Innovation in neurosurgery: less than IDEAL? A systematic review

Today, it is unusual to perform neurosurgical procedures in most countries without access to an operative microscope, state-of-the-art neuro-navigational systems, or even hemostatic agents such as a bipolar electrocautery devices. In fact, technological innovation has been the hallmark of neurosurgery, and the vast majority of procedures that are currently considered routine would not be possible at all without innovation. However, not all innovation is an improvement over the technology it seeks to supplant. Evidence of patient outcome superiority is often lacking or non-existent in the real-time of innovation. In neurosurgical disease, low incidence and high burden may further hinder systematic evaluation of any new technique. Regardless of these difficulties, it is vital that new technologies and procedures undergo a strategic and ethical clinical introduction [9].

As surgical innovation does not typically follow the same introductory path as novel pharmaceuticals, the IDEAL Collaboration, formed by surgeons and methodologists, introduced the IDEAL (Idea, Development, Exploration, Assessment, Long-term follow-up) framework in 2009 and have published several updates since [16, 23, 47, 48, 65]. The goal of the collaboration is to improve surgical research, especially research surrounding innovation, and to overcome obstacles and methodological problems inherent to surgery [29, 47].

The IDEAL framework describes five stages through which interventional therapeutic innovations typically pass, together with the characteristics and study design of each stage (Table 1, adapted from McCulloch et al.) [16, 23, 47, 48, 65]. Any study involving non-human pre-clinical assessment of a novel technique, including simulator or animal studies, is regarded as stage 0. Stage one describes a proof-of-concept study in the first human patient. Stage 2a consists of a prospective study in up to 30 patients conducted by surgeons responsible for the earlier stage(s). Involving surgeons with no prior experience in a larger prospective study usually takes place in stage 2b to assess the learning curve and further develop the procedure. In stage 3, the procedure should be stable and is investigated in a randomized controlled trial (RCT) that compares outcomes of the innovative procedure with the gold standard. Assessment of rare and long-term outcomes takes place in stage 4 (Table 1) [29, 47].

To assess whether the IDEAL framework has been used two different neurosurgical procedures were evaluated: an endoscopic endonasal approach for skull base meningiomas (EEMS) and the use of the Woven Endobridge (WEB device, ©Sequent Medical) for endovascular treatment of intracranial aneurysms. Traditionally, skull base meningiomas are resected using an open transcranial microscopic approach [36]. However, recently, EEMS has been introduced and has gained some traction in neurosurgical literature [36]. The WEB device is a new option for intracranial aneurysm treatment, consisting of an unfoldable, detachable metallic mesh that is placed into the aneurysm neck leading to flow disruption [35]. The WEB device was especially developed for bifurcation and wide neck aneurysms as an alternative to traditional clipping or coiling [35]. Since the two innovations, one a device and the other a procedure, are used in different fields of neurosurgery and were recently introduced, we chose these two as examples for neurosurgical innovations in general.

In this review, published literature on these two procedures was evaluated to assess whether they were introduced according to the stages of the IDEAL framework.

For EEMS, 576 abstracts and titles were screened, 110 were examined full text, and 26 papers were included (Fig. 1a) [1, 8, 12, 13, 17, 19‐21, 24‐26, 30, 32, 34, 37, 38, 52‐55, 62, 68, 70‐73]. Two cadaveric studies were categorized as stage 0 [12, 30]. No studies were categorized as stage 2, as none of the included studies reported outcomes of a prospective study with adequate informed consent [1, 8, 13, 17, 19‐21, 24‐26, 32, 34, 37, 38, 52‐55, 62, 68, 70‐73]. Even though four studies compared EEMS with an open transcranial approach, they did not do this in a prospective fashion, and no RCTs could be identified [8, 19, 20, 52]. Furthermore, there were no studies that examined long-term outcomes, and therefore no studies were categorized as stage 4 (Table 2). All other studies could not be categorized into an IDEAL stage.

