Natural-orifice transluminal endoscopic surgery: from the laboratory to routine implementation – an editor’s point of view

Papers in the June 2010 and the present issues of Endoscopy illustrate the problems that are posed by the development of natural-orifice transluminal endoscopic surgery (NOTES), and by the publication of the results of this technique. The first of these papers, by Fritscher-Ravens et al. [1], published in the June issue, focuses on the development of NOTES thoracoscopy in animals by crossing the esophageal wall, which has always been regarded as inviolable because of the risks of infection. The second paper, by Linke et al. [2], in this month’s issue, is already on routine application of hybrid NOTES surgery. Furthermore, also in this issue, A. Fritscher-Ravens [3] reports an application of technology derived from NOTES for the treatment of an esophageal leak, an occurrence which is frequently very challenging.

Problems related to the development of a new technique such as NOTES and the publication of early results are obviously a concern for the operators and, indirectly, for journal editors and publishers. As the co-editor of Endoscopy responsible for publications on NOTES, and as a former coordinator of the research committees of the European Society of Gastrointestinal Endoscopy (ESGE) and the Société Française d’Endoscopie Digestive (SFED), I wish to express some thoughts relevant to this issue.

So far, NOTES cannot be described as representing a breakthrough for patients in terms of quality of care. The lack of scarring and the possibly reduced pain and likelihood of adhesions associated with NOTES, although important to patients, cannot be said to constitute a major medical advance. However, NOTES has some attractions, perhaps more technological and strategic than medical. Firstly, after laparoscopic surgery, it is a very important step in the development of ”minimally invasive“ surgery as it uses natural orifices as routes. Secondly, the technique maximizes the interface between surgeons and endoscopists as well as that between rigid and flexible endoscopy. NOTES not only removes the anatomical frontier represented by the digestive wall but also definitively removes the psychological and physical barrier between surgeons and endoscopists, Thirdly, it allows the development of new tools, endoscopes, and accessories, which will be useful not only for NOTES, but also for intraluminal endoscopy, as shown in the present issue [3]. For these reasons, the development and evaluation of NOTES techniques should be encouraged, at the very least for obese patients or for parietal hernia repair, or for procedures which remain challenging for laparoscopic surgery or intraluminal endoscopy.

As a new field of investigation in medicine, NOTES constitutes a major opportunity to stimulate and organize high-quality clinical evaluation in surgery and endoscopy. It is possible to apply the scientific approach used by other specialties to assess diagnostic and therapeutic advances. For many years the medical community has worked hard to structure clinical research. Using precise methodological rules and structured statistical support, hepatologists, oncologists, and our colleagues in the field of inflammatory bowel disease have advanced step by step, comparing new techniques and treatments to current reference standards. They have become champions of a standardized scientific approach. So far, this has not been the case for surgeons and endoscopists conducting research, and the evolution of surgery and endoscopy has, to date, relied very little on a rigorous methodology, for several reasons:

It is frequently difficult to recruit the large number of patients required by statistical power calculations, and studies in the field of endoscopy are very often underpowered. Endoscopic surgical techniques are not always well codified and are largely dependent on the expertise and skill of the operators. Operators may have very specific modalities of recruitment which prevent inclusion of patients in randomized protocols, because of the risk of seeing the patient go to another specialist and be lost to recruitment. This is why it has often been difficult to conduct randomized studies comparing endoscopic and surgical techniques (such as for chronic pancreatitis, to treat Barrett’s esophagus, etc.). The operators themselves are frequently subjective in their attitude, approaching their work with artistic flair – hardly compatible with rigorous evaluation. National regulations for the evaluation of devices tend to be less stringent than those for the evaluation of drugs. The market for devices and thus the profit margins of device manufacturers are smaller than the drug market and the profits of drug companies. There is therefore less money available to spend on evaluating devices than on evaluating drugs. Increasing the money spent on evaluation would probably result in a dramatic increase in device costs. Device and endoscope manufacturers, particularly the smaller ones, frequently do not have a clinical research department. Devices can be modified very easily and rapidly, and although each change ought to be evaluated, not least for safety and ethical reasons, this remains impossible in practice. Furthermore, a device is often modified during or immediately after its evaluation, becoming no longer commercially available, and all the effort put into conducting the study is then obsolete (this is often the case for prostheses).

Although there has been a significant improvement in recent years in the quality of reported endoscopic and surgical research, we still lag behind other fields such as hepatology and oncology.

