Recommendations for data monitoring committees from the Clinical Trials Transformation Initiative.

Background/aims Use of data monitoring committees to oversee clinical trials was first proposed nearly 50 years ago. Since then, data monitoring committee use in clinical trials has increased and evolved. Nonetheless, there are no well-defined criteria for determining the need for a data monitoring committee, and considerable variability exists in data monitoring committee composition and conduct. To understand and describe the role and function of data monitoring committees, and establish best practices for data monitoring committee trial oversight, the Clinical Trials Transformation Initiative-a public-private partnership to improve clinical trials-launched a multi-stakeholder project. Methods The data monitoring committee project team included 16 individuals charged with (1) clarifying the purpose of data monitoring committees, (2) identifying best practices for independent data monitoring committee conduct, (3) describing effective communication practices, and (4) developing strategies for training data monitoring committee members. Evidence gathering included a survey, a series of focus group discussions, and a 2-day expert meeting aimed at achieving consensus opinions that form the foundation of our data monitoring committee recommendations. Results We define the role of the data monitoring committee as an advisor to the research sponsor on whether to continue, modify, or terminate a trial based on periodic assessment of trial data. Data monitoring committees should remain independent from the sponsor and be composed of members with no relevant conflicts of interest. Representation on a data monitoring committee generally should include at least one clinician with expertise in the therapeutic area being studied, a biostatistician, and a designated chairperson who has experience with clinical trials and data monitoring. Data monitoring committee meetings are held periodically to evaluate the unmasked data from ongoing trials, but the content and conduct of meetings may vary depending on specific goals or topics for deliberation. To guide data monitoring committee conduct and communication plans, a charter consistent with the protocol's research design and statistical analysis plan should be developed and agreed upon by the sponsor and the data monitoring committee prior to patient enrollment. We recommend concise and flexible charters that explain roles, responsibilities, operational issues, and how data monitoring committee recommendations are generated and communicated. The demand for data monitoring committee members appears to exceed the current pool of qualified individuals. To prepare a new generation of trained data monitoring committee members, we encourage a combination of didactic educational programs, practical experience, and skill development through apprenticeships and mentoring by experienced data monitoring committee members. Conclusion Our recommendations address data monitoring committee use, conduct, communication practices, and member preparation and training. Furthermore recommendations form the foundation for ongoing efforts to improve clinical trial oversight and enhance the safety and integrity of clinical research. These recommendations serve as a call to action for implementation of best practices that benefit study participants, study sponsors, and society.

Neuromonitoring with pulse-train stimulation for implantation of thoracic pedicle screws: a blinded and randomized clinical study. Part 1. Methods and alarm criteria.

OBJECT: Reports of the accuracy of existing neuromonitoring methods for detecting or preventing medial malpositioning of thoracic pedicle screws have varied widely in their claimed effectiveness. The object of this study was to develop, test, and validate a novel neuromonitoring method for preventing medial malpositioning of pedicle screws in the thoracic spine during surgery. METHODS: This is a prospective, blinded and randomized study using a novel combination of input (4-pulse stimulus trains delivered within the pedicle track) and output (evoked electromyography from leg muscles) to detect pedicle track trajectories that-once implanted with a screw-would cause that screw to breach the pedicle's medial wall and encroach upon the spinal canal. For comparison, the authors also used screw stimulation as an input and evoked electromyogram from intercostal and abdominal muscles as output measures. Intraoperative electrophysiological findings were compared with postoperative CT scans by multiple reviewers blinded to patient identity or intraoperative findings. RESULTS: Data were collected from 71 patients, in whom 802 screws were implanted between the T-1 and L-1 vertebral levels. A total of 32 screws ended up with screw threads encroaching on the spinal canal by at least 2 mm. Pulse-train stimulation within the pedicle track using a ball-tipped probe and electromyography from lower limb muscles correctly predicted all 32 (100%) of these medially malpositioned screws. The combination of pedicle track stimulation and electromyogram response from leg muscles proved to be far more effective in predicting these medially malpositioned screws than was direct screw stimulation and any of the target muscles (intercostal, abdominal, or lower limb muscles) we monitored. Based on receiver operating characteristic analysis, the combination of 10-mA (lower alarm) and 15-mA stimulation intensities proved most effective for detection of pedicle tracks that ultimately gave rise to medially malpositioned screws. Additional results pertaining to the impact of feedback of these test results on surgical decision making are provided in the companion report. CONCLUSIONS: This novel neuromonitoring approach accurately predicts medially malpositioned thoracic screws. The approach could be readily implemented within any surgical program that is already using contemporary neuromonitoring methods that include transcranial stimulation for monitoring motor evoked potentials.

