Clinical studies in support of premarket approval applications should ideally be randomized and blinded, the Food and Drug Administration maintains in recent guidance.
The FDA issued draft guidance for sponsors and staff Aug. 15 to help researchers and manufacturers design better quality clinical trials for device submissions.
The draft guidance spells out different clinical study designs that may be appropriate to support device approval, including the advantages and disadvantages of each.
But the FDA emphasized randomized, blinded (or masked) trials above all else, as other study designs may provide less-robust evidence and introduce bias.
These study designs, however, are generally the most expensive to carry out and difficult to enroll.
The FDA’s guidance acknowledges these studies might not be practical, feasible, or even ethical in all cases. In those situations, the onus is on the sponsor to justify why an alternative study design was chosen and how it will adequately control bias, the draft guidance emphasizes.
Some in the medical community have been critical of the relatively small proportion of premarket approval (PMA) pivotal trials that are randomized, controlled studies.
The guidelines apply mainly to PMA device trials, but could also inform the design of clinical trials for 510(k) devices, the FDA suggests.
FDA Wants the Gold Standard
Pivotal studies are meant to determine whether a new device is reasonably safe and effective, and whether the probable benefits outweigh the potential risks.
The FDA is addressing what specific factors go into its risk-benefit determinations in separate draft guidance also issued Aug. 15.
Comparative studies generally provide a higher level of evidence than single-arm trials, the clinical trials draft guidance explains.
Comparative trials may be parallel design, in which comparisons are made between groups treated with different therapies; paired, in which each subject receives all of the interventions or tests at the same time, such as with a "split-face" test where each side of the face is treated with a different device; or crossover, in which each subject receives two or more interventions at different, predetermined time points.
These study designs may be randomized or nonrandomized, but randomized, double-blinded, controlled studies are preferred, the FDA maintains.
The FDA recommends the device be compared with an active control, such as another effective therapy; or a placebo control, such as an ineffective device used in conditions that mimic the investigational device as much as possible.
"Deviation from this study design is especially problematic in situations where there is a possible placebo effect," the guidance notes.
Masking Trials
The FDA also prefers that pivotal trials be masked, or blinded, meaning participants in the trial have limited knowledge as to which intervention they were assigned.
"If study participants are not masked, it is very difficult to assess the size of the resulting bias, and it can threaten the scientific validity of an otherwise solid study, even when a truly objective end point is used," the guidance states.
If the trial subjects and investigators cannot be masked, the FDA strongly recommends that independent, third-party evaluators of the study measurements or end points be denied knowledge of the intervention assignment.
"Even if it is inconvenient or difficult, FDA recommends that masking be considered and attempted, if at all possible," the guidance notes.
But a range of other study options are available to sponsors who cannot conduct the ideal trial, the guidance clarifies.
In any case, the FDA strongly recommends that sponsors consult with the agency about trial design in a pre-submission meeting.
The sponsor’s investigational device exemption application should include not only the details of the proposed study design and why it was chosen, but also an explanation of alternative study designs that were considered and why they were deemed "inappropriate, impractical, or not possible," the guidance states.
This coverage is provided courtesy of "The Gray Sheet." This news organization and "The Gray Sheet" are owned by Elsevier.