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W2005763172 abstract "It is important that practicing clinicians understand the meaning and limitations of the terms “FDA approval” and “FDA clearance” for medical devices and recognize that “FDA clearance” is often granted with minimal documentation of efficacy.In the current issue of Gastroinestinal Endoscopy, von Renteln et al1von Renteln D. Schiefke I. Fuchs K.-H. et al.Endoscopic full-thickness plication for the treatment of GERD by application of multiple Plicator implants: a multicenter study (with video).Gastrointest Endosc. 2008; 68: 833-844Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar describe a modification of the technique for the application of the NDO Plicator (NDO Surgical Inc, Mansfield, Mass), one of a number of devices that have been introduced to the market over the last decade for endoluminal reflux therapy (ERT). The modification involves the use of multiple sutures (either 2 or 3) instead of the standard single suture to create a tighter closure at the esophagogastric (EG) junction. The study population is small (n = 41). As with most reports on ERTs, this one intentionally excluded patients with severe reflux. Also in keeping with most previously published reports, it focused primarily on the symptomatic response to intervention. The study demonstrates a superficially impressive response to intervention. At 6-month follow-up, the median GERD quality-of-life (GERD-QOL) score improved 76% (P < .001); with improvement in both heartburn and regurgitation (P < .001 for each). Seventy percent of the patients were no longer taking daily proton pump inhibitors (PPIs); 40% were no longer taking any medication, and an additional 25% were taking medication on an intermittent basis. Although statistically significant, the improvement in acid reflux by pH studies and of lower esophageal sphincter (LES) resting pressure can at best be described as modest. Also, the response of the endoscopic findings of esophagitis was variable.I said that the results were “superficially impressive” because of the limitations of the study design. A major concern is the subjective nature of the criteria used for determining the need for additional suture. If the space around the 5.8-mm videoendoscope as seen on retroflexed view was deemed insufficiently tight, the endoscopist placed 1 or 2 additional sutures between the last suture and the scope until a satisfactory closure was achieved. However, the most important problem is the absence of a randomized control group. Without a control, it is difficult for the reader to come to a meaningful conclusion about whether the modification in technique offers any advantage over the standard single-suture approach. The absence of a control group relegates this study to the “proof of concept” category of clinical trial. It demonstrates that skilled endoscopists can technically perform the modification of the standard full-thickness plication described. It tells us nothing about whether 2 (or 3) sutures are better than one. The lack of a control arm recapitulates the failure of a large proportion of the published studies on ERT, for if any conclusion can be drawn from the experience with ERTs, it is the importance of properly controlled trials in endoscopic clinical research.Endoluminal reflux therapies and the FDAThe seeds of endoluminal reflux therapy date back to the 1980s when O'Connor in the United States and Swain in the United Kingdom began experimenting with approaches to remodeling the EG junction for the purpose of enhancing the antireflux barrier—O'Connor by injecting Teflon (DuPont, Wilmington, Del) paste and dermal collagen, and Swain by applying sutures to the luminal side of the EG junction.2Lehman G.A. Endoscopic and endoluminal techniques for the control of gastroesophageal reflux: are they ready for widespread clinical application?.Gastrointest Endosc. 2000; 52: 808-811Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar In March, 2000, the Endocinch endoscopic suturing system (Bard Endoscopic Technologies, Murray Hill, NJ) became the first ERT to receive U.S. Food and Drug Administration (FDA) clearance for use in humans, followed a month later by the Stretta radiofrequency energy system (Curon Medical, Fremont, Calif). Many gastroenterologists were surprised to hear about ERT from the lay press and their own patients, rather than from scientific presentations or peer-reviewed journals. They were even more surprised when they heard the reports of the first clinical trials of these devices presented at Digestive Disease Week in May 2000 (only after the devices were already on the market) and recognized that the data were entirely uncontrolled and based primarily on subjective measures of efficacy. Over the next few years, a number of additional ERTs entered the market with similarly limited clinical evidence for efficacy.How did such a vaunted and feared regulatory body as the FDA, renowned for its demanding drug review process, let these devices pass onto the market on the basis of what appeared at the time, and perhaps even more in retrospect, to have been relatively weak data? This episode highlights a general ignorance among practicing physicians about the nature of the FDA's decision processes regarding medical devices.The FDA's mission statement is stated on its website3U.S. Food and Drug Administration Web site. Available at: http://www.fda.gov/opacom/morechoices/mission.html. Accessed March 24, 2008.Google Scholar as follows: “The FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation's food supply, cosmetics, and products that emit radiation. The FDA is also responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable and by helping the public get the accurate, science-based information they need to use medicines and foods to improve their health.”Under