For WEB devices, 6229 abstracts and titles were screened, 88 articles were examined full text, and 21 papers were included (Fig. 1b) [2, 5, 10, 11, 14, 15, 22, 27, 33, 35, 41‐43, 45, 56‐60, 64, 69]. Preclinical studies using rabbit models were classified as stage 0 [22, 64]. One study that acquired informed consent for treatment of two patients was categorized as stage 1, but did not describe the clinical problem that needed a solution [35]. Two studies with ethical approval for a prospective study and informed consent of included patients were categorized as stage 2a [2, 44]. The studies with larger populations that reported the outcomes of the WEBCAST trial and the French observatory trial were categorized as stage 2b [57, 60]. All other studies could not be categorized into an IDEAL stage, and no studies were categorized as stage 3 or 4 as no comparison was made with other treatment modalities and no long-term outcomes were evaluated (Table 3).

The results of this systematic review demonstrate that both the endoscopic endonasal transsphenoidal approach for resection of skull base meningiomas and WEB devices were not introduced according to the IDEAL Framework. Not only could not all IDEAL framework stages be identified, some of the early pre-clinical studies (stage 0) were performed long after the description of the first-in-man studies (for EEMS) or after publication of prospective studies (WEB devices) [12, 22, 30, 64]. Perhaps unsurprisingly, only five clinical studies could be categorized into an IDEAL stage. WEB device studies followed the IDEAL Framework more closely than EEMS, but only up to stage 2b [2, 35, 45, 57, 60]. In addition, only six WEB device studies acquired ethical approval for a prospective study in line with the IDEAL framework [2, 27, 45, 56, 60, 61]. No study reported patient selection for EEMS compared to five WEB device studies [27, 41, 45, 57, 60]. Furthermore, no studies were categorized as stage 3 as no clinical study (of either procedure) was a prospective comparison with the gold standard or was an RCT.

We believe that this is not unique to these two procedures specifically or to neurosurgery in general. For instance, a study investigating literature on laparoscopic colonic polyp resection found that its introduction into widespread use also did not follow the stages and recommendations of the IDEAL framework [18].

The introduction of novel neurosurgical techniques that result in a paradigm change, i.e., the first endovascular treatment of aneurysms, could be introduced according to some predefined framework such as IDEAL. However, in reality, novel surgical techniques are often the result of small stepwise changes to existing approaches (e.g., EEMS and the transcranial approach to pituitary adenomas). This makes it challenging to introduce innovations as EEMS according to all requirements of the IDEAL framework. Adherence to the IDEAL framework might not only be challenging because of small stepwise changes of existing approaches but also because of a lack of a universally accepted definition of neurosurgical innovation in general.

A major change in endonasal surgery was the introduction of the endoscope, in particular for pituitary adenomas [31]. With expansion of endoscopic technique and experience, a wider spectrum of tumors became resectable through the endonasal approach. However, in retrospect, one could argue that EEMS is indeed a valuable alternative to a classic craniotomy for specific indications.

The WEB device is also example of expanding endovascular experience, and because of new endovascular devices a wider array of pathologies is treatable. Compared to EEMS, WEB devices were studied in a prospective fashion with patient informed consent [2, 45, 57, 60]. However, the WEB device is already used clinically despite lack of comparison with other treatment options (a stage 3 study) [11, 14, 69]. The important question is whether this new technique could have been rigorously compared to established techniques prior to wide-spread adoption.

Overall, this review suggests that neurosurgical innovation (at least for the two procedures evaluated here) has not historically followed the IDEAL framework. On the one hand, this could simply be caused by a lack of awareness of the framework. On the other hand, a different distinct possibility for this could be related to feasibility. The IDEAL collaboration recognizes that, to improve the quantity and quality of surgical research, these proposals/recommendations would have to be practical and adapted to the process of innovation [47]. Indeed, the IDEAL Collaboration supports several recommendations for specific (alternative) study designs and reporting standards at different stages of the framework [16, 23, 47]. These alternatives could contribute to the quantity and quality of neurosurgical research.

