Important Considerations When Developing and Implementing a Clinical Trial – Case Studies from BRANY Audit Findings
Developing and running a clinical trial can be a large undertaking. There are many factors to consider when translating a research question into a full clinical trial, which can be particularly challenging for investigator-initiated studies that do not have a large support staff. BRANY has been working with new and experienced investigators for over 25 years. We’ve identified several key areas that are less commonly considered but necessary to address when implementing a clinical trial. Below are several real-world examples that BRANY has encountered.
Intra-protocol consistency
It is important when writing a protocol to avoid conflicting information. This is especially true when describing eligibility criteria and study procedures to ensure that all participants meet the same eligibility requirements and that data is collected consistently.
Case Example 1: The inclusion and exclusion criteria were duplicated in the Subject Population section of the protocol. An amendment intended to modify the eligibility criteria only changed the Subject Population section without making corresponding changes to the criteria themselves. Because the changes were not reflected in the correct section of the grant submission, an audit by the study’s sponsoring agency determined that multiple participants enrolled under the modified criteria should be considered ineligible, and their data could not be used.
Case Example 2: The schedule of activities table and the text description of individual procedures in subsequent sections did not match. This resulted in inconsistent data collection, potentially making the data from those assessments uninterpretable.
As seen in these two examples, there can be serious consequences for inconsistencies between protocol sections. It is best to avoid duplication of material within the protocol and instead reference the appropriate sections or the schedule of activities table, when necessary. Utilizing tools such as BRANY’s Protocol Builder can also assist in avoiding these conflicts. In addition, a careful review of the protocol and all future amendments is highly recommended, particularly when making changes to the eligibility criteria or schedule of activities.
Minimize and report conflicts of interest
To ensure patient safety and protect the integrity of the clinical trial, study staff should avoid conflicts of interest that might consciously or unconsciously bias their decisions. Any potential conflicts must be disclosed to the sponsoring agency, the IRB reviewing the study, and in some cases, to the participants as part of the informed consent form.
Case Example: Upon routine review of an imaging study, it was discovered that a family member of the PI was on the board of the vendor contracted to generate contrast agents used in the study. This potential conflict of interest was not disclosed to the IRB. The PI was later replaced, removing the potential conflict, but if the study had been federally funded, the lack of disclosure could be considered fraudulent under federal law, with possible civil and criminal penalties.
All potential conflicts of interest, including those of family members, should be reported to the IRB and sponsor to allow for determination of whether the conflict of interest warrants additional review or even exclusion from the clinical trial.
Data and Safety Monitoring Board (DSMB) independence
The DSMB plays an important role in ensuring the safety of clinical trial participants and providing oversight of data integrity. Many federal agencies have specific requirements for the composition of the DSMB, regulating specific roles, independence, and conflicts of interest.
Case Example: The DSMB for a NIMH-sponsored study was comprised of three individuals from the same department as the investigator, which does not meet the agency’s requirements. This resulted in the temporary suspension of the study until a new DSMB could be convened.
While not all sponsors have specific requirements, it is considered best practice to ensure that a DSMB is fully independent and has no potential conflicts of interest. An independent DSMB, in conjunction with the investigator’s oversight responsibilities, helps ensure that participant safety is protected and that data integrity is maintained.
Carefully consider participant compensation
It is often advantageous to offer compensation to research subjects for their participation in a clinical trial. Reimbursement of actual costs is generally acceptable, but any compensation that is intended to encourage or facilitate participation must be carefully considered to ensure that the amount of payment is appropriate and does not unduly influence participants’ decisions to participate.
Case Example 1: A study investigating illicit drug use was found to have abnormally high screen failure rate compared to related studies at the institution despite similar eligibility criteria. This caused the IRB to question whether the higher compensation offered for screening visits in this study might be considered an undue influence on the target population, and the study was temporarily closed to enrollment.
Case Example 2: A study offering compensation for the completion of an anonymous internet survey was targeted by a “bot farm.” Many of these invalid responses could be identified programmatically, but many other surveys had to be discarded to ensure that only legitimate responses were used in the analysis. Not only did this cost the study financially, but the resulting time taken to identify the invalid responses and the potential data loss of legitimate responses ultimately lead to the closing of the study prematurely.
As seen in these examples, participant compensation can have unexpected consequences beyond the ethical considerations inherent in these payments. An ongoing discussion with the IRB is an important part of any decision regarding participant compensation.