the Federal Food, Drug, and Cosmetic Act, the difference between drugs and medical devices is that drugs achieve their primary intended purposes through a chemical action, whereas medical devices do not. Drugs are regulated by the FDA's Center for Drug Evaluation and Research (CDER), whereas medical devices are regulated by the FDA's Center for Devices and Radiologic Health (CDRH). When a proposed product does not fall clearly into one of the two categories—drug or device—the FDA itself is authorized to determine which the product should be considered and thus, which center should take the lead in the approval process.4Maisel M.H. Medical device regulation: an introduction for the practicing physician.Ann Intern Med. 2004; 140: 296-302Crossref PubMed Scopus (138) Google Scholar To use a pertinent example, a procedure that involves injection of something into the EG junction (eg, the Enteryx co-polymer implantation system [EndoGastric Solutions, Inc, Redmond, Wash]) might be considered either a medical device (because of the delivery system) or a drug (because of the material injected). Ultimately, the FDA decided that it was primarily a medical device and subject to review by the CDRH.It seems that the CDER and the CDRH take somewhat different views of the balance between assuring efficacy and speeding innovation. This reflects, at least in part, the inherently different development cycle of drugs and medical devices. Although drugs take many years to develop and once introduced tend to stay on the market for decades, medical devices are often developed over a short period of time and tend to have a fairly brief period on the market before significant modifications are made. It appears to be the view of the CDRH that to impose a long approval process would be a barrier to introduction of new devices and, therefore, stifle innovation.The CDRH stratifies medical devices into 3 classes according to their perceived level of risk. At one end of the spectrum, Class I are devices that are thought to have a very low potential to do harm and are, with few exceptions, exempt from premarket submission at all. The manufacturers of Class I devices need only follow general guidelines concerning labeling and manufacturing practices. Class II includes devices that are deemed to have a somewhat higher level of risk. These devices must undergo premarket review by the CDRH under the 510k process. Under the 510k process, the manufacturer requests clearance based on the “substantial equivalence” of the device under consideration to another device (the “predicate device”) that is already available on the market. The process generally requires little if any clinical data to support the requirement that the device is “at least as safe and effective” as the predicate device (Food, Drug and Cosmetic Act, Section 513). The technical similarity and the similar use for which it is intended are considered sufficient in most cases. Devices that are passed by the FDA under the 510k process are given “FDA clearance.” Class III are devices that are believed to be sufficiently new, in terms of technical specification or intended use, to require a more detailed review through the premarket application (PMA) process. This process requires a great deal more effort, including clinical data that must provide “reasonable assurance of safety and effectiveness” (Food, Drug and Cosmetic Act, Section 515). Only devices that successfully pass through the PMA process are said to have been given “FDA approval.”The vast majority of new medical devices receive “FDA clearance” through the 510k process rather than “FDA approval” through a PMA application. It may come as a surprise to many that both ERT therapy devices that entered the market in 2000 were “cleared” through the 510k process rather than “approved” through a PMA application. Stretta was cleared on the basis of previous clearance of other radiofrequency devices manufactured by the same company (FDA 510k, K000245). Endocinch was cleared based on a somewhat vague reference to devices involving needles and sutures that had previously been cleared for use under endoscopic visualization (K994290). In fact, of the 5 ERTs ultimately authorized for use by the FDA, only one, Enteryx, received “FDA approval” through a PMA application (P20006).What was the efficacy data upon which the FDA made its decisions on the original ERTs? The clinical data provided as part of either a 510k or PMA application are apparently considered confidential and, therefore, not available to the public for review. The original 510k Summary for Endocinch and that for the Stretta state that the supporting material included data involving 64 and 47 patients, respectively. The PMA approval for Enteryx mentions 85 patients. No details concerning the clinical data are given in the documents available through the FDA website. It is clear from the initial clinical trials subsequently published in the medical literature, presumably including the patients mentioned in the 510k application, that none of these trials included a control population. Other ERTs may have received “FDA clearance” under the 510k process without any clinical data at all. The 510k Summary for the NDO Plicator referred to the Endocinch suturing system as the “predicate device” and did not mention clinical data being submitted (K023234). The more recent device, the EsophyX (EndoGastric Solutions, Inc), was awarded “FDA clearance” by reference to the NDO Plicator, again without mention of supporting clinical data (K071651).Where does this process of clearance by reference to “predicate devices” end? In 1976, an FDA-appointed panel classified all medical devices on the market at the time into one of the 3 risk classes described previously. Each subsequently 510k-cleared medical device bases its claim of safety and efficacy on a “predicate