Conduct and Monitor the study

Conducting the study

Once participants are enrolled, the study team can start to conduct the study and collect the data. The conduct of the study follows the procedures outlined in the study protocol as well as applicable guidelines, regulations, and standards.

A study team can include physicians, nurses, data managers, data entry specialists, pharmacists, laboratory support staff, administrative support staff, statisticians, patient advocates, and others. The team collects information (such as medical history, physical examination results, responses to questions, results of imaging studies) and biological specimens (such as blood samples, tissue samples, genetic tests) from participants according to the schedule described in the study protocol and the procedures described in the study’s Manual of Operations. Each study participant receives a detailed schedule of when data will be collected and what each visit involves; the study team arranges follow up and provides on-going education. Participant information is captured in the study’s data collection system (sometimes using specific forms, called “case report forms”), which can be paper or electronic.

The study team will meet periodically to review accrual, discuss progress, and address any problems. Adjustments to the study procedures may occur, including revisions of the protocol if necessary.

Monitoring the study

To ensure that study participants are protected and to ensure the integrity of the data being collected, studies are monitored while they are taking place. For instance, researchers are expected to follow applicable guidelines and standards when conducting a clinical study:

• International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use outlines international expectations for clinical research in its document on Good Clinical Practice, particularly, in sections 4, 5, 6, and 8.
• The FDA also describes the responsibilities of clinical investigators in Title 21 Part 312 Subpart D of the Code of Federal Regulations. The FDA has additional guidance documents related to Good Clinical Practice and maintains regulatory enforcement lists.
• Researchers are required to report adverse (negative) events to Institutional Review Boards and appropriate regulatory authorities. For events that are considered serious and unexpected, there is a shortened process. In its Clinical Safety Data Management E2A the ICH defines a serious event as any negative medical event that:
  • Results in death
  • Is life threatening
  • Results in hospitalization or prolongs ongoing hospitalization
  • Results in lasting or significant disability or incapacity
  • Is a birth defect or inborn abnormality
• FDA IND Safety Reporting Regulations require that researchers report all adverse events with the timeframe dependent upon the nature of the event.
• The NIH Notice on Adverse Event Safety Reporting to IRBs and the Office for Human Research Protection Guidance on Adverse Event Reporting provide general guidance on how researchers should conduct clinical studies.
• NIH-sponsored clinical research that uses genetically modified material for human gene transfer has a dedicated adverse event reporting mechanism, which is available through the Genetic Modification Clinical Research Information System (GeMCRIS).

The FDA describes situations in which a Data and Safety Monitoring Committee is used and provides recommendations on procedures and process in its guidance on Data Monitoring Committees. For example:

• The role of the Board or Committee is established before a clinical trial begins. Its functions typically include review of the protocol before it is implemented, review of study implementation and progress, and ongoing review of the accumulating data to detect evidence of early, significant benefit or harm for participants while the trial is in progress. This latter review serves as an additional protection for participants, beyond that provided by the IRB, but does not take the place of regulatory requirements for investigators to report serious and unanticipated adverse events to the FDA.
• The committee is normally responsible for defining its meeting schedule, based on the study's enrollment rate and the potential risk to participants.
• It may also establish "stopping rules" for halting the study based on:
  • How great a difference in effects is required to demonstrate clear clinical significance and make the data convincing to clinicians, and
  • Statistical techniques designed to preserve the final significance level of the trial.
• Who serves on the Committee depends on the research question and the funding mechanism of the study. Some mechanisms have these Committees built-in to their networks; other times, the Committee monitors the specific trial, so their membership is tailored to the expertise specific to that trial(s). Other features of the Committee include:
  • Five to seven members, including one or more of the following individuals: clinicians with expertise in the specific disease and/or treatment under study, biostatisticians, epidemiologists, and ethicists/patient advocates.
  • Members may also include a clinical researcher and a representative from the IRB.
  • Normally, members are not employees of the NIH or from the same institution as the principal investigator (PI).

NICHD staff may attend "open sessions" to provide the Committee with relevant updates in the field under study that might impact the Committee’s deliberations, to supply additional details on implementation or conduct of the trial, and to answer questions from Committee members.

The Committee recommends continuation, modification, or termination of the trial after each meeting. These recommendations are usually reported to the NICHD, any additional study sponsors, the clinical investigators, any data coordinating centers and the IRBs of participating institutions. through an established information flow. Typically the recommendations are accepted and implemented.

Resources for conducting and monitoring the study

• ICH Guidelines
  • Clinical Safety Data Management E2A
  • Good Clinical Practice Guidelines
• FDA Guidelines
  • Responsibilities of Sponsors and Investigators (Title 21 Part 312 Subpart D)
  • Guidances, Information Sheets, and Important Notices on Good Clinical Practice
  • Regulatory Activities Related to Good Clinical Practice
  • Investigational New Drug (IND) Safety Reporting Regulations
  • Guidance on Data Monitoring Committees
• NIH Guidelines
  • Notice on Adverse Event Safety Reporting to IRBs
  • GeMCRIS Web site
• Office of Human Research Protection
  • Office for Human Research Protection Guidance on Adverse Event Reporting

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