Regulatory Maintenance

UC San Diego is committed to the highest ethical and legal standards in the conduct of research. The Office of Research Compliance and Integrity facilitates research, innovation and education, responsibly for global excellence and is responsible for broad oversight, resources and education for the integrity and compliance issues relating to the conduct of research.  It is the responsibility of all members of the UC San Diego research community to be familiar with University policies related to the conduct of research.

Learn more on the Research Compliance and Integrity Office (RCI) website.

Study Management Tools

This section includes Clinical Trial study management tools, templates, and guidance for investigators conducting clinical trials.

Before You Begin The Clinical Trial

Protocol Template
A protocol is a document that describes the background, rationale, objectives, design, methodology, statistical considerations, and organization of a trial. The ICH Good Clinical Practice Guidelines specify some topics that should generally be included in a protocol. Many of the NIH institutes have their own protocol templates. Examples are available at the NIAID website.

Budget Development
Budget development involves three components:

1. Identifying the cost of all research items and services required for the study
2. Assigning financial responsibility for all items and services; and
3. Maintaining a process for recovering costs throughout the study.

Every investigator should have a clear financial management plan to adequately support their research endeavors. The plan should include a defined department process and a responsibility log which outlines the team members accountable for the process. For budget analysis assistance, complete a CTRI Service Request.

Feasibility Checklist
When approached with an invitation to participate in a clinical trial, the investigator usually receives a copy of the protocol or a protocol synopsis. It is very important to carefully review and evaluate the protocol and determine if appropriate patient population and resources are available for successfully completing the trial. The Sample Feasibility Checklist gives you a list of questions that you should consider before agreeing to participate in a trial.

Study Initiation

Regulatory Binder | Site Master File (SMF)

The Regulatory Binder (also called a Site Master File (SMF) or Investigator Site File (ISF) contains essential study documents which individually and collectively permit the evaluation of the conduct of the trail and the quality of the data produced.  Filing these documents in a timely manner and maintaining them throughout the stdy lifecycle can greatly assist in the successful management of a trial.  See the sample Regulatory Binder Table of Contents. 

Delegation of Responsibility Log

Conducting a clinical trial is clearly a team effort with every member in the study team playing an important role. However, the overall responsibility for a clinical trial rests with the Principal Investigator. The Principal Investigator then delegates specific responsibilities to various members within the team. These responsibilities should be formally assigned. The Delegation of Responsibility & Staff Signature Log helps track the responsibilities of the various team members (see sample delegation log here).

Study Flowsheet

For some studies creating simple reminders or worksheets will help staff obtain the required data in a timely fashion and greatly helps in reducing the number of missing data points. The Study Flowsheet can serve as a reminder to ensure that all protocol specific procedures are completed in a timely manner.

Schedule of Assessments

The protocol should clearly outline the activities that are to be performed for the research study. This includes a plan for administration of study treatment and a list of assessments and procedures that are to be performed for the duration of the study. The Schedule of Assessments lists all the study related activities and the time points at which they should be performed.

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Study Management Logs

Master Subject Log
Most clinical trials involve multiple study visits over an extended period of time. While it is very important to maintain subject privacy and confidentiality, a study coordinator's job also involves making sure that subjects come for their follow up visits on schedule. A study coordinators job is made much easier to have all the subject contact information in one place. In conjunction with the Subject Visit Schedule Log, the Master Subject Log helps to make the study coordinators job a bit easier.

Subject Screening and Enrollment Log
Usually a research team has to screen several subjects to find subjects who are eligible for participation in a particular study. No subject may be screened without informed consent, unless this was waived by an IRB. It is important to keep track of all the subjects who agreed to participate in a research study by signing the informed consent form. Some of these subjects may be screen failures, some may withdraw after a few visits while others go on to complete the study. The Screening / Enrollment / Withdrawal Log helps track study subjects.