Neuromonitoring with pulse-train stimulation for implantation of thoracic pedicle screws: a blinded and randomized clinical study. Part 2. The role of feedback.

OBJECT: The authors have reported in Part 1 of this study on a novel neuromonitoring test for the prevention of medial malpositioning of thoracic pedicle screws. In the present paper they examine the impact of providing the results of the test as intraoperative feedback to the surgical team. METHODS: This is the second part of a 2-part report of a prospective, blinded and randomized neuromonitoring study designed to lower the incidence of medially malpositioned thoracic pedicle screws. Details of the neuromonitoring technique and data supporting the alarm criteria used are contained in the companion article (Part 1). For the majority of pedicle screw placements, intraoperative test results were withheld from the study team (that is, the team members were blinded to the test results). However, for a limited number of pedicle sites the authors provided one of 2 forms of testing feedback to the surgical team: 1) "break the blind" feedback, if testing suggested that screw placement would result in direct contact between screw and the dura mater; and 2) "planned" feedback, beginning during the later stages of the study and provided for 50% of pedicle sites. Feedback gave the surgeon the opportunity to adjust the trajectory that the screw would ultimately take within the pedicle. The final screw position relative to the pedicle's medial wall for all sites in which feedback was withheld from the surgical team was compared with the screw position for those sites in which either form of feedback ("break the blind" or "planned") was provided to and acted upon by the surgical team. RESULTS: Of the 820 pedicle tracks tested among the 71 surgical cases included in this study, a total of 684 were operated upon without any form of feedback. Planned feedback was provided for an additional 107 pedicle tracks, of which 15 triggered an intraoperative alarm (evoked electromyogram response in leg muscles to stimulus intensity ≤ 10 mA) leading to a warning to the surgical team of a medially biased pedicle track. Finally, the blind was broken 29 times, in each case when testing revealed a particularly low threshold (≤ 4 mA) for evoked responses in leg muscles when stimulating along the pedicle track with the ball-tipped probe. As detailed in the companion paper to this one, there were 32 screws with threads lying at least 2 mm medial to the pedicle wall. In all 32 instances (100%), either these screws were in the "no feedback" category (n = 29) or they were in a feedback category but the surgeon elected to not revise the pedicle-track trajectory. Two patients returned to the operating room for revision of screw placements because the screws were encroaching upon the central canal; the pedicle tracks for these screws had been in the "no feedback" category. CONCLUSIONS: This is the first blinded and randomized study to prove that implementing a novel neuromonitoring strategy during placement of thoracic pedicle screws can significantly reduce the incidence of clinically relevant thoracic pedicle screw medial malpositioning.

Is in vivo manual palpation for thoracic pedicle screw instrumentation reliable?

OBJECT: Previous reports on the accuracy of manual palpation for thoracic pedicle screw placement have been restricted to cadaveric studies. Authors of the present novel study assessed the accuracy of manual palpation for the detection of medial and lateral pedicle breaches during thoracic spine surgery in living adult humans. METHODS: Pedicle tracks were created freehand and manually palpated using a ball-tipped probe. Postoperative CT scans of all implanted thoracic and L-1 screws were evaluated with respect to screw position and the pedicle wall. RESULTS: Five hundred twenty-five pedicle track/screw placements were compared. There were 21 pedicles with medial breaches measuring ≥ 2 mm. The surgeon correctly identified only 4 of these pedicle tracks as having a medial breach. The surgeon correctly identified 17 of 128 pedicles with a significant (≥ 2 mm) lateral breach. One hundred two screw placements had no measurable breach in any direction (medial, lateral, or foraminal). The surgeon correctly identified 98% of these ideally placed screws. CONCLUSIONS: In this real-time study of thoracic pedicle screw placement, the accuracy of manual palpation for detecting medial or lateral breaches that were ≥ 2 mm was disturbingly low. These findings are consistent with those in recent cadaveric evaluations of palpation accuracy and point to the critical need for more reliable alternative methods to assess pedicle integrity during the placement of thoracic pedicle screws for spine instrumentation surgery.

Intraoperative neuromonitoring: can the results of direct stimulation of titanium-alloy pedicle screws in the thoracic spine be trusted?