Documentation of eligibility criteria
It is important to document participants’ eligibility for a clinical trial in the source documents according to Good Clinical Practice (GCP) and other relevant guidelines. These source documents should include specific documentation of all inclusion and exclusion criteria.
Case Example 1: The routine audit of a multi-center trial found that many sites did not have full documentation of exclusion criteria, particularly criteria requiring a participant to have no history of specific conditions. These sites were required to reconfirm the eligibility of all enrolled participants.
Case Example 2: During review of a serious adverse event, the FDA determined that the participant did not meet the eligibility requirements for the study and that the event was directly attributable to improperly conducting the washout period required by the protocol. Upon further investigation, auditors discovered that multiple enrolled participants did not meet eligibility criteria and that the design of the washout period did not fully consider the participant’s safety. The trial was halted by the sponsoring agency and the PI faced disciplinary proceedings resulting in exclusion from participation in federal grants.
Full documentation of all criteria in the medical record is the gold standard, and routine monitoring or GCP audits can potentially identify gaps where this is not occurring. In addition, the creation of an inclusion/exclusion checklist can be used to confirm that all criteria were examined. This document can also double as documentation that the investigator or delegated individual reviewed all criteria and confirmed a participant’s eligibility.
Communication with other providers
While clinical trials are often performed by participants’ treating physician or specialist, it is important that all providers involved in participants’ care are aware of their enrollment in a clinical trial. This communication is particularly important when studying a multi-modal disease.
Case Example: During an unrelated compliance review, the reviewers discovered that a site was creating a separate “shadow chart” outside of the participants’ standard clinic records. As a result, other providers in the healthcare system were unaware of their participation. In several cases, medications that were exclusionary to the protocol were prescribed that required the participant to be withdrawn from the study when other alternatives might have been considered if the treating provider was aware of their involvement in a clinical trial.
Ideally, a central eMR system should be used as the clinical trial source documentation wherever possible. This provides the greatest transparency so that the researchers and other treating providers can make the best-informed decisions for the participants’ care and safety. It can also be helpful to send letters to any providers that are not connected to the researchers’ eMR system, informing them of their patients’ involvement in the clinical trial and to invite a continuing dialogue for any questions related to their participation.
Ensure appropriate billing
In some cases, a sponsor will directly reimburse the site for all procedures and assessments performed during a clinical trial. In many cases, however, Medicare and other insurance providers can be billed for routine, standard of care services that would be normally provided to treat the patient’s underlying disease. This reduces the overall cost of the trial to the sponsor, but there are many regulations regarding coverage and billing.
Case Example: The sponsor of a study agreed to pay for the surgery required to implant an experimental device. However, a financial audit revealed that the hospital incorrectly submitted the surgery claims to Medicare in addition to receiving payment from the sponsor. While inadvertent, double-billing violates the False Claims Act, placing the institution at considerable legal liability. These billing errors can lead to significant civil and criminal penalties for the institution and may also include disqualification from Medicare participation entirely.
When developing the budget for a study that involves billing insurance providers for allowable procedures, it is important to clearly identify what services can be billed to Medicare/insurance. A formal Medicare Coverage Analysis (MCA) should be created by the study team or an outside contractor such as BRANY. In addition, routine periodic review should be performed of all services associated with the clinical trial to ensure proper billing.
About the Author
Christopher Chadwick, MPH, has worked as a Compliance Auditor and Clinical Research Monitor for the BRANY Quality Assurance department for nine years. He conducts Good Clinical Practice (GCP) and regulatory compliance audits for clinical research sites and provides monitoring oversight for investigator-initiated Phase 1 and Phase 2 clinical trials. His expertise includes GCP and International Council for Harmonisation (ICH) guidelines and FDA regulations. He holds a Masters in Public Health with a focus on clinical trial design from the University of Rochester and a B.A. in Behavioral Biology from Johns Hopkins University.
Previously, Mr. Chadwick spent four years in the University of Rochester department of Neurology’s Clinical Trials Coordination Center. During this time, he served as the primary data manager for three large, multi-center clinical trials conducted by the Parkinson Study Group and Huntington Study Group. He later transitioned to the UR department of Orthopaedics where he served as the department’s clinical trials manager and QA coordinator for two years.