Subject Visit Schedule Log
Most coordinators work on several studies simultaneously. It is very difficult to keep track of subject visits especially when studies involve multiple visits over long periods of time. The Study Events Tracking Form  and Subject Visit Log will help you keep track of subject visits and will also help you calculate subsequent visits.

Case Report Form (CRF) resource from NINDS

Tracking and Reporting

Adverse Event Tracking

At every study visit, the subject should be observed for adverse events and should be asked about any adverse event that might have happened since the previous visit. Most of these adverse events might not meet the definition of an Unanticipated Problem Involving Risks to Subjects or Others. All study events need to be tracked meticulously in an Adverse Event Tracking Log (sample).

Protocol Deviation Information

Although it is important to follow the protocol very strictly, deviations do sometimes occur due to various reasons. Some protocol deviations might meet the definition of an Unanticipated Problem Involving Risks to Subjects or Others. The Protocol Deviation Tracking log (sample) tracks all the protocol deviations and serves as documentation of the determination of whether or not a particular deviation should be submitted to the IRB.

Note to File

A Note-to-File (sample) may be written by any member of the study team to provide additional information or clarification.

Accountability Logs

Device Accountability Log
Investigators are responsible for maintaining strict control over investigational devices to ensure that the device is used only for subjects enrolled in the study. The Device Accountability Log helps maintain study device inventory and can be included in the regulatory binder.

Drug Accountability Log
Investigators are responsible for maintaining strict control over investigational drugs to ensure that the drug/biologic is used only for subjects enrolled in the study. The Drug or Biologic Dispensing/Accountability Log helps maintain an inventory of drugs used during the study and can be included in the regulatory binder.

Specimen Log
Safety laboratory assessments are usually part of most clinical trials that involve an investigational test article. Biological materials might be sent to the local laboratory or to a central laboratory. The Specimen Log helps track samples that are collected from study subjects.

Need assistance or have clinical study management questions? Contact us.

Quality Management Practices

Ideally, every clinical trial should have a Clinical Trial Quality Management Plan (QMP) describing the tools that will be used to ensure study quality. The extent and nature of monitoring may be determined based on various considerations such as trial design, complexity, size, risks to subjects, and endpoints of the trial.

One of the benefits of developing and implementing a QMP includes developing proactive communication among clinical trial team members.  This benefits clinical trial teams by encouraging early identification and resolution of clinical trial problems and concerns. Implementing a Clinical Trial QMP can also encourage conformity with Standard Operating Procedure, Good Clinical Practice (GCP), Good Laboratory Practice, and UCSD policies and procedures.  This leads to an overall reduction in external (Sponsor, FDA) and internal (UCSD) data queries, and helps reduce clinical trial closeout time.

Quality Management Plans include all the activities undertaken to verify that the requirements for quality of the trial related activities have been fulfilled. Listed below are several logs and checklists that might help with quality management plan development:

• Chart Audit Tool
• Regulatory File Review Tool (sample)
• Monitoring Log

Industry sponsored clinical trials usually have a comprehensive monitoring plan. Regular monitoring of a trial is very helpful to verify compliance of the trial with currently approved protocol, Good Clinical Practice and applicable regulatory requirements.

Source Data are defined as all information in original records or certified copies of clinical findings, observations, or other activities that are necessary for reconstruction and evaluation of the trial. The records that contain source data are called Source Documents. Source Document Verification is an important part of monitoring.  Source data is verified by reviewing that all the data variables in the case report form accurately reflect information in the source documents.

Researchers may choose any option that is appropriate for the trial, some of the options include; a review of all data variables in the case report form for all enrolled subjects, a review of all CRF data for a percentage (e.g. 5%) of patients enrolled or even a review of only certain specified variables on all or some CRFs (for example, only the eligibility criteria).

​Essential Documents permit evaluation of the conduct of a trial and the quality of data produced. These documents serve to demonstrate compliance with standards of Good Clinical Practice and with all applicable regulatory requirements. Filing these documents in a timely manner can greatly assist in the successful CTQMP and management of a trial. 

