Quality Management Plan (QMP) Guidance

In its most basic form, ‘quality’ in the conduct of human subject research is defined by the absence of errors. Therefore, a Quality Management Plans (QMP) is a detailed strategy outlining how errors will be identified and assessed during the conduct of a study. ^[1,2] It is important to remember when developing a QMP that errors range in severity and their potential to introduce risk to subjects (e.g., minor documentation errors versus enrolling subjects without Institutional Review Board [IRB] approval). The goal of a QMP is to assist in conducting high quality research, which is research that protects subjects, is conducted in a compliant manner, and produces ‘good’ data with reliable conclusions. ^[3]

Traditionally, assessing quality has been reactive; errors are identified and addressed after the fact. The ideal method of quality management is proactive, which involves the study team implementing a process to continuously assess the quality of the research operation by building quality measures into a study during the development stage.

The increasing complexity of study protocols drives levels of site burden higher and, while causality has not been demonstrated, may adversely affect site performance ^[7]. Compounding this notion with data demonstrating that common deficiencies identified by the FDA during site inspections have remained unchanged over the past several years ^[6] further drives the need to put proactive QMP procedures into place.

As study protocols become increasingly complex and the requirement for single-IRB review becomes more common, study teams must be vigilant about maintaining the integrity of the study, protecting subjects and ensuring the quality of the data.^{[3, 5, 6]} Neglecting to identify and address errors may compromise study data, put subjects at undue risk, prevent the ability to meet protocol objectives, and put both the Investigator and the institution at risk with federal regulators (OHRP and FDA) and sponsors.

Implementing a QMP may help a study team to successfully achieve study objectives, while:

• Protecting the health, safety, and welfare of subjects
• Conducting research compliant with federal and state regulations and guidance, institutional policy, ethical principles and standards appropriate for the Principal Investigator’s (PI) discipline, and the study protocol
• Ensuring data accuracy and validity
• Improving site performance
• Mitigating risk to the Investigator, study team, and institution
• Preparing for external quality-related reviews (e.g., FDA inspections or sponsor audits) ^{[3, 4, 6]}

1. It is important to define the scope of what to review (reference Appendix A for examples):
   • Do you want to target compliance areas within or across several studies or conduct study-specific audits?
   • What regulations and policies are you held to for the specific study?
   • Do you want to consider incorporating continuous monitoring into your day-to-day practice?
2. A risk assessment ^[8,9] is a systematic process of evaluating the potential risks that may be involved in a projected activity or undertaking. Conducting a risk assessment in the context of the research will help to define what to review within your site or study-specific QMP (reference Appendix B for examples). Consider the following for each study to create your QMP:
   • Where will quality matter the most or have the greatest impact, especially when considering limited time and resources? E.g., dosing compliance and accountability of the study drug (if the research includes a study drug)
   • What specific problems have occurred previously? E,g., prior errors in obtaining consent
   • Where is the risk to the subject, the study staff, the institution, and/or data quality and integrity? E.g., collection of adverse events in a high-risk study
3. For funded trials where an external monitor will be reviewing all of the above elements, a modified review of the following may be adequate. Do not, however, assume external monitors assess and validate every risk area that is important to your site and your subjects; in particular, external monitors are not aware of specific institutional policies. ^[8] Prospectively identify specific issues within the approved protocol or through study implementation in which compliance may be problematic; put controls in place to assist you to mitigate problems and errors. Based on your risk assessment, identify specific areas to consider:
   • Informed Consent Process
   • Subject Eligibility
   • Protocol Adherence
   • Data and Safety Monitoring Plan (DSMP), including adverse event identification, collection, reporting, and any other protocol-defined events of clinical interest
   • Other Regulatory Expectations:
     • Appropriate/continued delegation of tasks
     • Investigational drugs/devices accountability and related regulatory reporting requirements
     • General data quality (is the data attributable, legible, contemporaneous, and complete, original, and accurate?) ^[10]
4. Consider repeating your risk assessment during the trial as unexpected events may occur. Be sure to disseminate the risk assessment results to the study team and discuss potential QMP adjustments.
5. Additional Points:
   • Verification of Data: A process that checks for accuracy and inconsistencies after data collection is done.  A best practice may involve a second person verifying data entries.
   • Good Documentation Practice:
     • Use of controls/processes to prevent the inadvertent use of outdated documents
     • Clear, legible, indelible handwriting
     • No entry space left empty (empty = not done)
     • Page numbering; version dates
     • Consistent time and date formatting (i.e., military time and date)
   • Regulatory Documentation: Written or electronic documents which demonstrate adherence to IRB approved protocol/amendment(s), IRB requirements, Good Clinical Practice, institutional policy, in accordance with applicable federal regulations, the Food and Drug Administration (FDA), and under the University’s Federal Wide Assurance (45 CFR 46). Necessary documentation items are detailed in the Research Study Site File Documentation Requirements.