At the innovation stage (stage 1), the recommendations include online registries for first-in-man innovations. No reports on the entry of a study in a registry were found in our review. Often in neurosurgery innovations take place in an acute setting, and only in retrospect is there clarity with regards to the innovation itself. However, it is possible that future innovations could be entered in a registry, especially in the case of new devices like the WEB device. Registries could help reduce positive reporting bias inherent to new innovations. Reports of both successes and failures of new technology are useful for ethical innovation [51].

At the second development stage recommendations include: prospective development studies, protocol and study registries for prospective development studies in surgery and development of agreed reporting standards and definitions for key outcomes [29, 47]. These recommendations were not met for the introduction of EEMS and by only four studies for WEB devices [2, 45, 57, 60].

Again, not all of these recommendations may be possible in neurosurgery. However, protocol and prospective study registries are feasible in the neurosurgical field and could help ensure that clinical results of all patients are transparent and methodologically sound. Furthermore, novel techniques could be reported using professionally accepted reporting guidelines for prospective (and if inapplicable, retrospective) studies that favor clear interpretation of the study design and study results. Also, open comparison of individual studies and applicability of the reported outcomes would be useful. Key patient-centered outcomes for various pathologies result in research with comparable and clinically meaningful results.

All studies described the surgical outcomes, and this is outstanding. One next step could be to unify informed consent and outcomes reporting, which should include both positive and negative findings, for emerging innovative procedures. Furthermore, one could argue this process should be done in a more uniform manner across the neurosurgical field. One method might be the use of centralized regulation as seen with medical device approval by the Food and Drug Administration (FDA) [39, 40]. Alternatively, institutions or neurosurgical societies could create guidelines for reporting of trial registration, prospective design and patient registries, effectively following the IDEAL framework to a certain extent [48]. Nevertheless, informed consent and ethical approval for a prospective study are, we believe, something that should always be feasible when evaluating a new neurosurgical procedure.

No prospective randomized studies or RCTs, the ‘default option’ at the third or exploration stage of the IDEAL framework, were identified [47]. This may be one area of the IDEAL framework that is not completely feasible in all types of neurosurgical innovation. As discussed, innovation occurs by incremental but gradual changes over a prolonged period of time, and an RCT may not be the preferred study design for numerous reasons: (1) It is ethically challenging and practically impossible to compare EEMS to an open approach as the endonasal approach is not applicable to all patients; (2) the number of patients with skull base meningiomas is relatively small, which makes it difficult to recruit enough patients for proper statistical analyses; (3) the difference in outcomes between an open and endonasal approach might be small and therefore difficult to prove, especially with point 2 in mind; (4) there could be a lack of clinical equipoise; (5) surgeons might not be willing to participate because of personal treatment preference or experience [46]; (6) surgeons have different skill levels; (7) the location, extent and size of meningiomas vary, complicating inter-patient comparability and randomization, again complicated by point 3; (8) concomitant factors can change during the trial, e.g., innovation in anesthesiology and perioperative care [6, 49]; (9) improvement of endoscopic endonasal meningioma surgery is a constantly evolving process with differences in every center, which contributes to the often reported difficulty in standardization for innovative surgical procedures, it is inefficient to conduct an RCT for every incremental technological advance, and the incidence of these lesions is quite low [6]. For these reasons, a “classical” RCT in low-volume, highly complex cases as with skull base meningioma resections or similar procedures might not be feasible. However, the IDEAL collaboration endorses various alternatives to this trial design at the third stage. These include case-matching studies and controlled interrupted-time series designs, but also modified RCTs with Baysean modifications to recruitment, randomization or analysis [47]. These study designs might be useful in neurosurgical innovation. Especially the introduction of prospective research databases and collaborative studies, endorsed by the IDEAL collaboration, seem valuable for low-volume, highly complex surgeries such as skull base meningioma resections. Also, the recommended additions to the RCTs that include learning curve evaluation, quality control and compliance measures could be feasible and helpful for innovations as EEMS.