• Sample Quality Management Plan
• Food and Drug Administration (FDA) Regulations

Data and Safety Monitoring

The NIH requires data and safety monitoring for all types of clinical trials, including physiologic, toxicity, and dose-finding studies (Phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III).

Monitoring should be commensurate with risks. The method and degree of monitoring needed is related to the degree of risk involved.  A monitoring committee is usually required to determine safe and effective conduct and to recommend conclusion of the trial when significant benefits or risks have developed or the trial is unlikely to be concluded successfully.

Data Safety Monitoring Plans

A Data and Safety Monitoring Plan (DSMP) is just one of the mechanisms used to ensure the safety of study subjects as well as maintain data validity, integrity, and scientific merit. DSMPs depend upon many variables, such as the degree of risk, disease being studied, subject population, and number of sites where the research is being conducted. Complex DSMPs frequently include a Data Safety Monitoring Board (DSMB).

NIH Data Safety Monitoring Plan Information and Templates

To assist investigators in complying with the NIH data safety monitoring policy, please visit guidance and sample DSMP templates on the NIH website.

DSMP Checklist

• Primary and secondary outcome measures
• Inclusion/exclusion criteria
• Sample size
• List of participating enrolling clinics or data collection centers
• Projected timetable
• Target population distribution (e.g., women, minorities, etc.)Data acquisition and transmission
• Data entry methods
• Data analysis plan
• Quality assurance plan
• Reporting mechanisms of AEs/SAEs to the IRB, FDA, and NIDA.
• Reporting mechanisms of IRB actions to sponsor or funder
• Report of changes or amendments to the protocol
• Trial stopping rules
• Conflict of interest
• Potential risks and benefits for participants
• Collection and reporting of AEs and SAEs
• Management of SAEs or other study risks
• Plans for Interim Analysis of efficacy data
• Responsibility for data and safety monitoring
• Frequency of DSM reviews
• Content of DSM report
• DSM Board Plan (if applicable)

The Data Safety Monitoring Board (DSMB)

DSMBs are made up of multidisciplinary members who are knowledgeable in the conduct of research, and should include those with backgrounds in biostatistics, experimental design, bioethics, and experts in the medical field of concern.  The DSMB advises investigators regarding the continuing safety of trial subjects and those yet to be recruited to the trial, as well as the continuing validity and scientific merit of the trial. 

The DSMB performs the following general functions:

• Objectively appraise a study’s progress
• Assess data quality via a formal and planned process
• Provide analytical expertise and rigor
• Determine the statistical significance of efficacy and/or risk‐benefit ratio

DSMBs are responsible for reviewing data and endpoints on a timeline set forth by the DSMP in the protocol, and are typically required for the following types of studies:

• More than minimal risk 
• Multiple study sites. It is more difficult to recognize a pattern of increased or unusual problems when investigators treat small fractions of the population separately
• Vulnerable population (pediatric, geriatric)
• Blinded studies 
• New therapies or science 
• Highly toxic therapies or dangerous procedures.
• High expected rates of morbidity or mortality in the study population.
• High chance of early termination of the study.

NCI guidelines are widely considered to be the most comprehensive and set forth requirements for DSMB composition and function; note that it is required that a majority of the members be drawn from outside the institution (or institute) conducting the study. DSMB membership is usually comprised of:

• Experts in the fields of medicine and science that are applicable to the study,
• Statistical experts,
• Lay representatives, and
• Other who can offer an unbiased assessment of the study progress

DSMB Collaboration with the IRB

The DSMB is not specifically required to communicate with the IRB, but the intent is clear that the important information get to the IRB.

Data Safety Tools, Templates and Related Guidance

Related Guidance, Tools & Templates

• FDA Guidance for Clinical Trial Sponsors
• NIH Policy for Data and Safety Monitoring
• Further Guidance on a Data and Safety Monitoring for Phase I and Phase II Trials
• Webinar: Oversight of Clinical Investigations

UCLA Presentations:

• Managing the Practice of Research

Safety Reporting to the IRB

UCSD requires researchers to report any unanticipated problems involving risks to subjects or others in a timely manner. Unanticipated problems are problems that (1) are not expected given the nature of the research procedures and the subject population being studied; and (2) suggest that the research places subjects or others at a greater risk of harm or discomfort related to the research than was previously known or recognized.