Deciding the frequency of conducting your audits is dependent on several things: identified risks, findings from previous audits, staff turnover, significant changes in regulations, policies, or processes, availability of resources, and breadth and complexity of the protocol/study. Resources should be allocated specifically naming who is responsible for what with a due date assigned. ^{[8, 11]}

After some experience with your QMP, you’ll get a feel for which areas of your operation are prone to problems and would benefit from more frequent audits. The flipside, of course, is that there may be processes in your department that run smoothly and will not derive a benefit from frequent audits. The audit schedule can be revised as your process develops but be aware when your QMP plan is contained in the protocol, a revision may require a protocol amendment.

Ongoing application of your QMP and audit follow-up:

• For non-compliance and internal control deficiencies, monitor timely completion of corrective action.
• For audits that identified major issues, schedule follow-up re-review at a specific point in time (e.g., 6 months after audit).
• Routine monitoring: Include research-related audits on your annual audit plan.
• If you have ‘an event’ of significant non-compliance, conduct a root cause analysis and revisit your QMP.

Schedule an annual review of your QMP to review prior year results to determine the upcoming year’s QMP.

Examples for when to conduct reviews and review strategy:

• Consenting, Eligibility, and Adverse Events
  • Review the signed consent, eligibility, and adverse events in the first enrolled subject and subsequently every fifth enrolled subject
  • Review 2 subject charts per month
  • Review every signed consent plus eligibility plus adverse events (80% review)
• Protocol adherence
  • Review the data and safety monitoring plan annually or quarterly dependent on timing defined in approved plan
  • Review a specific component of the protocol after each subject is enrolled (i.e. height, weight, blood pressure collected)
• Regulatory Documentation
  • Review all regulatory documentation prior to enrolling the first subject and annually (perhaps with Continuing Review)
  • Use a checklist to confirm proper filing of regulatory documents with each modification

Once you’ve decided what to review and when to conduct reviews:

• Create site or study-specific documents and/or tools. What you decide to review will determine what you use, e.g. Microsoft Word, Excel spreadsheet, Access database, or a RedCap data collection form. Explore our self-audit tools.
• Discuss the site-specific QMP with the study team; provide education as needed
• Allocate a specific time on the calendar at regular intervals to conduct the audits
• Have resources available, e.g. study protocol, regulations, policies
• Select a sample population to audit specific compliance components (i.e. square root + 1)
• Execute the plan: conduct the audit(s)

To be effective, QMP reviews need to be objective and therefore, it may be best for someone independent from the study team to conduct the review when possible (or at least, as independent as possible). Options include:

• Partnering with another investigator or coordinator within your department/division to conduct each other’s reviews
• Partnering with another investigator or coordinator external to your department/division to conduct each other’s reviews (see note below)
• Having senior level or back-up coordinator conduct reviews

When determining who will conduct QMP reviews you may want to consider the reviewer’s level of experience in conducting research. While new study personnel should be exposed to the process, collaborating with experienced personnel will provide them more insight to the review process. Furthermore, if you are working within the scope of a department/division (versus within the scope of a specific study), it may also be helpful to designate a ‘QMP Leader’; someone whose responsibility could include leading the study team in developing the QMP and assigning QMP-related tasks. Of course, these individuals should always work with the Investigator and the research team to develop and execute the QMP.

If review by an independent individual or experienced personnel isn’t possible or there is no designated QMP Leader, don’t let that deter you from implementing a QMP. You will still benefit from conducting your own internal reviews–just be sure to seek advice when you need it!

QMP training

If necessary, an essential step to take before implementing the plan is training the staff who will conduct reviews. As the study team should be involved in the development of the QMP, they should require minimal training. If using a QMP is unfamiliar for a study team, OHSP Division of Quality Improvement (OHSP-QI) is available for consultation. OHSP-QI will provide on-site consultation to research team members regarding implementing a QMP specific to their study.