device” that, in turn, bases its claim on a series of other “predicate devices,” forming a trail that leads back to (1) one of the originally classified devices, or (2) a device that received actual “FDA approval” as part of a PMA application process since 1976.Endoluminal devices in retrospectIt is instructive to review the few randomized, sham-controlled studies of endoluminal reflux therapy that became available since the original devices entered the U.S. market. In a study of the Stretta procedure, 35 patients received radiofrequency treatment and 29 received sham treatment. At 6 months, more radiofrequency-treated patients than sham-treated patients were without daily heartburn symptoms (61% vs 33%, P = .05), and more had a > 50% improvement in their GERD-QOL score (61% vs 30%, P = .03). However, there was no statistically significant difference in medication use or in objective measures of acid reflux by pH studies.5Corley D.A. Katz P. Wo J.M. et al.Improvement of gastroesophageal reflux symptoms after radiofrequency energy: a randomized, sham-controlled trial.Gastroenterology. 2003; 125: 668-676Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar In a study of the Enteryx procedure, 32 patients received implantations, whereas 32 were sham-treated. Because patients were allowed to cross over to the alternative treatment at 3 months, only the comparisons at the 3-month follow-up are meaningful. At 3 months, the implantation group were more likely to have had ≥50% reduction in use of PPIs (81% vs 53%, P = .023). A higher proportion of the implantation patients had been able to completely stop PPI use (68% vs 41%, P = .033). GERD-QOL score was also better in the implantation group (67% vs 22%, P < .001). More sham-treated patients crossed over to the alternative therapy (81% vs 19%, P < .001). However, acid reflux measured by pH studies did not improve in either group.6Devière J. Costamagna G. Neuhaus H. et al.Nonresorbable copolymer implantation for gastroesophageal reflux disease: a randomized sham-controlled multicenter trial.Gastroenterology. 2005; 128: 532-540Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar In a study of the NDO Plicator, 78 patients received full-thickness plication, whereas 81 patients were sham-treated. At 3-month follow-up, the plication group had better GERD-QOL scores (56% vs 18.5%, P < .001) and were more likely to have stopped taking PPIs (50% vs 24%, P = .002). In this study, the plication group did improve the percentage time with pH < 4 (7 vs 10 [18%], P < .001), whereas the sham group did not (10 vs 9 [–3%], P = .686).7Rothstein R. Filipi C. Caca K. et al.Endoscopic full-thickness plication for the treatment of gastroesophageal reflux disease: a randomized, sham-controlled trial.Gastroenterology. 2006; 131: 704-712Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar Finally, in a study of Endocinch, 22 patients received endoscopic suturing procedure, whereas 24 were sham-treated. Although there was a slight difference in PPI consumption at 3 months, there was no difference in any subjective or objective parameter of reflux between the 2 groups by 12 months.8Montgomery M. Hakanson B. Ljungqvist O. et al.Twelve months' follow-up after treatment with the EndoCinch endoscopic technique for gastro-oesophageal reflux disease: a randomized, placebo-controlled study.Scand J Gastroenterol. 2006; 41: 1382-1389Crossref PubMed Scopus (55) Google ScholarConclusionsWhat should we take away from the ERT experience to date? Some years ago, Hebrew National, the manufacturer of kosher food products, ran a brilliant television advertisement for their kosher hot dogs. As an actor, dressed as Uncle Sam, prepared to bite into a delicious-looking frankfurter, he was repeatedly interrupted by a voiceover that listed the various less-than-healthy things that could legally be put into a frankfurter under federal government guidelines. Uncle Sam was only able to go ahead and enjoy himself when he was finally reassured that Hebrew National hot dogs did not contain these unsavory things because the company “answered to a higher authority.”It would seem that the ERT experience carries a similar message. For whatever reason, the standards set by the FDA for medical devices seem less than what might be expected. It is important that we, the practicing clinicians, understand the meaning and limitations of the terms “FDA approval” and “FDA clearance,” and recognize that “FDA clearance” is often granted with minimal documentation of efficacy. Even when clinical studies are submitted in support of the FDA premarket review processes, those studies do not necessarily meet the standards commonly expected by the scientific community. Further, the placebo effect in the treatment of reflux disease is sufficiently potent that studies that depend on subjective clinical responses alone, especially without clear objective responses, must be taken with a healthy amount of skepticism.Randomized, controlled studies that can withstand critical review are just as important for the evaluation of new endoscopic therapy as they are for clinical trials of drugs, whether FDA policies require them or not. It is important that practicing clinicians understand the meaning and limitations of the terms “FDA approval” and “FDA clearance” for medical devices and recognize that “FDA clearance” is often granted with minimal documentation of efficacy.In the current issue of Gastroinestinal Endoscopy, von Renteln et al1von Renteln D. Schiefke I. Fuchs K.-H. et al.Endoscopic full-thickness plication for the treatment of GERD by application of multiple Plicator implants: a multicenter study (with video).Gastrointest Endosc. 