Even though an RCT for WEB devices could be challenging, especially because of the above-mentioned reasons 3–9, an RCT is possible and could have been conducted prior to wide-spread European adoption [35]. However, in the absence of a traditional RCT, a Baysian RCT or registry could have also been helpful to establish its efficacy and safety. In fact, application of all stages of the IDEAL framework in a more strategic fashion could be possible in technological innovations like the WEB device. To date, the WEB device appears to be efficacious and safe, but a more rigorous and transparent process for the introduction of this type of technology could potentially help prevent deleterious outcomes, as seen with the Poly Implant Prothèse (PIP) breast implants and metal-on-metal hip prostheses [4, 28, 67]. Currently, proof of safety and efficacy is required by the FDA for class III devices (the most invasive devices), but this is not standardized [39, 40]. Therefore, a change in regulation that results in a closer adherence to the IDEAL framework could lead to a more uniform implementation [48].

At the fourth or long-term study stage, the emphasis is on rare and long-term outcomes. We did not identify any (stage 4) studies reporting long-term outcomes of EEMS or WEB devices. We believe that in addition to a closer adherence to the ‘IDEA’ part of the IDEAL framework, attention to the long-term outcomes of innovations such as EEMS or WEB devices would greatly benefit innovation in neurosurgery. Registries are an appropriate study design for this purpose, although representativeness of the data is a potential limitation. Efforts made to ensure that data entry is complete help strengthen the representativeness of the registry [47]. Reporting fatigue can compromise comprehensive data collection; therefore, the development of concentrated, outcome relevant registries are optimal. Also, the use of registries with patient informed consent for surveillance of specific established techniques in neurosurgery is desirable, especially for use of new materials like the WEB device.

In general, innovation in low-volume, highly complex (neuro)surgical cases might benefit from alternatives to traditional RCTs. For example, in a “cohort multiple RCT,” some, but not all, patients are randomly assigned to a specific treatment and are followed up regularly over time, blending a RCT with an observational study with some of their respective benefits [7, 63, 66]. A potential stage 3 study on a low-volume, highly complex surgical innovation could include the following: (1) patient informed consent; (2) ethical approval; (3) strict definition (and registration) of indications for treatment; (4) prospective observational design; (5) registration in a trial registry; (6) random allocation of a standard treatment group or the well-defined innovative procedure; (7) regular follow-up on relevant outcomes for patients; (8) reporting of all outcomes; (9) collaboration of multiple centers.

This, however, does not address the issue of which innovative procedures merit such a study. “Big data” could fill the gap with regard to identification of trial-worthy innovations. The use of the electronic medical record, the digitization of patient outcomes and the computational capacity now available to the typical researcher have opened the door to detailed and comprehensive analysis of pre-trial data. Indeed, these types of large data sets could become a new level of evidence in and of itself if an RCT is not feasible [3].

The introduction of EEMS and WEB devices did not follow the stages as described by the IDEAL framework. The introduction of WEB devices followed the IDEAL Framework more closely, but only up to stage 2b. We believe this is not unique to neurosurgery or to these techniques, and it simply may not be feasible to follow this framework in its current iteration for all types of innovation. Despite this, informed consent, ethical approval and rigorous outcomes reporting are important elements of the IDEAL framework, which could serve to improve the quality of both experimental and alternative neurosurgical study designs. Alternatives to traditional RCTs and the use of “big data” could be useful modifications of the IDEAL framework. We believe that neurosurgical innovation and research could be improved by following a framework such as (a modified version of) IDEAL. This would improve evidence-based practice and potentially patient outcomes. After all, methodologically sound prospective studies, which require informed consent, ethical approval and equipoise, are feasible in neurosurgery.