UNLABELLED: OBJECTVIE: Intraoperative neuromonitoring of thoracic-level pedicle screw implantation for detecting breaches in the pedicle cortex has adopted methods originally developed in the early 1990s for stainless steel (SS) alloy screws used at lumbosacral levels. In our recent attempts to monitor thoracic-level pedicle screw placement, we were surprised to find that these widely used stimulation parameters were largely ineffectual when stimulating directly through titanium alloy (Ti-alloy) pedicle screws. The objectives of this study, then, were twofold: (1) to report the number of episodes in which intraoperative neuromonitoring of thoracic screw position failed to detect a medially directed breach (or malplacement) in a previously described and limited sample set; and (2) to compare the frequency-specific impedance of a sample of Ti-alloy pedicle screws to comparably sized screws made of SS alloys. We predicted that Ti-alloy screws would demonstrate impairment in conduction properties that could help explain the difficulties we, and others, have recently experienced with neuromonitoring of thoracic pedicle screw placement. METHODS: Based on threshold values for train-of-four stimulation of spinal motor pathways, we quantified the incidence of medial breaches of thoracic-level pedicles in a small cohort of subjects. We also evaluated the conductive properties of Ti-alloy pedicle screws and compared these with SS screws. Eleven pedicle screws were examined using energy-dispersive x-ray spectroscopy to identify their alloys, after which DC resistance and AC impedance for each screw was measured. Furthermore, a subset of five screws was used to investigate the current delivery under dynamic testing conditions. RESULTS: Postoperative computed tomography of 6 subjects revealed 10 instances of significant medial screw malpositioning, out of a total of 88 screws placed. In each of these 10 instances, direct stimulation of thoracic pedicle screws at intensities considered in the literature to be clinically significant (i.e., ≤11 mA) failed to predict these medial pedicle breaches, yet each breach was reliably identified with low-intensity stimulation applied via a ball-tipped probe. For in vitro studies, most screws made of titanium alloys had higher resistance and impedance at tested frequencies compared with their SS counterparts. Moreover, there was widespread variability in conduction properties between Ti-alloy screws, whereas SS screws behaved in a more homogeneous manner. CONCLUSIONS: When compared with screws made of SS, most Ti-alloy pedicle screws behaved more like semiconductors, showing conduction properties that were highly frequency dependent. These properties likely contributed to the difficulties we encountered in interpreting thoracic screw placements based on stimulus-evoked electromyography from direct screw stimulation.

Pulse-train stimulation for detecting medial malpositioning of thoracic pedicle screws.

STUDY DESIGN: Thoracic pedicle screw location and the current needed to stimulate adjacent neural tissue was evaluated using brief, high-frequency pulse trains and monitoring electromyography (EMG) from muscles in the lower limbs. OBJECTIVE: To establish a safe and reliable method for detecting medial malpositioning of pedicle screws placed in the thoracic spine during instrumentation and fusion. SUMMARY OF BACKGROUND DATA: Neurophysiologic studies for testing thoracic pedicle screw placement used single-pulse stimulation and monitored EMG from thoracic-innervated muscles. We propose that with this approach, stimulation fails to activate lower motor neurons innervated by spinal cord axons, such that medial malplacement of screws will go largely undetected. METHODS: EMG was monitored from multiple lower-limb muscles. Pedicle tracks were created free-hand, using a curved pedicle finder. A ball-tipped probe-insulated along its shaft-was used to palpate the walls of the pedicle tracks. During probing, constant-current, high-frequency 4-pulse stimulus trains were delivered through the ball tip, and the minimum current (i.e., threshold) needed to evoke EMG was determined for each pedicle track. The threshold current for stimulation through each screw was also determined. Postoperative serial computed tomography scans of all implanted thoracic and L1 screws were rated with respect to screw position and the pedicle wall. RESULTS: A total of 116 screws were implanted in 7 subjects. Two pedicle tracks were redirected during surgery because of particularly low thresholds to stimulation. Definite medial defects were found in 19 screws, 18 of which were detected by the experimental technique. For these screws, the average threshold to probe stimulation of their associated pedicle tracks was 7.9 +/- 4.6 mA, much lower than current thresholds for less medially placed pedicle tracks. Stimulation of these screws resulted in high thresholds (19.8 +/- 5.3 mA) when a response was evoked at all; stimulating 8 of these 19 medially malpositioned screws failed to elicit any lower-limb EMG at considerably higher (25 or 30 mA) stimulus intensities. CONCLUSION: This preliminary study supports the hypothesis that high-frequency stimulus pulse trains areeffective at detecting defects in the medial wall of pedicles in the thoracic spine during instrumentation, thereby improving on techniques using single-pulse stimulus protocols.