2008; 68: 833-844Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar describe a modification of the technique for the application of the NDO Plicator (NDO Surgical Inc, Mansfield, Mass), one of a number of devices that have been introduced to the market over the last decade for endoluminal reflux therapy (ERT). The modification involves the use of multiple sutures (either 2 or 3) instead of the standard single suture to create a tighter closure at the esophagogastric (EG) junction. The study population is small (n = 41). As with most reports on ERTs, this one intentionally excluded patients with severe reflux. Also in keeping with most previously published reports, it focused primarily on the symptomatic response to intervention. The study demonstrates a superficially impressive response to intervention. At 6-month follow-up, the median GERD quality-of-life (GERD-QOL) score improved 76% (P < .001); with improvement in both heartburn and regurgitation (P < .001 for each). Seventy percent of the patients were no longer taking daily proton pump inhibitors (PPIs); 40% were no longer taking any medication, and an additional 25% were taking medication on an intermittent basis. Although statistically significant, the improvement in acid reflux by pH studies and of lower esophageal sphincter (LES) resting pressure can at best be described as modest. Also, the response of the endoscopic findings of esophagitis was variable. It is important that practicing clinicians understand the meaning and limitations of the terms “FDA approval” and “FDA clearance” for medical devices and recognize that “FDA clearance” is often granted with minimal documentation of efficacy. It is important that practicing clinicians understand the meaning and limitations of the terms “FDA approval” and “FDA clearance” for medical devices and recognize that “FDA clearance” is often granted with minimal documentation of efficacy. I said that the results were “superficially impressive” because of the limitations of the study design. A major concern is the subjective nature of the criteria used for determining the need for additional suture. If the space around the 5.8-mm videoendoscope as seen on retroflexed view was deemed insufficiently tight, the endoscopist placed 1 or 2 additional sutures between the last suture and the scope until a satisfactory closure was achieved. However, the most important problem is the absence of a randomized control group. Without a control, it is difficult for the reader to come to a meaningful conclusion about whether the modification in technique offers any advantage over the standard single-suture approach. The absence of a control group relegates this study to the “proof of concept” category of clinical trial. It demonstrates that skilled endoscopists can technically perform the modification of the standard full-thickness plication described. It tells us nothing about whether 2 (or 3) sutures are better than one. The lack of a control arm recapitulates the failure of a large proportion of the published studies on ERT, for if any conclusion can be drawn from the experience with ERTs, it is the importance of properly controlled trials in endoscopic clinical research. Endoluminal reflux therapies and the FDAThe seeds of endoluminal reflux therapy date back to the 1980s when O'Connor in the United States and Swain in the United Kingdom began experimenting with approaches to remodeling the EG junction for the purpose of enhancing the antireflux barrier—O'Connor by injecting Teflon (DuPont, Wilmington, Del) paste and dermal collagen, and Swain by applying sutures to the luminal side of the EG junction.2Lehman G.A. Endoscopic and endoluminal techniques for the control of gastroesophageal reflux: are they ready for widespread clinical application?.Gastrointest Endosc. 2000; 52: 808-811Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar In March, 2000, the Endocinch endoscopic suturing system (Bard Endoscopic Technologies, Murray Hill, NJ) became the first ERT to receive U.S. Food and Drug Administration (FDA) clearance for use in humans, followed a month later by the Stretta radiofrequency energy system (Curon Medical, Fremont, Calif). Many gastroenterologists were surprised to hear about ERT from the lay press and their own patients, rather than from scientific presentations or peer-reviewed journals. They were even more surprised when they heard the reports of the first clinical trials of these devices presented at Digestive Disease Week in May 2000 (only after the devices were already on the market) and recognized that the data were entirely uncontrolled and based primarily on subjective measures of efficacy. Over the next few years, a number of additional ERTs entered the market with similarly limited clinical evidence for efficacy.How did such a vaunted and feared regulatory body as the FDA, renowned for its demanding drug review process, let these devices pass onto the market on the basis of what appeared at the time, and perhaps even more in retrospect, to have been relatively weak data? This episode highlights a general ignorance among practicing physicians about the nature of the FDA's decision processes regarding medical devices.The FDA's mission statement is stated on its website3U.S. Food and Drug Administration Web site. Available at: http://www.fda.gov/opacom/morechoices/mission.html. Accessed March 24, 2008.Google Scholar as follows: “The FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation's food supply, cosmetics, and products that emit radiation. The FDA is also responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable and by helping the public get the accurate, science-based information they need to use medicines and foods to improve their health.”Under the Federal Food, Drug, and Cosmetic Act, the difference between drugs and medical devices is that drugs achieve their primary intended purposes through a chemical action, whereas medical devices do not. Drugs are regulated by the FDA's Center for Drug Evaluation and