Nevertheless, NOTES is a new area of research activity, and as a blank canvas represents a major chance to restructure clinical research in the fields of endoscopy and surgery. Sadly, in reality, this has not happened to date, as evidenced by the explosion in the number of NOTES procedures performed, particularly in South America, and in the number of the training courses already organized before the techniques have been formally validated. Undeniably, some parts of the mainstream press are more interested in sensationalism than in scientific articles, which are frequently heavy and dry; and it cannot be denied that the profit and the need for self-promotion, by both the operators and the device manufactures, are some of the driving forces behind the development of NOTES. And last, but not the least, there is competition between the medical journals to be the ones to publish the papers on innovations at an early stage, on the basis that this will lead to a large number of citations at a later date, thus increasing the journal’s impact factor – possibly at the expense of quality. Finally, and understandably, NOTES generates excitement and stimulates a pioneering spirit, and some think that trying to control its evaluation could slow its growth.

For all these reasons, up until the present the evaluation of NOTES techniques has been wild and chaotic, although less so than that of laparoscopic surgery several years ago. NOTES has not taken off in the way that laparoscopic surgery did. True, the step taken with NOTES is much greater than was the case with laparoscopic surgery, and many are hesitant, aware of the risks it poses to patients. Critics of NOTES frequently question the purpose and value of this technique compared to laparoscopic surgery, which has established benefits. At last, for the first time, a number of American and European scientific societies [the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), the American Society for Gastrointestinal Endoscopy (ASGE), the European Association for Endoscopic Surgery (EAES), and ESGE] have made a great effort to supervise the conduct of the evaluation of NOTES. The white paper prepared jointly by SAGES and ASGE [4] is a milestone and a very useful road map for this evaluation. A pragmatic step-by-step approach has been privileged, as demonstrated by the article of Linke et al. [2] on hybrid NOTES.

Lack of scientific rigor from operators, surgeons, and endoscopists is not the only reason for the somewhat chaotic evaluation in the NOTES field. There are also more fundamental causes. NOSCAR (the Natural Orifice Surgery Consortium for Assessment and Research), Euro-NOTES, and all the scientific societies are not legal authorities and they cannot impose any control on evaluation, especially in emerging countries. Ethical regulations are different in each country, and despite the well-known Declaration of Helsinki on ethical principles for medical research involving human subjects, there are no clear international rules regarding the members and functioning of ethical committees or institutional review boards (IRBs). Even within Europe, the criteria for gaining ethical approval vary from one country to another. In some countries obtaining ethical approval is such a prolonged bureaucratic process that it precludes companies conducting their research there. Up to now, obtaining the CE mark has been based on technical or technological criteria and very little on clinical evaluation or medical benefits. The European directive on medical devices published in 1993 was amended in 2007. The new directive clarifies the need for clinical evaluation and this has to be applied in 2010. For example, until 2010, companies often referred to clinical data relating to similar devices to justify their CE marking application, but now the companies will more and more have to conduct their own evaluation. National agencies in Europe are more involved with reimbursement of costs relating to the equipment, device, or the technique than the performance of early clinical studies. A device must be shown to have clear medical benefits only at the stage of reimbursement, rarely before. In addition, it should be noted that patient opinion, which often serves as an argument in favor of NOTES, is frequently unreliable: patient views are easily swayed either by emphasizing the benefits (e. g., absence of scarring) or risks (e. g., of infection) of the procedure.

There are standards of care for a disease, quality indicators for an already established instrumental technique, criteria for credentialing and privileging an operator, and guidelines about training. But the early phases in the life of an instrumental technique are not well regulated as they are for a drug. The development of any new instrumental technique comprises two steps. The first takes place in the laboratory and is conducted on animals, and the second is conducted on humans, starting with the first human case and ending in routine application in clinical practice. The second step is theoretically well codified and controlled by IRBs, but for NOTES the frontier between clinical evaluation and routine application is very permeable. The rules are not well applied – but at least we have rules. It is the first step, the preclinical stage, that requires pressing attention and formal standardization. Currently there are no recommendations concerning the development of an instrumental technique in translational medicine. We have guidelines relating to ethical issues that must be followed during animal experiments, but there is no evidence to suggest when a technique is deemed to be sufficiently safe, effective, and above all reproducible to be transposed to humans. For example, the number of animal experiments required before a technique can be transposed to human remains imprecise.

In the absence of any standards, work of variable quality is produced. Frequently, ethics committees do not have enough technical expertise to decide at what point a technique has been sufficiently evaluated to be ready to be applied in humans. Currently, the decisions on the number of animal procedures that need to be performed, the efficacy and the safety of the technique, and the reproducibility of the maneuvers and of the results are judged subjectively, by the individual operator or, at most, a team developing the technique. All too often, the authors who submit a paper to Endoscopy on the first human application of a NOTES technique admit that they are still working on animals to improve the technique whilst already applying it in patients!

It should be acknowledged that animal models are not always appropriate and are not true equivalents of the human body. For example, the esophagus of the pig is very fragile, with a mobile muscularis propria, and pig esophagus is not a very good model on which to test or train mucosectomy or endoscopic submucosal dissection. So we must admit that human studies are conducted not only to evaluate the clinical value of a technique but also to refine it. Furthermore, the pigs used in most studies are in good physical condition, whereas the condition of patients can be highly variable. In this regard, the approach of Fritscher-Ravens et al. [1], of using compromised animals to test their technique, is original and interesting, although obviously these animals cannot fully reproduce the human conditions.

