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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
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
Trial phase |
Definition |
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.
When designing a clinical trial, it is important to define a number of parameters in order to generate meaningful results. These parameters include5:
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
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
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.
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
Component |
Definition |
Purpose |
Randomization | Patients are randomly assigned to one of the trial arms (experimental or control) | Reduces investigator and sample bias |
Stratification | 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 |
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.
Endpoints |
Definition |
Advantages |
Limitations |
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.
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
Grade |
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 |
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.
Adverse event |
Grade 1 |
Grade 2 |
Grade 3 |
Grade 4 |
Grade 5 |
Cytopenias | |||||
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 | |||||
Hepatic failure | N/A | N/A | Asterixis; mild encephalopathy; limitation of self-care | Moderate to severe encephalopathy; coma; life-threatening consequences | Death |
Renal | |||||
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 |
Other | |||||
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. PMID: 23295802
Unger JM, Hershman DL, Albain KS, et al. Patient income level and cancer clinical trial participation. J Clin Oncol. 2013;31(5):536-542. PMID: 23295802
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. PMID: 30856272
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. PMID: 30856272
Therasse P. From clinical trials to evidence-based medicine: how to build the evidence! EJC Suppl. 2003;1(6):55-65.
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.
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.
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.
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. PMID: 27881517
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. PMID: 27881517
Chin R, Lee BY. Principles and Practice of Clinical Trial Medicine. Amsterdam, The Netherlands: Academic Press; 2008.
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. Bethesda, Maryland: National Cancer Institute; 2001.
National Cancer Institute. Cancer Clinical Trials: The In-Depth Program. Bethesda, Maryland: National Cancer Institute; 2001.
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.
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.
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. PMID: 17339574
Stanley K. Design of randomized controlled trials. Circulation. 2007;115(9):1164-1169. PMID: 17339574
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. PMID: 19826358
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. PMID: 19826358
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, 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 9, 2020.
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 9, 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.
US Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
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