgent intervention indicated||Death|
ADL=activities of daily living; ANC=absolute neutrophil count; LLN=lower limit of normal; ULN=upper limit of normal.
- Unger JM, Hershman DL, Albain KS, et al. Patient income level and cancer clinical trial participation. J Clin Oncol. 2013;31(5):536-542.
- Unger JM, Vaidya R, Hershman DL, Minasian LM, Fleury ME. Systematic Review and Meta-Analysis of the Magnitude of Structural, Clinical, and Physician and Patient Barriers to Cancer Clinical Trial Participation. J Natl Cancer Inst. 2019;111(3):245-255.
- Therasse P. From clinical trials to evidence-based medicine: how to build the evidence! EJC Suppl. 2003;1(6):55-65.
- Learn about clinical studies. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/about-studies/learn. Accessed February, 12, 2020.
- The FDA's drug review process: ensuring drugs are safe and effective. US Food and Drug Administration website. https://www.fda.gov/drugs/resourcesforyou/consumers/ucm143534.htm. Accessed February, 12, 2020.
- ClinicalTrials.gov protocol registration data element definitions for interventional and observational studies. ClinicalTrials.gov website. https://prsinfo.clinicaltrials.gov/definitions.html. Updated June 29, 2017. Accessed February, 12, 2020.
- Zhang X, Zhang Y, Ye X, Guo X, Zhang T, He J. Overview of phase IV clinical trials for postmarket drug safety surveillance: a status report from the ClinicalTrials.gov registry. BMJ Open. 2016;6(11):e010643. doi: 10.1136/bmjopen-2015-010643.
- Chin R, Lee BY. Principles and Practice of Clinical Trial Medicine. Amsterdam, The Netherlands: Academic Press; 2008.
- National Cancer Institute. Cancer clinical trials: the in-depth program. https://accrualnet.cancer.gov/sites/accrualnet.cancer.gov/files/InDepth_Book_m.pdf. Reprinted September 2002. Accessed June 4, 2018.
- National Cancer Institute at the National Institutes of Health. Use of Placebos. https://www.cancer.gov/about-cancer/treatment/clinical-trials/what-are-trials/placebo.
- Cancer.net. Placebos in Cancer Clinical Trials. https://www.cancer.net/research-and-advocacy/clinical-trials/placebos-cancer-clinical-trials. Accessed February 20, 2018.
- Stanley K. Design of randomized controlled trials. Circulation. 2007;115(9):1164-1169.
- 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(5):386-394.
- US Department of Health and Human Services, Food and Drug Administration, Oncology Center of Excellence, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Clinical trial endpoints for the approval of cancer drugs and biologics: guidance for industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-trial-endpoints-approval-cancer-drugs-and-biologics. Published December 2018. Accessed August 21, 2019.
- US Department of Health and Human Services, National Institutes of Health, National Cancer Institute. List of Codes and Values. https://ctep.cancer.gov/protocolDevelopment/codes_values.htm. Accessed March 09, 2020.
- US Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.