Research (CDER), whereas medical devices are regulated by the FDA's Center for Devices and Radiologic Health (CDRH). When a proposed product does not fall clearly into one of the two categories—drug or device—the FDA itself is authorized to determine which the product should be considered and thus, which center should take the lead in the approval process.4Maisel M.H. Medical device regulation: an introduction for the practicing physician.Ann Intern Med. 2004; 140: 296-302Crossref PubMed Scopus (138) Google Scholar To use a pertinent example, a procedure that involves injection of something into the EG junction (eg, the Enteryx co-polymer implantation system [EndoGastric Solutions, Inc, Redmond, Wash]) might be considered either a medical device (because of the delivery system) or a drug (because of the material injected). Ultimately, the FDA decided that it was primarily a medical device and subject to review by the CDRH.It seems that the CDER and the CDRH take somewhat different views of the balance between assuring efficacy and speeding innovation. This reflects, at least in part, the inherently different development cycle of drugs and medical devices. Although drugs take many years to develop and once introduced tend to stay on the market for decades, medical devices are often developed over a short period of time and tend to have a fairly brief period on the market before significant modifications are made. It appears to be the view of the CDRH that to impose a long approval process would be a barrier to introduction of new devices and, therefore, stifle innovation.The CDRH stratifies medical devices into 3 classes according to their perceived level of risk. At one end of the spectrum, Class I are devices that are thought to have a very low potential to do harm and are, with few exceptions, exempt from premarket submission at all. The manufacturers of Class I devices need only follow general guidelines concerning labeling and manufacturing practices. Class II includes devices that are deemed to have a somewhat higher level of risk. These devices must undergo premarket review by the CDRH under the 510k process. Under the 510k process, the manufacturer requests clearance based on the “substantial equivalence” of the device under consideration to another device (the “predicate device”) that is already available on the market. The process generally requires little if any clinical data to support the requirement that the device is “at least as safe and effective” as the predicate device (Food, Drug and Cosmetic Act, Section 513). The technical similarity and the similar use for which it is intended are considered sufficient in most cases. Devices that are passed by the FDA under the 510k process are given “FDA clearance.” Class III are devices that are believed to be sufficiently new, in terms of technical specification or intended use, to require a more detailed review through the premarket application (PMA) process. This process requires a great deal more effort, including clinical data that must provide “reasonable assurance of safety and effectiveness” (Food, Drug and Cosmetic Act, Section 515). Only devices that successfully pass through the PMA process are said to have been given “FDA approval.”The vast majority of new medical devices receive “FDA clearance” through the 510k process rather than “FDA approval” through a PMA application. It may come as a surprise to many that both ERT therapy devices that entered the market in 2000 were “cleared” through the 510k process rather than “approved” through a PMA application. Stretta was cleared on the basis of previous clearance of other radiofrequency devices manufactured by the same company (FDA 510k, K000245). Endocinch was cleared based on a somewhat vague reference to devices involving needles and sutures that had previously been cleared for use under endoscopic visualization (K994290). In fact, of the 5 ERTs ultimately authorized for use by the FDA, only one, Enteryx, received “FDA approval” through a PMA application (P20006).What was the efficacy data upon which the FDA made its decisions on the original ERTs? The clinical data provided as part of either a 510k or PMA application are apparently considered confidential and, therefore, not available to the public for review. The original 510k Summary for Endocinch and that for the Stretta state that the supporting material included data involving 64 and 47 patients, respectively. The PMA approval for Enteryx mentions 85 patients. No details concerning the clinical data are given in the documents available through the FDA website. It is clear from the initial clinical trials subsequently published in the medical literature, presumably including the patients mentioned in the 510k application, that none of these trials included a control population. Other ERTs may have received “FDA clearance” under the 510k process without any clinical data at all. The 510k Summary for the NDO Plicator referred to the Endocinch suturing system as the “predicate device” and did not mention clinical data being submitted (K023234). The more recent device, the EsophyX (EndoGastric Solutions, Inc), was awarded “FDA clearance” by reference to the NDO Plicator, again without mention of supporting clinical data (K071651).Where does this process of clearance by reference to “predicate devices” end? In 1976, an FDA-appointed panel classified all medical devices on the market at the time into one of the 3 risk classes described previously. Each subsequently 510k-cleared medical device bases its claim of safety and efficacy on a “predicate device” that, in turn, bases its claim on a series of other “predicate devices,” forming a trail that leads back to (1) one of the originally classified devices, or (2) a device that received actual “FDA approval” as part of a PMA application process since 1976. The seeds of endoluminal reflux therapy date back to the 1980s when O'Connor in the United States and Swain in the United Kingdom began experimenting with approaches to remodeling the EG junction for the purpose of enhancing the antireflux barrier—O'Connor by injecting Teflon (DuPont, Wilmington, Del) paste and dermal collagen, and Swain by applying sutures to the luminal side of the EG junction.2Lehman G.A. Endoscopic and endoluminal techniques for the control of gastroesophageal reflux: are they ready for widespread clinical application?.Gastrointest Endosc. 