Proactive strategies to consider

• Present and/or coordinate educational sessions
• Create and distribute tip sheets on how to avoid compliance issues
• Make tools and resources accessible to facilitate compliance
• Demonstrate compliance/audit function
• Be available for and willing to answer questions and serve as a resource
• Attend clinical staff and researcher lab meetings to reinforce plan and clarify any misconceptions
• Regular/routine audits: Make them a part of the day-to-day operations.

Reporting findings

• Have an understanding in place prior to the review to address what the escalation process is for findings.
• Always report findings to the Principal Investigator and the primary Study Coordinator.
• In some cases, it may be necessary to report findings to Research/Department Administrator or Supervisor/Manager if there are safety concerns or serious deficiencies noted.

Note: As part of the University of Rochester’s Human Research Protection Program, staff are obligated to protect the rights, dignity, welfare, and privacy of research subjects by adhering to the highest ethical standards and to comply with applicable federal and state regulations, as well as institutional policies. As such, staff conducting QMP related reviews must be cognizant of protecting the privacy and confidentiality of the information reviewed, as well as reporting requirements required by the Reviewing IRB. Study teams choosing to partner with staff in other departments should have frank discussions about the management of review findings, prior to entering into such a relationship. Additional information regarding the management of review findings is available in the section below

• Discuss the findings with the Investigator and study team members
• Assess the scope and source of the problem
• Determine needed actions and develop a response

Consider the following: Is this a ‘minor’ or ‘major’ finding (see examples below)? Are vulnerable populations involved? Was the finding a one-time error or is it widespread? What is the source of the error? Is the error the result of a flaw in the process or was it due to lack of oversight? If it was widespread, are there trends in timing, across study personnel, or with a specific process?

‘Minor’ examples

• Used pencil to sign consent
• Did not correct a cross out
• Misdated an event on a case report form
• Missing IRB approval documentation

‘Major’ examples

• Issue that potentially impacts subject safety, e.g., failure to assess an adverse event
• Missing documentation of consent
• Enrolled an ineligible subject
• Failed to complete study procedures, as defined by the protocol
• Inadequate investigational product accountability

Based on the scope and source of the error, develop an appropriate corrective and/or preventative action. At a minimum, all errors require a corrective action. Preventative actions should also be considered when there are systematic or process-related issues, multiple ‘minor’ errors that are similar in nature are identified, or a single but significant incident of non-compliance occurs.

‘Immediate Fix’ (Corrective Action)

• Correct the immediate problem
• Document what the finding was, what caused the error and what was done to resolve the issue (e.g., documentation, notification to PI/subject/study team, data corrections)
• Example: A note to file was created, signed and dated to clarify that the SF-36 measure was not completed during Study Visit 2, as the subject refused.

‘Big-Picture Fix’ (Preventative Action)

• Prevent re-occurrence of the problem
• Document the solution that will be used to address the source of the problem. Be specific; use a simple, sustainable, and measurable solution (e.g., process change, re-training, protocol/CRF revisions. Note that while re-training may be helpful in some cases, it is not always effective as a standalone measure.)
• Example: A secondary study coordinator will cross-check regulatory files annually, at the time of continuing review.

For studies reviewed and approved by the Research Subjects Review Board (RSRB), reference the OHSP Policy 801: Reporting Research Events and the associated Guideline for Reporting Research Events. Does the finding involve increased risk to subjects or others (serious, related and unanticipated)?

• If yes, report the event to the RSRB within 10 calendar days
• If no, report the event in summary at the time of continuing review

For studies reviewed and approved by an External Reviewing IRB (e.g., WCG, another independent IRB, or institutional IRB), report per their reporting policies/standards.

Implement the corrective and preventative action plan. The plan should be implemented in a timely manner and demonstrated via your study documentation.

If a preventative action measure was implemented, re-evaluate the measure to determine whether it’s been effective at addressing the original error.

• Identify the specific strengths and weaknesses in current practice. Note what is working and what needs to be addressed.
• Additional considerations:
  • Create a database of findings ether in excel spreadsheet or REDCap.
  • Maintain a yearly departmental summary of findings for leadership and resources to aid in compliance for each finding.
  • Use the data to feed into protocol design and to monitor quality.
• ‘When things go wrong, which they will do on occasion’…use the resources available including your IRB Coordinator, OHSP Policy 801: Reporting Research Events, the University integrity hotline (585-756-8888), or other monitoring body (e.g. sponsor/monitor).