Clinical Researcher—June 2019 (Volume 33, Issue 6)

PEER REVIEWED

Seema Garg, MS, MBA, CQA, CSSGB

Most of the time when someone in charge at a research site first brings up their desire for a quality management system (QMS), the first thought that comes to many staff members’ minds is “Oh no! We have to buy another expensive software product!” But does a QMS really have to come in the form of software or a full-scale program? It can, but it does not have to. A QMS can simply be a set of procedures and processes that ensures the consistency and compliance of any task being performed.

I have been auditing clinical research sites for a while, and a few of the things that I find quite amazing for almost all sites include their dependency on monitoring and their lack of a site-level QMS.

Who’s in Charge?

When presented with a concerning study audit finding, most clinical research coordinators (CRCs) that I have dealt with during this process will respond to the effect that “Our monitor didn’t ask us about this.” It’s almost as if the site staff are on a robotic cycle of answering queries and findings from sponsors, monitors, and contract research organizations (CROs), so if no one asks about something, they assume that they don’t have to do it.

There is a certain lack of understanding on part of the staff that it is the site’s responsibility to operate according to the regulations and protocol, and that the monitoring is simply a verification of the site’s operations. The regulations require the investigator and the study staff to conduct the study according to the protocol and regulatory requirements, and the sponsor to guide and oversee the clinical site through monitoring, auditing, and other processes.{1}

However, somewhere along the way, the dependence of site staff on monitoring has become an all-inclusive check for everything they do for the study, which is not always possible, especially with risk-based monitoring models.{2} One of the reasons this may have happened is because there are no formal education or training requirements for the CRC position; most of the training comes in an on-the-job fashion and this on-the-job training has a great emphasis on being trained by the monitors during the site initiation visits.{3}

Where’s the Quality?

The lack of a site-level QMS at many sites is the second thing that amazes me. Most of the clinical sites I have audited will have a standard operating procedure (SOP) for conducting informed consent, but not an overall QMS.

Most study staff think of a QMS to be the sponsor’s responsibility. However, a clinical site should also have its own QMS through which the site would ensure continuity and consistency of site processes, training of study staff, maintenance of essential documents, and site readiness for an audit or an inspection.

Examples of activities that should be included in a clinical site QMS would be:

Training SOP describing requirements for regulatory training and protocol-specific training before any staff can be assigned to a study.
Continuity SOP describing the process of study handover from one staff member to another, and how will new staff be trained if the staff changes without a proper handover.
Informed consent process SOP.{4}
Good Documentation Practices (GDP) SOP describing documentation and correction process of regulated data.
Source documents SOP describing the process of generation and maintenance of source documents.{5}
Internal assessment SOP describing process of clinical site’s own internal assessment of its studies.
Inspection readiness SOP describing what the site would need to do to prepare and host a regulatory inspection.

Many sites don’t have these SOPs, or if they do, the procedures have not been read or revised by anyone in years. It may not be possible for smaller sites to implement all these procedures at the same time; however, it is important to start somewhere and then keep going. If a clinical site implements two SOPs a year, in three to four years it would have most of the needed SOPs. If the SOPs are reviewed and revised every two to three years, they will become second nature for the site staff as a routine part of conducting all clinical research studies.

An inspection readiness SOP is the most common one that I find lacking at sites. Most site staff have not experienced a regulatory inspection and are unfamiliar with how they are handled in terms of logistics and staff conduct.

Most site staff don’t consider a lack of inspection readiness as a risk because the low probability of being inspected by a regulatory agency if they are not conducting high-risk studies or are not a high-enrolling site. This attitude can be an issue in itself, as the site staff become complacent and things start to fall between the cracks.

Case Studies

About a year after a site has started a long-term study, the assigned CRC leaves the site without training other staff on the regulatory procedures and systems required to continue the proper conduct of the study. The new study staff starts to miss procedures like calling subjects for follow-up visits, answering data queries from data management, re-consenting subjects on revised consents, etc.

If the site had an SOP for study continuity, it would have allowed the outgoing staff member to conduct a proper handover to a newly assigned staff member—bringing him or her up to speed on the ongoing study with minimal disruption to timelines and participants.
Additionally, a site internal assessment procedure would have helped, as it would have required the site to audit itself at least annually to see where other procedures were lacking.

A site enrolls a subject and during a follow-up visit, a CRC notices a note in the subject’s file from a case manager indicating that the subject cannot read. The principal investigator decides to discontinue the subject from the study upon his confirmation of being illiterate. If the site had an informed consent SOP, it would have required an assessment of the reading and comprehension capabilities of the subject during the consent process. This would have allowed the enrollment and retention of the subject with the help of a literate, legally acceptable representative serving as witness.
A site generates its own source documents and worksheets and the case report forms (CRFs) are provided by its sponsors. Neither the site nor the sponsor of a current study have provided space on their documents for study personnel to initial and date for the procedures being performed or entries being made on these documents. The study keeps going until a monitor makes an observation that the source documents and CRFs are not attributable. If the site had a source documentation and GDP SOP, the site staff would have been trained to make this observation themselves and correct the forms.

Conclusion

A QMS does not have to be a large system; indeed, it can be simple and flexible. Conducting research in compliance with regulations and the protocol is first and foremost the clinical research site’s responsibility—sponsors, monitors, and auditors can verify compliance, but the site staff are the ones who must comply.

References

E6(R2) Good Clinical Practice: Integrated Addendum to E6(R1); International Council for Harmonisation; Guidance for Industry (March 2018). https://www.fda.gov/downloads/Drugs/Guidances/UCM464506.pdf
U.S. Food and Drug Administration Guidance for Industry for Oversight of Clinical Investigations—A Risk-Based Approach to Monitoring (August 2013). https://www.fda.gov/downloads/Drugs/Guidances/UCM269919.pdf
Solberg LB, Kolb HR, Prikhidko A, Behar-Horenstein LS. 2018. Ensuring representativeness in competencies for research coordinators. Clin Res 32(5). https://acrpnet.org/2018/05/15/ensuring-representativeness-competencies-research-coordinators/
21 CFR Part 50—Protection of Human Subjects. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=50
U.S. Food and Drug Administration Guidance for Industry on Electronic Source Data in Clinical Investigations (September 2013). https://www.fda.gov/downloads/drugs/guidances/ucm328691.pdf