2000; 52: 808-811Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar In March, 2000, the Endocinch endoscopic suturing system (Bard Endoscopic Technologies, Murray Hill, NJ) became the first ERT to receive U.S. Food and Drug Administration (FDA) clearance for use in humans, followed a month later by the Stretta radiofrequency energy system (Curon Medical, Fremont, Calif). Many gastroenterologists were surprised to hear about ERT from the lay press and their own patients, rather than from scientific presentations or peer-reviewed journals. They were even more surprised when they heard the reports of the first clinical trials of these devices presented at Digestive Disease Week in May 2000 (only after the devices were already on the market) and recognized that the data were entirely uncontrolled and based primarily on subjective measures of efficacy. Over the next few years, a number of additional ERTs entered the market with similarly limited clinical evidence for efficacy. How did such a vaunted and feared regulatory body as the FDA, renowned for its demanding drug review process, let these devices pass onto the market on the basis of what appeared at the time, and perhaps even more in retrospect, to have been relatively weak data? This episode highlights a general ignorance among practicing physicians about the nature of the FDA's decision processes regarding medical devices. The FDA's mission statement is stated on its website3U.S. Food and Drug Administration Web site. Available at: http://www.fda.gov/opacom/morechoices/mission.html. Accessed March 24, 2008.Google Scholar as follows: “The FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation's food supply, cosmetics, and products that emit radiation. The FDA is also responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable and by helping the public get the accurate, science-based information they need to use medicines and foods to improve their health.” Under the Federal Food, Drug, and Cosmetic Act, the difference between drugs and medical devices is that drugs achieve their primary intended purposes through a chemical action, whereas medical devices do not. Drugs are regulated by the FDA's Center for Drug Evaluation and Research (CDER), whereas medical devices are regulated by the FDA's Center for Devices and Radiologic Health (CDRH). When a proposed product does not fall clearly into one of the two categories—drug or device—the FDA itself is authorized to determine which the product should be considered and thus, which center should take the lead in the approval process.4Maisel M.H. Medical device regulation: an introduction for the practicing physician.Ann Intern Med. 2004; 140: 296-302Crossref PubMed Scopus (138) Google Scholar To use a pertinent example, a procedure that involves injection of something into the EG junction (eg, the Enteryx co-polymer implantation system [EndoGastric Solutions, Inc, Redmond, Wash]) might be considered either a medical device (because of the delivery system) or a drug (because of the material injected). Ultimately, the FDA decided that it was primarily a medical device and subject to review by the CDRH. It seems that the CDER and the CDRH take somewhat different views of the balance between assuring efficacy and speeding innovation. This reflects, at least in part, the inherently different development cycle of drugs and medical devices. Although drugs take many years to develop and once introduced tend to stay on the market for decades, medical devices are often developed over a short period of time and tend to have a fairly brief period on the market before significant modifications are made. It appears to be the view of the CDRH that to impose a long approval process would be a barrier to introduction of new devices and, therefore, stifle innovation. The CDRH stratifies medical devices into 3 classes according to their perceived level of risk. At one end of the spectrum, Class I are devices that are thought to have a very low potential to do harm and are, with few exceptions, exempt from premarket submission at all. The manufacturers of Class I devices need only follow general guidelines concerning labeling and manufacturing practices. Class II includes devices that are deemed to have a somewhat higher level of risk. These devices must undergo premarket review by the CDRH under the 510k process. Under the 510k process, the manufacturer requests clearance based on the “substantial equivalence” of the device under consideration to another device (the “predicate device”) that is already available on the market. The process generally requires little if any clinical data to support the requirement that the device is “at least as safe and effective” as the predicate device (Food, Drug and Cosmetic Act, Section 513). The technical similarity and the similar use for which it is intended are considered sufficient in most cases. Devices that are passed by the FDA under the 510k process are given “FDA clearance.” Class III are devices that are believed to be sufficiently new, in terms of technical specification or intended use, to require a more detailed review through the premarket application (PMA) process. This process requires a great deal more effort, including clinical data that must provide “reasonable assurance of safety and