NIH Collaboratory investigators described the unique, unexpected challenges researchers face when clinical practice guidelines and policies change during the conduct of an ePCT in an article in Clinical Trials (Curtis et al. 2019).

Key Lessons:

• Study teams often need to monitor, adapt, and respond to practice guidelines during design and the course of the trial.
• Routine collaboration between ePCT researchers and health systems stakeholders throughout the trial can help ensure research and QI are optimally aligned to support high-quality patient-centered care.

“PCTs are an important means of producing high-quality evidence needed to better inform clinical practice. However, when guidelines or reimbursement policies change during the conduct of a PCT, the ethical obligation to gather information to develop evidence-based practices may conflict with the primary ethical obligation to participants.” (Curtis et al. 2019)

Based on their aggregate experience within the NIH Collaboratory, the authors provide broad recommendations and strategies for overcoming these challenges, including:

• Protecting the well-being of patients
• Involving partners, health system leaders, and the entity charged with data and safety monitoring
• Actively monitoring changes and site-level responses to them
• If changes to the standard of care are merited, investigators should provide equal opportunity and support for the recommended changes. During the design phase, investigators should communicate with the entities charged with creating guidelines to understand what evidence is needed and to anticipate possible future changes.

“The ability to appropriately address the tension between modifications to clinical guidelines and the need to generate quality evidence to support those guidelines is a crucial consideration for the fulfilment of a learning health system.” (Curtis et al. 2019)

Case Example: ICD-Pieces

ICD-Pieces was designed to assess the possibility of improving care for patients with a triad of conditions that includes chronic kidney disease, diabetes, and hypertension. One specific intervention was maintaining blood pressure less than 140/90 mm Hg in the implementation group—reflecting guideline-concordant care—while the control group received usual care (Curtis et al. 2019). However, during the conduct of the trial, new blood pressure guidelines from the American College of Cardiology/American Heart Association lowered the definition of high blood pressure to 130/80 mm Hg and recommended this as a new standard of care (Whelton et al. 2017). Of note, the studies that prompted the new guidelines did not include patients with the triad of conditions—chronic kidney disease, diabetes, and hypertension—and some, but not all, professional societies relevant to patients in ICD-Pieces adopted the new guidelines (Curtis et al. 2019). The research team discussed potentially making changes in the protocol based on the new guidelines with the Data Safety and Monitoring Board (DSMB). However, given the lack of consensus and evidence, the DSMB recommended that investigators not modify the protocol.

Case example: STOP CRC

STOP CRC was designed to assess the possibility of improving the rates of colorectal-cancer screening by mailing fecal immunochemical testing tests to patients at Federally Qualified Health Centers (Coronado et al. 2014). The team facilitated conversations with a variety of partners to overcome a policy-level barrier, as described in the video below.

Case Example: PROVEN

The PROVEN trial was designed to determine if showing advance care planning videos in nursing homes affects the rates of hospitalization of frail, multi-morbid patients for whom aggressive medical interventions are not likely to be effective (Mitchell et al. 2020). When the trial was beginning the implementation phase, the US Center for Medicaid and Medicare Services (CMS) introduced a new billing code for advance care planning that reimbursed physicians and nurse practitioners for discussing advance directives with patients and their family members. Initially, the investigative team thought this would bolster their intervention and worried that both intervention and control sites would increase such discussions, undermining the investigators’ ability to detect an effect. Instead, because CMS required that a nurse practitioner or physician have the discussion, and the PROVEN intervention was implemented by facility social workers, this change in reimbursement policy could not be integrated into the PROVEN intervention. However, some providers responded more quickly than did others to the change in reimbursement, resulting in differential uptake of advance care planning, which could have impacted the outcomes of the trial (Curtis et al. 2019).