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Monitoring NCI-Sponsored Clinical Trials
Protections for patients in cancer studies come into play at various times before and during a clinical trial. Before a trial can start enrolling patients, for example, it must be approved by an Institutional Review Board (IRB), located at the hospital or other site where the study will be conducted. The IRB's task is to ensure that the trial will not expose patients to inappropriate or unethical risks. Each patient considering a trial must also receive full and detailed information about the study, including potential risks and benefits, during the informed consent process.
In addition to these basic protections, mandated by federal regulations, the National Cancer Institute (NCI) has established a program for continuous monitoring of all trials that it conducts or sponsors. The purpose of monitoring is to ensure both the safety of participants and the quality of the data collected. This fact sheet briefly describes three major components of NCI's monitoring system: - Data and Safety Monitoring Boards
- Quality Assurance Monitoring
- Adverse Event Reporting
Data and Safety Monitoring Boards (DSMBs)
Each of NCI's phase III trials (large studies that compare two or more approaches) is monitored by a Data and Safety Monitoring Board. A DSMB's main objectives are to: - ensure that patients in the clinical trial are protected
- ensure that evaluation of interim results and decisions about continuing, modifying, or terminating a clinical trial and reporting results are made competently
- ensure that the credibility of clinical trial reports and the ethics of clinical trial conduct are above reproach
DSMBs are made up of physicians, statisticians, other scientists, and laypersons, the majority of whom must have no affiliation with the institution leading the study. Meetings are held once a year or more often depending on the nature and volume of the trials being monitored. At meetings, members review the conduct of trials, accrual (enrollment figures), protocol compliance, adverse events (the side effects of the treatments under study), and outcome data. They then develop recommendations concerning whether to close the trial, report the results, or continue accrual or followup.
For more information: Policy of the National Cancer Institute for Data and Safety Monitoring of Clinical Trials; http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm
Quality Assurance Monitoring
NCI has several ways of assuring the quality of the data collected during clinical trials. Many trials, for example, have committees for central review of major elements, such as pathology, radiotherapy, surgery, and administration of investigational agents. Data quality control programs have been developed and are utilized by data management and statistical centers to help identify and correct or clarify inconsistencies and inaccuracies in submitted data.
One component of NCI's quality assurance program is on-site monitoring, or audits, of the procedures, documents, and data pertaining to a trial at a particular institution. Institutions are audited once every three years or more often. Auditors review three main categories of information: 1) conformance to Institutional Review Board and informed consent requirements, 2) shipping, storage, and use of drugs and other agents, and 3) individual patient cases.
Examples of major deficiencies that may be found during audits include: - Registration and/or treatment of a patient prior to full IRB approval
- An informed consent form signed after the patient started on treatment
- A patient not meeting all eligibility criteria specified by the protocol
- Inability to track the receipt, use, and disposition of investigational agents supplied by NCI
- Lack of source documentation to verify that agents were distributed to investigators and administered to patients appropriately
- Tumor measurements or evaluation of disease status not performed according to protocol
- Failure to assess and report toxicities and adverse events according to the protocol
- Protocol-specified laboratory tests or diagnostic studies not documented
In reporting results, auditors use the ratings Acceptable, Acceptable Needs Followup, or Unacceptable. For components rated less than Acceptable, the institution must submit a written response and/or corrective action plan. A re-audit is mandatory for any component rated as Unacceptable.
For more information: Guidelines for Monitoring of Clinical Trials for Cooperative Groups and CCOP Research Bases; http://www3.cancer.gov/prevention/ccop/.
Adverse Event Reporting
An adverse event is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medical treatment or procedure regardless of whether it is considered related to the medical treatment or procedure. NCI investigators report adverse events in clinical trials through both routine and expedited reports as specified in each protocol. The latter are required for serious or unexpected events, including 1) a life-threatening event, 2) the first occurrence of any unexpected event, regardless of the level of severity, or 3) death while on the study or within 30 days of treatment. These events must be reported to NCI's Cancer Therapy Evaluation Program (CTEP) within 24 hours and followed up with a written report within 10 working days.
At CTEP, physicians review each submitted report, classify the adverse event according to whether it is likely to have been related to the agent or to the patient's underlying disease, and decide whether further action is necessary. The prime consideration is whether the new findings affect the safety of patients enrolled in ongoing NCI-sponsored trials. If so, CTEP takes immediate steps to notify investigators and the Food and Drug Administration.
In addition, other measures may be taken, including: - Communicating the new information by sending written notice directly to investigators
- Altering existing research by modification of protocols or discontinuing or suspending one or more trials
- Investigating the reaction by initiating special clinical or preclinical studies
- Altering the process of informed consent by modifying existing informed consent forms or informing current patients of new findings
For more information: NCI Guidelines: Adverse Event Reporting Requirements for NCI Investigational Agents; http://ctep.cancer.gov/reporting/adeers.html.
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