effectiveness” (Food, Drug and Cosmetic Act, Section 515). Only devices that successfully pass through the PMA process are said to have been given “FDA approval.” The vast majority of new medical devices receive “FDA clearance” through the 510k process rather than “FDA approval” through a PMA application. It may come as a surprise to many that both ERT therapy devices that entered the market in 2000 were “cleared” through the 510k process rather than “approved” through a PMA application. Stretta was cleared on the basis of previous clearance of other radiofrequency devices manufactured by the same company (FDA 510k, K000245). Endocinch was cleared based on a somewhat vague reference to devices involving needles and sutures that had previously been cleared for use under endoscopic visualization (K994290). In fact, of the 5 ERTs ultimately authorized for use by the FDA, only one, Enteryx, received “FDA approval” through a PMA application (P20006). What was the efficacy data upon which the FDA made its decisions on the original ERTs? The clinical data provided as part of either a 510k or PMA application are apparently considered confidential and, therefore, not available to the public for review. The original 510k Summary for Endocinch and that for the Stretta state that the supporting material included data involving 64 and 47 patients, respectively. The PMA approval for Enteryx mentions 85 patients. No details concerning the clinical data are given in the documents available through the FDA website. It is clear from the initial clinical trials subsequently published in the medical literature, presumably including the patients mentioned in the 510k application, that none of these trials included a control population. Other ERTs may have received “FDA clearance” under the 510k process without any clinical data at all. The 510k Summary for the NDO Plicator referred to the Endocinch suturing system as the “predicate device” and did not mention clinical data being submitted (K023234). The more recent device, the EsophyX (EndoGastric Solutions, Inc), was awarded “FDA clearance” by reference to the NDO Plicator, again without mention of supporting clinical data (K071651). Where does this process of clearance by reference to “predicate devices” end? In 1976, an FDA-appointed panel classified all medical devices on the market at the time into one of the 3 risk classes described previously. Each subsequently 510k-cleared medical device bases its claim of safety and efficacy on a “predicate device” that, in turn, bases its claim on a series of other “predicate devices,” forming a trail that leads back to (1) one of the originally classified devices, or (2) a device that received actual “FDA approval” as part of a PMA application process since 1976. Endoluminal devices in retrospectIt is instructive to review the few randomized, sham-controlled studies of endoluminal reflux therapy that became available since the original devices entered the U.S. market. In a study of the Stretta procedure, 35 patients received radiofrequency treatment and 29 received sham treatment. At 6 months, more radiofrequency-treated patients than sham-treated patients were without daily heartburn symptoms (61% vs 33%, P = .05), and more had a > 50% improvement in their GERD-QOL score (61% vs 30%, P = .03). However, there was no statistically significant difference in medication use or in objective measures of acid reflux by pH studies.5Corley D.A. Katz P. Wo J.M. et al.Improvement of gastroesophageal reflux symptoms after radiofrequency energy: a randomized, sham-controlled trial.Gastroenterology. 2003; 125: 668-676Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar In a study of the Enteryx procedure, 32 patients received implantations, whereas 32 were sham-treated. Because patients were allowed to cross over to the alternative treatment at 3 months, only the comparisons at the 3-month follow-up are meaningful. At 3 months, the implantation group were more likely to have had ≥50% reduction in use of PPIs (81% vs 53%, P = .023). A higher proportion of the implantation patients had been able to completely stop PPI use (68% vs 41%, P = .033). GERD-QOL score was also better in the implantation group (67% vs 22%, P < .001). More sham-treated patients crossed over to the alternative therapy (81% vs 19%, P < .001). However, acid reflux measured by pH studies did not improve in either group.6Devière J. Costamagna G. Neuhaus H. et al.Nonresorbable copolymer implantation for gastroesophageal reflux disease: a randomized sham-controlled multicenter trial.Gastroenterology. 2005; 128: 532-540Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar In a study of the NDO Plicator, 78 patients received full-thickness plication, whereas 81 patients were sham-treated. At 3-month follow-up, the plication group had better GERD-QOL scores (56% vs 18.5%, P < .001) and were more likely to have stopped taking PPIs (50% vs 24%, P = .002). In this study, the plication group did improve the percentage time with pH < 4 (7 vs 10 [18%], P < .001), whereas the sham group did not (10 vs 9 [–3%], P = .686).7Rothstein R. Filipi C. Caca K. et al.Endoscopic full-thickness plication for the treatment of gastroesophageal reflux disease: a randomized, sham-controlled trial.Gastroenterology. 2006; 131: 704-712Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar Finally, in a study of Endocinch, 22 patients received endoscopic suturing procedure, whereas 24 were sham-treated. Although there was a slight difference in PPI consumption at 3 months, there was no difference in any subjective or objective parameter of reflux between the 2 groups by 12 months.8Montgomery M. Hakanson B. Ljungqvist O. et al.Twelve months' follow-up after treatment with the EndoCinch endoscopic technique for gastro-oesophageal reflux disease: a randomized, placebo-controlled study.Scand J Gastroenterol. 