“The FDA currently recommends well-conducted randomized controlled trials (RCTs) using concurrent control and objective endpoints for critical limb ischemia (CLI) trials,” said Eleni Whatley, PhD, a lead reviewer on the Plaque Modification Devices Team in the Office of Cardiovascular Devices at the U.S. Food & Drug Administration, in her AMP 2020 Virtual talk on the topic.
These types of trials “will yield high quality data to support regulatory and clinical decision making and it's important that the trial mirror the clinical practice for which the device will be indicated,” she added.
That said, the FDA also recognizes that this isn’t easy to do. CLI patients are heterogeneous with multiple comorbidities and, given the limitations, the FDA “strongly recommends” standardizing treatment as much as possible, including during the procedure and follow-up care for wounds, etc, in order to reduce potential confounders and improve interpretability of the data.
What not to do? Don’t try to sneak in Rutherford 3 patients to speed up enrollment and don’t unnecessarily exclude the sickest patients with diabetes and other comorbidities.
About the less sick patients, Dr. Whatley said: “As these patients don't fit the true definition of CLI, the FDA does not believe it is appropriate to include them.” As for those who are sicker, she said, “these patients are truly representative of the CLI population” and should not be excluded.
For device evaluation, the Agency generally recommends a primary safety endpoint of freedom from below-the-knee MALE + POD (major adverse limb events with perioperative death) at 30 days. For effectiveness, they suggest looking at a composite of limb salvage and primary patency at a minimum of 6 months, with longer-term data to be provided.
“There are numerous open questions regarding primary and point assessment for CLI trials,” said Dr. Whatley. For one, consistency in definitions is important, and there are not widespread recommendations regarding the exact definition that is appropriate.
“For example, within these specific primary endpoints, there may be minor differences in how major reintervention is defined or what amputations are included,” she said.
Also, while a six-month endpoint is considered acceptable, given the severity of the disease in this patient population, longer-term data, including 12 months and beyond is important in demonstrating robustness of treatment.
Secondary endpoints, including device, technical and procedural success, wound healing, limb salvage, clinically-driven TLR, and quality of life outcomes, are important to capture outcomes important to patients, clinicians, and regulators, she noted.
“We recommend collecting as much information as possible to better understand the benefits and risks associated with your device, because from our experience, the data in this patient population can sometimes be uninterpretable,” said Dr. Whatley.
The FDA is particularly interested in wound healing, given the importance this endpoint has for clinicians and patients. However, there are numerous open questions and concerns related to wound care assessments too.
“Currently there is a lack of rigorous and uniform methods for collection and assessment of wound care data. This includes a lack of photographical documentation and characterization for assessment, a lack of independent review and blinding of evaluators, and it is also important to understand how different wound care practices at different sites confound wound healing results,” reported Dr. Whatley.
Given all the difficulties in studying these patients and devices, the FDA recommends standardizing and harmonizing definitions and treatment strategies to the extent possible, “and appreciates any collaboration in this regard,” she noted.
“Given the limited high-quality data available, there remains that ample opportunity for learning in this area, particularly as early studies will better inform later studies, which will lead to improvements in clinical outcomes,” said Dr. Whatley.
And one final note: “As we all know, COVID-19 has had a huge impact on our daily lives, but has also had a profound effect on clinical trials. The safety of clinical trial patients is of utmost importance, therefore, various modifications to study design, protocol, or allowance of protocol deviations may be needed to ensure patient safety.”
Anticipating issues, the FDA issued a guidance document on the conduct of clinical trials of medical products during COVID-19. The full document can be found here.