It is very challenging, or idealistic – or perhaps too late? – to make some suggestions about the further development of a NOTES technique from animals to routine clinical use. What could these suggestions look like?

Firstly, as the need for experimental studies in animals is increasing in the field of surgery and endoscopy, scientific societies should encourage working groups on the standardization of instrumental techniques on animals prior to their use in humans. The purpose is to produce guidelines on how animal studies are conducted and on the goals to be reached. The scientific societies should also set the limits: When do we need animals studies? Certainly for the development of cholecystectomy by the transgastric route, but probably not when the only modification is the bend of an endoscope or the length of a sphincterotome. These guidelines should be communicated to IRBs.

Next, when an operator or a team think they have acquired enough data and expertise on the safety, efficacy, and reproducibility of a new NOTES technique in animals to conduct their first human procedure, we suggest that this team should be audited by independent experts under the auspices of a national or international scientific society. Evaluation of reproducibility might even require that this technique be repeated by another team, since whether a technique can be replicated by another team is the definition of reproducibility.

Thirdly, the strengthening of European requirements relating to animal and then clinical evaluation of medical devices (the 2010 directive) should be implemented, in order to avoid promotional selling of new devices under the cover of a poorly conducted study or of a registry which in the end will never come into being. Conversely, apart from comparative studies, which are time-consuming and require major funding, well-controlled registries should be encouraged in order to better meet the need for evaluation. This could be also the case for new techniques.

Finally, what is the position of an editor who receives articles in this new field? The editor cannot require the same quality of assessment for a new technique as for a technique that is already well-established: for example, the calculation of the number of animals to be included is often rough, and generally, statistically speaking, this number is insufficient. Should we require the sacrifice of a whole herd of pigs to evaluate a side effect which is not very common? Of course not. Sample size calculation is theoretically based on precise statistical analysis, but in practice it is more pragmatic than that, and is balanced between the minimum number of animals required, in order to limit potential suffering, and having enough animals to avoid repetitions of experiments.

In relation to studies which include animal survival, can we demand survival times of several years in order to ascertain that there are no long-term effects or that the efficacy is long-lasting? Of course not; but, for example, studies evaluating the role of NOTES to prevent peritoneal adhesions are frequently too short. It is obvious that animal testing will never cover all the risks and will never succeed in avoiding all surprises when the operator proceeds to clinical studies. We must accept some compromise on this matter, and we have to focus on publishing studies that have a solid rationale, which provides a sufficient answer, even if imperfect or incomplete by this rationale, which clearly discusses the limits of the method, and which also puts the importance of the observed results into context. The editor cannot totally rely on the IRB approval for animal and human studies to be sure that all ethical issues have been covered, and the opinions of reviewers on this particular point are very important. The editor must also accept the fact that the development of new instrumental techniques is subject to very little regulation (see above), and he or she cannot play the policeman, in the place of international or national authorities or scientific societies, in controlling the evaluation of instrumental techniques. The editor must also accept that the animal is not always an ideal model and should relativize the need for a rigorous methodology in animals, and must also accept that the technique can still be improved in patients. The editor must also realize that the articles submitted for publication are only the visible part of the NOTES iceberg and should not discourage publication.

It is a difficult and relatively subjective compromise. The purpose is to raise the quality level, but not to impose a level that would block research and publication and enthusiasm for a new technology. Some involvement of the scientific societies or of the authorities to set specific guidelines concerning animal studies on instrumental techniques could be of great help. How to define and control adequate evaluation and stability of an instrumental technique in animals is a major issue.

Competing interests: None

References

• 1 Fritscher-Ravens A, Cuming T, Eisenberger C F. et al . Randomized comparative long-term survival study of endoscopic and thoracoscopic esophageal wall repair after NOTES mediastinoscopy in healthy and compromised animals.  Endoscopy. 2010;  42 468-474
• 2 Linke G R, Tarantino I, Hoetzel R. et al . Transvaginal rigid-hybrid NOTES cholecystectomy: evaluation in routine clinical practice.  Endoscopy. 2010;  42 571-575
• 3 Hampe J, Schniewind B, Both M, Fritscher-Ravens A. Use of endoscopic NOTES closure device for full thickness suturing of a postoperative anastomotic esophageal leakage.  Endoscopy. 2010;  42 595-598
• 4 Rattner D, Kalloo A. ASGE/SAGES Working Group . ASGE/SAGES Working Group on Natural Orifice Translumenal Endoscopic Surgery. October 2005.  Surg Endosc. 2006;  20 329-333