2006; 41: 1382-1389Crossref PubMed Scopus (55) Google Scholar It is instructive to review the few randomized, sham-controlled studies of endoluminal reflux therapy that became available since the original devices entered the U.S. market. In a study of the Stretta procedure, 35 patients received radiofrequency treatment and 29 received sham treatment. At 6 months, more radiofrequency-treated patients than sham-treated patients were without daily heartburn symptoms (61% vs 33%, P = .05), and more had a > 50% improvement in their GERD-QOL score (61% vs 30%, P = .03). However, there was no statistically significant difference in medication use or in objective measures of acid reflux by pH studies.5Corley D.A. Katz P. Wo J.M. et al.Improvement of gastroesophageal reflux symptoms after radiofrequency energy: a randomized, sham-controlled trial.Gastroenterology. 2003; 125: 668-676Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar In a study of the Enteryx procedure, 32 patients received implantations, whereas 32 were sham-treated. Because patients were allowed to cross over to the alternative treatment at 3 months, only the comparisons at the 3-month follow-up are meaningful. At 3 months, the implantation group were more likely to have had ≥50% reduction in use of PPIs (81% vs 53%, P = .023). A higher proportion of the implantation patients had been able to completely stop PPI use (68% vs 41%, P = .033). GERD-QOL score was also better in the implantation group (67% vs 22%, P < .001). More sham-treated patients crossed over to the alternative therapy (81% vs 19%, P < .001). However, acid reflux measured by pH studies did not improve in either group.6Devière J. Costamagna G. Neuhaus H. et al.Nonresorbable copolymer implantation for gastroesophageal reflux disease: a randomized sham-controlled multicenter trial.Gastroenterology. 2005; 128: 532-540Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar In a study of the NDO Plicator, 78 patients received full-thickness plication, whereas 81 patients were sham-treated. At 3-month follow-up, the plication group had better GERD-QOL scores (56% vs 18.5%, P < .001) and were more likely to have stopped taking PPIs (50% vs 24%, P = .002). In this study, the plication group did improve the percentage time with pH < 4 (7 vs 10 [18%], P < .001), whereas the sham group did not (10 vs 9 [–3%], P = .686).7Rothstein R. Filipi C. Caca K. et al.Endoscopic full-thickness plication for the treatment of gastroesophageal reflux disease: a randomized, sham-controlled trial.Gastroenterology. 2006; 131: 704-712Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar Finally, in a study of Endocinch, 22 patients received endoscopic suturing procedure, whereas 24 were sham-treated. Although there was a slight difference in PPI consumption at 3 months, there was no difference in any subjective or objective parameter of reflux between the 2 groups by 12 months.8Montgomery M. Hakanson B. Ljungqvist O. et al.Twelve months' follow-up after treatment with the EndoCinch endoscopic technique for gastro-oesophageal reflux disease: a randomized, placebo-controlled study.Scand J Gastroenterol. 2006; 41: 1382-1389Crossref PubMed Scopus (55) Google Scholar ConclusionsWhat should we take away from the ERT experience to date? Some years ago, Hebrew National, the manufacturer of kosher food products, ran a brilliant television advertisement for their kosher hot dogs. As an actor, dressed as Uncle Sam, prepared to bite into a delicious-looking frankfurter, he was repeatedly interrupted by a voiceover that listed the various less-than-healthy things that could legally be put into a frankfurter under federal government guidelines. Uncle Sam was only able to go ahead and enjoy himself when he was finally reassured that Hebrew National hot dogs did not contain these unsavory things because the company “answered to a higher authority.”It would seem that the ERT experience carries a similar message. For whatever reason, the standards set by the FDA for medical devices seem less than what might be expected. It is important that we, the practicing clinicians, understand the meaning and limitations of the terms “FDA approval” and “FDA clearance,” and recognize that “FDA clearance” is often granted with minimal documentation of efficacy. Even when clinical studies are submitted in support of the FDA premarket review processes, those studies do not necessarily meet the standards commonly expected by the scientific community. Further, the placebo effect in the treatment of reflux disease is sufficiently potent that studies that depend on subjective clinical responses alone, especially without clear objective responses, must be taken with a healthy amount of skepticism.Randomized, controlled studies that can withstand critical review are just as important for the evaluation of new endoscopic therapy as they are for clinical trials of drugs, whether FDA policies require them or not. What should we take away from the ERT experience to date? Some years ago, Hebrew National, the manufacturer of kosher food products, ran a brilliant television advertisement for their kosher hot dogs. As an actor, dressed as Uncle Sam, prepared to bite into a delicious-looking frankfurter, he was repeatedly interrupted by a voiceover that listed the various less-than-healthy things that could legally be put into a frankfurter under federal government guidelines. Uncle Sam was only able to go ahead and enjoy himself when he was finally reassured that Hebrew National hot dogs did not contain these unsavory things because the company “answered to a higher authority.”" @default.
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W2005763172 title "Endoluminal reflux therapy: what do “FDA clearance” and “FDA approval” mean?" @default.
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