Determining which adverse events or problems need to be reported can sometimes be tricky.  We encourage you to learn more about safety reporting to the IRB.  Please see the following materials for additional guidance:

• OHRP Unanticipated Problem Guidance

• FDA AE Reporting to IRBs Guidance

• FDA Safety Reporting Guidance for INDs

• FDA Mandatory Reporting- Form 3500A

• FDA IND Regulations

• UCSD IRB Reportable Event Information

• FDA IDE Regulations 

Safety Committee Resources

UCSD Institutional Review Board

Post Approval Reporting. The Principal Investigator is responsible for submitting to the IRB ongoing reports of events that may adversely affect the safety of participants or the conduct of the research, and any information relevant to the conduct of the approved research. The types of events and information that may need to be reported to the IRB include, but are not limited to:

• Adverse Events
• Violations, Deviations, and Incidents
• Updated Study Safety Information

An unanticipated problem is an event or outcome that meets the following criteria: 1) unexpected; 2) related or possibly related to participation in the research; and 3) places subjects or others at a greater risk of harm than was previously known or recognized. All unanticipated problems need to be reported to the IRB via webIRB, though not all adverse events, violations, incidents or deviations are unanticipated problems. For details, please see the UCSD Office of IRB administration website here.

UCSD Environment, Health & Safety

Training & Outreach. In-class and online training courses are available to assist you in meeting regulatory training requirements along with videos, publications and other resources to help promote safety on campus.

Forms and Templates. Additional resources, including sample forms, templates, and examples are available via the UCSD EH&S Blink website.

Registration for Clinical Research Trials

Interventional studies with health outcomes must be registered, and may be required to report results, in ClinicalTrials.gov. This requirement applies to:

1. All NIH-funded trials, including phase 1 studies and clinical trials of behavioral or non-FDA-regulated interventions (Registration and Results required).
2. Clinical trials involving FDA-regulated drug, biologic and device products (Registration and Results required).
3. Studies that will bill routine costs to Medicare or any other insurer (Registration required).
4. Any study intended for publication in a journal recognized by the ICMJE (Registration required).

Those responsible for conducting a clinical trial must make sure that they are in compliance with the trial registration requirements of the Food and Drug Administration (FDA), the National Institutes of Health (NIH), the International Committee of Medical Journal Editors (ICMJE), and as required by other organizations with policies on clinical trial registration for transparency and publication.

Section 801 of the Food and Drug Amendments Act, known as FDAAA 801, requires registration of studies meeting the definition of “Applicable Clinical Trial” on a government web site called ClinicalTrials.gov.

The US National Institutes of Health (NIH) final policy of 2016 established the expectation that all investigators conducting clinical trials funded in whole or in part by the NIH will ensure that these trials are registered and results information is submitted to ClinicalTrials.gov. Compliance with FDAAA is a legal requirement and a term and condition of the NIH award. All competing applications (new and renewal) and progress reports for NIH grants (including cooperative agreements) supporting clinical trials must include a certification of compliance with FDAAA.

The International Committee of Medical Journal Editors (ICMJE) requires, and recommends that all medical journal editors require, as a condition of consideration for publication, registration of [all] clinical trials in a public trials registry at or before the time of first patient enrollment.

Effective January 1, 2015, Center for Medicare and Medicaid Services (CMS) will require a clinical trial identifier (NCT#) be reported on all billing claims for items/ services related to a qualifying clinical trial(s). If your study will bill routine costs to Medicare or any other insurer, the study must be registered on ClinicalTrials.gov to obtain the NCT#.

ClinicalTrials.Gov Registration and Results Reporting of Clinical Studies