Is it time for a change?

Each of the seven cervical total disk replacements (cTDR) currently available in the United States has undergone a clinical trial providing evidence of safety and efficacy that supports U.S. Food and Drug Administration (FDA) premarket approval. Sufficient similarity exists among the trials to constitute a de facto consensus regarding the basic trial structure for cTDR—a two-arm, noninferiority, randomized, controlled trial (RCT) with anterior cervical discectomy and fusion (ACDF) as the active control. Given a decade of clinical experience in the United States with these devices and the absence of recalls, the question now is whether cTDR clinical trials should still be structured in this fashion.

In this article, we examine RCTs and alternatives that may be appropriate.

Courtesy of Centinel Spine

The consensus pivotal trial

Since 2007, seven cTDR devices have entered the U.S. market with a one-level indication (Table 1). Table 2 summarizes the typical features of cTDR pivotal trials and devices, although there is variation in each feature.

In device design, cobalt-chromium-molybdenum (Co-Cr-Mo) alloy articulating with ultra-high-molecular-weight-polyethylene (UHMWPE) has been most common. Due to the relatively low loads and stresses imparted to cTDRs, many novel bearing combinations have been approved or are in trials.

Trial designs have been two-arm RCTs compared to ACDF. In all RCTs, the critical parameters are the P-value cutoff (false-positive rate of 0.05) and the power (typically 80 percent to 90 percent) or similar Bayesian parameters. In noninferiority (NI) trials, the primary outcome of the experimental arm—which cannot fall below the control arm by more than the NI margin—is another critical parameter.

In most trials, the NI margin has historically been 10 percent, yet the method for choosing the margin scientifically is complex. Although sponsors have designed trials around 12.5 percent and 15 percent NI margins, they have been asked by FDA to analyze the trials with a 10 percent NI margin.

The primary endpoint

The definition of the primary endpoint is central to both the trial data and its relationship to historical data. The primary endpoint has consistently been a binary composite endpoint for which multiple safety and efficacy endpoints must be met. For each cTDR trial, the neck disability index has been the primary patient-reported outcome measure.

The consensus primary composite endpoint has five components. The first three include neurologic status, adverse events, and secondary surgeries. All trials required the absence of neurologic deterioration (maintenance or improvement) in some form. The consensus requires no device or procedure-related serious adverse events (DPR-SAEs), although several trials attempted to subset SAEs further. With respect to secondary surgical interventions (SSIs), the consensus requires no SSIs for a success, yet some trials attempted to subset SSIs as related to failure, device failure, or need to modify the implant.

The most variable endpoint is radiographic criteria. Criteria in various trials included maintenance of disk height, motion (or its absence), heterotopic ossification in the TDR arm, nonunion in the fusion arm, and composite measures. In our view, there is no consensus on radiographic endpoints or the imaging modalities used to assess them.

Alternatives to the consensus

Alternatives to the consensus pivotal trial fall into three categories. Most simply, sponsors could opt for a one-arm, prospective, observational study of the investigational device and compare it to controls from a preexisting trial with a similar structure. This option has already been successfully pursued by one sponsor.

An advantage of this approach is that it is less burdensome to patients who are wary of being randomized to ACDF when they can obtain a TDR through routine clinical care. Another potential advantage is that some surgeons now feel there is not clinical equipoise between the arms, as the evidence in favor of cTDR as a class has accumulated over time. The single-arm study avoids this problem. One disadvantage to this alternative is that care must be taken to control bias that would otherwise be controlled by randomization and to structure the experimental arm as the control arm. As a practical matter, only sponsors who have access to the data from at least one successful prior trial can pursue this approach.

The other two alternatives to the consensus trial are more radical. FDA does undertake some internal reviews of the spectrum of data across multiple prior regulatory submissions. With permission of the sponsors, these could be published as normative data characterized statistically and anonymously without reference to individual devices. If such published data were sufficiently robust, it might act as a historical control for future submissions.

The final alternative would be to down-classify cTDR to a class II device, given the robust body of clinical trial data with intermediate-term follow-up for TDR as a class. Although class II status does not by itself obviate a requirement for clinical data (510(k) with clinical), it might lessen the perceived need if paired with the publication of normative data.

Both of these latter recommendations are worth considering but may be challenging to implement. Down-classification typically requires a sponsoring organization with a wealth of information to argue that a class III device does not potentially pose high risk and that “general and special controls” are adequate. Even for a common cTDR design, defining such controls may or may not be possible. Also, the publication of statistically characterized normative data from prior trials may not be sufficiently robust and fine-grained to serve as the control for a prospective, observational study of a complex surgical device with multiple primary and secondary safety and efficacy endpoints.

Conclusion

As a class, cTDR has intermediate-term follow-up from pivotal RCTs as well as a decade of clinical experience in the United States. This raises the question of whether investigational device exemption trials need to continue as before or if a less-burdensome regulatory pathway exists. RCTs remain a gold-standard, but prospective observational studies controlled with existing RCT data are appropriate for select sponsors and devices.

References

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Raymond Golish, MD, PhD, MBA, is chair of the AAOS Biomedical Engineering Committee. He can be reached at ray@golish.com.

Steven M. Kurtz, PhD, is a member of the AAOS Orthopaedic Device Forum and the leader of ASTM F04 division task groups for medical grade UHMWPE and PEEK. He can be reached at skurtz@exponent.com.

Richard D. Guyer, MD, is codirector of the Center for Disc Replacement at Texas Back Institute and a past president of the North American Spine Society. He can be reached at rguyer@texasback.com.